European Commission Directive 2000/39/EC

establishing a First List of Indicative Occupational

Exposure Limit Values at European Community
level in implementation of council directive 98/24/EC
on the protection of the health and safety of workers
from the risks related to chemical agents at work
This consultative document is issued by the Health and Safety Commission in compliance with
its duty to consult, under Sections 16(2) and 50(3) of the Health and Safety at Work etc
Act 1974.

Comments should be sent to:

Carole Sullivan
Health and Safety Executive
Health Directorate, Chemicals Policy Division
6th Floor, South Wing, Rose Court
2 Southwark Bridge, London SE1 9HS
Tel: 020 7717 6341
e-mail: carole.sullivan@hse.gsi.gov.uk
to reach her no later than 1 May 2001

The Commission tries to make its consultation procedure as thorough and open as possible. Responses to this
consultative document will be lodged in the Health and Safety Executive’s Information Centres after the close of the
consultation period where they can be inspected by members of the public or be copied to them on payment of the
appropriate fee to cover costs.
Responses to this consultative document are invited on the basis that anyone submitting them agrees to their being dealt
with in this way. Responses, or parts of them, will be withheld from the Information Centres only at the express request
of the person making them. In such cases a note will be put in the index to the responses identifying those who have
commented and have asked that their views, or part of them, be treated as confidential.

CONSULTATIVE
DOCUMENT
Further single copies of this document may be obtained from HSE Books – see back cover
 European Commission Directive 2000/39/EC establishing a First List of Indicative
Occupational Exposure Limit Values at European Community level in implementation
of council directive 98/24/EC on the protection of the health and safety of workers from
the risks related to chemical agents at work.

CONSULTATION DOCUMENT
Contents Page
SUMMARY 1

WHAT ARE IOELVs? 2

HOW DOES THE HSC PROPOSE TO IMPLEMENT IOELVS? 2

CAN HSC SET A DIFFERENT LIMIT TO THE IOELV? 3

WHAT IS BEING PROPOSED IN THE 1st IOELV DIRECTIVE? 4

Substances already implemented through 2nd ILV Directive. 4
New limits. 5
Summary of consultation documents issued. 6

PROPOSALS FOR IMPLEMENTING IOELV SUBSTANCES 7

Table A: Summary of all proposals substance by substance 8

PROPOSALS FOR CHANGES TO THE LIST OF MELS 10

Proposals for new substances 10

PROPOSALS FOR CHANGES TO THE LIST OF OESs 13

Proposal to change OESs following review 13
Proposal to revised entries for ILV substances 14

REGULATORY IMPACT/COST BENEFIT ASSESSMENTS 16

AMENDMENT TO CD156 AND CD157 17

INVITATION TO COMMENT 19

Appendices

APPENDIX 1: Draft copy of 1st consolidated IOELV directive 20

APPENDIX 2: Summary of progress so far 24
APPENDIX 3: Summary criteria documents 26
APPENDIX 4: Explanatory note: CBA methodology for RIAs 85
APPENDIX 4A: Summary RIAs 87
APPENDIX 5: Replying to this consultative document 89

i
SUMMARY
Indicative Occupational Exposure Limit Values (IOELVs) are concentrations of a hazardous
substance in air proposed by the European Commission under the framework of the Chemical
Agents Directive (CAD). Member States are obliged to introduce an occupational exposure
limit (OEL) for these substances in accordance with national legislation and practice that
takes the IOELV into account.

The first IOELV Directive (2000/39/EC) is due to be implemented by 31 December 2001 and
lists 63 substances. In May 2000 the Health and Safety Commission (HSC) consulted on
proposals to implement IOELVs for 29 substances (CD156) and for a further 6 substances
(CD157). For 19 substances the existing national limit was considered to meet the
requirements of the Directive (although we have now decided to consult on Cumene).

This document (CD166) sets out HSC’s proposals for 9 substances as well as proposals for
three substances already partly covered by earlier CDs:
Chlorobenzene** Phenol**
Cumene 1,2,4-Trichlorobenzene
Dihydrogen selenide Xylene, mixed isomers
Ethylbenzene* m-Xylene
2-Methoxy-1-methylethyl acetate o-Xylene
Orthophosphoric acid p-Xylene
* see also CD156 **see also CD157

This document also contains an amendment to CD156 and CD157 with revised proposals
for 7 substances. The reasons for the need to reconsult are summarised in the main text
(paragraphs 7-9). If you commented on CD156 or CD157 you may wish to check the revised
proposals. For one remaining substance, Piperazine, HSE is not yet able to present formal
proposals. These will be consulted on early in 2001 via HSE’s web site at
http://www.hse.gov.uk (paper copies of the proposals will be available on request).

All the agreed limits must be in place by 31 December 2001 and will be published in the 2001
or the 2002 edition of HSE’s ‘EH40 - occupational exposure limits’. Limits resulting from
IOELV proposals will not come into effect until 31 December 2001.

We would like your comments on these proposals. A form is included at the back of this
booklet to help you to do this. It summarises the questions set out in the main text.

Please feel free to copy this consultative document more widely. Further copies are available
from the address on the back cover and on the Internet on the HSE web site (see above). The
HSC seeks to inform its decision-making by consulting a wide range of interested bodies.
Although these proposals have already been discussed by a panel of scientific experts you
may have views or further information of which they are not aware. For example, you may
have data relating to whether a particular limit can reasonably be achieved in the workplace.

Your comments are important. Please do take a few minutes to fill in the response form at the
back of this booklet.

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WHAT ARE INDICATIVE OCCUPATIONAL EXPOSURE LIMIT VALUES
(IOELVs)?

1. IOELVs, previously known as Indicative Limit Values (ILVs), are European legal
limits which are set to protect the health of workers in the European Union from the ill health
effects of hazardous substances in the workplace. IOELVs are therefore broadly the same as
the Occupational Exposure Standard element of the British system of limits to protect
workers against ill-health. The European Commission (EC) made proposals for IOELVs for
63 substances and these have been agreed by Member States. A copy of the Directive
(2000/39/EC) which was published in the Official Journal on 8 June 2000 is at Appendix 1.
Member States must have limits in place for all these substances by 31 December 2001.

2. The Annex of Appendix 1 lists the IOELVs substance by substance. These limits are
based on recommendations by the European Commission’s (EC) Scientific Committee on
Occupational Exposure Limits (SCOEL) which has considered the scientific information
available on each substance. They do not address practicability of the proposals in appropriate
workplaces; such issues can be raised by Member States through the EC’s committee system
and can be taken into account when setting national limits. Member States are obliged,
however, to set a legal limit that takes the IOELV into account.

HOW DOES THE HEALTH AND SAFETY COMMISSION PROPOSE TO

IMPLEMENT IOELVs?
3. The Health and Safety Commission (HSC) proposes to implement the IOELVs in this
Commission Directive through our domestic system of occupational exposure limits (OELs).
These OELs are set to help employers meet their legal responsibilities under the Control of
Substances Hazardous to Health Regulations 1999 (COSHH) which require employers to
prevent, or if this is not reasonably practicable, adequately control, employees’ exposure to
hazardous substances. There are two types of limits - Maximum Exposure Limits (MELs)
and Occupational Exposure Standards (OESs). These are expressed as concentrations of a
hazardous substance in the air, averaged over a specified period of time referred to as a time
weighted average (TWA). Two time periods are used: 8 hour (based on an average shift) and
15 minute. The 15 minute short term exposure limits (STELS) are set to help prevent effects,
such as eye irritation, which may occur after only a few minutes exposure to the substance.

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4. OESs and MELS are legal limits. They are approved each year by the Health and
Safety Commission (HSC) and published in HSE’s publication ‘EH40 - occupational
exposure limits’. A MEL is set for substances which may cause the most serious health
effects, such as cancer and occupational asthma: health effects for which no ‘safe’ levels of
exposure can be determined or for which safe levels may exist but at a concentration that is
not yet achievable in the workplace. To comply with COSHH, exposure should be reduced as
far below the MEL as is reasonably practicable and should not exceed the MEL when
averaged over the specified reference period. For substances given a short term MEL (15
minute reference period) the level of exposure should never be exceeded.

5. An OES is set at a level at which (based on current scientific knowledge) there is no

indication of risk to the health of workers who breathe it in day after day. If exposure to a
substance that has an OES is reduced to that level, then adequate control has been achieved. If
this level is exceeded, the reason must be identified and measures to reduce exposure to the
OES limit set out in EH40 put into action as soon as is reasonably practicable.

6. Domestic limits are normally set on the recommendations of the Health and Safety
Commission’s Advisory Committee on Toxic Substances (ACTS) and its Working Group on
the Assessment of Toxic Chemicals (WATCH). The recommendations are based on a
thorough critical assessment of the available information on the substance in question.
Information on WATCH and ACTS, the agendas and summaries of their meetings are
available on the Internet on the HSE home page at http://www.hse.gov.uk. For more
information on employers’ duties under COSHH, see HSE’s leaflet ‘COSHH - a brief guide
to the regulations’ INDG136 (rev1): available from HSE Books.

CAN HSC SET A DIFFERENT LIMIT TO THE IOELV - AND IF SO, HOW
DIFFERENT AND ON WHAT GROUNDS?

7. While each substance will need individual consideration, it is clear that any
substantial deviation from the IOELV will need to be justified. While a range of technical
factors may be relevant in any particular case, grounds of reasonable practicability will
always need to be considered.

3
8. ACTS and HSC have considered this view when formulating these proposals. Your
comments would be especially appreciated on the question of reasonable practicability.

Implications of this advice for previous proposals

9. HSE has looked again at all the IOELV proposals contained in CD156 and CD157
and has reconsidered the limit values for 7 substances based on the views set out in paragraph
7 - the new proposals are listed on page 20 in an amendment to the earlier CDs. HSC's
proposals have been amended accordingly and we are now taking this opportunity to
reconsult on the revised proposals.

WHAT IS BEING PROPOSED IN THE FIRST CONSOLIDATED IOELV

DIRECTIVE?
10. The Directive proposes limits for 63 substances in total. These include:

SUBSTANCES ALREADY IMPLEMENTED THROUGH 2ND ILV DIRECTIVE

11. Twenty-three of the substances listed in this consolidated Directive are contained
within the 2nd ILV Directive, which was implemented in Great Britain in 1997. These
substances are identified in Appendix 2. Britain had to take account of the ILVs but no time
limit was imposed for the adoption of a limit. This has now changed because IOELVs now
come under the umbrella of the Chemical Agents Directive 98/24/EC (CAD). Britain is
obliged to set limits by the relevant implementation date, taking account of the IOELV, for all
substances named in any directives made under CAD. HSE has therefore scrutinised the
limits set for these 23 substances to check that they meet the requirements in CAD and fully
take account of the IOELVs. As a result of this scrutiny, HSE was satisfied that 19 of the 23
substances met the requirements of CAD. ACTS endorsed this view. HSC proposes no
further consultation on 18 of these, but one substance, Cumene, is included in this CD
following adoption of the position outlined in paragraph 7 above.

12. HSE’s scrutiny revealed that the limits for the remaining four of the 23 substances do
not yet comply with the requirements of CAD. The four substances which do not fully take
account of the IOELV are:

Ÿ 2-Methoxy-1-methylethyl acetate;

4
 Ÿ Orthophosphoric acid;
Ÿ 1,2,4-Trichlorobenzene;
Ÿ Dihydrogen selenide.

HSC’s proposals for these four substances and Cumene are set out in this CD; and

NEW LIMITS
13. The EC is introducing new limits for 40 substances in this consolidated IOELV
directive. After scrutiny by HSE to establish those IOELVs that were broadly acceptable,
ACTS agreed a list of substances that required more detailed review. The list included
substances where there were issues over practicability, scientific soundness, and the degree of
discrepancy between the existing British limit and the proposed IOELV. Substances which
were judged not to require a detailed review and substances which were already being
reviewed as part of the domestic programme were the subject of two previous consultation
documents. This document covers all but one of the remaining substances, which have now
been reviewed. We are not yet in a position to make formal proposals for Piperazine; these
will be consulted on early in 2001 via HSE’s web site at http://www.hse.gov.uk (paper copies
of proposals will be available on request).

5
SUMMARY OF CONSULTATION DOCUMENTS ISSUED:

CD 156:
mid May - mid August 2000
IOELV substances judged not to require review by HSC/E:
Acetone† Heptan-3-one†
Ammonia, anhydrous n-Heptane
2-Butanone Hydrogen fluoride
2-Butoxyethanol 1-Methoxypropanol-2
2-Butoxyethyl acetate 5-Methylheptan-3-one
e-Caprolactam 5-Methylhexan-2-one†
Chloroform 4-Methylpentane-2-one†
1,2-Dichlorobenzene 2-Phenylpropene
1,4-Dichlorobenzene Phosgene
1,1-Dichloroethane Silver, metallic
Dimethylether Sodium azide
Ethylbenzene - see also CD166 Sulfotep
Ethylene glycol Tetrahyrofuran†
Fluorides, inorganic 1,1,1-Trichloroethane
Fluorine

CD 157: CD 166:
mid May - mid August 2000 February - May 2001
IOELV substances already being IOELV substances judged to be most in
reviewed under the domestic programme: need of detailed review:
n-Butylacrylate Chlorobenzene - MEL proposal
Cyclohexanone† Phenol - MEL proposal
Diethylether† Xylene, mixed isomers, pure
Triethylamine o-Xylene
Chlorobenzene - OES withdrawal p-Xylene
Phenol - OES withdrawal m-Xylene
[Note: Chloroethane is a 2nd IOELV Former ILV substances which have not
Directive proposal] fully taken account of the IOELV:
2-Methoxy-1-methylethylacetate
Orthophosphoric acid
1,2,4-Trichlorobenzene
Dihydrogen selenide - MEL proposal
Cumene
IOELV substance not reviewed by
HSC/E
Ethylbenzene - Skin notation
† = substances covered by the amendment to CD156 and CD157 which is included in this CD
HSE is not yet able to consult on formal proposals for Piperazine which will be consulted on
via HSE’s web site at http://www.hse.gov.uk in the new year.

6
PROPOSALS FOR IMPLEMENTING IOELV SUBSTANCES INTO THE
NATIONAL LIMIT SETTING SYSTEM.

14. HSC’s proposals for implementing 12 IOELV substances (including one substance
carried forward from CD156) into the national limit setting system are set out in the
following paragraphs and are summarised substance by substance in Table A below. An
amendment which covers 7 substances previously consulted on in CDs 156 and 157 is also
included at Table B (page 17). HSE has decided to reconsult on these proposals in the light of
more recent legal advice (see paragraphs 7 to 9).

15. Included at Appendix 3 is a summary criteria document for each of the 20 substances
under discussion to help you to understand the reasons why the limit is being proposed. All of
the summaries are in EH64 format. The grey box in the top left corner indicates whether the
limit has been changed to reflect SCOEL recommendations or is an existing domestic
occupational exposure limit. Where no recent WATCH review has been conducted the
summary has been prepared using the relevant SCOEL review document (known as a
SCOEL-SEG/SUM). For substances which had previously been reviewed by WATCH (so
already had a summary document) the existing document has been revised to incorporate both
SCOEL’s and WATCH’s views and retain the analytical method. For substances which have
recently been reviewed by WATCH, and where WATCH have taken into account the IOELV,
the summary has been prepared using the WATCH review package and subsequent
discussions. Copies of the full WATCH documentation are available through HSE public
information centres (see back cover).

7
Table A IOELV HSE current OEL HSC WATCH
proposal reviews
MEL OES
Substance Name
a) 8-hr TWA a) 8-hr TWA a) 8-hr TWA
b) STEL b) STEL b) STEL
CAS number
c) Notation c) Notation c) Notation
Chlorobenzene a) 10 ppm a) - a) 50 ppm - Withdraw 2000
108-90-7 OES* and
introduce 8 hr
TWA MEL of
1 ppm
b) 20 ppm b) - b) - - Introduce
STEL MEL of
3 ppm
c) - c) - c) - - Introduce Sk
notation

Cumene a) 20 ppm a) - a) 25 ppm - Retain 8 hr 1991

98-82-8 TWA OES
b) 50 ppm b) - b) 75 ppm - Revise
STEL OES to
50 ppm
c) Sk c) - c) Sk - Retain Sk
notation

Dihydrogen a) 0.02 ppm a) - a) [0.05 ppm -Introduce 1998

selenide withdrawn] IOELV value
7783-07-5 as MEL
b) 0.05 ppm b) - b) - -Introduce
IOELV value
as STEL MEL
c) - c) - c) - - No change

Ethylbenzene a) 100 ppm a) - a) 100 ppm a) and b) see -

100-41-4 b) 200 ppm b) - b) 150 ppm CD156

c) Sk c) - c) - - Introduce Sk
notation

2-Methoxy-1- a) 50 ppm a) - a) 50 ppm - Retain 8 hr 1998

methylethyl- TWA OES
acetate b) 100 ppm b) - b) 150 ppm - Revise
108-65-6 STEL OES
c) Sk c) - c) - - Introduce Sk
notation

8
 Table A IOELV HSE current OEL HSC WATCH
proposal reviews
MEL OES
Substance Name
a) 8-hr TWA a) 8-hr TWA a) 8-hr TWA
b) STEL b) STEL b) STEL
CAS number
c) Notation c) Notation c) Notation
Orthophosphoric a) 1 mg.m-3 a) - a) - - Introduce 8 1998
acid hr TWA OES
7664-38-2 of 1 mg.m-3
b) 2 mg.m-3 b) - b) 2 mg.m-3 - Retain STEL
OES
c) - c) - c) - - No change

Phenol a) 2 ppm a) - a) 5 ppm - Withdraw 2000

108-95-2 OES* and
introduce 8 hr
TWA MEL of
2 ppm
b) - b) - b) 10 ppm - Withdraw
STEL OES*
c) Sk c) - c) Sk - Retain Sk
notation

1,2,4- a) 2 ppm a) - a) 1 ppm - Retain 8 hr 1998

Trichlorobenzene TWA OES
120-82-1 b) 5 ppm b) - b) - -Introduce
IOELV value
as STEL OES
c) Sk c) - c) Sk - Retain Sk
notation
m-Xylene a) 50 ppm a) - a) 100 ppm - Amend 8 hr 2000
108-38-3 b) 100 ppm TWA OES to
c) Sk 50 ppm
o-Xylene a) 50 ppm
b) - b) 150 ppm - Amend
95-47-6 b) 100 ppm
STEL OES to
c) Sk
100 ppm
p-Xylene a) 50 ppm
106-42-3 b) 100 ppm c) - c) Sk - Retain Sk
c) Sk notation and
Xylene, mixed a) 50 ppm introduce
isomers, pure b) 100 ppm BMGV
1330-20-7 c) Sk

* Consulted on in CD157

9
PROPOSALS FOR CHANGES TO THE LIST OF MAXIMUM EXPOSURE LIMITS
Proposals for new substances

16. It is proposed that the following three substances be added to the list of MELS. HSE
has issued Chemical Hazard Alert Notices (CHANs) for these substances in the interim.
Summary criteria documents explaining the rationale behind the proposals are attached at
Appendix 3.

Reference Periods

Long-term exposure limit Short-term exposure limit

(8-hour TWA reference (15 minute reference period)
period)
Substance CAS Notes ppm mg.m-3 ppm mg.m-3
Number
Chlorobenzene 108-90-7 Sk notation 1 4.5 3 13.6
Dihydrogen 7783-07-5 - 0.02 0.07 0.05 0.17
selenide
Phenol 108-95-2 Sk notation 2 7.8 - -

Chlorobenzene
17. Chlorobenzene was one of the IOELV substances judged to be in need of further
review by ACTS/WATCH. These recommendations reflect their latest advice.

18. You will see from Table A that the HSC proposal for chlorobenzene is lower than the
IOELV Directive which recommends an 8 hour limit of 10 ppm and a STEL of 20 ppm. Also,
HSC is recommending a Sk notation. HSE based its review to WATCH on a collaborative
review by the Swedish National Institute for Occupational Health and the USA National
Institute for Occupational Safety and Health, first published in 1992. This post-dated the EU
criteria document SEG/CDO/22B used by SCOEL to make its recommendation summarised
in SEG/SUM42C. Both the collaborative review and the SCOEL summary were included in
the information presented to WATCH.

19. The proposal to withdraw the OES was included in a Consultative Document
(CD157) agreed by HSC and published in May 2000.

Question 1: Do you agree with the 8 hour TWA MEL proposal for chlorobenzene?

If you disagree, please explain why.

10
Question 2: Do you agree with the STEL MEL proposal for chlorobenzene?
If you disagree, please explain why.

Question 3: Do you agree with the Sk notation proposal for chlorobenzene?

If you disagree please explain why.

Dihydrogen selenide
20. Dihydrogen selenide is one of the substances previously covered by the 2nd ILV
Directive. WATCH considered the occupational exposure limits for hydrogen selenide in
1998 and concluded that there was insufficient data to identify a safe level of exposure.
ACTS endorsed WATCH's recommendation to withdraw the existing OES and considered
setting a MEL. But ACTS concluded that because usage patterns showed very few people are
exposed to this substance; and those levels of exposure are negligible, a MEL was not
appropriate. However, HSE is now required to set a limit in order to meet the requirements of
CAD. The MEL proposal reflects the values in the IOELV Directive.

21. No RIA for this MEL proposal has been conducted. This is because a preliminary cost
assessment based on information provided by the industry indicated that costs would be
negligible because the substance is well controlled already.

Question 4: Do you agree that the IOELV should be adopted as an 8 hour TWA MEL
for dihydrogen selenide?
If you disagree, please explain why.

Question 5: Do you agree that the IOELV should be adopted as a STEL MEL
for dihydrogen selenide?
If you disagree, please explain why.

Phenol

22. Phenol has been in the ACTS/WATCH review programme since 1992: A key issue
of mutagenicity took some time to resolve, because of the need to acquire further scientific

11
information. In 2000 WATCH and ACTS agreed that consideration of a MEL was warranted
and agreed that a proposal to withdraw the current OES should go to external consultation.

23. The proposal to withdraw the OES was included in a Consultative Document
(CD157), agreed by HSC and published in May 2000. The MEL proposal reflects the value
and notation in the IOELV Directive.

Question 6: Do you agree that the IOELV should be adopted as an 8 hour TWA MEL
for phenol?
If you disagree, please explain why.

Question 7: Do you agree that it is not necessary to set a STEL MEL for phenol?
If you disagree, please explain why.

Question 8: Do you agree that the Sk notation should be retained?

If you disagree please explain why.

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PROPOSALS FOR CHANGES TO THE LIST OF OCCUPATIONAL EXPOSURE
STANDARDS

PROPOSAL TO CHANGE OESs FOLLOWING REVIEW

24. Summary criteria documents explaining the rationale behind the proposed
occupational exposure limits for the substances detailed in this section are attached at
Appendix 3. They reflect the views of SCOEL and/or WATCH, as appropriate.

Xylene, m-, o-, p- and mixed isomers, pure

25. Xylenes are IOELV substances judged to be in need of further review by
ACTS/WATCH. These recommendations reflect their latest advice.

26. WATCH concluded that the data support the maintenance of OESs for xylenes and
recommended an 8-hour TWA OES of 50 ppm which directly corresponds to the 8-hour
TWA IOELV. The maintenance of a Skin notation was also supported as was HSE’s proposal
to establish a BMGV for xylenes. However, for the STEL OES, WATCH recommended 150
ppm, in contrast to the STEL IOELV of 100 ppm. The reasons for this are summarised in the
draft EH64 summary criteria document. ACTS recommended the adoption of the IOELV
STEL.

Question 9: Do you agree with the 8 hour TWA OES proposal for xylenes?
If you disagree, please explain why.

Question 10: Do you agree with the STEL OES proposal for xylenes?
If you disagree, please explain why.

Question 11: Do you agree that the Sk notation should be retained?

If you disagree please explain why.

Question 12: Do you agree with the proposal to develop a BMGV for xylenes?
If you disagree please explain why.

13
Ethylbenzene

27. Proposals for an 8 hour OES and STEL OES for ethylbenzene were consulted on in
CD156. A decision on the skin notation was deferred until the review of xylenes was
completed. It is now proposed to adopt the skin notation proposed in the IOELV Directive.

Question 13: Do you agree that the Sk notation should be adopted?

If you disagree please explain why.

PROPOSALS TO REVISE FOUR ENTRIES FOR ILV SUBSTANCES WHICH

CURRENTLY DO NOT FULLY COMPLY WITH CAD

Orthophosphoric acid
28. In 1998 WATCH decided that an 8 hour TWA OES was not needed because the
STEL would be protective of health. However an 8 hour TWA IOELV has been set and so we
are proposing to amend the entry in order to comply with CAD.

Question 14: Do you agree that the IOELV should be adopted as an 8 hour TWA OES
for Orthophosphoric acid?
If you disagree, please explain why.

1,2,4-Trichlorobenzene
29. In 1998 WATCH decided that a STEL OES was not needed because the 8 hour TWA
OES would be protective of health. However a STEL IOELV has been set and so we are
proposing to amend the entry in order to comply with CAD.

Question 15: Do you agree that the IOELV should be adopted as a STEL OES
for 1,2,4-Trichlorobenzene?
If you disagree, please explain why.

2-Methoxy-1-methylethylacetate

30. In 1998 WATCH decided that a STEL OES was required and set this at 150 ppm
based on the three times rule. However, an IOELV STEL has been set at 100 ppm. In order to
comply with CAD we are proposing to revise the STEL OES to 100 ppm.

14
31. In 1998 WATCH decided that a Sk notation was not necessary, however one is now
needed to comply with CAD.

Question 16: Do you agree with the STEL OES proposal for 2-Methoxy-1-methylethyl
acetate?
If you disagree please explain why.

Question 17: Do you agree with the Sk notation proposal for 2-Methoxy-1-methylethyl
acetate?
If you disagree please explain why.

Cumene
32. Cumene was last considered by WATCH in 1991. The STEL OES WATCH
recommended was 75 ppm, in contrast to the STEL IOELV of 50 ppm and this difference is
considered to be significant. The reasons for SCOEL’s recommendation are summarised in
the draft EH64 summary criteria document. SCOEL based its evaluation on the same data as
WATCH and so there are not considered to be any scientific grounds on which to challenge
the IOELV.

Question 18: Do you agree with the STEL OES proposal for Cumene?
If you disagree please explain why.

15
REGULATORY IMPACT/COST BENEFIT ASSESSMENTS
33. Before any new piece of legislation can be introduced, the Health and Safety
Commission is obliged to have carried out an assessment of the costs it would impose on
industry and the benefits it is expected to bring. Since October 1998, this assessment is
included in the Regulatory Impact Assessment (RIA). Annex 4 of this document gives a
description of the methodology behind the formulation of cost benefit assessments (CBAs)
for RIAs and a general statement on their application. An RIA is not carried out when the
legislation does not impose additional costs to industry.

34. HSE has examined what costs and benefits will result from the implementation into
the national limit setting system of the directive as a whole. This RIA shows that total one-off
costs, as a result of capital expenditure, were estimated to be about £0.4 million (1999/2000
prices), while the ten-year present value of the recurring costs was £8.8 million (1999/2000
prices). Recurring costs are incurred mainly as a result of increased use of respiratory
protective equipment (RPE) and increased monitoring to check compliance with the new
limit. Thus, the total cost to society of implementing the whole Directive is £9.2 million
(1999/2000 prices) over 10 years, in present value terms. The RIA could not quantify any of
the health benefits resulting from the introduction of this Directive. However, it was noted
that there are negative health effects associated with exposure to the substances covered by
the Directive and that reducing exposure may lead to health benefits.

35. In addition, individual RIAs were carried out for two of the three MEL proposals and
summaries are presented at Annex 4A. An initial assessment for one MEL proposal,
dihydrogen selenide, indicated that costs would be negligible and so a full RIA was not
conducted.

36. Copies of the RIA for the directive as a whole and individual RIAs for two of the four
MEL candidates are available on request from the HSE. If you would like a copy of any of
these documents, please contact Carole Sullivan in the Chemical Policy Division, Health and
Safety Executive, Rose Court, 2 Southwark Bridge, London SE1 9HS. If you have any
comments on the RIAs we would welcome these also.

16
AMENDMENT TO CD 156 AND CD 157

37. The following substances were first consulted on in CD156 or CD157 and are subject
to an existing domestic limit or a proposed domestic limit which is significantly higher than
the IOELV. Proposals for limits that are lower than the IOELV or only slightly higher are not
affected. This is in the light of new advice that significantly higher limits could be open to
challenge.

38. The following substances are affected (revised proposals are in italics):

Table B Previous HSC IOELV proposal Revised proposal

OES proposal
Substance name a) 8 hr TWA a) 8 hr TWA
b) STEL b) STEL
c) Notation c) Notation

CD 156
Acetone a) 750 ppm a) 500 ppm a) Consult on IOELV
b) 1500 ppm b) - b) Retain STEL
Heptan-3-one a) 50 ppm a) 20 ppm a) Consult on 35 ppm
(health-based SCOEL
recommendation prior
to applying ‘preferred
number’ system).
b) 100 ppm b) - b) Retain STEL
c) Sk c) - c) Retain Skin notation
5-Methylhexan-2-one a) 50 ppm a) 20 ppm a) Consult on IOELV
b) 100 ppm b) - b) Retain STEL
c) Sk c) - c) Retain Skin notation
4-Methylpentan-2-one a) 50 ppm a) 20 ppm a) Consult on IOELV
b) 100 ppm b) 50 ppm b) Consult on IOELV
c) Sk c) - c) Retain Skin notation
Tetrahyrofuran a) 100 ppm a) 50 ppm a) Consult on IOELV
b) 200 ppm b) 100 ppm b) Consult on IOELV
c) Sk c) Sk c) Retain Skin notation
CD 157
Cyclohexanone a) 20 ppm a) 10 ppm a) Consult on IOELV
b) 50 ppm b) 20 ppm b) Consult on IOELV
c) Sk c) Sk c) Retain Skin notation
Diethyl ether a) 400 ppm a) 100 ppm a) Consult on IOELV
b) 500 ppm b) 200 ppm b) Consult on IOELV

17
39. A higher limit than the IOELV could be set if certain criteria are met. The position is
further explained in paragraph 7 of this CD and it is important that you consider this carefully
when formulating your response.

40. We propose that the above values are adopted as OESs unless we receive information
from this consultation exercise to suggest that there are grounds by which HSE could
justifiably recommend setting a higher limit to HSC. Summary criteria documents explaining
the rationale behind the revised proposals are attached at Appendix 3.

Question 19: Do you agree with the proposal to adopt the IOELVs for Acetone,
Cyclohexanone, Diethyl ether, 5-Methylhexan-2-one,
4-Methylpentan-2-one and Tetrahyrofuran and the health-based SCOEL
recommendation for Heptan-3-one?

Bearing in mind the position set out at paragraph 7 of the main CD, if
you disagree with any of these proposals please state which ones and
explain why.

18
INVITATION TO COMMENT
41. The Health and Safety Commission would welcome comments on proposals set out in
this Consultative Document. We will acknowledge all responses and give full consideration
to the substance of arguments in the development of proposals; we may also contact you
again, if, for example, we have a query. For the convenience of readers, all the questions are
repeated in a form set out in Appendix 5 which you may find helpful to use for your reply.

42. If you reply to this consultative document in a personal capacity, rather than as a
postholder of an organisation, you should be aware that information you provide may
constitute “personal data” in the terms of the Data Protection Act 1998. For the purposes of
this Act, HSE is the “data controller” and will process the data for health, safety and
environmental purposes. HSE may disclose these data to any person or organisation for the
purposes for which it was collected, or where the Act allows disclosure. You have the right to
ask for a copy of the data and to ask for inaccurate data to be corrected. Please note all replies
will be made public unless you specifically state you wish yours to be made confidential.

43. The Health and Safety Commission/Executive would also like to know what you think
about this consultation, both the content and layout. The response form at Appendix 5
includes a few separate questions on this aspect of the consultation. Your views may help to
improve further consultations. If you are not satisfied with the way in which this consultation
exercise has been conducted you can complain by contacting:

Mr Chris Rowe
Health and Safety Executive
Room 602
Rose Court
2 Southwark Bridge
London
SE1 9HS.

19
 APPENDIX 1 - DIRECTIVE
16.6.2000 Official Journal of the European Communities L 142/47
COMMISSION DIRECTIVE 2000/39/EC
of 8 June 2000
establishing a first list of indicative occupational exposure limit values in implementation of
Council Directive 98/24/EC on the protection of the health and safety of workers from the
risks related to chemical agents at work
(Text with EEA relevance)

THE COMMISSION OF THE EUROPEAN COMMUNITIES,

Having regard to the Treaty establishing the European
Community,
Having regard to Council Directive 98/24/EC of 7 April
1998 on the protection of the health and safety of workers
from the risks related to chemical agents at work(1) and in
particular Article 3(2) thereof,
Having regard to the opinion of the Advisory Committee on
safety, hygiene and health protection at work,
Whereas:
(1) Pursuant to Directive 98/24/EC, the Commission is to
propose European objectives in the form of indicative
occupational exposure limit values for the protection of
workers from chemical risks, to be set at Community
level.
(2) The Commission, in carrying out this task is assisted by
the Scientific Committee for occupational exposure
limits to chemical agents (SCOEL), instituted by
Commission Decision 95/320/EC(2).
(6) Directive 80/1107/EEC has been repealed with effect
from 5 May 2001 by Directive 98/24/EC.
(7) It is appropriate to reenact, in the framework of
Directive 98/24/EC, the indicative occupational
exposure limit values which had been established by
Directives 91/322/EEC and 96/94/EC in the
framework of Directive 80/1107/EEC.
(8) The list set out in the Annex contains the substances
set out in the Annex to Directive 96/94/EC and
incorporates a number of other agents for which
indicative occupational exposure limit values have
been recommended by SCOEL, following the
evaluation of the latest available scientific data on
occupational health effects and taking into account the
availability of measuring techniques. In view of the
foregoing and in the interests of clarity Directive
96/94/EC should be recast.
(9) It is necessary to establish short-term exposure limit
values for certain substances to take account of effects
arising from short-term exposure.

(3) For any chemical agent for which indicative
occupational exposure limit values are established at
Community level, Member States are required to
establish a national occupational exposure limit value,
taking into account the Community limit value,
determining its nature in accordance with national
legislation and practice.
(10) For some agents, it is necessary to have regard also to
the possibility of penetration through the skin, in order
to ensure the best possible level of protection.
(11) This Directive constitutes a practical step towards the
achievement of the social dimension of the internal
market.

(4) Indicative occupational exposure limit values should be
regarded as an important part of the overall approach to
ensuring the protection of the health of workers at the
workplace, against the risks arising from hazardous
chemicals.
(5) A first and a second list of indicative occupational
exposure limit values were established by Commission
Directives 91/322/EEC(3) and 96/94/EC(4) in the
framework of Council Directive 80/1107/EEC of 27
November 1980 on the protection of workers from the
risks related to exposure to chemical, physical and
biological agents at work(5).
(12) The measures provided for in this Directive are in
accordance with the opinion of the Committee
instituted by Article 17 of Council Directive
89/391/EEC of 12 June 1989 on the introduction of
measures to encourage improvements in the health and
safety of workers at work (6),
HAS ADOPTED THIS DIRECTIVE:
Article 1
Community indicative occupational exposure limit values
are hereby established for the chemical agents set out in the
Annex.

(1) OJ L 131, 5.5.1998, p. 11. (6) OJ L 183, 29.6.1989. p. 1.

(2) OJ L 188, 9.8.1995, p. 14.
(3) OJ L 177, 5.7.1991, p. 22.
(4) OJ L 338, 28.12.1996, p. 86.
(5) OJ L 327, 3.12.1980, p. 8.
20
L 142/48 Official Journal of the European Communities 16.6.2000

Article 2 Article 4

Member States shall establish national occupational Directive 96/94/EC is repealed with effect from the date
exposure limit values for the chemical agents listed in the referred to in Article 3(1).
Annex, taking into account the Community values.
Article 5
Article 3
This Directive shall enter into force on the 20th day
1. Member States shall bring into force the laws, following its publication in the Official Journal of the
regulations and administrative provisions necessary to European Communities.
comply with this Directive by 31 December 2001 at the
latest. They shall forthwith inform the Commission thereof. Article 6

When Member States adopt these provisions, they shall This Directive is addressed to the Member States.
contain a reference to this Directive or be accompanied by
such a reference at the time of their official publication. Done at Brussels, 8 June 2000.
Member States shall determine how such reference is to be
made.

2. Member States shall communicate to the Commission For the Commission

the text of the provisions of national law which they adopt
Anna DIAMANTOPOULOU
in the field covered by this Directive.
Member of the Commission

21
 ANNEX

INDICATIVE OCCUPATIONAL EXPOSURE LIMIT VALUES

Limit values
(4)
Eight hours Short-term(5) Notation(3)
Einecs(1) CAS(2) Name of agent
3(6) (7) 3(6) (7)
mg/ m ppm mg/ m ppm
200-467-2 60-29-7 Diethylether 308 100 616 200 -
200-662-2 67-64-1 Acetone 1210 500 - - -
200-663-8 67-66-3 Chloroform 10 2 - - Skin
200-756-3 71-55-6 1,1,1-Trichloroethane 555 100 1110 200 -
200-834-7 75-04-7 Ethylamine 9,4 5 - - -
200-863-5 75-34-3 1,1-Dichloroethane 412 100 - - Skin
200-870-3 75-44-5 Phosgene 0,08 0,02 0,4 0,1 -
200-871-9 75-45-6 Chlorodifluoromethane 3600 1000 - - -
201-159-0 78-93-3 Butanone 600 200 900 300 -
201-176-3 79-09-4 Propionic acid 31 10 62 20 -
202-422-2 95-47-6 o-Xylene 221 50 442 100 Skin
202-425-9 95-50-1 1,2-Dichlorobenzene 122 20 306 50 Skin
202-436-9 95-63-6 1,2,4-Trimethylbenzene 100 20 - - -
202-704-5 98-82-8 Cumene 100 20 250 50 Skin
202-705-0 98-83-9 2-Phenylpropene 246 50 492 100 -
202-849-4 100-41-4 Ethylbenzene 442 100 884 200 Skin
203-313-2 105-60-2 e-Caprolactam (dust and vapour) 10 - 40 - -
203-388-1 106-35-4 Heptan-3-one 95 20 - - -
203-396-5 106-42-3 p-Xylene 221 50 442 100 Skin
203-400-5 106-46-7 1,4-Dichlorobenzene 122 20 306 50 -
203-470-7 107-18-6 Allyl alcohol 4,8 2 12,1 5 Skin
203-473-3 107-21-1 Ethylene glycol 52 20 104 40 Skin
203-539-1 107-98-2 1-Methoxypropanol-2 375 100 568 150 Skin
203-550-1 108-10-1 4-Methylpentan-2-one 83 20 208 50 -
203-576-3 108-38-3 m-Xylene 221 50 442 100 Skin
203-603-9 108-65-6 2-Methoxy-l-methylethylacetate 275 50 550 100 Skin
203-604-4 108-67-8 Mesitylene (Trimethylbenzenes) 100 20 - - -
203-628-5 108-90-7 Chlorobenzene 47 10 94 20 -
203-631-1 108-94-1 Cyclohexanone 40,8 10 81,6 20 Skin
203-632-7 108-95-2 Phenol 7,8 2 - - Skin
203-726-8 109-99-9 Tetrahydrofuran 150 50 300 100 Skin
203-737-8 110-12-3 5-Methylhexan-2-one 95 20 - - -
203-767-1 110-43-0 Heptan-2-one 238 50 475 100 Skin
203-808-3 110-85-0 Piperazine 0,1 - 0,3 - -
203-905-0 111-76-2 2-Butoxyethanol 98 20 246 50 Skin
203-933-3 112-07-2 2-Butoxyethyl acetate 133 20 333 50 Skin

22
 Limit values
(4)
Eight hours Short-term(5) Notation(3)
Einecs(1) CAS(2) Name of agent
3 (6) (7) 3 (6) (7)
mg/ m ppm mg/ m ppm
204-065-8 115-10-6 Dimethylether 1920 1000 - - -
204-428-0 120-82-1 1,2,4-Trichlorobenzene 15,1 2 37,8 5 Skin
204-469-4 121-44-8 Triethylamine 8,4 2 12,6 3 Skin
204-662-3 123-92-2 Isopentylacetate 270 50 540 100 -
204-697-4 124-40-3 Dimethylamine 3,8 2 9,4 5 -
204-826-4 127-19-5 N,N-Dimethylacetamide 36 10 72 20 Skin
205-480-7 141-32-2 n-Butylacrylate 11 2 53 10 -
205-563-8 142-82-5 n-Heptane 2085 500 - - -
208-394-8 526-73-8 1,2,3-Trimethylbenzene 100 20 - - -
208-793-7 541-85-5 5-Methylheptan-3-one 53 10 107 20 -
210-946-8 626-38-0 1-Methylbutylacetate 270 50 540 100 -
211-047-3 628-63-7 Pentylacetate 270 50 540 100 -
620-11-1 3-Pentylacetate 270 50 540 100 -
625-16-1 Amylacetate, tert 270 50 540 100 -
215-535-7 1330-20-7 Xylene, mixed isomers, pure 221 50 442 100 Skin
222-995-2 3689-24-5 Sulphotep 0,1 - - - Skin
231-634-8 7664-39-3 Hydrogen fluoride 1,5 1,8 2,5 3 -
231-131-3 7440-22-4 Silver, metallic 0,1 - - - -
231-595-7 7647-01-0 Hydrogen chloride 8 5 15 10 -
231-633-2 7664-38-2 Orthophosphoric acid 1 - 2 - -
231-635-3 7664-41-7 Ammonia, anhydrous 14 20 36 50 -
231-954-8 7782-41-4 Fluorine 1,58 1 3,16 2 -
231-978-9 7783-07-5 Dihydrogen selenide 0,07 0,02 0,17 0,05 -
233-113-0 10035-10-6 Hydrogen bromide - - 6,7 2 -
247-852-1 26628-22-8 Sodium azide 0,1 - 0,3 - Skin
252-104-2 34590-94-8 (2-Methoxymethylethoxy)- 308 50 - - Skin
propanol
Fluorides, inorganic 2,5 - - - -
1
EINECS: European inventory of existing chemical substances
2
CAS: Chemical abstract service registry number
3
A skin notation assigned to the OEL identifies the possibility of significant uptake through the skin
4
Measured or calculated in relation to a reference period of eight hours time weighted average
5
A limit value above which exposure should not occur and is related to a 15-minute period, unless otherwise specified
6
mg/m3 : milligrams per cubic metre of air at 20oC and 101,3 KPa
7
ppm : parts per million by volume in air (ml/m3)

23
 APPENDIX 2 - Summary of progress
CAS No. NAME OF AGENT Existing ILV limit CD156 CD157 CD166 WATCH
meets does consider-
CAD not ation of
reqt. meet IOELV
CAD [or ILV]
reqt
60-29-7 Diethylether ü ü« -
67-64-1 Acetone ü ü« -
67-66-3 Chloroform ü -
71-55-6 1,1,1-Trichloroethane ü -
75-04-7 Ethylamine ü -
75-34-3 1,1-Dichloroethane ü -
75-44-5 Phosgene ü -
75-45-6 Chlorodifluoromethane ü -
78-93-3 Butanone ü -
79-09-4 Propionic acid ü -
95-47-6 o-Xylene ü 2000
95-50-1 1,2-Dichlorobenzene ü -
95-63-6 1,2,4-Trimethylbenzene ü -
98-82-8 Cumene ü ü [1991]
98-83-9 2-Phenylpropene ü -
100-41-4 Ethylbenzene ü ü -
105-60-2 e-Caprolactam (dust and ü -
vapour)
106-35-4 Heptan-3-one ü ü« -
106-42-3 p-Xylene ü 2000
106-46-7 1,4-Dichlorobenzene ü -
107-18-6 Allyl alcohol ü -
107-21-1 Ethylene glycol ü -
107-98-2 1-Methoxypropanol-2 ü -
108-10-1 4-Methylpentan-2-one ü ü« -
108-38-3 m-Xylene ü 2000
108-65-6 2-Methoxy-l-methyl- ü ü [1998]
ethylacetate
108-67-8 Mesitylene ü -
(Trimethylbenzenes)
108-90-7 Chlorobenzene ü ü 2000
108-94-1 Cyclohexanone ü ü« 1999
108-95-2 Phenol ü ü 2000
109-99-9 Tetrahydrofuran ü ü« -
110-12-3 5-Methylhexan-2-one ü ü« -
110-43-0 Heptan-2-one ü -

110-85-0 Piperazine - see footnote 2000

24
 CAS No. NAME OF AGENT Existing ILV limit CD156 CD157 CD166 WATCH
111-76-2 2-Butoxyethanol ü -
112-07-2 2-Butoxyethyl acetate ü -
115-10-6 Dimethylether ü -
120-82-1 1,2,4-Trichlorobenzene ü ü [1998]
121-44-8 Triethylamine ü 1999
123-92-2 Isopentylacetate ü -
124-40-3 Dimethylamine ü -
127-19-5 N,N-Dimethylacetamide ü -
141-32-2 n-Butylacrylate ü 2000
142-82-5 n-Heptane ü -
526-73-8 1,2,3-Trimethylbenzene ü -
541-85-5 5-Methylheptan-3-one ü -
626-38-0 1-Methylbutylacetate ü -
628-63-7 Pentylacetate ü -
620-11-1 3-Pentylacetate ü -
625-16-1 Amylacetate, tert ü -
1330-20-7 Xylene, mixed isomers, ü 2000
pure
3689-24-5 Sulphotep ü -
7664-39-3 Hydrogen fluoride ü -
7440-22-4 Silver, metallic ü -
7647-01-0 Hydrogen chloride ü -
7664-38-2 Orthophosphoric acid ü ü [1998]
7664-41-7 Ammonia, anhydrous ü -
7782-41-4 Fluorine ü -
7783-07-5 Dihydrogen selenide ü ü [1998]
10035-10-6 Hydrogen bromide ü -
26628-22-8 Sodium azide ü -
34590-94-8 (2-Methoxymethyl ü -
ethoxy)-propanol
Fluorides, inorganic ü -

Totals 18 5 29 6 12 +
«7
« Reconsulting following adoption of recent legal advice
Note: HSE is not yet able to present formal proposals for piperazine.

25
 APPENDIX 3

Summary criteria documents

The following summary criteria documents in EH64 format are attached:

MEL proposals: Chlorobenzene

Dihydrogen selenide
Phenol

Proposals to revise OESs: Xylene

Ethyl benzene
1-Methoxypropyl acetate
1,2,4-Trichlorobenzene
Orthophosphoric acid
Cumene
Revised proposal from CD156
or CD 157: Acetone
Cyclohexanone
Diethylether
Heptan-3-one
5-Methylhexan-2-one
4-Methylpentan-2-one
Tetrahydrofuran

26
 MEL PROPOSAL
R36/37/38: Irritating to eyes, respiratory system and
skin
CHLOROBENZENE
It is possible that the UK will submit a proposal to the
maximum exposure limits relevant European Working Group with a view to
getting the CHIP classification amended in this way.
8-hour TWA: 1 ppm (4.7 mg.m-3)
OCCURRENCE AND USE
15-minute STEL: 3 ppm (14 mg.m-3)
Chlorobenzene is not manufactured in the UK and is
Notation: Skin only used as a process solvent or chemical intermedi-
subject to consultation ate and as a laboratory reagent. Approximately 20
companies use chlorobenzene as a process solvent or
chemical intermediate. The numbers exposed during
its use in the chemical industry is estimated to be
IDENTITY AND PROPERTIES between 100 and 300. The numbers exposed during its
Chemical Name Chlorobenzene use as a laboratory reagent could be more, however,
CAS No: 108-90-7 such workers are likely to have very infrequent
exposures.
EEC No: 602-033-00-1
Formula: C6 H5 Cl EXPOSURE
Synonyms: monochlorobenzene, MCB Of 38 reported recent personal air sampling results
chlorobenzol, CB, from a user of chlorobenzene, one was at 3 ppm
phenyl chloride, 8-hour TWA, the others all below 1 ppm. Earlier
chlorobenzol, results at one chemical site were up to 6 ppm 8-hour
TWA, with 83% of results less than 1 ppm 8-hour
benzene chloride TWA. At another site the highest personal air
Molecular weight: 112.56 sampling result was 0.2 ppm 8-hour TWA. The
Physical state: Colourless liquid highest exposure data received was from a company
who used chlorobenzene until the end of 1998 as a
Boiling Point: 131.6 oC
chemical intermediate. Exposures were up to 329 ppm
Melting point: - 44.9 oC for the duration of the task (1 to 2 hours) and 59 ppm
Vapour pressure: 15.81 hPa at 25 oC when time weighted over the 8 hour shift. Peak
exposures would have been higher than these values.
11.73 hPa at 20 oC
Exposure data modelled with the Estimation and
Solubility in water: 293 mg.l-1 at 25 oC
Assessment of Substance Exposure (EASE) model
LogPo/w: 2.84 gave results of 4.6 to 6.7 ppm 15-min TWA for
Saturated vapour concentration: 15526 ppm (1.55%) sampling, 1.3 to 50 ppm 15-min TWA for tanker
unloading, and 1 to 100 ppm 15-min TWA for vessel
charging. These represent short term exposures. These
Conversion factors: 1 ppm = 4.68 mg.m-3 at 20 oC are likely to be overestimates and will be dependent
1 mg.m-3 = 0.21 ppm on the nature of the controls in place. The above short
term exposure compares reasonably well with the full
shift exposure. For example, 3.5 ppm 8-hour TWA for
Chlorobenzene is currently classified for health effects
a worker exposed during tanker unloading (30
under the Chemicals (Hazard Information and Packag-
minutes) and quality control sampling (2 periods of 15
ing for Supply) Regulations 1994 (CHIP) as Harmful,
minutes). Occupational exposure during repackaging
to be labelled with the following risk phrases:-.
of chlorobenzene and laboratory use are thought to be
R10: Flammable generally lower than the above values.
R20: Harmful by inhalation It is therefore concluded that exposure is generally
R51/53: Toxic to aquatic organisms, may cause below 50 ppm 8-hour TWA and in most cases below
long term adverse effects in the aquatic 10 ppm 8-hour TWA. It is further concluded that the
environment data demonstrates that it is likely that control to less
than 5 ppm 8-hour TWA is reasonably practicable.
The available data for chlorobenzene indicate that it Although exposures of higher than this have been
also meets the criteria for classification as Irritant, obtained it was not felt that these represented the
and that the following risk phrase may be majority of exposures and what it is reasonably practi-
appropriate:- cable to achieve.

27
 MEL PROPOSAL
There is little information about short-term exposures.
Short term exposures of up to 100 ppm 15-min TWA
were modelled using EASE. However, the higher
values represented only modest assumptions about
standards of control. If realistic controls are incorpo-
rated, the model predicts exposures below 10 ppm.
Dermal exposure can occur during the use of chloro-
benzene, where operators come into contact with
surfaces contaminated from splashing or condensed
vapour, or as a result of direct contact onto the skin.
During its use in chemical plants, where it is used in
generally closed systems, dermal exposure is only
likely during activities such as sampling and the
uncoupling of pipes. A range of 0 to 0.1 mg.cm-2.day-1
was predicted using EASE assuming that there may be
at most incidental (i.e. one significant) contact in a
shift. However, on most days no such accidental
contacts will occur and exposure will towards the
bottom of this range.
ATMOSPHERE MEASUREMENT
Indicating colourimetric tubes for short-term measure-
ments of chlorobenzene in air are commercially avail-
able and capable of detecting 0.5 ppm. Other
chlorinated hydrocarbons can interfere with different
sensitivities. Real-time instruments with infra-red or
photo-acoustic detection that can detect less than 1
ppm are also available. Personal exposure to vapour in
air can be measured by pumped sampling on charcoal
tubes (solvent desorption method NIOSH 1003)1 or
Tenax (thermal desorption method MDHS 72)2 and
analysis by gas chromatography. Earlier NIOSH data
published as method S1333 suggests that the carbon
tube method, with carbon disulphide and coconut shell
charcoal, may not meet the >75% desorption
efficiency criterion below 5 ppm at the maximum
sample volume of 40 litres. This factor is sensitive to
the type of carbon and the addition of solvent modifi-
ers. Synthetic carbons are better than coconut shell
charcoal. OSHA have indicated a preference for 1%
dimethylformamide in carbon disulphide4. With
respect to other factors, solvent desorption methods
would generally comply with EN 4825 on overall
uncertainty and with EN 10766 on environmental
effects above 5 ppm. The pumped thermal desorption
method MDHS 72 has a detection limit of <0.02 ppm
for a 10 litre sample. MDHS 72 has been partially
validated for chlorobenzene and is likely to comply
with EN 482 and EN 1076 for both long-term and
short-term sampling at <1 ppm where desorption
efficiency was >97%. Diffusive sampling is feasible
on carbon-type badge devices with solvent desorption
(MDHS 88)7. However, uptake rates are generally
lower than pumped flow-rates and the desorption
efficiency criterion of >75% may not be met below 15
ppm for 8 hours. Carbon-type diffusive badges are
28
unlikely to be suitable for 15 minute sampling below
25 ppm. Users must verify the solvent desorption
efficiency of chlorobenzene with their chosen collec-
tion medium, otherwise their procedure may not
comply with EN 1076 or EN 8388 at low concentra-
tions. Thermal desorption diffusive tube samplers are
feasible (MDHS 80)9 and have adequate sensitivity for
the measurement of <0.1 ppm for 8-hr sampling and
of <3 ppm for 15 minute sampling.
BIOLOGICAL MONITORING
Biological monitoring may be a useful aid to the
assessment of occupational exposure to
chlorobenzene. There are no data to relate metabolite
concentrations to health effects but there are data to
show a good correlation between levels of
4-chlorocatechol in urine samples collected at the end
of shift and inhaled chlorobenzene. After exposure to
chlorobenzene at 1 ppm for 8 hours, the urine concen-
tration of 4-chlorocatechol would be around 5
mmol.mol-1creatinine (6.4 mg.g-1).
There are several methods for the determination of
4-chlorocatechol in urine10,11,12,13. All are based on
hydrolysis of glucuronide and sulphate conjugates of
4-chlorocatechol and HPLC with UV detection. The
most recent and well validated method is that of
Heinrich-Ramm. This method was developed and
evaluated to support the DFG biological monitoring
programme.
Briefly: the method hydrolyses 5ml of urine, contain-
ing 3-ethylphenol internal standard, in 25% HCl at
90oC for 2 hours and after cooling extracts the chloro-
catechol into diethyl ether. The ether extract is trans-
ferred to a clean vial and the ether removed under
nitrogen. The residue is redissolved in HPLC mobile
phase and injected into a C18 column at 34 oC. Detec-
tion is at 205 nm. The method is linear from 0.5
mg.l-1 to 50 mg.l-1 with a detection limit of 0.1 mg.l-1
and a coefficient of variation for within-day impreci-
sion of 2.3% and a day to day imprecision of 4.9%.
No interfering peaks have been found in chroma-
tograms at levels greater than 0.5 mg.l-1 from people
not occupationally exposed to chlorobenzene.
TOXICOKINETICS
Few data on the toxicokinetics of chlorobenzene in
humans are available. The data which are available
relate to metabolism and excretion. The available
animal data largely relate to the inhalation and oral
routes of exposure. There are no data regarding the
dermal route of exposure.
Human and animal studies show that chlorobenzene is
absorbed to a substantial extent via the oral and
inhalation routes, but do not allow quantification of
absorption via these routes. From the physico-
chemical properties of chlorobenzene and by analogy
 MEL PROPOSAL
with other chlorobenzenes it is predicted that chloro-
benzene will be readily absorbed via the dermal route.
Following absorption chlorobenzene is distributed
throughout the body, principally to the fat, liver, lungs
and kidneys. Given the lipid solubility of chloroben-
zene it is likely to accumulate in body fat, although
this may depend on the extent of metabolism.
Comparative in vitro studies suggest qualitatively
similar metabolic profiles in rats, mice, rabbits,
guinea-pigs and humans. In vitro data also indicate
that human liver microsomes are twice as efficient as
mouse liver microsomes in metabolising chloroben-
zene and also that human liver microsomes have a
greater affinity for chlorobenzene than mouse liver
microsomes.
In vitro and in vivo human and animal data indicate
that chlorobenzene is initially oxidised by the micro-
somal cytochrome P450 system to a reactive arene
oxide, which has the potential to bind with rat and
mouse liver, kidney and lung DNA, RNA and
proteins.
The arene oxide is subsequently converted either via
non-enzymic reactions to 3 and 4 isomers of chloro-
phenol or via enzymic activity to a glutathione (GSH)
conjugate or to dihydrodiol derivatives. The GSH
conjugates are either eliminated unchanged in the
faeces or are transformed to more water soluble
products and are excreted in the urine as
4-chlorophenylmercapturic acid. The dihydrodiol
derivatives are converted principally to
4-chlorocatechol and to a lesser extent to
3-chlorocatechol which are also excreted in the urine.
Animal and human studies have shown that excretion
of chlorobenzene and/or its metabolites in the urine is
rapid (within 24 hours). In instances of high exposure
concentrations, both inhalatory and orally, unchanged
chlorobenzene has also been detected in expired air,
the proportion of chlorobenzene exhaled increasing
with increasing exposure concentration, indicating
saturation of metabolism.
HEALTH EFFECTS
Animal studies
Chlorobenzene is of moderate acute toxicity in rats
and mice following single inhalation exposures of
chlorobenzene vapour, with 6-hour LC50 values of 13
and 8.6 mg.l-1 in rats and mice respectively. Chloro-
benzene is of low acute toxicity following single oral
exposure in rats, rabbits and guinea-pigs, with LD50
values of >2250 mg.kg-1. The mouse however appears
to be slightly more sensitive following single oral
exposures, with LD50 values in the range 1400 - 2300
mg.kg-1. Chlorobenzene is of low acute toxicity in the
rabbit following single dermal exposures with LD50
values of >2000 and >7500 mg.kg-1 being identified.
29
Signs of acute toxicity in animals exposed to chloro-
benzene via all routes include hyperaemia of the
mucous membranes, increased salivation and lacrima-
tion and evidence of disturbance of the central
nervous system. Pathological findings of hypertrophy
and necrosis of the liver and of the proximal tubules
of the kidneys are reported. In all acute exposure
studies death generally occurred as a result of respira-
tory failure.
Limited animal data indicate that direct contact with
liquid chlorobenzene is irritating to both the skin and
eyes. No useful data are available regarding the
potential of chlorobenzene to cause irritation to the
respiratory tract. However, given the skin/eye irritancy
it can be predicted that chlorobenzene is likely to be
capable of causing respiratory tract irritation.
Chlorobenzene did not induce skin sensitisation in a
guinea-pig maximisation study. There are no data
regarding the potential of chlorobenzene to cause
respiratory tract sensitisation.
With respect to repeated dose toxicity, animal data
indicate that the liver, kidneys and possibly the
haematopoietic tissues are the target organs of chloro-
benzene toxicity.
Inhalation studies demonstrate that in rats no effects
on the liver occurred following chlorobenzene
exposures of up to 75 ppm for 24 weeks . At 250 ppm
for 24 weeks and at 150 and 450 ppm for ~22 weeks
liver weights were increased by 13 to 36% compared
with controls with evidence of minimal to moderate
hepatocellular hypertrophy in males at 150 and
450 ppm for ~22 weeks but not in animals at 250 ppm
for 24 weeks. In dogs no adverse liver effects were
observed following exposures to 165 or 300 ppm for
90 days. Decreased liver weights (magnitude not
reported) and vacuolisation of the hepatocytes were
reported following exposures to 440 ppm for 90 days.
No adverse liver effects were reported in rabbits at
exposures of up to 250 ppm for 24 weeks.
Data from 90-day and 2-year oral gavage studies in
both rats and mice suggest that the liver changes
induced are similar to those following inhalation
exposure but also indicate a sensitive marker for
MCB-induced liver changes is elevated levels of
urinary porphyrin. No adverse liver effects, including
changes in porphyrin levels were observed in either
species at doses of 60, 125 or 250 mg.kg-1.day-1 for
90 days. At 500 and 750 mg.kg-1.day-1 for 90 days
increased liver weights (up to ~100%), increased
urinary porphyrin levels and centrolobular hepatocel-
lular degeneration were observed in rats (all mice in
these test groups had died). No evidence of liver
damage was reported in rats in a 2-year study at doses
up to 120 mg.kg-1.day-1 (the highest dose tested) or in
mice at 60 mg.kg-1.day-1. In male mice and only at
120 mg.kg-1 bw.day-1 an increased incidence of
neoplastic nodules in the liver was observed. No
evidence of liver toxicity in dogs was reported to
occur in animals administered 27 mg.kg-1 bw.day-1 for
 MEL PROPOSAL
13 weeks. Hepatotoxicity (nature and severity not
reported) was reported in dogs administered 54 and
273 mg.kg-1.day-1 for 90 days.
Although data from a 2-year oral study in mice clearly
indicate a NOAEL for liver effects of 60 mg.kg-1
bw.day-1 hepatotoxicity (not specified) was reported
in dogs at 54 mg.kg-1.day-1 for 90 days. Overall there-
fore, it is it is not possible to identify a clear NOAEL
for the liver effects resulting from chlorobenzene
exposure.
Kidney damage was observed in male rats (increased
incidence of tubular and interstitial kidney lesions and
proximal tubule degeneration, regeneration &
necrosis) and in the dog (cytoplasmic vacuolisation of
the epithelium of the collecting tubules or unspecified
histopathological changes) following both inhalation
and oral exposures, and in the mouse following oral
exposure (proximal tubule degeneration, regeneration
& necrosis). However in each species the kidney
effects were only manifest at exposure concentrations
or doses equal to or greater than those inducing liver
damage. No evidence of kidney damage was reported
in the available rabbit inhalation study.
Animal data also indicate that haematological changes
occur in rats, mice, rabbits and dogs following inhala-
tion exposures to chlorobenzene, and in rats, mice and
dogs following oral exposures. The inhalation data
suggest that the mouse is the more sensitive species
with respect to the development of haematological
changes.
Data from the available repeated rat inhalation study
show no haematological changes following exposure
to 75 ppm for 11 or 24 weeks (the 11 week time-point
being an interim sacrifice in the 24 week study).
Haematological changes were observed in the same
study in animals at 250 ppm both at 11 and 24 weeks;
changes reported were in PMNs, platelets, white
blood cell, reticulocyte and monocyte numbers. In the
two available rat oral studies (a 90-day and a 2-year
study) in which haematological analysis was
conducted (no interim analyses were conducted in
either study), no haematological changes were
reported at dose levels of 60, 120 (the top-dose tested)
mg.kg-1.day-1 for 2 years or at 60, 125 or 250
mg.kg-1.day-1 for 90 days. An increased mortality rate
in animals administered 500 mg.kg-1.day-1 for 90 days
limited the extent of haematological analyses
conducted, consequently no adverse findings in
standard haematological parameters were reported.
However at necropsy an increased incidence of
myeloid depletions in bone marrow were observed in
these animals. In animals administered 750
mg.kg-1.day-1 for 90 days, (the increased mortality rate
did not limit haematological analyses in this group)
reduced white blood cell and reticulocyte counts and
lymphoid and/or myeloid depletions in thymus, spleen
and bone marrow were reported.
30
In the repeated inhalation study in mice, haemato-
logical effects (changes in white blood cell, lympho-
cyte, monocyte and neutrophil numbers) were
observed at exposures of 21 ppm for 3 months and at
550 ppm for 3 weeks. As these were the only concen-
trations and time points investigated a no effect level
cannot be identified for haematological changes in the
mouse exposed via inhalation. No changes in standard
haematological parameters were reported in the
animals at doses of up to 250 mg.kg-1.day-1 for 90
days, or up to 120 mg.kg-1.day-1 for 2 years (the
top-dose tested). However, blood analysis was only
conducted at the end of the dosing period in both of
these studies. In the 90 day study animal deaths
prevented blood analysis at the higher doses (500 and
750 mg.kg-1.day-1). However, at necropsy evidence of
mild to moderate myeloid depletions of the bone
marrow and minimal to moderate lymphoid necrosis
or depletion of the thymus were observed in animal at
250, 500 and 750 mg.kg-1.day-1 for 90 days.
In the repeated inhalation study in rabbits haemato-
logical changes (changes in PMNs, platelets, white
blood cell, reticulocyte and monocyte numbers) were
observed following exposure to 75 and 250 ppm, the
only concentrations tested. No oral rabbit studies are
available.
In the available repeated inhalation exposure studies
in dogs, haematological analysis was only conducted
in the 90 day study. In this study, no treatment-related
haematological changes were reported at 165 or 330
ppm. At 440 ppm, reduced leukocyte counts (not
quantified) were reported, as well as evidence of
aplastic bone marrow at necropsy. No findings were
reported in animals at lower exposure concentrations.
In the repeat oral study in dogs no effects on haema-
topoietic tissues were reported at doses of 27 mg.kg-1
bw.day-1 for 90 days. An increased number of
immature leukocytes was observed at 54 mg.kg-1
bw.day-1, and histopathological changes in the haema-
topoietic tissues (nature and severity of response not
reported) were observed in animals administered 273
mg.kg-1 bw.day-1.
Taking all of the available data together there are
some indications that chlorobenzene may produce
changes in haematological parameters. However, there
is clearly significant variation in the observations
made and uncertainty remains over whether or not the
changes are chance findings or indicative of a real
treatment-related effect. Furthermore, if the findings
are considered to be related to treatment, then there is
uncertainty in the identification of a NOAEL.
In terms of genotoxicity, negative results have been
reported in bacterial studies and in studies in mammal-
ian cells in vitro with respect to chromosome aberra-
tions, SCE and UDS at non-cytotoxic concentrations.
However, a clear and dose-related positive result has
been reported in an in vitro gene mutation assay in
mouse lymphocytes, in the presence of metabolic
activation.
 MEL PROPOSAL
There are no reliable data from mutagenicity studies
conducted in vivo according to validated test methods.
Overall, in light of the positive in vitro data and the
fact that chlorobenzene has not been adequately tested
in vivo uncertainties remain with respect to the in vivo
genotoxic potential of chlorobenzene.
Oral (gavage) carcinogenicity studies with chloroben-
zene did not induce an increased incidence in any
tumour type in rats of either sex at doses of up to 120
mg.kg-1.day-1 or in mice of either sex at doses of up to
60 mg.kg-1.day-1. Although survival rates in top-dosed
animals were slightly reduced compared with controls,
no clinical signs of toxicity, changes in body weights
or gross treatment-related lesions were observed.
Therefore it is uncertain whether the top-doses tested
were actual maximum tolerated doses (MTDs) and
therefore whether the studies were in fact adequate for
the determination of carcinogenic potential.
No carcinogenicity studies via the inhalation or
dermal routes are available.
No evidence for effects on fertility or reproductive
performance were observed in a two generation study
in which rats were exposed to up to 450 ppm chloro-
benzene vapour. No adverse histopathalogical
findings in the gonads were observed in males at up to
150 ppm or in females at up to 450 ppm An increased
incidence (severity not reported) of degeneration of
the testicular germinal epithelium in males exposed to
450 ppm was noted at necropsy. Despite these lesions
there were no adverse effects on the fertility or repro-
ductive performance of these animals. No adverse
histological findings were observed in the gonads of
rats or rabbits, following repeated inhalation
exposures of up to 250 ppm (1138 mg.m-3) for
24 weeks.
Bilateral atrophy of the seminiferous epithelium was
noted in dogs exposed to 273 ppm (~1500 mg.m-3)
chlorobenzene vapour for 90 days.
No adverse histological findings were observed in the
gonads of rats or mice following repeated oral dosing
of up to 750 mg.kg-1.day-1 for 90 days or 120
mg.kg-1.day-1 and 60 mg.kg-1.day-1 for 2 years, respec-
tively, or in dogs following administration of up to
273 mg.kg-1.day-1 for 90 days.
No evidence of any chlorobenzene treatment-related
developmental effects have been observed in rats,
mice or rabbits, at doses up to 590 ppm on days
5-16/18 of gestation, this being the highest concentra-
tion tested. Evidence of some degree of maternal
toxicity (reduced food consumption and body weight
gain and increased liver weights) was observed at
590 ppm (2685 mg.m-3) in all species tested.
Overall, it is concluded that chlorobenzene is not a
reproductive toxicant.
Human data
31
The only information available on the effects of
chlorobenzene in humans derive from isolated case
reports of poisoning, occupational exposure studies or
one volunteer study. No data on the actual levels of
exposure are reported in any of the case reports, and
interpretation of the occupational exposure studies is
confounded by exposure to mixtures of other
substances. In a human volunteer study, some
individuals self-reported sensations of disagreeable
odour and drowsiness (4/4), a heavy feeling in the
head and/or headache (3/4), a throbbing pain in the
eyes (2/4) and a sore throat (1/4) during exposure to
60 ppm chlorobenzene of an unspecified purity for
3-hours in the morning, followed by a 4-hour exposure
period in the afternoon, with a 1-hour interval in
between.
BASIS FOR SETTING THE LIMIT
There are no reliable human data available on which
to base an occupational exposure limit for chloroben-
zene. The evidence from a range of animal species
indicates that the liver and bone marrow are the key
target organs of chlorobenzene toxicity in experimen-
tal animals. From the information available, the
relevance of the animal data on these effects to human
health is uncertain. Given that they might be relevant,
it is not possible to identify a clear NOAEL for the
liver effects of chlorobenzene in animals.
In relation to the haematological effects observed with
chlorobenzene, the pattern of information suggests
that the mouse may be more sensitive to these effects
than other experimental species. However, haemato-
logical investigations have not been systematically
carried out in all studies, and there is significant
variability in the results available from different
studies. This leads to uncertainty as to whether or not
the reported changes in individual studies represent
reliable toxicological observations or chance findings.
However, it is perhaps significant that chlorobenzene
is structurally similar to benzene, which is metabo-
lised in a similar manner to chlorobenzene, both
molecules undergoing initial ring hydroxylation.
Therefore, the well-documented haematological
effects of benzene add weight to the concern for
haematological changes with chlorobenzene. From
the information available for chlorobenzene, it is not
possible to identify a clear NOAEL for haematologi-
cal changes across the experimental species examined;
changes were reported in mice following repeated
exposure to 21 ppm, the lowest airborne concentration
tested.
In light of the positive in vitro genotoxicity data and
the inadequate in vivo testing of chlorobenzene there
are uncertainties regarding the in vivo mutagenic
potential of chlorobenzene.
In the only available carcinogenicity study, no
increase in the incidence of any tumour type was
 MEL PROPOSAL
observed in rats or mice. However, as it is uncertain
whether the top doses tested were maximum tolerated
doses (MTDs). the adequacy of this study and there-
fore of the negative result is questionable Therefore
in the absence of any other relevant data, there remain
uncertainties with respect to the carcinogenic potential
of chlorobenzene.
Exposure data demonstrate that control to less than
5 ppm (8-hour TWA) is reasonably practicable, and
that most results are below 1 ppm. Although higher
exposure results have been obtained, these are not
typical and exceed what it is reasonably practicable to
achieve. The available toxicological data do not
identify clear positive evidence for serious effects on
human health at 1 ppm or 5 ppm; rather, the position
is one of uncertainty.
WATCH concluded that chlorobenzene did not fulfill
the criteria for an OES and recommended that ACTS
should give consideration to setting a MEL. Because
an occupational exposure limit is required to fulfill
British obligations under the Chemical Agents Direc-
tive and the Indicative Occupational Exposure Limit
Value (IOELV) Directive, a MEL is necessary.
Taking into account the above information and the
IOELV, ACTS considered that values of 1 ppm
(8-hour-TWA) and 3 ppm (STEL) are appropriate.
Based on the predicted high level of dermal absorp-
tion, it is concluded that a ‘Skin’ notation is required.
Although no biological monitoring guidance value has
been set, the methods and relationships set out in the
biological monitoring section above may be useful in
monitoring exposure.
This substance is included in the 1st Consolidated
Indicative Limit Occupational Exposure Limit Values
Directive (2000/39/EC), with values of 10 ppm
(8-hour TWA) and 20 ppm (STEL). WATCH and
ACTS took into account the limit values in this Direc-
tive in their deliberations on British limit values for
this substance.
REFERENCES
1. NIOSH Manual of Analytical Methods, Method
1003 (1994), Hydrocarbons, halogenated, 4th Ed.,
National Institute of Occupational Safety and Health,
Cincinatti, USA.
2. Health and Safety Executive Methods for the Deter-
mination of Hazardous Substances, Volatile organic
compounds in air... pumped solid sorbent tubes,
thermal desorption, MDHS 72, HSE Books 1993,
ISBN 0 11 885692 8.
3. Taylor D G, Kupel R E and Bryant J M (1977),
Documentation of NIOSH validation tests, DHEW
(NIOSH), Publ No 77-185.
4. OSHA Chemical Sampling Information, Chloroben-
zene (1998), http://www.osha-slc.gov/
32
ChemSamp_data/CH_227000.html.
5. British Standards Institution, Workplace atmos-
pheres - General requirements for the performance of
procedures for the measurement of chemical agents,
European Standard BS EN 482:1994, ISBN 0 580
23644 7.
6. British Standards Institution, Workplace atmos-
pheres - Pumped sorbent tubes for the determination
of gases and vapours, European Standard BS EN
1076:1997, ISBN 0 580 28358 5.
7. Health and Safety Executive Methods for the Deter-
mination of Hazardous Substances, Volatile organic
compounds in air... diffusive samplers, solvent desorp-
tion, MDHS 88 HSE Books 1997 ISBN 0 7176 2401
3.
8. British Standards Institution, Workplace atmos-
pheres - Diffusive samplers for the determination of
gases and vapours - Requirements and test methods,
European Standard BS EN 838:1996, ISBN 0 580
26240 5.
9. Health and Safety Executive, Volatile organic
compounds in air... diffusive samplers, thermal
desorption, MDHS 80, HSE Books 1995, ISBN 0
7176 0913 8.
10. Heinrich-Ramm R. 3,4 Dihydrochlorobenzene
(4-chlorocatechol). In DFG Deutsche Forschungsge-
meinschaft Analyses of Hazardous Substances in
Biological Materials volume 6 Jurgen Angerer &
Karl-Heinz Schaller eds published by Wiley-VCH
1999 ISSN 0179-7247.
11. Kumagai S, Matsunaga I (1995) Effect of varia-
tion of exposure to airborne chlorobenzene on internal
exposure an concentrations of urinary metabolite.
Occupational & Environmental Health 52: 65-70.
12. Kusters E, Lauwreys R (1990) Biological monitor-
ing of exposure to monochlorobenzene. Int Arch
Occup & Environ Health 62: 329-331.
13. Ogata M., Taguchi T., Hirota N., Shimada Y. and
Nakae S. (1991) Quantitation of urinary chloroben-
zene metabolites by HPLC: concentration of
4-chlorocatechol and chlorophenols in urine and of
chlorobenzene in biological specimens of subjects
exposed to chlorobenzene. Int. Arch. Occup. Environ.
Health. 63, 121-128.
14. Hellman B. (1993) NIOH and NIOSH basis for an
occupational health standard: Chlorobenzene. Arbete
Och Hälsa1992:31 ISBN: 91-7045-183-4.
15. Cole J. and Skopek T.R. (1994) Somatic mutant
frequency, mutation rates and mutational spectra in
the human population in vivo. Mutation Research.
304, 33-105.
16. Dilley J.V. (1977) Toxic evaluation of inhaled
chlorobenzene (monchlorobenzene) - Final report.
Stanford Research Institute for National Institute for
 MEL PROPOSAL
Occupational Safety and Health, USA. Project number
PB276623.
17. Dilley J.V. and Lewis T.R. (1978) Toxic evalua-
tion of inhaled chlorobenzene. Toxicol. and Appl.
Pharmacol. 45, 327.
18. Fel’dt E.G. (1985) Evaluation of the mutagenic
hazards of benzene and some of its derivatives.
Gigiena I Sanitariya 7, 21-23.
19. Kluwe W.M., Dill G., Persing R. and Peters A.
(1985) Toxic responses to acute, subchronic and
chronic oral administration of monochlorobenzene to
rodents. J. Toxicol. Environ. Health. 15, 745-767.
20. Major J., Kemeny G. and Tompa A. (1992/3)
Genotoxic effects of occupational exposure in the
peripheral blood lymphocytes of pesticide preparing
workers in Hungary. Acta. Medica. Hungarica.
49(1-2), 79-90.
21. Mohtashamipur E., Triebel R., Straeter H. and
Norpoth K. (1987) The bone marrow clastogenicity of
eight halogenated benzenes in male NMRI mice.
Mutagenesis. 2(2), 111-113.
22. Nair R.S., Barter J.A., Schroeder R.E., Knezevich
A. and Stack C.R. (1987) A two generation reproduc-
tion study with monochlorobenzene vapor in rats.
Fundamental and Applied Toxicology. 9, 678-686.
23. NTP (1985) Toxicology and carcinogenesis
studies of chlorobenzene in F344/N rats and B6C3F1
mice (gavage studies). US Dept. of Health and Human
Services, NTP, Technical report Series No.261.
24. Zub M. (1978) Reactivity of the white blood cell
system to toxic action benzene and its derivatives.
Acta. Biologica Cracoviensia (Zoologia). 21,
163-174.

33
 MEL PROPOSAL
Hydrogen selenide is not manufactured in the UK or
HYDROGEN SELENIDE the European Union. There are three major suppliers
of the substance in the UK. Approximately 60 kg per
maximum exposure limits
annum are used in the UK. It is transported in
8-hour TWA: 0.02 ppm (0.07 mg.m-3)
cylinders as a minor component (1% to 5%) in a
15-minute STEL: 0.05 ppm (0.17 mg.m-3)
carrier gas such as hydrogen.
subject to consultation The major use of hydrogen selenide world-wide is as a
dopant gas in the preparation of semiconductor
materials for use in lasers etc. It is also used in the
chemical synthesis of metallic selenides,
IDENTITY AND PROPERTIES organoselenium compounds and emulsions. Small
Chemical Name: Hydrogen selenide quantities of the gas may be liberated during a number
CAS No: 7783-7-5 of production processes in which selenium compounds
EC Index No: 034-002-00-8 (Selenium may be present such as the manufacture of glass and
compounds except ceramics, the vulcanisation of rubber and during the
cadmium sulphoselenide) manufacture of lead batteries.

Formula: H2Se In the UK, its use in the preparation of semiconductor

materials is thought to be the only use. It is understood
Synonyms: Selenium hydride
that up to six companies use hydrogen selenide as a
dihydrogen selenide dopant gas for the production of gallium arsenide
selane; selenium wafers for use in lasers, solar cells and other
dihydride. optoelectronic equipment. Furthermore, in the UK
Vapour pressure: Gas at 20 o C; 9.5 bar hydrogen selenide may be produced as a by-product
and liberated during processes where selenium
Melting point: -66 oC
compounds may be present such as the smelting of
Boiling point: -41 oC alloys, during lead battery manufacture and during the
Conversion factor: 1 ppm = 3.37 mg.m-3 at production of studio glasses.
20 oC EXPOSURE
Hydrogen selenide is a colourless, extremely Occupational exposure to hydrogen selenide may
flammable gas with a foul, pungent odour. It has an occur during the fitting and removal of gas cylinders,
odour threshold of 0.3 ppm. during its dilution for supply and during its use as a
dopant gas in the semiconductor industry. In these
Hydrogen selenide is not in the Approved Supply List;
situations, up to 30 employees may be potentially
the risk (R) phrases given below apply to elemental
exposed. No occupational exposure data was available
selenium and selenium compounds:
from the suppliers of the gas or the main users in the
R23/25: Toxic by inhalation and if swallowed
UK. HSE does not have any workplace exposure data
R33: Danger of cumulative effects for hydrogen selenide.
During dilution of the gas, the Estimation and
OCCURRENCE AND USE
Assessment of Substance Exposure (EASE) computer
Hydrogen selenide occurs naturally when produced by model was not used because the level at which the
the reaction of selenium with organic matter or when sensor alarm in the gas cabinet is pre-set can be
nascent hydrogen is in contact with soluble selenium interpreted as a ceiling value for operator exposure.
compounds. The gas is produced commercially by the However, the EASE model was used to predict
reaction of acids or water on metal selenides or by exposure to the gas during the changing of cylinders
passing hydrogen and selenium vapour over pumice at prior to use as a dopant gas. The cylinder changing is
177oC. It can also be produced adventitiously e.g. by a short term task of about 5 minutes and the gas is
the action of water on some slags. used in a 1% concentration, therefore, the calculated
15 minute reference period is between 0.002-0.010

34
 MEL PROPOSAL
ppm. However, exposure would be negligible because
the workers would wear self contained breathing
apparatus during cylinder changing.
In the event of leakage in the reaction chamber and
release into the glove box and the surrounding
environment during the production of gallium arsenide
wafers, the EASE model predicts that exposure would
be between 0-0.1 ppm 8-hour Time Weighted
Average (TWA). As the process is complete within
3 hours, the exposure is calculated to range between
0-0.0003 ppm using a 1% concentration. However,
occupational exposure is expected to be negligible
because of the safety procedures adopted including the
use of self contained breathing apparatus should
workers re-enter a contaminated room.
In those processes where there is the potential for
hydrogen selenide to be produced and liberated, such
as during lead battery manufacture, exposure is
expected to be negligible. When water or acid react
with selenium in slag, dross or waste, exposure may
be higher. However, these events are infrequent and
any exposure is expected to be short lived because the
gas will be quickly dissipated by natural ventilation.
It is expected that from the EASE data and from
discussions with industry that exposure to hydrogen
selenide can be controlled to less than the 0.02 ppm
8-hour TWA and 0.05 ppm STEL. Most exposure will
be short term exposure such as cylinder changing and
it is expected that here exposure will be much less
than the proposed limits.
MEASUREMENT
Workplace air monitoring
A method for the determination of volatile inorganic
hydrides in workplace air has been published by the
National Institute for Occupational Health (NIOH) in
Norway (Hetland et al, 1991). This method was
developed for measurement of arsine, stibine and
phospine, but NIOH have subsequently shown it to be
effective for measuring hydrogen selenide. Samples
are collected on silver nitrate coated membrane filters
and analysed, after digestion, by electrothermal atomi-
sation atomic absorption spectrometry. Alternative
means of analysis such as inductively coupled plasma
atomic emission spectrometry or inductively coupled
plasma mass spectrometry can be employed. Using
any of these analytical techniques, the method has an
adequate detection limit for making measurements for
comparison with the 0.02 ppm 8-hour TWA and 0.05
ppm STEL.
35
Biological monitoring
There are no recent reports which describe biological
monitoring in hydrogen selenide exposure. The rapid
conversion of hydrogen selenide to selenium when in
contact with moist body surfaces suggests that
hydrogen selenide exposure will contribute to body
burden of selenium. Selenium intake can be
monitored by urinary total selenium levels and
validated analytical methods are widely reported.
However, wide potential differences in dietary intake
of selenium and possible dietary supplementation are
potential confounders in discriminating occupational
exposure from environmental sources. Hydrogen
selenide does not meet the criteria for a biological
monitoring guidance value.
TOXICOKINETICS
There are very limited data on the toxicokinetics of
hydrogen selenide. As hydrogen selenide is a gas the
lungs are the main route of exposure. Observations of
the formation of deposits of red (elemental) selenium
in the nasal passages of humans and animals following
inhalation of hydrogen selenide indicate that it can be
oxidised to elemental selenium on contact with moist
surfaces. However, no quantitative absorption data are
available and it is unclear whether hydrogen selenide
is directly absorbed. Though the absorption of
elemental selenium has been demonstrated, there are
no data indicating how, or in what form, it is
absorbed. No reliable information is available on
distribution or excretion following exposure to
hydrogen selenide. There is also no information on
skin absorption of hydrogen selenide gas, although as
the substance is a gas, significant skin absorption is
not anticipated.
HEALTH EFFECTS
Animal studies
Hydrogen selenide is very toxic, with a 4-hour LC50
value of 2.7 ppm (9 mg.m-3) in the guinea pig. Deaths
result from direct lung damage. Immediate eye and
nose irritation occur at concentrations above 64 ppm.
As it is a gas, there are no oral or dermal studies. No
reliable repeated exposure data are available.
There are no data available for sensitising, genotoxic,
carcinogenic or reproductive effects.
 MEL PROPOSAL
Human data
Only limited data are available in humans. Following
single exposures to unknown concentrations in
workers, severe irritation to the eyes and upper
respiratory tract and breathing difficulties have been
reported. Early reports (Dudley and Miller, 1941), of
uncertain reliability, indicate that men could not work
without respiratory protection at concentrations above
5.0 mg.m-3 (1.5 ppm). In relation to the effects of
repeated exposure there is an absence of reliable
exposure data. Symptoms of nausea, vomiting,
metallic taste in the mouth, dizziness and extreme
lassitude have been reported within one month of
exposure to hydrogen selenide at estimated levels of
1-5 mg.m-3 (0.3-1.5 ppm) following the incorporation
of selenious acid in etching ink. The exposure level
was estimated by using the subjective measurement of
odour tolerance and hydrogen selenide concentration
as reported by Dudley and Miller (1941). A laboratory
worker exposed to hydrogen selenide at least once
weekly for a year experienced health effects similar to
those associated with selenium; nausea, vomiting,
abdominal pain, garlicky breath, transverse ridges of
the nails and dental caries. In addition, the individual
also experienced chronic diarrhoea, conjunctivitis and
nasal stuffiness.
There are no human data on sensitisation,
genotoxicity, carcinogenicity or reproductive toxicity
of hydrogen selenide.
BASIS FOR SETTING A LIMIT
There is a very limited toxicity database for hydrogen
selenide (Shackleton et al, 1992). The critical health
effect is severe irritation to the respiratory tract.
Although marked respiratory tract irritancy has been
reported in humans exposed to hydrogen selenide,
there are no reliable data from human studies
concerning the dose-response characteristics for this
effect. In guinea pigs, an 8-hour exposure to 0.3 ppm,
the lowest concentration tested, resulted in the deaths
of 50% of the animals due to direct lung damage.
Overall, it is not possible from the limited data
available to identify a NOAEL for respiratory
irritation. WATCH concluded that there were
insufficient data to derive an OES.
Hydrogen selenide is included in European Directive
2000/39/EC, with an Indicative Occupational
Exposure Limit of 0.02 ppm (8-hour TWA) and 0.05
36
ppm (STEL). SCOEL applied an uncertainty factor of
20 to the NOAEL of 0.3 ppm to allow for limitations
of the reporting. The values were then rounded up in
order to meet the requirements of the preferred value
approach of the SEG. This was felt to provide an
adequate margin of protection because the calculation
allowed for 100% absorption and the very steep dose
response relationship is recognised as producing a
more reliable NOAEL. This resulted in a
recommendation for an 8 hour TWA of 0.02 ppm,
which is not contradicted by the level indicated for
systemic exposure to elemental selenium. A STEL (15
minutes) of 0.05 ppm was recommended to limit
peaks in exposure which could result in irritation.
ACTS took into account the limit values in this
Directive in their deliberations on British limit values
for this substance and recommended an 8-hour TWA
MEL at 0.02 ppm and a STEL at 0.05 ppm.
There is no evidence to indicate that either a "skin"
notation or a Sen notation is warranted for hydrogen
selenide. The criteria for establishment of a biological
monitoring guidance value are not met.
REFERENCES
SEG/CDO/18 (1991). Criteria document for an
occupational exposure limit for hydrogen selenide.
Prepared by Industrial Toxicology Unit, Institute of
Occupational Health, Birmingham.
Dudley H C and Miller J W (1941) Toxicology of
selenium. VI. Effects of subacute exposure to hydro-
gen selenide Journal of Industrial Hygiene and
Toxicology 23 (10) pp 470-477
Hetland S Martinsen I Radziuk B and Thomassen Y
(1991) Species analysis of inorganic compounds in
workroom air by atomic spectrometry Analytical
Sciences Vol 7 Supplement pp 1029-1032
Shackleton S Smillie M V Levy L S Fletcher A C
Harrington J M Binks S P Chipman J K and Glass D
C (1992) Occupational Exposure Limits: Criteria
Document for Hydrogen Selenide. Commision of the
European Communities EUR 14239 pp 1-58.
 MEL PROPOSAL

MEASUREMENT
PHENOL
Workplace air measurement
maximum exposure limit
Indicating colorimetric tubes for short-term measure-
8-hour TWA: 2 ppm (7.8 mg.m-3) ments of phenol in air are commercially available and
Notation: Skin capable of detecting 0.5 ppm. They are subject to
interferences from cresols. Instrumental methods
subject to consultation based on infra-red or photo-acoustic detection are
capable of selective detection of phenol in the low
ppm region. Long-term measurements may be made
IDENTITY AND PROPERTIES by pumped sampling on XAD-7 sorbent, desorbing
with methanol and analysis by high-performance
Chemical Name: Phenol liquid chromatography (OSHA 32) 1 or gas chroma-
Cas No: 108-95-2 tography (NIOSH 2546) 2,3. The detection limit of
OSHA 32 is less than 0.02 ppm for a 24 litre air
EINECS No: 203-632-7
sample. The performance of OSHA 32 complies with
Formula: C6H5OH EN 482 9 on overall uncertainty and substantially
Synonyms: Carbolic acid, complies with the storage, desorption efficiency and
oxybenzene, phenol environmental factor requirements of EN 1076 10.
alcohol NIOSH 2546 has the same sampling procedure as
OSHA 32 therefore similar compliance with EN
Saturated vapour
standards is likely, but the liquid chromatography
concentration: 200 ppm (20 oC) procedure of OSHA 32 is generally recommended,
Boiling point: 181.75 oC unless it is required to measure individual cresol
Conversion factor: 1 ppm = 3.91 mg.m3 isomers in addition to phenol, when NIOSH 2546
would be more suitable. Alternatively, thermal desorp-
(at 20 oC) tion of Chromosorb 106 or Tenax TA sorbent tubes
Phenol is a white crystalline solid which liquefies on followed by gas chromatography is feasible (MDHS
contact with water. It has a characteristically acrid 72) 4. This method has not been validated for phenol
odour and a sharp burning taste. with respect to storage and desorption efficiency at
Phenol is classified under the Chemicals (Hazard low concentrations. If these factors were addressed,
Information and Packaging for Supply) Regulations MDHS 72 would be suitable where it was required to
1994 (CHIP) as Toxic and Corrosive, to be labelled measure phenol and volatile organic compounds
with the R phrases: together.
R24/25: Toxic in contact with the skin and if Biological Monitoring
swallowed Biological monitoring may be a useful aid to the
R34: Causes burns assessment of occupational exposure to phenol. There
are no data to relate metabolite concentrations to
OCCURRENCE AND USE health effects but there are data to show a good corre-
lation between levels of total phenol (after hydrolysis
Phenol is not manufactured in the UK. The estimated
of conjugates) in urine samples collected at the end of
imports into the UK in 1998 amounted to around
shift and inhaled phenol. Two out of three studies
85,000 tonnes with less than 3000 tonnes exported. It show good agreement; for example exposure to
is used as a starting material for the production of a phenol at 2 ppm for 8h the urine concentration of
variety of chemicals, the most important being phenol would be around 100 mg.g-1 creatinine (120
phenolic resins. It has a minor use in specialised paint mmol.mol-1). Phenol is found in the urine of people
strippers. not occupationally exposed to phenol and comes from
EXPOSURE the diet.
Using more recent specific methods for urinary phenol
There are few people exposed to phenol as a chemical analysis the background levels are generally less than
starting material but very many are exposed varying 10 mg.g-1 creatinine (12 mmol.mol-1) and rarely above
concentrations of free phenol from the resins which 20 mg.g-1 creatinine (24 mmol.mol-1).
are ubiquitous. The Health & Safety Laboratory has analysed 92 urine
Around 25,000 people may be exposed to phenol from samples for phenol from a range of unknown
the use of resins as sand binders in foundries and exposures and 90% of the results were less than 14
thermal decomposition of the resins releases phenol mg.g-1 creatinine.
into the atmosphere.
37
 MEL PROPOSAL
There are numerous methods for the determination of
phenol in urine and the wide range reflects the
comparative ease of analysis of phenol by common
analytical techniques. The essential features of an
analytical method for the determination of phenol in
urine are; an efficient hydrolysis of the glucuronide
and sulphate conjugates; a specific chromatographic
separation of phenol form other urine components; a
detection limit of <1mg.l-1 and a coefficient of varia-
tion of <5% for within day determinations and <10%
for day to day determinations.
There are two international quality assurance schemes
which include urinary phenol in their list of analytes.
One is run by the University of Erlangen and one by
the Finnish Institute of Occupational Health.
TOXICOKINETICS
Some toxicokinetic data in humans are available and
phenol has been extensively studied in toxicokinetic
studies in animals5 Data show that phenol is well
absorbed via the oral, inhalation and dermal routes in
both humans and animals. There are no data
concerning the tissue distribution of phenol in
humans. However, animal data indicate that phenol
and its metabolites are widely distributed throughout
the body. Once absorbed, phenol is rapidly and
extensively metabolised. Metabolites identified in
human serum and urine, following oral administration
of phenol, were mainly phenyl sulphate (~80%) and
phenyl glucuronide (~15%). Small amounts of the
glucuronide and sulphate conjugates of hydroquinone
and catechol are also formed. A similar profile of
metabolites has also been identified in animals; the
proportion of conjugates of hydroquinone formed
increases with dose. Little or no free phenol is
detected in the blood of animals. Elimination of
phenol and its metabolites from the body occurs
rapidly via the urinary tract. Essentially all of the
absorbed dose (>95%) is excreted in the urine within
24 hours. There is no evidence of accumulation in the
body. No information is available on whether phenol
can cross the placenta or whether it can be transferred
to pups via breast milk.
HEALTH EFFECTS
Animal Studies
Phenol is of moderate acute toxicity. Estimated oral
LD50 values of 400-550 mg.kg-1 in the rat and 300
mg.kg-1 in mice have been obtained. Dermal LD50
values obtained for the rat and rabbit are 661 mg.kg-1
and 1400 mg.kg-1 respectively. There are no inhalation
LC50 data for phenol vapour.
Studies in the guinea pig have shown phenol to be
corrosive to skin and eyes. Marked ocular and nasal
irritation was reported in rats exposed to 234 ppm
phenol vapour for 8 hours. In an Alarie sensory
irritation study, evidence of sensory irritation was
demonstrated in mice inhaling 166 ppm (0.637 mg.l-1)
38
phenol vapour. Phenol did not cause skin sensitisation
in a guinea pig maximisation test.
Animal repeated inhalation studies are limited. Those
available are old studies which are poorly reported;
only a single modern good quality study (conducted in
the rat) is available. Overall, the data indicate that in
the rat, the species which has been most extensively
studied, no significant effects are observed following
exposure to 5 ppm phenol vapour continuously for 90
days or intermittently to concentrations somewhere in
the range of 25 - 52 ppm for 74 days. Continuous
exposure to 25 ppm produces some clinical evidence
of CNS effects. Studies in a number of other species
indicate that there are some species differences.
Similar to the rat, the monkey and mouse show no
signs of toxicity following continuous exposure to 5
ppm phenol for 90 days; the effects of higher exposure
concentrations have not been investigated. In the
rabbit and guinea pig, degenerative damage to the
lung, liver, kidney and heart is seen at a concentration
somewhere between 26 - 52 ppm, with the guinea pig
being the more sensitive species; lower exposure
concentrations have not been investigated. It is not
possible to clearly characterise the dose response
relationship for inhalation exposure to phenol due to
the fact that most studies have investigated only a
single exposure level. Repeated oral exposure studies
in the rat indicate that the kidney, liver, spleen and
thymus are the main target organs, with some evidence
of CNS effects also. Effects on these organs are
observed, when phenol is administered via oral
gavage, at 40 mg.kg-1.day-1 and above for 2 weeks,
with mortalities occurring at 120 mg.kg-1.day-1. No
systemic effects are observed at 4 mg.kg-1.day-1.
However, via drinking water, no toxicological
significant effects are observed following treatment
with up 334 mg.kg-1.day-1 for 13 weeks6. There is
evidence, in mice, of a reduction in red blood cells at
doses of 1.8 mg.kg-1.day-1 and above7. However, this
effect has not been observed consistently across
species and therefore its reliability is uncertain.
The potential mutagenicity of phenol has been well
investigated in bacterial and mammalian somatic cells
in vitro and in somatic cells in vivo. Phenol is
negative in standard Ames tests with and without
metabolic activation. In mammalian cell assays in
vitro, overall the evidence indicates that phenol is
genotoxic. Positive results have been obtained in
standard gene mutation and chromosome aberration
studies, with supporting evidence from a number of
non-standard studies (SCE, UDS, micronucleus
assay).
In relation to effects in somatic cells in vivo, phenol
has been well explored in the bone marrow
micronucleus assay via the oral and intraperitoneal
routes and in a transgenic mouse study8. In the bone
marrow micronucleus studies, although both positive
and negative findings have been obtained, overall, the
weight of evidence indicates that phenol has genotoxic
 MEL PROPOSAL
activity in this assay. Phenol gave negative results in a
transgenic mouse assay, in the liver, lung and bone
marrow; however, in this same study, the potential for
phenol to cause mutagenicity in tissues at the site of
contact (skin and nasal epithelium) could not be
adequately assessed. In overall conclusion, the weight
of evidence indicates that phenol should be regarded
as having genotoxic potential in somatic cells in vivo.
The Department of Health Committee on
Mutagenicity has also considered the available
mutagenicity data for phenol and concluded that
"occupational exposure to phenol is associated with a
risk of mutagenicity, but it is not possible to quantify
this risk. Overall, there is insufficient evidence to
support a threshold approach to risk assessment with
respect to inhalation or dermal exposure".
Phenol has not been adequately tested for
mutagenicity in germ cells and no reliable conclusions
in relation to the genotoxic potential of phenol in germ
cells in vivo can be reached from the available data.
Phenol was not carcinogenic to rats and mice, in a
well conducted drinking water study in which animals
were given either 2500 or 5000 ppm phenol in
drinking water for 103 weeks. However, its potential
carcinogenicity via the inhalation route, particularly
towards the respiratory tract, has not been explored
and, given its irritant and genotoxic properties there
are concerns for potential carcinogenicity.
Phenol has been tested in a number of studies for
reproductive toxicity. A single multi-generation study
is available in rats in which phenol was administered
via the drinking water. No adverse effects on fertility
or reproductive performance were observed even at
exposure levels causing general toxicity in the parents.
In relation to developmental toxicity, there are a
number of studies which have adequately explored the
potential for developmental toxicity. In mice, a higher
incidence of cleft palate was observed at 280
mg.kg-1.day-1 only in the presence of severe maternal
toxicity (mortalities). In rats, increased post
implantation loss and reductions in fetal weight/litter
are observed at doses which also cause severe
maternal toxicity. These developmental effects are
considered likely to be a secondary non-specific
consequence of maternal toxicity. Overall, from the
studies available there is no evidence that phenol
causes direct reproductive effects.
Human data
There are numerous reports of lethality following
acute oral or dermal exposure to phenol, although
there are few reliable quantitative exposure data
associated with them. Bronchospasm, nephrotoxicity,
cardiac dysrhythmia and CNS effects have been
reported following non-lethal acute exposure, but
again, no reliable quantitative exposure data for
situations concerned are available.
Phenol itself is corrosive and diluted phenol solutions
may be corrosive or irritating to the skin, depending
on concentration and exposure duration. There was no
reporting of any irritation of the eyes or respiratory
39
tract in volunteers inhaling 2.6 - 5.2 ppm phenol
vapour for 8 hours in a toxicokinetics study or in
workers exposed repeatedly to up to approximately 3
ppm for 7 hours per day.
Phenol was reported to be negative in a human skin
sensitisation test. From a long history of phenol
exposure, there is no evidence for the ability of phenol
to cause occupational asthma in humans nor would
this potential be expected from its known properties.
People accidentally receiving repeated oral exposure
to phenol in solution at 10 - 240 mg.day-1, reported
diarrhoea, mouth sores and darkened urine. No effects
were observed 6 months after exposure.
There are no human studies available on the
genotoxicity of phenol. The epidemiological studies
available investigating the carcinogenic potential of
phenol to humans are complicated by the lack of
adequate exposure data for phenol, and by the
confounding presence of other organic substances in
the work place, and therefore no reliable conclusions
can be drawn from them. However, in view of the
positive genotoxicity findings in animals raising
concerns for carcinogenicity, these endpoints are also
of concern for humans.
There are no human data available on the potential of
phenol to affect reproduction. However, given the
clear negative evidence for reproductive effects in
animals, no concerns for humans are indicated.
BASIS FOR A LIMIT
The lead health effect of concern for phenol is
genotoxicity. WATCH endorsed the view of the
Committee on Mutagenicity, and agreed that it was
not possible to identify precisely a level of exposure
below which there would be no concern. Therefore,
the OES criteria are not met. Given the concerns for
genotoxicity at current occupational exposure levels,
the MEL criteria are met. In view of the concerns for
genotoxicity, control of exposure over the work shift
is desirable and hence an 8-hour TWA MEL is
appropriate. WATCH was of the view, however, that
the in vivo mutagenicity and carcinogenicity data
suggested that phenol was not an especially potent
occupational genotoxin, and that this should have a
bearing on the magnitude of the MEL. As significant
skin absorption is predicted, with subsequent concerns
for genotoxicity once absorbed, a ‘Skin’ notation is
considered appropriate. In view of the lack of
evidence for occupational asthma a ‘Sen’ notation is
not warranted.
In relation to biological monitoring, reliable,
non-invasive methods are available, and a relationship
between airborne levels and biological values has
been established, as noted above. However, at this
stage no specific recommendation for a BMGV is
proposed.
 MEL PROPOSAL
Taking account of the recommendations from Unpublished draft report of Covance. Report No.
WATCH, and the practicability, costs and benefits of 501/2-D5140.
levels of control, ACTS agreed that a MEL is
appropriate. Because an occupational exposure limit is 9. BSI, Workplace atmospheres - General
required to fulfill British obligations under the requirements for the performance of procedures for
Chemical Agents Directive and the Indicative the measurement of chemical agents, European
Occupational Exposure Limit Value (IOELV) Standard BS EN 482:1994, ISBN 0 580 23644 7.
Directive, a MEL is necessary. 10. BSI, Workplace atmospheres - Pumped
Taking into account the above information and the sorbent tubes for the determination of gases and
IOELV, ACTS considered that a value of 2 ppm vapours, European Standard BS EN 1076:1997,
(8-hour TWA), with a ‘Skin’ notation is appropriate. ISBN 0 580 28358 5.
This substance is included in the EU first consolidated
Indicative Limit Occupational Exposure Limit Values
Directive (2000/39/EC). WATCH and ACTS took
into account the limits shown in this Directive in
making recommendations for limit values for this
substance.

REFERENCES
1. Occupational Health and Safety
Administration, US Dept of Labor, Phenol and
Cresol, Method 32, November 1981.

2. Pendergrass S M, An alternative method for

the analysis of phenol and o-, m- and p-cresol by
capillary GC/FID, Am. Ind. Hyg. Assoc. J., 1994. 55:
1051-1054.

3. NIOSH Manual of Analytical Methods, 4th

Ed., 1994, US Dept of Health and Human Services
publication 94-113, Cresols and Phenol, Method
2546.

4. Health and Safety Executive, Volatile

compounds in air pumped solid sorbent tubes,
thermal desorption, MDHS 72, HSE Books 1993,
ISBN 0 11 885692 8.

5. Phenol, CEC DGV Criteria Document

SEG/CDO/6A (1991) Danish Technological Institute.

6. CMA - Chemical Manufactures Association

(1998a); A 13-week neurotoxicity study of phenol
administered in the drinking water to the rat.
Unpublished report No: 97439

7. Hsieh, G-C, Sharma, RP, Parker, RDR,

Coulombe, RA Jr (1992). Immunological and
neurobiochemical alterations induced by repeated oral
exposure of phenol in mice. Eur. J. Pharmacol.
228:107-114.

8. Covance (1999). Phenol: Induction of LacZ-

mutation in tissues of treated MutaTM Mice.

40
 REVISED OES PROPOSAL
ratings. It is used in chemical manufacture and as a
solvent. The isomer p-xylene is used to make
XYLENE dimethylterephthalate and terephthalic acid, which are
occupational exposure standards used in the production of polyester fibre, film and
fabricated items; o-xylene is used to produce phthalic
anhydride for phthalate plasticisers; m-xylene is used
8-hour TWA: 50 ppm (221 mg.m-3)
for manufacturing isophthalic acid which is an
15-minute STEL: 100 ppm (442 mg.m-3) intermediate in the manufacture of polyester resins.
Mixed xylenes are used in surface coatings, adhesives,
Notation: Skin printing inks, and rubber coatings.
Biological Monitoring
Health Guidance Value: 650 mmol.mol-1 *
EXPOSURE
* (methyl hippuric acid per mol creatinine
in urine) The total number of persons exposed to xylene in the
subject to consultation UK is not known, but because of its widespread use in
paints and varnishes, and petroleum, it is expected to
be tens of thousands.
IDENTITY AND PROPERTIES
Chemical Name: Xylene In general, the chemical and the oil/gas industries
have the lowest exposures as most processes are
CAS No: 1330-20-7 enclosed.
EEC No: 601-022-00-9
The highest reported result in the offshore industry
Empirical formula: C6H4(CH3)2
was 2.85 ppm for an 8hr TWA. For the onshore oil
(o, m, and p- isomers) industry the range of full shift exposures was broader;
Synonyms: xylol, dimethylbenzene less than 0.01 to 24.4 ppm, reflecting the more
dispersive uses of petroleum onshore, including
Sat. Vap. Concentration: about 8,000 ppm at 20 oC distribution and retail distribution and sale. The
Boiling point: 137-144 oC highest short term exposure reported for the onshore
oil industry was 37 ppm, 15 min TWA for top
Conversion factor: 1ppm = 4.34 mgm-3 at 20 oC loading road tankers.

Xylene is an aromatic hydrocarbon with a
characteristic odour, perceptible at about 1 ppm.
Commercial xylenes are mixtures of the three isomers
and may contain up to 20% ethyl benzene. Xylene is
a clear, colourless, mobile fluid which is insoluble in
water and miscible in organic solvents.
Xylene is classified as harmful and irritant under the
Chemicals (Hazard Information and Packaging for
Supply) Regulations 1994 (As Amended) and labelled
as follows:
R20/21: Harmful by inhalation and in contact
with skin
R38: Irritating to skin
R10: Flammable
OCCURRENCE AND USE
Xylene is produced mainly from crude oil in the UK,
but some also arises from coking processes. Xylene is
also recovered from waste solvent streams by
fractional or steam distillation. It is a component of
petrol; the use of xylene in petroleum products is
increasing due to the reductions in the benzene
content of petroleum and the need to maintain octane
The highest result reported for this review was for
loading mixing vessels in the paint manufacturing
industry with an exposure result of 458 ppm. The
circumstances under which that exposure was
measured were not reported but the geometric mean
for all loading activities in that company was 5.1 ppm,
with a 95th percentile of 79 ppm, which suggests that
the high result may have been an outlier. Few short
term exposures were reported; the highest was 133
ppm for floor cleaning with xylene. The potential for
higher short term exposures clearly exist where
controls are poor; particularly during loading, and
cleaning operations.
Paint spraying activities had a broad range of results
which reflects the wide variation in the percentage
xylene in many of the products, and in the levels of
control achieved. Reported results varied from 0.2
ppm to 291 ppm. Exposures in the rubber coating
industry were up to 121 ppm, 8hr TWA. Short term
exposures in the dispersive industries, such as painting
and rubber coating ranged up to 155 ppm.
It is felt that, given the application of appropriate
controls, all sectors can achieve control of exposure to

41
 REVISED OES PROPOSAL
xylene to below 50 ppm, 8 hr TWA and most could
achieve 20 ppm within the bounds of reasonable
practicability. Some industries with less well
developed controls in place could probably achieve 20
ppm, but would require changes to working practices.
They would also require a higher level of investment
in controls than other sectors.
All industries with adequate controls in place can
achieve control to below 100 ppm for short term
exposures; the oil and chemical industries are already
achieving control below 50 ppm. The more dispersive
industries could meet this level of control with best
practice. Some sectors would need to invest in more
controls and improve working practices to achieve this
level of control.
Dermal exposure during manufacturing processes is
likely to be low as most processes are largely
enclosed. The main opportunity for dermal exposures
arises during cleaning activities where thinners
containing xylene are in use for up to several hours
per day, for example when cleaning out reservoirs and
filling lines during paint manufacture.
The possibility of dermal exposure is also high in the
rubber coating industry where manual handling of
dough containing xylene occurs frequently. For these
activities dermal exposures of up to 5mg.cm-2.day-1
have been estimated using EASE. Although these
estimates are likely to be higher than actual exposures
due to the percentage of xylene in the cleaning
solvents and the likely use personal protective
equipment, dermal exposure is likely to be a
significant route of exposure in these industries.
MEASUREMENT
Air Monitoring
Xylene consists of o-, m- and p- isomers typically in
the ratio 1:2:1, but usually technical or commercial
xylene also contains about 20% ethylbenzene. The
ethylbenzene content can vary considerably depending
on origin and grade.
Indicating detector tubes for short-term measurement
of xylene in air are commercially available. They may
be subject to interferences from styrene, toluene and
acetaldehyde. Instrumental methods based on
infra-red or photoacoustic detection are capable of
selective detection of xylene down to the 1 ppm level.
Xylene in air is primarily in the vapour phase. The
aerosol fraction may be significant when a product
containing xylene is sprayed, although methods
intended to measure vapour alone are usually
acceptable up to 100 ppm TWA. Where xylene
concentrations in spraying are high enough to justify
respiratory protection, diffusive methods may give
results biased high or low, depending on sampler
position. Recommended methods for long-term and
42
short-term TWA personal exposure are based on
collection on a sorbent such as charcoal or Tenax by
diffusive1-3, or pumped1,4,5, sampling, followed by
thermal or solvent desorption and gas
chromatography. The analytical method principles are
well known and relatively straightforward. Both
solvent and thermal desorption methods substantially
comply with EN 4826 with respect to overall
uncertainty. They also comply with EN 1076
(pumped)7 and EN 838 (diffusive)8 standards with
respect to storage, recovery and environmental
factors, except that the pumped thermal desorption
method based on MDHS 72 is too sensitive for
long-term monitoring around the level at the existing
OES of 100 ppm. In 8-hour TWA monitoring with
any of these methods, the limit of quantitation is 0.05
ppm or better.
Biological Monitoring
Biological monitoring may be a useful aid to the
assessment of occupational exposure to xylene. There
is potential for systemic toxicity from dermal
absorption and biological monitoring may be a useful
aid to assessing the efficacy of PPE
There are readily available and widely used
non-invasive methods for biological monitoring based
on analysis of methyl hippuric acid (MHA)
metabolites in urine samples.
There are ample data showing a good correlation
between levels of MHA and xylene in air although
the levels observed or predicted by regression
equations vary widely. The reasons for this variation
may include differences in isomer composition of
mixed xylenes and inter-individual differences in
metabolism. However, the most significant reason for
differences in levels of MHA is a difference in
absorbed dose. This could be caused by dermal as
well as inhalation exposure and/or increased
ventilation rates due to body size or work activity.
Using the more controlled volunteer studies 9-13 as a
guide the range of urinary MHA values that could be
expected in end of shift samples after exposure to
xylene at 50 ppm for 8 hours is 930 mg.g-1 to 1400
mg.g-1 with two studies around giving 1100 .mg.g-1
Combining data from all five volunteer studies gives a
mean MHA value of 1111 mg.g-1 after exposure to 50
ppm m-xylene for the biological monitoring health
guidance value. In SI units the value is 650
mmol.mol-1 creatinine. MHA values in people not
occupationally exposed are generally less than 2
mg.g-1 (< 1 mmol.mol-1).
Analysis of xylene in breath has also been used,
though less widely than urinary methyl hippuric acid.
Because of the rapid change in blood and breath
xylene concentrations after the end of exposure the
 REVISED OES PROPOSAL
timing of breath collection is important. In volunteer
studies breath samples collected 30 min after exposure
to 50 ppm show or predict values of 1 to 2.9 ppm9-13.
However, for occupational studies a more convenient
sampling time could be 10 minutes after the end of
shift (so workers are not held up on their way home)
and using the Loizou et al study11 as a guide, the
breath xylene concentration after exposure to 50 ppm
would be around 1.6 ± 0.3 ppm (66 ± 12 nmol.l-1)
Measurement of methyl hippuric acid in urine
There are numerous methods for the determination of
methyl hippuric acid in urine either based on gas
chromatography after derivatisation14-16 or HPLC with
UV detection 17-23 .
The wide range of methods used for MHA reflect the
comparative ease of analysis by common analytical
techniques. The essential features of an analytical
method for the determination of MHA are; a specific
chromatographic separation of MHA isomers from
other urine components (for total MHA the separation
of m- and p- isomers is not needed); a detection limit
of around 20 mg.l-1 and a coefficient of variation of
<5% for within day determinations and <10% for day
to day determinations and internal quality assurance.
There are two international quality assurance schemes
which include urinary MHA in their list of analytes.
One is run by the University of Erlangen and one by
the Finnish Institute of Occupational Health.
Confounding factors
Xylene is metabolised by Cyp 2E1, alcohol
dehydrogenase and aldehyde dehydrogenase to methyl
benzoic acid and then conjugated with glycine to form
methyl hippuric acid. Any co-administration of
substance which also use these pathways will
potentially interfere with xylene metabolism. The
most likely interferences are alcohol and aspirin.
Alcohol taken during xylene exposure will tend to
increase blood and breath xylene levels and reduce
MHA levels24. Aspirin, at therapeutic doses can
reduce the concentration of MHA in end of exposure
urine samples by 50%25. As a consequence, any
coadministrtion of alcohol, aspirin or similar
substances should be noted when collecting the
samples.
TOXICOKINETICS26
In experimental animals, xylene is rapidly absorbed
following inhalation exposure and well absorbed
following exposure via the oral and dermal routes. In
humans, xylene is well absorbed via the inhalation and
dermal routes. Xylene is highly soluble in blood and
fat, and widely distributed around the body, including
the brain. Accumulation of xylene in animal body fat
and brain tissue has been demonstrated following
inhalation exposure for 1 or 2 weeks. In human
43
volunteers, only an estimated 4% of the administered
dose was retained in subcutaneous fat following
intermittent inhalation exposure, suggesting low
accumulation potential. Transplacental transfer of
xylene to the fetus occurs in experimental animals and
humans. Xylene metabolism is extensive in both
experimental animals and humans, being metabolised
to methylbenzoic acid and excreted in the urine
following conjugation with glycine or glucuronic acid,
with no differences between isomers. Small amounts
of unchanged xylene can be detected in the expired
air.
HEALTH EFFECTS
Animal studies 26
Xylene is of low acute toxicity. Acute inhalation
exposure of rats and mice produced 6-hour LC50
values of 3,900- 6,000 ppm. Oral LD50 values of
3,500 - 8,700 mg.kg-1 have been reported in the mouse
and rat. Death is caused by respiratory failure
following CNS depression.
A single application of liquid xylene can cause skin
irritation, with eschar formation and blistering
reported after repeated exposure. The limited data
available indicate that liquid xylene has eye irritation
potential. No skin sensitisation data and no
information on respiratory sensitisation are available.
In repeated exposure studies the principal expression
of toxicity is ototoxicity in the rat; otherwise xylene
has been shown to have low toxicity via the oral and
inhalation routes following repeated exposure. In a
study which specifically investigated hearing loss,
deficits were reported mainly at high frequencies
following repeated exposure to 800 ppm, the lowest
exposure used, and above for 6 weeks. A no effect
level was not determined and reversibility was not
assessed. In more general toxicity studies, no
toxicologically significant findings were reported
following inhalation exposure for 5h per day for 13
weeks to 810 ppm in rats and dogs, or oral
administration to rats and mice at 1000 - 2000
mg.kg-1.day-1 for 13 weeks. No data are available on
systemic effects following repeated dermal exposure,
but similarly low toxicity is anticipated .
Xylene has been well examined for genotoxic
potential. No evidence of in vitro genotoxicity was
observed in tests involving in bacterial or mammalian
cells. Xylene was not genotoxic in vivo in mouse
bone marow micronucleus or mouse bone marow
cytogenetics tests, liver UDS or rodent dominant
lethal tests. Overall, xylene is not genotoxic.
There was no evidence of carcinogenicity following
oral administration in the rat or mouse although the
 REVISED OES PROPOSAL
data in the male rat were limited. Overall, these data
provide reassurance that xylene does not have
carcinogenic potential.
No fertility effects were observed in the rat following
inhalation at concentrations of up to 500 ppm in a one
single-generation study. A number of other older
developmental toxicity studies are available which
inconsistently report delayed development and
increased post-implantation loss at, and occasionally
below, maternally toxic concentrations. However,
these studies have severe limitations, in particular
most are very briefly reported such that it is not
possible to judge their quality or draw any firm
conclusions. Because of the difficulty in deriving
reliable dose-response information from the older
studies, attention is focused on the recent good-quality
studies 27,28 for the identification of a NOAEL for
developmental toxicity. In these studies, no
convincing evidence of developmental toxicity was
seen at exposure levels of up to 500 ppm. There might
be concerns regarding developmental toxicity above
500 ppm, but the profile is unclear.
Human studies 26
The exposure-response relationships for the effects of
xylene on the CNS have been reasonably well
investigated in human volunteer studies. In these
studies, there was no reporting of CNS symptoms and
no deficits in performance in neurobehavioural tests
with single exposures to constant concentrations up to
300 ppm for up to 4 hours. However, effects on
reaction time were observed at 200 ppm 4-hour TWA
when peak exposures of between 5-30 minutes
duration to 400 ppm were administered. Body sway
testing gave variable results, with both increases and
decreases being reported for this endpoint, all of
which were within the range of normal control values,
suggesting that these changes represent chance
findings and are not of biological significance.
Overall, the results from studies involving single
exposures to xylene indicate that exposures to
constant concentrations up to 300 ppm for 4 hours
produce no effects on CNS performance or symptoms.
However, the introduction of short periods (5-30
mins) of exposure to 400 ppm against a background
of 200 ppm (4-hour TWA) leads to effects on reaction
time, indicating CNS depression.
There is only one study29 in which the effects of
repeated exposure to xylene on the CNS have been
investigated. In this study, volunteers were exposed to
100 ppm for 6 hours per day over a one week period,
and the results showed a trend for a decline in
performance in reaction time tests (by approximately
3-26%), with the magnitude of effect becoming
greater throughout the study. However,
exposure-related effects were observed on the first day
44
of exposure in this study, an observation not
supported by the results of single exposure studies
with exposures of up to 300 ppm for 4 hours, and in
this respect the results of the study seem inconsistent
with other reported findings. Overall, the results of
this study suggest that repeated exposures to 100 ppm
can affect CNS performance, although there is perhaps
some uncertainty about the reliability of these results.
At higher levels of exposure, headache, nausea,
vomiting, vertigo and dizziness have been reported
following single inhalation exposures to 700 ppm.
These symptoms are consistent with the known CNS
depressant effects of xylene exposure. Loss of
consciousness occurs at an estimated level of 10,000
ppm. Extreme exposures can lead to death via
respiratory depression.
There is only limited information available relating to
eye, nose and throat irritancy. Human volunteers
have been exposed to xylene concentrations of up to
290 ppm for 4 hours in neurobehavioural studies and
although irritancy was not specifically investigated,
complex vision tests were conducted and sometimes
questionnaires on subjective symptoms were
administered, and these indicated no local irritant
effects. No changes in respiratory rate measurements
and no symptoms of nose and throat irritation were
reported in volunteers exposed to mixed xylenes at
concentrations up to 400 ppm30. These findings were
supported by another study in which no symptoms of
throat irritation were reported at concentrations of up
to 700 ppm31. In a study designed to investigate eye
irritancy in human volunteers, eye irritation was
reported at concentrations of 460 ppm or above. There
were no symptoms of eye irritation following
exposure to 110 ppm for 15 minutes30. In an early
study32 eye irritancy was reported with very brief (3-5
minute) exposures of human volunteers to 200 ppm
mixed xylenes, but the reliability of this information is
doubtful taking into account the design and reporting
of the study, and the inconsistency with other more
recent findings. Overall therefore, a clear threshold for
the development of eye irritation cannot be readily
identified from the data available, but would appear to
lie somewhere between 290 - 460 ppm.
In a human skin sensitisation study no evidence of
skin sensitising potential was reported. From its
widespread use, there is no evidence that xylene cause
sensitisation by skin contact.
The only data available relating to repeated exposure
in the workplace comprise reports of subjective
symptoms following exposure to mixtures of solvents
including xylene. Therefore this information is of
limited use in the determination of effects of repeated
exposure to xylene. There are no human data relating
to genotoxicity or carcinogenicity but the available
animal evidence indicates that xylene would not be
genotoxic or carcinogenic in humans. There are no
human data concerning effects on fertility or
 REVISED OES PROPOSAL
development. However, animal data indicate no
grounds for concern for these effects at occupationally
relevant levels of exposure
BASIS FOR THE LIMIT
From the available toxicology and occupational
exposure information it was concluded that the data
support an OES position for xylene.
The key health effects of relevance were eye irritancy
and CNS depression.
There is only limited information available relating to
local irritancy and a clear threshold for the
development of eye irritation cannot be readily
identified. However, from the data available, it would
appear to lie somewhere between 290 - 460 ppm.
In relation to effects on the CNS, human volunteer
data indicate that there is an absence of CNS effects
following single exposures to constant concentrations
up to 300 ppm for 4 hours. However, the introduction
of short periods (5-30 mins) of exposure to 400 ppm
leads to effects on reaction time, indicating CNS
depression.
There is only one study in which the effects of
repeated exposure to xylene on the CNS have been
investigated. Although there is uncertainty about the
reliability of the results of this study, the findings
suggest the possibility that repeated exposures to 100
ppm can lead to effects on the CNS. In the absence of
other information to confirm or refute this finding and
in view of the achievability of an exposure level of 50
ppm (8-hour TWA), WATCH decided to express
caution in making their recommendation for an OES
of 50 ppm 8-hour TWA.
A STEL OES is also considered appropriate to control
for short term peaks in exposure which might lead to
eye irritancy and effects on the CNS. It was agreed
that exposure-response information and achievability
of control of exposure indicate the suitability of a
STEL of 150 ppm 15-minute TWA.
Xylene is included in the 1st Consolidated Indicative
Limit Occupational Exposure Limit Values Directive
(2000/39/EC), with values of 50 ppm (8-hour TWA)
and 100 ppm (STEL) and a skin notation.
Taking into account the above information and the
IOELV, ACTS considered that values of 50 ppm
(8-hour-TWA) and 100 ppm (STEL) are appropriate.
Xylene is well absorbed across the skin following
dermal contact and thereby has the potential to
contribute to systemic toxicity, hence “Sk” notation is
45
appropriate. As there is no evidence for occupational
asthma with exposure to xylene, a “Sen” notation is
not warranted. Xylene meets the criteria for biological
monitoring given that control of inhalation exposure
alone may not be sufficient to control exposure, and
that biological monitoring methods and data are
available.
There are readily available and widely used
non-invasive methods for biological monitoring based
on analysis of methyl hippuric acid (MHA)
metabolites in urine. Data from five volunteer studies
gives a mean MHA value of 1111 mg.g-1 after
exposure to 50 ppm. In SI units the value is 650
mmol.mol-1 creatinine, therefore it was recommended
that 650 mmol.mol-1 creatinine is an appropriate
Biological Health Guidance Value.
REFERENCES
1. OSHA Analytical Methods Manual, US Dept of
Labour, Xylenes (o-, m-, p-isomers), Ethylbenzene,
method 1002, August 1999.
2. Methods for the Determination of Hazardous
Substances MDHS 80, Volatile compounds in
air...diffusive samplers, thermal desorption,
ISBN 0 7176 0913 8, HSE Books (1995).
3. Methods for the Determination of Hazardous
Substances MDHS 88, Volatile compounds in
air...diffusive samplers, solvent desorption ISBN 0
7176 2401 3, HSE Books (1997).
4. NIOSH Manual of Analytical Methods, 4th Ed.,
1994, US Dept of Health and Human Services
(NIOSH) Publ No 94-113, Hydrocarbons, Aromatic,
method 1501.
5. Methods for the Determination of Hazardous
Substances MDHS 72, Volatile compounds in
air...pumped solid sorbent tubes, thermal desorption,
ISBN 0 11 885692 8, HSE Books (1993).
6. British Standards Institution, Workplace
atmospheres - General requirements for the
performance of procedures for the measurement of
chemical agents, European Standard BS EN
482:1994, ISBN 0 580 23644 7.
7. British Standards Institution, Workplace
atmospheres - Pumped sorbent tubes for the
determination of gases and vapours, European
Standard BS EN 1076:1997, ISBN 0 580 28358 5.
8. British Standards Institution, Workplace
atmospheres - Diffusive samplers for the
determination of gases and vapours - Requirements
and test methods, European Standard BS EN
838:1996, ISBN 0 580 26240 5.
 REVISED OES PROPOSAL
9. Jang JY, Droz PO, Berode M (1997)Ethnic
differences in biological monitoring of several
organic solvents. 1. Human exposure experimental.
Int Arch Occup environ Health 69, 342-349.
10. Laparé S Tardiff R, Brodeur J (1993) Effect of
various exposure scenarios on the biological
monitoring of organic solvents in alveolar air. Int
Arch Occup Environ Health 64, 569-580.
11. Loizou GD, Jones K, Akrill P, Dyne D, Cocker J
(1999) Estimation of the dermal absorption of
m-xylene vapour in humans using breath sampling
and physiologically based pharmacokietic analysis.
Toxicological Sciences 48, 170-179.
12. Tardif R, Sato A, Laparé S, Brodeur J (1994)
Ethanol induce modification of m-xylene
toxicokinetics in humans. Occup & Environ Med 51,
187-191.
13. Tardif R, Laparé S, Plaa GL, Brodeur J (1991)
Effect of simultaneous exposure to toluene and xylene
on their respective biological exposure indices in
humans. Int Arch Occup Environ Health 63: 279-284
14. Buratti M, Pellegrino O, Valla C, Fustinoni S,
Brambilla G, Colombi A (1999)
Gas chromatography-electron-capture dection of
urinary methyl hippuric acid isomers as biomarkers
of environmental exposure to xylene. J Chrom B 723:
95-104
15. Minoia C, Meroni G, Aprea C et al (1996)
Environmental and urinary values as markers of
exposure to hydrocarbons in urban areas. Science of
the total environment 192; 163-182
16. Fustinoni S, Giampiccolo R, Pulvirenti S, Buratti
M, Colombi A. (1999) Headspace solid-phase
microextraction for the determination of benzene,
toluene, ethylbenzene and xylenes in urine. J Crom B
723 105-115
17. Miller M J, Edwards JW (1999)
Possible preferential metabolism of xylene isomers
following occupational exposure to mixed xylenes Int
Arch Occup Environ Health 72: 89-97
18. Kramer A, Linnert M, Wrbitzky R, Angerer J,
(1999) Occupational chronic exposure to organic
solvents XVII. Ambient and biological monitoring of
workers exposed to xylenes. Int Arch Occup Environ
Health 72: 52-55.
19. Burrini C (1998) Determinazione simultanea di
acido ippurico, acidi o-, m-, p-, metilippuric,
acidomandelico e acido fenilgliossilico nelle urine
mediante HPLC. Med Lav 89, 5 504-411.
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20. Moon HD, Paik NW, Shim YB (1997) Analysis of
some metabolites of organicsolvents in urine by
high-[erformance liquid chromatography with
β−cyclodextrin. J Chrom B 694, 367-374.
21. Mao IF, Chen ML, Lo EW (1996) Simultaneous
determination of urinary metabolites of
toluene,xylene,styrene and ethyl benzene by solid phse
extraction technique and high performance liquiud
chromatographic/photodiode array detection.
Intern,J Environ Anal Chem 64, 1-9.
22. Inoue O, Seij K, Suzuki T, Watanabe T,
Nakatsuka H, Satoh H, Ikeda M (1991) Simultaneous
determination of hippuric acid, o-, m-, and
p-methylhippuric acid, phenylglyoxylic acid and
mandelic acid by HPLC. Bull Environ Toxicol. 47,
204-210.
23. Lewalter J, Schucht Th (1984) Aromatic
carboxylic acids (phenylglyoxylic acid; o-,
m-/p-methyl hippuric acids; benzoic acid. in
Deutsche Forschungsgemeinschaft. Analyses of
hazardous substances in biological materials. Volume
2 pages 52-66. Published by VCH eds Angerer J,
Schaller HK.
24. Riihimaki V, Savolainen K, Pfaffli P, Pekari K,
Sipel HW, Laine A (1982). Metabolic interactions
between m-xylene and ethanol. Arch Toxicol 49,
253-63.
25. Campbell L, Wilson HK, Samuel A, Gompertz D
(1988) Interactions of m-xylene and aspirin
metabolism in man. Br. J. Ind. Med .45, 127-132.
26. Bell G M, Shillaker R O, Padgham M D J, and
Standring P, (1992), Toxicity Review, Xylenes,
London Health and Safety Executive.
27. Hass U, and Jakobsen B J, 1993, Prenatal toxicity
of xylene inhalation in the rat: a teratogenicity study.
Pharmacol and Toxicol. 73, 20 - 23.
28. Hass U, Lund S P, Simonsen, L, and
Schaich-Fries, A., 1995, Effects of prenatal exposure
to xylene on postnatal development and behaviour in
rats. Neurotox and Teratol, 17, (3) 341-349.
29. Savolainen K, Riihimaki, V and Linnoila, M,
1979. Effects of short-term xylene exposure on
psychophysiological functions in man. Int Arch.
Occup. Environ. Health. 44, 201-211.
30. Hastings L, Cooper C P, and Burg W, 1984.
Human sensory response to selected hydrocarbons,
Adv Mod Environ toxicol. 6 (chapter 14,) 255-270.
 REVISED OES PROPOSAL
31. Carpenter C P, Kinkead E R, Geary D L Jr,
Sullivan L J, and King J M, 1975. Petroleum
hydrocarbon toxicity studies V. Animal and human
responses to vapours of mixed xylenes. Toxicol Appl
Pharmacol. 33, 543 - 558.

32. Nelson K W, Ege J F Jr, Morwick R. Woodman L

E, and Silverman L, 1943. Sensory response to certain
industrial solvent vapours, .J Ind. Hyg. Toxicol. 25
(7), 282-285.

47
 REVISED OES PROPOSAL
and occurs in gasoline and, in small amounts, in
ETHYLBENZENE tobacco smoke. The production rate in the EU is in
Recommendation of the EC excess of 1 000 tonnes per annum. Occupational
Scientific Committee on exposure to pure ethylbenzene is uncommon as it
Occupational Exposure Limits usually occurs together with other solvents such as
xylene.
8 hour TWA: 100 ppm (442mg/m3)
Notation: Skin
HEALTH SIGNIFICANCE
occupational exposure standard Ethylbenzene is well-absorbed through the lungs and
3 skin. The majority is rapidly eliminated in the urine,
15-minute STEL: 150 ppm (663mg/m )
but small amounts may be retained in fatty tissues.
subject to consultation
With the exception of [ ] this summary is prepared
Ethylbenzene has anaesthetic properties at high
from the SCOEL SEG SUM.
exposure levels (Yant et al, 1930), suggesting that
CNS effects may also be important at lower
IDENTITY AND PROPERTIES exposures. Changes in noradrenaline and dopamine
Chemical name: Ethylbenzene levels in the hypothalamus have been observed in rats
exposed to 2 000 ppm (8840 mg/m3) ethylbenzene for
Synonyms: Phenylethane
6 hours/day for 3 days (Anderson et al, 1981),
EINECS No: 202-849-4 although no behavioural changes were reported.
EEC No: 601-023-00-4
CAS No: 100-41-4 In a 28 day inhalation study, the NOAELs were 382
MWt: 106.17 ppm (1688 mg.m-3) in rats and mice and 782 ppm
Vapour pressure: 2 kPa at 20 °C. (3456 mg.m-3) in rabbits. Minor effects, such as
increased liver weight and leukocyte counts, were
Melting Point: -94.9°C
seen at the LOAELs 7782 ppm (3456 mg/m3) in rats
Boiling Point: 136.2 °C and mice and 1610 m (7116 mg.m-3) in rabbits (Cragg
Conversion factor (20°C): 4.42 mg/m3 = 1 ppm et al, 1989). A subchronic inhalation study of
ethylbenzene (6 h/d, 5 d/week for 13 weeks) has also
been reported by NTP (1992). Increased liver weights
Ethylbenzene is a flammable, colourless liquid with an
were seen in male rats exposed to 250 ppm (1105
aromatic odour. It has a vapour density of 3.7 times
mg.m-3) and female rats exposed to 500 (2210
that of air and is explosive in the range 1.2 - 6.8 % in
mg.m-3). Increased kidney weights were seen at higher
air. The odour threshold is about 2 ppm (9 mg.m-3) .
exposure levels. No microscopic lesions associated
Ethylbenzene is listed in the current Approved Supply
with either liver or kidney weights were observed.
List under the Chemical (Hazard Information and
Increased lung weights and signs of lung inflammation
Packaging for supply) Regulations 1994 (CHIP) as
were seen in almost all rats exposed at and above 250
flammable and harmful, to be labelled with risk (R)
ppm (1105 mg/m3) ethylbenzene, but the incidence
phrases:
and severity of the lesions were not dose-related
R11: Highly flammable (NTP, 1992).
R20: Harmful by inhalation

Decreased numbers of pregnancies were noted in

OCCURRENCE AND USE
Ethylbenzene is used in the production of styrene and
it is an important solvent in the rubber and plastics
industries. It is a constituent of technical grade xylene
48
female rats exposed to 100 or 1000 ppm (442 or 4 420
mg/m3) for 6-7 h/d during the pregestation period
(Hardin et al., 198 1). This effect was not dose-related
 REVISED OES PROPOSAL
and the study was not considered to be an adequate
basis for proposing exposure limits.
There are no adequate data on carcinogenic effects.
Ethylbenzene was not mutagenic in the Drosophila
recessive lethal test (Donner et al., 1980) or in
Salmonella (NTP, 1992) and did not induce
chromosomal aberrations or sister chromatid
exchanges in Chinese hamster ovary cells or
micronuclei in peripheral blood of mice (NTP, 1992).
However a positive result was obtained in the L5178Y
tk+/tk- mouse lymphoma asssay (McGregor et al.,
1988).
The critical effect of ethylbenzene is irritation of the
eye, nose and throat. There is practically no
information on toxic effects of ethylbenzene alone in
humans because exposure generally occurs in
combination with other solvents. An exposure level of
200 ppm (884 mg/m3) has been reported to be
irritative (Ruth, 1986), although limited details were
given.
The concentration of inhaled ethylbenzene necessary
to depress the respiratory rate in mice by 50% due to
sensory irritation (RD50) was calculated to be about 1
430 ppm (6 321 mg/m3) over a period of about 5 mins
(De Ceaurriz et al, 1981). If the response was
measured after a longer exposure period (30 mins),
depression of the respiratory rate was found to occur
at a concentration of 4060 ppm (17, 945 mg/m3)
which probably can be explained by a fade in response
due to adaptation (Nielsen and Alarie, 1982).
RECOMMENDATION
The report by Ruth (1986), of irritation in humans at
200 ppm (884 mg/m3), was considered to be the best
available basis for proposing occupational exposure
limits. The recommended 8-hour TWA is 100 ppm
(442 mg/m3) and is not contradicted by the study of
De Ceaurriz et al., (1981), reporting an RD50 of 1430
ppm (6321 mg/m3) for inhibition of respiratory
irritation in mice. A 'skin' notation is recommended
as dermal absorption could contribute substantially to
the total body burden.
49
[A STEL (15 mins) of 150 ppm (663 mg/m3) is
proposed to limit peaks of exposure which could
result in irritation. This is lower than the value
recommended by SCOEL, but maintains the existing
level of worker protection under the current domestic
limit.]
At the levels recommended, no measurement
difficulties are foreseen.
KEY BIBLIOGRAPHY
Ÿ Anderson, K., Fuxe, K., Nilsen, 0. G., Toftgard,
R., Eneroth, P. and Gustafsson, J-A. (1981),
'Production of discrete changes in dopamine and
noradrenaline levels and turnover in various parts
of the rat brain following exposure to xylene,
ortho-, meta-, and para-xylene, and ethylbenzene',
Toxicol. Appl. Pharmacol., 60, pp. 535-548.
Ÿ Cragg, S. T., Clarke, E. A., Daly, I. W, Miller, R.
R., Terrill, J. B. and Oullette, R. E. (1989),
'Subchronic inhalation toxicity of ethylbenzene in
mice, rats and rabbits', Fund. Appl. Toxicol., 13,
pp. 399-408.
Ÿ De Ceaurriz, J. C., Micillino, J. A., Bonnet, P.
and Guenier, J. P. (198 1), 'Sensory irritation
caused by various industrial airborne chemicals',
Toxicol. Letts., 9, pp. 137-143.
Ÿ Donner, M., Maki-Paakkanen, J., Norppa, H.,
Sorsa, M. and Vainio, H. (1980), 'Genetic
toxicology of xylenes', Mutat. Res., 74, pp.
171-172.
Ÿ Engstrom, K. and Elovaara, E. (1986), 'Nordiska
expertgruppen for gransvardesdolumentation, 67.
67. Ethylbensen'. Arbete och Halsa, 19, pp. 1-43
(in Swedish).
Ÿ Hardin, B. D., Bond, G. R, Sikov, M. R.,
Andrew, F. D., Beliles, R. P. and Niemeier, R. W.
(1981), 'Testing of selected workplace chemicals
 REVISED OES PROPOSAL
for teratogenic potential', Scand. J. Work
Environ. Health Suppl., 4, pp. 66-75.

Lundberg, P. (1987), 'Scientific basis for Swedish

occupational standards VIII. Consensus report for
ethylbenzene', Arbete och Halsa, 39, pp. 74-81.

McGregor, D. B., Brown, A., Cattanach, R, Edwards,

L, McBride, D., Riach, C. and Caspary, W. J. (1988),
'Responses of the L5178Y tk+/tk- mouse lymphoma
cell forward mutation assay: Ill Coded chemicals',
Environ. Mol. Mutagen., 72, pp. 85-154.

Ÿ Nielsen, G. D. and Alarie, Y. (1982), 'Sensory

irritation, pulmonary irritation and respiratory
stimulation by airborne benzene and
alkylbenzenes: Prediction of safe industrial
exposure levels and correlation with their
thermodynamic properties', Toxicol. Appl.
Pharmacol., 65, pp. 459-477.

Ÿ NTP (1992), 'Toxicity studies of ethylbenzene

(CAS No 100-41-4) in F344/N rats and B6C3F1
mice (inhalation studies)', National Toxicology
Program., NIH Publication No 92-3129, NIH,

Ÿ Ruth, J. H. (1986), 'Odour thresholds and

irritation levels of several chemical substances: A
review', Am. Ind. Hyg. Assoc., J. 47, pp.
A142-A151.

Ÿ Yant, W. P., Schrenk, H. H., Waite, C. P. and

Patty, F. A. (1930), 'Acute response of guinea
pigs to vapours of some new commercial organic
compounds. II. Ethylbenzene', Publ. Health Rep.,
45, pp. 1241-1250.

50
 REVISED OES PROPOSAL

those based on ethylene glycol, which are known as

the 'E-series' and those based on propylene glycol
1-METHOXYPROPYL which are known as the 'P-series'. PGMEA belongs to
ACETATE the P-series.

occupational exposure standard PGMEA is currently classified under the Chemicals

(Hazard Information and Packaging for Supply)
8-hour TWA: 50 ppm (275 mg.m-3) Regulations 1994 (CHIP) as flammable and irritant. It
Recommendation of the EC must be labelled with the R-phrases :
Scientific Committee on R10: Flammable
Occupational Exposure Limits R36: Irritating to the eyes
-3
15-minute STEL: 100 ppm (550 mg.m )
Notation: Skin
OCCURRENCE AND USE
subject to consultation PGMEA does not occur naturally and it is not
manufactured in the UK. It is manufactured in 3 EU
IDENTITY AND PROPERTIES countries (France, Germany and the Netherlands) by
Chemical Name: 1-Methoxypropyl acetate five different companies all of whom may supply to
CAS No: 108-65-6 the UK market.
EINECS No: 203-603-9 The three main uses for PGMEA in Great Britain are
Empirical formula: C6H12O3 as coatings, cleaners and printing inks and allied
processes.
Synonyms: Propylene glycol methyl ether
acetate
1-Methoxy-2-propanol acetate EXPOSURE
Propylene glycol-1-mono-methyl As PGMEA is used in a wide variety of industries, it
ether-2-acetate (PGMEA) is difficult to establish the total number of workers
that are potentially exposed. There is relatively little
1-Methoxy propylacetate-2-acetic
measured exposure data. PGMEA has a low vapour
acid
pressure and is generally only present as a minor
2-Methoxy propyl-2-acetate
component in the working solutions that are used
2-Methoxy-1-methylethylacetate industrially. Furthermore, PGMEA is often present
Melting point: Approximately - 20 oC with solvents that are, or are perceived to be, of
greater toxicological concern.
Boiling point: 145.8 oC at 101.3 kPa
The only available measured exposure data are from a
Vapour Pressure: 490 Pa at 20 oC
paint formulator and a supplier to the screen printing
Conversion factor: 1 ppm = 5.5 mg.m-3 at 20 oC
industry. Exposure measurements taken during the
formulation of paints were all below 5 ppm. All but
PGMEA is a colourless, volatile, neutral propylene
one of the exposure measurements in the screen
oxide-based glycol ether with a mild ester-like odour.
printing industry were less than 10 ppm.
It is soluble in water and also miscible with most
organic solvents. It has a volatility, viscosity and In the absence of a significant amount of actual data
solvent power similar to those of the ethylene from industry, the EASE model was used to predict
glycol-based ether acetates. that exposures are expected to be between 0.1 and 30
ppm, the upper level quoted representing the
The term glycol ethers and their esters covers a wide
application of a solvent containing a relatively high
range of oxygenated hydrocarbon solvents that are
concentration of PGMEA, with a brush and without
used in a variety of industrial applications. The glycol
any LEV. For dermal exposure, the EASE predictions
ethers are often subdivided into two major series:
are between 0.05 and 0.25 mg.cm-2.day-1, the upper
51
 REVISED OES PROPOSAL
limit being applicable for coating or cleaning
operations in which the operator does not wear any
gloves.
MEASUREMENT
Workplace air monitoring
Short-term measurement in air can be performed by
colourimetric detector tubes calibrated for some
ethers, but tubes that are manufacturer-calibrated
specifically for PGMEA are not available. They are
subject to interferences from alcohols, esters and
aromatic compounds, therefore detector tubes may not
be suitable for the measurement of PGMEA in mixed
solvents. Long-term measurement is either by pumped
sampling on charcoal followed by solvent desorption
with dichloromethane/methanol and gas
chromatography1,2 or, alternatively, charcoal diffusive
samplers may be used with a similar analytical
method3. A pumped thermal desorption method based
on MDHS 724, using Tenax or Chromosorb 106
packed tubes as sorbent, is suitable for measurement
of low concentrations in the range 0.001-10 ppm.
Alternatively, thermal desorption may be used with
similar tubes sampling diffusively5.
Biological monitoring
The rapid hydrolysis of PGMEA in the body to
PGME means that the analysis of propylene glycol
monomethyl ether (PGME) can be used as a basis for
biological monitoring. There are analytical methods
available for the determination of PGME in blood,
urine and breath. However, the invasive nature of
blood sampling means that it is not a preferred
approach. Breath PGME analysis, although
non-invasive, is very dependent on the time of sample
collection. Overall, biological monitoring based on
measurement of PGME in end-of-shift urine samples
is non-invasive and is the preferred approach. The
mean half life of PGME in urine is 120 minutes.
The analytical method for PGME in urine is based on
solvent extraction with ethylacetate followed by
derivatisation with trimethylsyilyl imidazole and
detection by capillary gas chromatography-mass
spectrometry6. The method has a detection limit of 1
µmol.l-1. PGME is stable in urine at room temperature
52
or in a refrigerator (+4 oC) for at least one month and
for more than 6 months when stored at -200 oC.
TOXICOKINETICS
There are no data in relation to the toxicokinetics of
PGMEA in humans. In animals, PGMEA is very well
absorbed via the inhalation and oral routes7,8.
Although there are no data in relation to dermal
absorption, based on its physicochemical properties
and comparison with the corresponding glycol ether
alcohol, PGME, PGMEA is predicted to be well
absorbed across the skin. Once absorbed, PGMEA
and its metabolites are widely distributed around the
body, with the greatest amounts found in the liver and
skin following oral dosing and inhalation exposure in
rats. Following absorption, PGMEA undergoes rapid
and extensive enzyme hydrolysis to PGME, with
concomitant formation of acetic acid (although no
studies to confirm this are available). PGME is then
further metabolised by direct conjugation with
sulphate and glucuronic acid or by O-demethylation to
propylene glycol. No unchanged PGMEA is
detectable in plasma or urine in rats exposed orally or
by inhalation. The major routes of excretion are the
breath and urine, with about 60% of the administered
dose exhaled as CO2, derived from further metabolism
of propylene glycol, and 25% excreted as urinary
metabolites within 48 hours post dosing. Minor faecal
excretion occurs. There is no evidence for
bioaccumulation.
HEALTH EFFECTS
Animal studies
There are no data on the absorption of PGMEA, but,
by analogy with PGMEA it is likely that it will be well
absorbed by inhalation and percutaneously.
The acute toxicity of PGMEA to experimental animals
is low. Direct application of the liquid is irritating to
the eyes of rabbits; irritation of the skin is described as
mild.
The critical effect of PGMEA is irritation of the nasal
mucosa. Repeated exposure of mice to 300, 1000 and
3000 ppm (1650, 5500 and 16,500 mg.m-3) PGMEA,
6h/d, 4-5d/w for 2 weeks resulted in a dose-related
degeneration of the olfactory epithelium in all
exposure groups, accompanied by metaplastic changes
and signs of inflammation in the mid- and high- dose
 REVISED OES PROPOSAL
groups (Miller et al, 1984)9. Degeneration of the
olfactory epithelium was observed in rats only at the
high exposure. The authors suggested that these
lesions were due to acetic acid resulting from the
hydrolysis of PGMEA in the nasal epithelium. No
signs of systemic toxicity were found in mice. In rats,
increased liver weights were noted in the females and
kidney changes in the males of the high exposure
group.
There are no data concerning the genotoxicity,
carcinogenicity or reproductive toxicity of PGMEA.
However, as PGMEA is rapidly hydrolysed to
PGME, similar negative results might be expected.
Human data
There are no human data available in relation to the
health effects of exposure to PGMEA.
BASIS FOR SETTING THE LIMIT
PGMEA is of low systemic toxicity following single
and repeated exposure. It is not a sensitiser and there
are no concerns for genotoxicity, carcinogenicity or
reproductive toxicity. The lead health effect of
concern for PGMEA is local degenerative damage to
the nasal epithelium following repeated inhalation
exposure, for which there will be an identifiable
threshold of effect. Therefore, from consideration of
the health effects, the criteria for an Occupational
Exposure Standard (OES) are met. There are no
human data relevant to the establishment of an OES.
A 2-week repeated inhalation exposure study in rats
and mice is considered to be the most appropriate
basis from which to derive an OES. From this study, a
LOAEL of 300 ppm was identified for slight
degenerative changes to the olfactory epithelium in
mice. Given that this study is of relatively short
duration, and does not allow the identification of a
clear NOAEL and in view of the absence of human
data, it is considered appropriate to establish an OES
at 50 ppm (8-hour TWA). This provides a six-fold
margin below the LOAEL for minimal local tissue
damage in mice.
There is no evidence that PGMEA has sensitising
properties and thus a ‘Sen’ notation is not required.
In relation to biological monitoring, although PGMEA
is predicted to be readily absorbed across the skin,
because there is no concern for systemic toxicity,
53
biological monitoring would not provide any useful
information directly related to toxicity. Therefore a
biological monitoring guidance value is not proposed.
PGMEA is included in the 1st Consolidated Indicative
Limit Occupational Exposure Limit Values Directive
(2000/39/EC), with values of 50 ppm (8-hour TWA)
and 100 ppm (STEL) and a skin notation. The
following is an extract from the SCOEL
SEG/SUM/39A:
The study of Miller et al (1984), establishing a
LOAEL of 300 ppm (1650 mg.m-3), for irritation
of the olfactory epithelium of mice, was
considered to be the best available basis for
proposing occupational exposure limits. An
uncertainty factor of 5 was considered appropriate
to allow for the absence of a NOAEL and of
human data. Taking into account the preferred
value approach, the recommended 8-hour TWA is
50 ppm (275 mg.m-3). A STEL (15 minutes) of
100 ppm (550 mg.m-3) was proposed to limit peak
exposure which could result in irritation. A skin
notation was recommended as dermal absorption
could contribute substantially to the total body
burden.
REFERENCES
1 Health and Safety Executive (1987). Methods
for the Determination of Hazardous Substances
MDHS 21. Glycol ether and glycol ether acetate
vapours in air. Laboratory method using charcoal
adsorbent tubes, solvent desorption and gas
chromatography ISBN 0 7176 0115 3 HSE Books.
2 US Occupational Safety and Health
Administration (1993). OSHA Manual of analytical
methods. 99 Propylene glycol monomethyl
ethers/acetates. USDOL/OSHA.
3 Health and Safety Executive (1997). Methods
for the Determination of Hazardous Substances
MDHS 88. Volatile Organic Compounds in Air.
Laboratory method using diffusive samplers, solvent
desorption and gas chromatography. ISBN 0 7176
2401 3 HSE Books.
4 Health and Safety Executive (1992). Methods
for the Determination of Hazardous Substances
MDHS 72. Volatile Organic Compounds in Air.
Laboratory method using pumped solid sorbent tubes,
 REVISED OES PROPOSAL

thermal desorption and gas chromatography. ISBN 0

7176 0362 8 HSE Books.
5 Health and Safety Executive (1995). Methods
for the Determination of Hazardous Substances
MDHS 80. Volatile Organic Compounds in Air.
Laboratory method using diffusive solid sorbent
tubes, thermal desorption and gas chromatography.
ISBN 0 7176 0913 8 HSE Books.
6 Jones K, D Dyne, J Cocker, HK Wilson (1997).
A biological monitoring study of
1-methoxy-2-propanol: analytical method
development and a human volunteer study. Sci Total
Environ. 199; 23-30.
7 Criteria document of occupational exposure
limits. Henschler D (ed). 1-Methoxypropyl-2- acetate.
VCH Weinheim, 1990.
8 Arbete Och Hälsa (1990). NEG and NIOSH
basis for an occupational health standard. 32:
Propylene glycol ethers and their acetates.
9 Miller, RR., Hermann, E.A., Young, J.T.
Calhoun, P.E. and Kastl, P.E. (1984). Toxicol. Appl.
Pharmacol. 75, 521

54
 REVISED OES PROPOSAL

In the UK 1,2,4-TCB is also used in a brightener

1,2,4-TRICHLOROBENZENE solution in lead/tin plating baths and laboratory
applications such as gel permeation chromatography.
occupational exposure standard
The current UK market for 1,2,4-TCB is estimated at
8-hour TWA: 1 ppm (7.6 mg.m-3) around 5 tonnes per annum, part of which is exported.
Notation: Skin
EXPOSURE
Recommendation of the EC
It is estimated that up to 200 workers may be exposed
Scientific Committee on
during the re-packaging of 1,2,4-TCB for sale, its
Occupational Exposure Limits
subsequent use and during the dismantling of
15-minute STEL: 5 ppm (37.8 mg.m-3) transformers where prior to 1986 it was used as a
subject to consultation viscosity modifier for PCBs.
A limited amount of exposure data was available from
IDENTITY AND PROPERTIES industry. The EASE exposure model was used to
Chemical name: 1,2,4-Trichlorobenzene supplement the available data.

CAS No: 120-82-1 From the available industry data and EASE
predictions, inhalation exposures are generally below
EINECS No: 204-428-0
1 ppm 8-hour TWA with the highest being during the
Synonyms: 1,2,4-TCB,
manufacture of plastic pellets in the production of
unsymmetrical trichlorobenzene high performance wire and cable products. Short term
Formula: C6H3Cl3 (15-minute) exposures are generally below 2 ppm with
the highest occurring in the production of brightener
Melting point: 17 oC
solution and during re-packaging prior to sale.
Vapour pressure: 43.3 Pa at 25 oC
Odour threshold: 3 ppm MEASUREMENT

Conversion factor: At 20 oC 7.55 mg.m-3= 1 ppm Air monitoring

1,2,4-Trichlorobenzene is a clear, colourless liquid
with a characteristic aromatic odour. It has a vapour
density of 6.3 times that of air. It is insoluble in water;
sparingly soluble in alcohol; miscible with ether,
benzene, petroleum ether and carbon disulphide.
1,2,4-Trichlorobenzene (1,2,4-TCB) is not currently
listed in the Approved Supply List and therefore it
must be self-classified by the supplier).
OCCURRENCE AND USE
There is no UK manufacturer of 1,2,4-TCB. It is
imported into the UK by a single chemical supplier
and then sold on via a number of intermediaries.
The main use for 1,2,4-TCB is in the manufacture of
high performance insulation for use in wire and cable
products. The single company using 1,2,4-TCB in this
process use between 3 and 4 tonnes per annum
obtained directly from a supplier in the USA.
There are no detector tubes available specifically for
use with 1,2,4-TCB. The Gastec tube 'Vinyl Chloride
131La' is capable of measuring TCB, although no
information is available on the levels of sensitivity and
the colour change is subject to interferences.
A method using a pumped XAD-2 tube and PTFE
pre-filter/solvent desorption is available; NIOSH
Method 5517 'Polychlorobenzenes'1 is suitable for
long- and short-term monitoring. Three generic
sorbent tube/GC analysis methods are also available,
described in MDHS 282, MDHS 723 and MDHS 804.
Also of relevance for additional information on the
analysis of 1,2,4-TCB is EPA Method TO-145.
Biological monitoring
Biological monitoring is possible by measuring
trichlorobenzene in blood and/or its metabolites in
urine. However, adequately validated analytical
methods are not available and there are no data on
which to base a Biological Monitoring Guidance
Value.

55
 REVISED OES PROPOSAL
TOXICOKINETICS6
There are no data available relating to the metabolism
of 1,2,4-TCB in humans. In rats the substance is
readily absorbed by the oral route and bioavailability
following inhalation would also be predicted to be
high. Toxicity data indicate that dermal absorption
occurs but probably to a much lesser degree than via
the oral route. Absorbed 1,2,4-TCB rapidly distributes
to all organs and high concentrations of unmetabolised
compound can be found in the fat, skin and liver. High
concentrations of 1,2,4-TCB metabolites are found in
the kidneys and muscle tissues. 1,2,4-TCB is
metabolised to trichlorophenols which are mainly
excreted as glucuronic acid conjugates in the monkey
and rabbit but as cysteine conjugates in the rat. The
main route of elimination is via the urine, but
elimination also occurs via the faeces and exhaled air.
There is evidence that 1,2,4-TCB metabolites undergo
enterohepatic recycling before being finally removed
from the body.
HEALTH EFFECTS6
Animal studies
1,2,4-TCB is of moderate acute toxicity by the oral
route with an oral LD50 in rats of around 1000 mg/kg.
Doses of 750 mg.kg-1 or more induced sedation,
narcosis, prostration and general malaise whereas no
signs of toxicity were observed following a single oral
dose of 630 mg.kg-1. The liver was identified as the
main target organ. High oral doses also caused
bleeding of the stomach mucosa. Inhalation of
atmospheres saturated with 1,2,4-TCB vapour (around
420 ppm) for up to 7.5 hours did not cause any
mortality. Lachrymation, salivation, laboured
breathing and discoordination were the main signs of
toxicity observed. The dermal LD50 lies at around
5000 mg.kg-1.
1,2,4-TCB was not identified as a skin or eye irritant
in animal models, nor in the test results reported was
there any evidence that it induced skin sensitisation
although this end-point has been poorly studied.
In repeated dosing studies, 1,2,4-TCB appears to
affect primarily the liver, manifested as increased liver
size, disrupted porphyrin metabolism and at higher
doses histopathological change. This can be seen in
animals exposed by the inhalation and dermal routes;
56
comparable effects also occur following oral
administration. The most sensitive marker of
1,2,4-TCB induced toxicity in inhalation studies
appears to be an increase in urinary porphyrin
excretion. A NOAEL of 3 ppm has been identified for
this effect in a 90-day inhalation study in rats. For the
oral route a NOAEL of 10 mg.kg-1.day-1 has been
reported, although urinary porphyrins were not
measured. By the dermal route in rabbits, systemic
toxicity only emerged when dose levels of 450
mg.kg-1.day-1 or more were applied; no systemic
toxicity was present at 150 mg.kg-1 or less.
A structural analogue, hexachlorobenzene, is known
to produce similar effects in experimental animals and
humans resulting from inhibition of the enzyme
uroporphyrinogen decarboxylase. Presumably
1,2,4-TCB operates via the same mechanism. The
available evidence indicates that rats and humans are
approximately equally sensitive to the effects of
hexachlorobenzene and therefore a similar
interspecies comparison has been assumed for
1,2,4-TCB.
The genotoxicity of 1,2,4-TCB has not been
extensively investigated. Negative results have been
obtained in bacterial and mammalian cells in vitro.
Conflicting results have been reported from different
mouse micronucleus studies, but the most reliable
evidence indicates that 1,2,4-TCB is not genotoxic.
Carcinogenicity has been investigated in the mouse in
a study involving dietary administration. 1,2,4-TCB
induced liver tumours, probably by a mechanism
involving liver toxicity. In view of the known
hepatotoxicity of hexachlorobenzene in humans, it is
possible that the liver tumours seen in mice might
have some relevance for human health.
There was no evidence in fertility and developmental
toxicity studies that 1,2,4-TCB had any adverse
effects on reproduction.
Human data
No reliable human data are available.
BASIS FOR SETTING THE LIMIT
1,2,4-TCB is included in the 1st Consolidated
Indicative Occupational Exposure Limit Values
Directive (2000/39/EC), with values of 2 ppm (8-hour
TWA) and 5 ppm (STEL) and a skin notation.
 REVISED OES PROPOSAL

There are no reliable human data on which to base a 2 HSE (1990). MDHS 28 Chlorinated hydrocarbon
limit. However, animal evidence indicates that the solvent vapours in air. Health and Safety Executive,
liver is the key target organ of toxicity for 1,2,4-TCB, Methods for the determination of hazardous
and the most sensitive marker for liver changes substances. HMSO, London
appears to be an elevation in urinary porphyrins; the 3 HSE (1992). MDHS 72 Volatile organic
NOAEL and LOAEL for this effect from repeat compounds in air. Health and Safety Executive,
exposure inhalation studies were 3 and 10 ppm, Methods for the determination of hazardous
respectively. As the substance is not genotoxic, liver substances. HMSO, London
tumours produced in a mouse carcinogenicity study
4 HSE (1995). MDHS 80 Volatile organic
are thought likely to arise from chronic toxicity in this
compounds in air. Health and Safety Executive,
organ. Hence, control for hepatotoxicity would also
Methods for the determination of hazardous
control for any carcinogenic effects. Overall, based on
substances. HMSO, London.
the toxicological data, the criteria for an Occupational
Exposure Standard (OES) are met. 5 US EPA (1989). TO-14 (2nd supplement)
Compendium of methods for the determination of
The available evidence on the structural analogue
toxic compounds in ambient air. US Environmental
hexachlorobenzene suggests that for 1,2,4-TCB
Protection Agency, Research Triangle Park, NC
toxicity, the rat is a reasonable model for humans. An
27711.
OES of 1 ppm (8 hour TWA) is considered
appropriate to protect against health effects in 6 Henschler D (ed.) (1992). Trichlorobenzene (all
humans. This value is a factor of 3 below the NOAEL isomers). In: Occupational toxicants, critical data
in rats and a factor of 10 below the LOAEL in this evaluation for MAK values and classification of
species, which are considered an adequate margin carcinogens, Vol. 3. VCH, Weinheim.
taking account of the fact that lead effect is a very 7. SEG/SUM/35C: Henschler, D (ed): Criteria
sensitive marker for biochemical change. The document of occupational exposure limits: 1,2,4-
Trichlorobenzene (14.05.1990) VCH-Weinheim.
occupational hygiene assessment indicates that control
to the proposed OES is readily achievable across all
user industries.
A STEL (15-minutes) of 5 ppm has been proposed by
the EU Scientific Committee on Occupational
Exposure Limits (SCOEL)7 to limit peaks in exposure
which could result in irritation.
1,2,4-TCB can be absorbed across the skin and might
contribute to systemic toxicity as a consequence,
although there are few relevant data on this property.
Overall, the assignment of a Skin notation is deemed
to be warranted. There is no evidence of sensitising
properties, so a Sen notation is not warranted.
Adequately validated analytical methods for
biological monitoring are not available and there are
no data on which to base a BMGV.

REFERENCES
1 NIOSH (1994). (2) 5517 (Rev 15-8-94)
Polychlorobenzenes. National Institute of
Occupational Safety and Health, US Dept of Health
and Human Services.

57
 REVISED OES PROPOSAL
from phosphatic ores by digestion of the rock by
ORTHOPHOSPHORIC ACID sulphuric acid. The furnace process burns elemental
phosphorus in excess air to give diphosphorus
Recommendation of the EC Scien-
pentoxide which is then hydrated. Orthophosphoric
tific Committee on Occupational
acid is used in the manufacture of fertilisers and
Exposure Limits
detergents.
8-hour TWA: 1 mg.m-3
occupational exposure standard EXPOSURE
15-minute STEL: 2 mg.m-3 Workplace exposures are likely to be minimal due to
containment of the processes during manufacture and
subject to consultation
use. The principle risk of exposure is from inhalation
of aerosol and from splashes and spillages.
IDENTITY AND PROPERTIES

Chemical name: Orthophosphoric acid MEASUREMENT

There are several established methods for the
CAS No: 7664-38-2
determination of orthophosphoric acid in air.1-4
EEC No: 231-633-2
Phosphate salts, if present, will give rise to positive
EEC Index No: 015-011-00-6 interferences. Established methods for the
Formula: H3PO4 determination of orthophosphoric acid in air involve
collection on a filter1, 2 or using a sorbent tube
Synonym: Phosphoric acid
containing a glass fibre filter plug and washed silica
Melting Point: 42.35oC
gel3,4. OSHA method ID-1111 and NIOSH method P
Boiling point: 261oC & CAM 2162 have the advantage that the inhalable
Conversion factor: 4.08 mg.m-3 = 1 ppm fraction of the aerosol can be collected by mounting
(20oC, 101 kPa) the filter in a suitable sampler, as described in MDHS
145, while NIOSH methods 79033 and P & CAM4 do
Orthophosphoric acid can take the form of a white not collect a well characterised fraction of the aerosol.
crystalline solid or viscous liquid. It is a weak tribasic Samples are analysed using spectrophotometry2 or
acid. Orthophosphoric acid is very soluble in cold iron chromatography1,3,4 after desorption with water or
water and soluble in alcohol. The vapour pressure is eluent (0.003 M Na2CO3/0.0024 M NaHCO3).
highly temperature and concentration dependent. AT
room temperature orthophosphoric acid is likely to TOXICOKINETICS
occur predominantly in aerosol form, although vapour No significant toxicokinetic information is available.
may be appreciable at high temperatures. There are
several ‘condensed’ forms of orthophosphoric acid [eg HEALTH EFFECTS
H4P2O7, H5P3O10 and (HPO3)n], giving rise to a Animal Studies
possibility of concentrations in excess of 100% Although the reliability of the very low inhalation
H3PO4. Concentrations are therefore expressed in LC50 value in mice is open to question, the substance
terms of P2O5 content. Orthophosphoric acid is would appear to be toxic by this route. It is also
classified under the CHIP Regulations (1994) to be moderately toxic to rodents via the oral route. The
labelled (depending on concentration) with the risk acute dermal toxicity in rabbits is low. The substance
(R) phrases: is corrosive to rabbit skin and severely irritating to the
eye.
Irritant: R36/38 >10-25% H3PO4
Corrosive: R34 >25% H3PO4 In a poorly reported study, ‘chronic’ inhalation of
phosphoric acid aerosol was claimed to cause
OCCURRENCE AND USE
irritation of the respiratory tract.
Orthophosphoric acid is manufactured by one of two
methods. In the wet process it is produced directly
58
 REVISED OES PROPOSAL
The substance has yielded negative results in bacterial
mutagenicity assays, the only genotoxicity data
available. There are no adequate reproductive toxicity
or carcinogenicity investigations in animals.
Human data
No clearly reliable human acute inhalation data are
available. As in other species the substance is
corrosive, with moderate to severe subjective stinging
responses being recorded following dermal or ocular
application of very dilute solutions. Widespread
corrosion of the gastrointestinal tract has been
reported in one case of oral ingestion.
No useful human data are available on the effects of
repeated inhalation exposure. Consumption of
moderate amounts of orthophosphoric acid in the diet
failed to indicate any toxicity.
No reliable human data on the carcinogenic potential
of orthophosphoric acid are available. In addition, no
human data are available on its potential to cause
genotoxicity or reproductive toxicity.
BASIS FOR SETTING THE LIMIT
Due to the minimal useful data available on
phosphoric acid, data on diphosphorus pentoxide was
also considered (diphosphorus pentoxide readily
hydrolyses to phosphoric acid). The combined data
suggested that the critical health effect is respiratory
irritation. An occupational exposure standard is
proposed at 2 mg.m-3 over a 15-minute reference
period. Control to below this limit should be
achievable. This limit is proposed to be consistent
with the OES set for diphosphorous pentoxide.
Orthophosphoric acid is included in the 1st
Consolidated Indicative Occupational Exposure Limit
Values Directive (2000/39/EC), with values of 1
mg.m-3 (8-hour TWA) and 2 mg.m-3 (STEL). SCOEL6
advised that further data allowing a more accurate
determination of the threshold level of irritation are
required. Data on diphosphorus pentoxide were taken
as the basis for setting a limit. SCOEL recommended
an 8 hour limit of 1 mg.m-3 and a 15 minute limit of 2
mg.m-3 based on the limited data available and
recommended that additional exposure studies are
required. The STEL is consistent with the STEL OES
set for diphosporus pentoxide.
59
A ‘skin’ notation was not considered necessary as
skin absorption would not contribute significantly to
the normal body load of phosphate.
NOTE
See also the summary for diphosphorus pentoxide.
REFERENCES
1 US Occupational Safety and Health Administration.
OSHA Analytical methods manual: Method ID-111 -
Phosphoric acid in workplace atmospheres. US
Department of Labor, OSHA Salt Lake City Technical
Center (1985). ISBN 0 9 3671266 X.
2 US National Institute For Occupational Safety and
Health. NIOSH Manual of analytical methods, 2nd
Edition, Volume 1: Method & CAM 216 - Phosphoric
acid in air. US Department of Health and Human
Services (NIOSH) Publication 82-100 (1982).
3 US National Institute For Occupational Safety and
Health. NIOSH Manual of analytical methods, 3rd
Edition: Method 7903 - Acids, Inorganic. US
Department of Health and Human Services (NIOSH)
Publication 84-100 (1984).
4 US National Institute For Occupational Safety and
Health. NIOSH Manual of analytical methods, 2nd
Edition, Volume 7: Method & CAM 339 - Inorganic
acids in air. US Department of Health and Human
Services (NIOSH) Publication 82-100 (1982).
5 Methods for the determination of hazardous
substances MDHS 14 (Rev) General methods for the
gravimetric determination of respirable and total
inhalable dust. ISBN 0 7176 0509 4 HSE Books
(1993).
6 SEG/CDO/7 Criteria document for occupational
exposure limit values for phosphoric acid. Prepared by
Environmental Resources Ltd., London (1990)
OTHER USEFUL PUBLICATIONS
Toxicity review of phosphoric acid, phosphorus
pentoxide, phosphorusoxychloride, phosphorus
trichloride, phosphorus pentachloride and
phosphorus pentasulphide HSE Toxicity Review 30
(Payne et al, 1994) ISBN 0 7176 0669 4 HSE Books.
 REVISED OES PROPOSAL
[OCCURRENCE AND USE
CUMENE Cumene occurs as a minor constituent of petroleum
occupational exposure standard and of solvents derived from it. Over 100 000 tonnes
per annum are manufactured in the UK by reaction of
8 hour TWA: 25 ppm (125 mg.m-3)
benzene with propylene. The major part is used as
Recommendation of the EC Scien- raw material for the production of phenol and the
tific Committee on Occupational associated products, acetone and alpha-methylstyrene.
Exposure Limits
15-minute STEL: 50 ppm (250 mg.m-3)
EXPOSURE
Notation: Skin
About 100 workers in the UK are likely to be exposed
subject to consultation
to cumene during its production and main usage, with
some further exposures during loading and unloading
With the exception of [ ] this summary is prepared
of road tankers and ships. There are further
from the SCOEL SEG SUM
possibilities for exposure arising from minor
IDENTITY AND PROPERTIES applications and the handling of materials in which it
is a constituent. The limited data available indicate
Chemical Name: Cumene
that exposures are controlled to well below 50 ppm
CAS No: 98-82-8
(8-hour TWA) and generally below 5ppm.
EEC No: 601-024-00-X
Formula: C6H5CH (CH3)2
MEASUREMENT
Synonyms: Isopropylbenzene, 1-methyl
Cumene vapour in air can be determined by pumped
ethylbenzene; 2-phenyl
sampling through a Chromosorb 106 tube with
propane;
thermal desorption or through a charcoal tube with
Saturated vapour solvent desorption1, or using a diffusive Tenax or
concentration: 3900 ppm at 20°C Chromosorb sampler with thermal desorption2;
Boiling point: 152°C analysis is by gas chromatography. Colorimetric
detector tubes may be used to estimate cumene
Conversion factor: 1 ppm = 5.00 mg.m-3 at 20°C
concentrations, but they are not specific.]

Cumene is an aromatic hydrocarbon, and is a

colourless mobile liquid with a strong aromatic odour
and dense vapour. It is insoluble in water but is
soluble in most organic solvents. It has a vapour
density of 4.2 times that of air, and is explosive in the
range of 0.9 - 6.5% in air. Cumene is classified under
the CHIP 2 Regulations (1994) as irritant, to be
labelled with risk (R) phrases:
METABOLISM
Cumene is well-absorbed through the lungs and, by
analogy with toluene and xylene, it is assumed to be
absorbed through the skin, although no satisfactory
study is available to demonstrate this. In animals and
humans absorbed material is metabolised and excreted
mainly as a 2-phenylpropan-2-ol conjugate.

R10: Flammable
HEALTH EFFECTS
R65: Harmful: may cause lung damage if
Animal studies
swallowed
Cumene has a low to moderate acute toxicity to
R37: Irritating to respiratory system
animals, with lethal concentrations in excess of 1000
R51/53: Toxic to aquatic organisms, may cause
ppm (5000 mg.m-3) (Smyth et al, 1951). The critical
longterm adverse effects in the aquatic
effect is irritation of the respiratory tract and CNS
environment
effects. RD50 values of 2000 - 2500 ppm (10,000 -

60
 REVISED OES PROPOSAL
-3
12,500 mg.m ) have been reported in mice
(Kristiansen et al, 1986; Nielsen and Alarie, 1982).
Increased activity and gait abnormalities were
reported in rats exposed to 500 ppm (2500 mg.m-3)
cumene for 6 hours, with no effects observed at 100
ppm (500 mg.m-3 )(Bushy Run Research Center,
1989).
Depression of the CNS and increases in liver, kidney
and adrenal weights were observed following
exposure of rats to 500 and 1200 ppm (2500 and 6000
mg.m-3) for 90 days (Bushy Run Research Center,
1989). An increased incidence of cataracts was also
noted in this study at 100, 500 and 1200 ppm (500,
2500 and 6000 mg.m-3), but due to the genetic
disposition of the animals for this lesion, this
observation is not suitable as basis for standard
setting. Following repeated administration of 244
ppm (1220 mg.m-3) for 6 weeks or continuous
exposure to 30 ppm (150 mg.m-3) for 90 days, to rats
dogs or monkeys, no toxic effects were observed
(Jenkins et al, 1970).
There are no data available on the carcinogenicity of
cumene. From the data available, there is no
evidence that cumene is genotoxic (Florin et al, 1980;
Simmon et al, 1977) or teratogenic (Bushy Run
Research Center, 1989).
No human toxicity data are available.
BASIS FOR SETTING THE LIMIT
The study conducted at the Bushy Run Research
Center (1989), establishing a NOAEL of 100 ppm
(500 mg.m-3) for CNS effects in a 90d study in rats,
was considered to be the best available basis for
proposing occupational exposure limits. A STEL (15
mins) of 50 ppm (250 mg.m-3) was proposed to limit
peaks of exposure which could result in irritation. A
“skin” notation was recommended as dermal skin’
notation was recommended as dermal absorption
could contribute substantially to the total body burden.
[WATCH had previously considered that, in the
absence of human data, it was appropriate to apply an
uncertainty factor of 4 to the NOAEL of 100 ppm.
Consequently WATCH recommended an 8-hour
TWA of 25 ppm (125 mg.m-3). Although SCOEL
have now recommended an 8-hour TWA of 20 ppm
61
this difference is not considered to be significant and
so the domestic limit has been retained.]
REFERENCES
1. Methods for the determination of hazardous
substances MDHS 36 (Rev) Toluene in air -
Laboratory method using pumped charcoal
adsorption tubes, solvent desorption and gas
chromatography ISBN 0 11 885960 9 HSE Books
(1990).
2. Methods for the determination of hazardous
substances MDHS 66 (Rev) Mixed hydrocarbons (C5
to C10) in air - Laboratory method using porous
polymer diffusion samplers, thermal desorption and
gas chromatography
ISBN 0 7176 0867 0 HSE Books (1995)
KEY BIBLIOGRAPHY
WATCH (1992) Cumene: Criteria Document for an
occupational exposure limit
ISBN 0-7176-0767-4 HSE Books (1994)
Bushy Run Research Centre (1989). Cumene
(isopropylbenzene) fourteen-week vapor inhalation
study in rats with neurotoxicity evaluation. Project
report 52-628.
Florin, I., Rutberg, L., Curvall, M and Enzell, CR
(1980). Screening of tobacco smoke constinuents for
mutagenicity using the Ames test. Toxicology 15,
219-232.
Jenkins, L J, Jones, R A and Siegel, J (1970). Long
term inhalation screening studies of benzene, toluene,
p-xylene and cumene on experimental animals.
Toxicol. Appl. Pharmacol. 16, 818-823.
Kristiansen, U, Hansen, L, Nielsen, G D and Holst E
(1986). Sensory irritation and pulmonary irritation of
cumene and n-propanol: mechanisms of receptor
activation and desensitization. Acts Pharmacol. et
Toxicol. 59, 60-72.
Nielsen, G D and Alarie Y (1982). Sensory irritation,
pulmonary irritation and respiratory stimulation by
airborne benzene and alkylbenzenes: prediction of
safe industrial exposure levels and correlation with
their thermodynamic properties. Toxicol. Appl.
Pharmacol. 65, 459-477.
 REVISED OES PROPOSAL
Simmon, V F, Kauhanen, K and Tardiff, R G (1977).
Mutagenic activity of chemicals identified in drinking
water. Progress in Genetic Toxicology. (Eds. Scott,
D, Bridges, B A and Sobels F H) Elsevier/North
Holland Biomedical Press. 249-258.
Smyth H F, Carpenter C P and Weil, C S (1951).
Range-finding toxicity data. List IV A M A Arch.
Ind. Hlth. 4, 119 - 122.

62
 REVISED OES PROPOSAL
R67: Vapours may cause drowsiness and
ACETONE dizziness
Recommendation of the EC OCCURRENCE AND USE
Scientific Committee on Acetone is a normal body metabolite and may occur in
Occupational Exposure Limits small quantities in exhaled air of all mammals. It also
8-HOUR TWA: 500 ppm (1210 may be formed by various types of degradation or
mg.m-3) combustion of organic materials from agricultural and
industrial activities. It is widely used in industry as a
occupational exposure standard solvent for cellulose acetate and nitrocellulose, and for
15-minute STEL: 1500 ppm (3630 acrylic paints, varnishes, lacquers, adhesives, printing
mg.m-3) inks and other resin solutions. It is also used as a
degreasing agent and a raw material for chemical
subject to consultation
syntheses. The production rate in the EU is about 106
With the exception of [ ] this summary is prepared
tonnes per annum.
from the SCOEL SEG SUM
HEALTH SIGNIFICANCE
IDENTITY AND PROPERTIES
An average of 45% of inhaled acetone will be
Chemical Name: Acetone
absorbed (Wigaeus et al, 1981), but percutaneous
CAS No: 67-64-1 absorption is likely to be comparatively low. Most of
Einecs No: 200-662-2 the absorbed acetone is metabolised, becoming
EEC No: 606-001-00-8; incorporated into normal intermediary metabolism,
but an increasing proportion is exhaled at higher blood
Formula: CH3COCH3
concentrations (Owen et al, 1982).
Synonyms: 2-Propanone; dimethyl
The critical effects of acetone are considered to be
ketone; methyl ketone
irritation of mucous membranes and neurobehavioural
Vapour pressure: 24.7 kPa at 20 °C effects.
Saturated Vapour Exposure of volunteers to acetone for 6 hours per day
Concentration: ~ 231,000 ppm at 20 °C for 1 or 6 days resulted in mucous membrane irritation
Melting point: -95.4 °C at 500 and 1 000 ppm (1210 and 2420 mg.m-3), with
minimal effects of 250 ppm (605 mg.m-3) and none at
Boiling point: 56.2 °C
100 ppm (242 mg.m-3) (Matsushita et al, 1969 a and
Conversion factor: 2.42 mg/m3 = 1 ppm at b). No symptoms were reported in any of the groups
20oC, 101 kPa towards the end of the exposure sessions, indicating
Acetone is a clear colourless liquid with a sweetish sensory adaptation. Exposure at higher levels will
aromatic odour. The vapour density is 2.0 times that often be tolerable to workers, with complaints of
of air and it is explosive in the range 2.2 - 13.0% in irritation generally commencing at 8 hour time
air. The odour threshold is about 13 ppm (31 mg/m3). weighted exposures above 1 000 ppm (2420 mg.m-3)
Acetone is listed in the current Approved Supply List (Raleigh and McGee, 1972). More recently, irritation
under the Chemical (Hazard Information and of the eyes, mouth and throat in volunteers exposed to
Packaging for supply) Regulations 1994 (CHIP) as 1000 ppm (2420 mg.m-3) acetone for 4 or 8 hours was
flammable and irritant, to be labelled with risk (R) confirmed by Seeber et al (1992a).
phrases: The neurotoxicity of acetone has been documented in
R11: Highly flammable a number of experimental studies. In juvenile
R36: Irritating to the eyes baboons exposed continuously to 500 ppm (1210
mg.m-3) acetone for 7 days, an increase in response
R66: Repeated exposure may cause skin
time was seen for a complex operant discrimination
dryness or cracking task (Geller, et al, 1979). When mice were exposed to

63
 REVISED OES PROPOSAL
a continuous series of 30 min acetone exposure
sessions at six levels increasing from 100 to 56 000
ppm (242 to 135 520 mg.m-3), a schedule-controlled
type of operant behaviour showed decreased response
rates at 1 000 ppm (2 420 mg.m-3) and above (Glowa
and Dews, 1987).
Increases in simple visual reaction time were seen in
six subjects exposed to 250 or 500 ppm (605 or 1210
mg.m-3) for 6 hours per day in an exposure chamber
for six consecutive days (Matsushita et al, 1969b).
In a more extensive study, 22 volunteers exposed to
250 ppm (605 mg.m-3) acetone for 4 hours in an
exposure chamber, small but statistically significant
decreases were found in two measures of a dual task
test (Dick et al, 1989). Choice reaction time, visual
vigilance, memory scanning and postural sway
showed no changes, whilst minimal differences were
seen in the profile of moods test. However, this study
is not considered suitable to use as a basis is
proposing occupational exposure limits. Exposure of
16 volunteers to about 1000 ppm (2420 mg.m-3)
acetone for 4 or 8 hours, simple and choice reaction
time, memory scanning by the Sternberg paradigm and
spontaneous motor activity failed to show any clear
relationship to exposure (Seeber et al, 1992b; 1994).
Information on the chronic effects of acetone is not
available.
Acetone has generally been shown to be negative in
mutagenicity assays (Maron et al, 1981). Data on
carcinogenicity are lacking.
A development study conducted with rats and mice
exposed to acetone intermittently during gestation
produced evidence of embryotoxicity but no
significant increase in malformations. A NOAEL of 2
200 ppm (5 324 mg.m-3) was reported (NTP, 1988).
Administration of acetone to rats in the drinking water
for 13 weeks of approximately 3400 mg.kg-1.day-1
resulted in decreased motility and increased
abnormalities of the sperm, but no histopathological
lesions, (NTP, 1991). No effects were seen in male
mice treated similarly at doses up to 4858
mg.kg-1.day-1 (NTP, 1991) or in male rats given
acetone in the drinking water at a dose of 1071
mg.kg-1.day-1 for 6 weeks (Larsen et al, 1991).
Acetone exposure to rats causes induction of
cytochrome P450 enzymes particularly P450 2E1,
64
which is also found in humans (Pattern et al, 1986).
Experimental studies suggest that some induction and
resultant potentiation of toxicity due to other solvents
may occur at acute and doses of 0.05 ml.kg-1
(Charbonneau et al, 1988), corresponding to a
blood-acetone concentration of 100 mg.l-1 and above
(Charbonneau et al, 1986). Blood concentrations at
that magnitude can be achieved in volunteers after an
8 hour exposure to acetone at 1000 ppm (2420
mg.m-3) (Blaszkewicz et al, 1992). However, no
potentation could be detected in rats exposed to 1 000
ppm (2420 mg.m-3) acetone (Charbonneau et al,
1986).
RECOMMENDATION
Taking into account the reports noted above of
irritation and neurobehavioural effects in volunteers
and workers, it is considered that symptoms may
occur at acetone exposures of 1 000 ppm ( 2420
mg.m-3) or greater. In view of the mild nature of the
symptoms, and because tolerance develops in workers,
an uncertainty factor of 2 was considered adequate.
The recommended 8-hour TWA is 500 ppm (1210
mg.m-3). No 'skin' notation was considered to be
necessary.
[Account was taken of the rapid response to exposure,
the uncertainties of dose-response data and the need
to provide protection for workers across the whole
range of industries handling acetone, including those
only occasionally exposed and unacclimatised. A
STEL (15 mins) was set to limit peaks in exposure at
1500 ppm (3630 mg.m-3) which is not expected to lead
to lead to adverse health effects, although some
workers may consider it unpleasant.]
At the levels recommended, no measurement
difficulties are foreseen.
KEY BIBLIOGRAPHY
Blaszkewicz, M., Golka, K., Vangala, R.R,
Kiesswetter, E., Seeber, A. and Bolt, H.M. (1992),
'Biologische Uberwaching bei Aceton-und
Ethylacetatexposition unter simulierten
MAK-Bedingungen'. Verh. Dtsch. Ges. Arbeitsmed.,
31, pp. 141-144.
Charbonneau, M., Brodeur, J., du Souich, P. and Plaa,
G.L (1986). 'Correlaton between acetone-potentiated
 REVISED OES PROPOSAL
CC14-induced liver injury and blood concentrations
or oral administration'. Toxicol. Appl. Pharmacol., NTP (1988). Report No PNL-6768.
84, pp 286-294.
NTP (1991) NIH Publ. 31-3122.

Charbonneau, M, Perreault, F, Greselin, E, Brodur, J

Owen, O E, Trapp, V E Skutches, C L, Mozzoli, M A
and Plaa G.L (1986). 'Assessment of the minimal
Hoeldtke, R D, Boden, G and Reichardt, Jr, G A
effective dose of acetone for potentiation of the
(1982), 'Acetone metabolism during diabetic
hepatotoxicity induced by trichloroethylene-carbon
ketoacidosis', Diabetes, 31, pp 242-248.
tetrachloride mixtures'. Fundam. Appl. Toxicol. 10,
pp 431-438.
Patten, C J Ning, S M Lu, A H H and Yang, C S
(1986), 'Acetone-inducible cytochrome P-450:
Dick, R B, Setzer, J V Taylor, B J and Shukla, R.
purification, catalytic activity and interaction with
(1989), 'Neurobehavioural effects of short duration
cytochrome b5', Arch. Biochem. Biophys, 251, pp
exposures to acetone and methyl ethyl ketone', Br J
629-638.
Ind. Med 46, pp 111-121.

Raleigh, R L and McGee, W A (1972), 'Effects of

Geller, I, Gause, E, Kaplan, H and Hartmann, R J
short, high-concentration exposures to acetone as
(1979), 'Effects of acetone, methyl ethyl ketone and
determined by observation in the work area', J Occup
methyl isobutyl ketone on a match-to-sample task in
Med 14, pp 607-610.
the baboon'., Pharmacol. Biochem. Behav., 11, pp.
401-406.
Seeber, A, Keisswetter, E, Vangala, R R Blaszkewicz,
M and Golka, K (1992b), 'Combined exposure to
Glowa, J R and Dews, P B (1987), 'Behavioral
organic solvents: An experimental approach using
toxicology of volatile organic compounds, IV,
acetone and ethyl acetate', Appl Psychol Int Rev, 41,
Comparison of the rate-decreasing effects of acetone,
pp 281-292.
ethyl acetate, methyl ethyl ketone, toluene and carbon
disulfide on schedule-controlled behaviour in mice', J
Am. Coll, Toxicol, 6, pp 461-469. Seeber, A, Keisswetter, E and Blazkewicz (1992a),
'Correlations between subjective disturbances due to
acute exposure to organic solvents and internal dose',
Larsen, J J, Lykkegaard, M and Ladefoged, O (1991),
Neurotoxical, 13, pp 265-271.
'Infertility in rats induced by 2,5-hexanedione in
combination with acetone,' Pharmaco, Toxicol, 69, pp
43-46. Seeber, A, Keisswetter, E and Blazkewicz, Golka, K,
M Vangal, R R, and Iregren (1994), 'Exposure to
acetone and neurobehavioural effects: Comparison of
Maron, D., Katzenellebogen, J and Ames, B N (1981),
two experiments and a field study', Int Arch Occup
'Compatibility of organic solvents with the
Environ Health (submitted for publication).
Salmonella/microsome test', Mutat. res, 88, pp.
343-350.
Wigaeus, E, Holm, S and Aastrand, I (1981),
'Exposure to acetone. Uptake and elimination in man',
Matsushita, T, Coshima, E Miyaki, H, Maeda, K,
Scand J Work Environ, Health, 7 pp 84-94.
Takeuchi, Y and Inoue, T (1969b), 'Experimental
studies for determining the MAC value of acetone,
2.Biological reactions in the 'six-day exposure' to
acetone', Sangyo Igaku, 11, pp 507-515.

65
 REVISED OES PROPOSAL

CYCLOHEXANONE In the UK cyclohexanone is used in large quantities in

the manufacture of caprolactone. Cyclohexanone is
used in the manufacture of a range of pesticides
Recommendation of the EC including herbicides, fungicides and insecticides.
Scientific Committee on Cyclohexanone is used in the manufacture of several
Occupational Exposure Limits types of coating materials, for example, paints,
8-hour TWA: 10 ppm (40.8 mg.m-3) magnetic coatings and printing inks, silk screen print-
ing inks in particular. In the silk screen printing
15-minute STEL: 20 ppm (81.6 mg.m-3)
industry it may also be found in ink thinners and silk
Notation: Sk screen cleaning fluids.
Cyclohexanone is also used in the manufacture of
subject to consultation some general purpose adhesives.
There is some laboratory scale use of cyclohexanone.
IDENTITY AND PROPERTIES
EXPOSURE AND CONTROL
Chemical Name: Cyclohexanone
CAS No: 108-94-1 A large number of workers may be exposed to
cyclohexanone. Exposure data are limited to a few of
EEC No: 606-010-00-7 the use areas, for example, use in the chemical
industry and use in the printing industry. These levels
Empirical formula: C6H6O
were generally well below 20 ppm (8-hour TWA).
Synonyms: pimelic ketone
Exposures are likely to be below 20 ppm (8-hour
ketohexamethyene TWA) where cyclohexanone is used in contained
hexanon processes or where emissions are controlled by the use
nadone of local exhaust ventilation. Elevated exposures can
sextone occur in maintenance and in some more diffusive uses,
however, in these situations RPE and PPE are
Vapour pressure: 0.69 kPa at 25oC generally used.
Melting point: -45oC
Boiling point: 155oC MEASUREMENT

Conversion factor: Indicating colorimetric tubes for short-term measure-

1 ppm = 4.08 mg.m-3
1 mg.m-3 = 0.25 ppm
Cyclohexanone is a colourless to pale yellow liquid
with an odour suggestive of peppermint and acetone.
It has a vapour density of 3.4 times that of air and is
explosive over the range 1.1 to 9.4%. The odour
threshold is approximately 0.12 ppm. Cyclohexanone
is listed in the current Approved Supply List under the
Chemical (Hazard Information and Packaging for
supply) Regulations 1994 (CHIP) as Harmful, to be
labelled with the following risk (R) phrases:
R20 Harmful by inhalation
R10 Flammable
OCCURRENCE, PRODUCTION AND USE
Cyclohexanone is produced by the catalytic dehydro-
genation of cyclohexanol or by the oxidation of cyclo-
hexane. Manufacture of cyclohexanone does not take
place within the UK. Within the EC, manufacture is
known to occur in Germany, the Netherlands and
Italy.
66
ments of cyclohexanone in air are commercially avail-
able and capable of detecting 2 ppm. They are subject
to interferences from other ketones. Long-term
measurements may be made by pumped sampling on
sorbent tubes, followed by solvent or thermal desorp-
tion and gas chromatography. NIOSH method 13001,
involving pumped sampling on coconut shell charcoal
and desorption with carbon disulphide, may not
comply with BS EN 1076 with respect to desorption
efficiency and storage below 25 ppm, particularly at
high humidity. Some types of synthetic carbon
molecular sieve may be more suitable, provided
samples are refrigerated, but no validation details are
available. The performance of NIOSH method 1300
with coconut shell charcoal is sensitive to environ-
mental factors and is not recommended. OSHA
method 01 uses Chromosorb 106 as the sorbent and
desorption with carbon disulphide2. OSHA validation
demonstrated compliance with BS EN 1076 with
respect to storage and recovery at 25 ppm. Compli-
ance at 2 ppm is likely but was not validated. Alterna-
tively, Chromosorb 106 or Tenax tubes may be
thermally desorbed from tube-type samplers in
suitable apparatus. The pumped thermal desorption
method MDHS 72 complies with BS EN 1076 with
respect to storage and desorption efficiency3. A
 REVISED OES PROPOSAL
commercial badge-type diffusive sampler containing
Chromosorb 106 and intended for solvent desorption
has been partially validated for cyclohexanone4. Full
testing to BS EN 482 or BS EN 838 has not been
carried out, but the diffusive badge method is likely
to comply with respect to overall uncertainty and
environmental factors, provided it contains a polymer
sorbent and not activated carbon. The tube-type diffu-
sive method using either Chromosorb 106 or Tenax
sorbent has been validated for cyclohexanone and
substantially complies with BS EN 482 and BS EN
838 with respect to uncertainty and environmental
factors, including concentration, exposure time and
humidity(5,6). The detection limit of the pumped
thermal desorption method is less than 0.05 ppm for a
10 litre air sample. The detection limit of the diffu-
sive thermal desorption method is less than 0.1 ppm
for an 8-hour exposure.
BIOLOGICAL MONITORING
Biological monitoring of occupational exposure to
cyclohexanone is possible. There are no data to relate
metabolite concentrations to health effects but there
are data to show a good correlation between levels of
the metabolites cyclohexanol and cyclohexanediols in
urine samples collected at the end of shift and inhaled
cyclohexanone. Although the four published studies
differ in their predicted urinary metabolite values, two
are in broad agreement and predict that after exposure
to cyclohexanone at, for example, 20 ppm for 8-hours
the urine concentration of cyclohexanol would be
around 4 mmol.mol-1 . Cyclohexanediols can also be
measured but their longer half life means that with
repeated exposure they may accumulate and their
concentration in end of shift urine samples will
increase during the week. As an example, after
repeated daily exposure to 20 ppm for 8-hours the
concentration of 1,2- and 1,4-cyclohexanediols in end
of shift urine samples on the 4th day would be around
90 and 45 mmol.mol -1 respectively.
TOXICOKINETICS
Human data indicate that cyclohexanone is well
absorbed following inhalation or ingestion.
Absorption of liquid cyclohexanone through the skin
can be predicted from the results of acute toxicity
studies in animals. Data from studies in animals and
humans indicate that following absorption
cyclohexanone and/or its metabolites are widely
distributed, notably to the liver, kidneys, muscle
tissue, and central nervous system.
Data from human poisonings indicate that
cyclohexanone is metabolised to cyclohexanol and
1,2- and 1,4-cyclohexanediols. Exposure to < 100
ppm 8-hour TWA in human volunteers indicates that
only a small amount of cyclohexanone is excreted
unchanged in the urine suggesting extensive
metabolism. Most absorbed cyclohexanone undergoes
67
first pass metabolism in the liver, probably by ethanol
dehydrogenase, to cyclohexanol. A small amount of
cyclohexanol may be conjugated with gluconuride and
excreted via the urine, or alternatively, further
metabolised by hydroxylation to 1,2-, and
1,4-cyclohexanediols. Urinary excretion data suggest
that initial metabolism to cyclohexanol is relatively
rapid. Subsequent metabolism to 1,2- and 1,4-
cyclohexanediol is less rapid with elimination
half-lives of 16 and 18 hours respectively, and these
metabolites were still present in the urine 72 hours
after exposure ceased demonstrating some potential
for accumulation of these metabolites, on repeated
daily exposure.
A similar pattern of metabolism has been observed in
experimental animals. Generally, with increasing
doses of cyclohexanone, the formation of conjugated
cyclohexanol accounted for a greater proportion of the
metabolites excreted possibly due to the saturation of
the metabolic pathway from cyclohexanol to
cyclohexanediols. Quantitatively, there is some
limited information to indicate that there is greater
metabolism of cyclohexanol to cyclohexanediols in
humans compared to experimental animals.
The principal route of elimination of metabolites is via
the urine. No data are available on excretion of
cyclohexanone or its metabolites via the faeces or
expired air. Studies of humans exposed to
cyclohexanol have shown that unchanged
cyclohexanol may be excreted in expired air and this
suggests that the metabolite cyclohexanol generated
from cyclohexanone may be excreted via this route .
HEALTH EFFECTS
Animal Studies
Cyclohexanone is of low to moderate acute toxicity
via inhalation, with rat 4h LC50 values of between
10.7 and 32.5 mg.l-1 (2700-8100 ppm). Signs of CNS
depression and respiratory tract irritation are observed
at high exposure concentrations. Cyclohexanone is of
low to moderate toxicity via ingestion, with rat LD50
values of between 1300 - 3500 mg.kg-1. Decedents
show peritoneal and intestinal congestion,
pneumonitis, bronchitis, hepatic cirrhosis, diffuse
glomerulo-tubular nephritis and CNS depression.
Cyclohexanone is of low to moderate acute toxicity
via contact with the skin, with LD50 values in the
rabbit of between 794 - 3160 mg.kg-1, although no
information is available on the cause of death. In
other studies, rabbits exposed via the skin to
near-lethal doses of cyclohexanone showed signs of
narcosis.
In animals, tests show that liquid cyclohexanone has
the potential to irritate the skin. Liquid
cyclohexanone instilled into the eyes of rabbits caused
“severe” irritation, with prolonged damage. In
 REVISED OES PROPOSAL
repeated exposure studies animals exposed to
cyclohexane vapour showed lacrimation.
Cyclohexanone has the potential to irritate the
respiratory tract following a single exposure to
relatively high airborne exposure concentrations.
Studies in guinea pigs and mice showed no evidence
of skin sensitisation potential. There are no data
relating to respiratory sensitisation. However, the lack
of chemical reactivity of cyclohexanone and its
metabolites towards nucleophilic groups suggests that
it lacks the potential to behave as a hapten. This and
the absence of skin sensitisation potential suggests that
cyclohexanone does not have respiratory sensitisation
potential.
The toxicity of cyclohexanone following repeated
exposure using occupationally relevant routes of
exposure has not been well investigated. Many of the
available studies are of uncertain or poor quality with
inadequate reporting.
A poorly reported 10-week inhalation study in rabbits
revealed “barely demonstrable degenerative changes
in the liver and kidneys” at the lowest exposure
concentration of 190 ppm7. Histopathology was not
performed on tissues/organs at the higher
concentrations tested. However, between 309 ppm to
773 ppm conjunctival irritation was observed. All
animals exposed to 1414 ppm survived, showing
lethargy in addition to conjunctival irritation. After 3
weeks exposure to 3082 ppm, narcosis, laboured
breathing, weight loss and deaths were observed. No
haematological findings were observed at any
exposure level. The toxicological significance of the
effects seen in the liver and kidneys is uncertain.
However, effects on the liver were seen at
comparatively high exposure concentrations in other
repeated exposure studies, and therefore, this finding
cannot be considered as irrelevant to human health
and 190 ppm is regarded as the LOAEL. A further
inhalation study in rats established a NOAEL of 100
mg.kg-1.day-1 for intravenous injection of
cyclohexanone12.
Data on effects via ingestion are available from
studies with limited reporting in which cyclohexanone
was administered via the drinking water to rats and
mice. The studies reported only investigations of
bodyweight and histopathology.
Rats administered up to 4700 ppm cyclohexanone in
their drinking water for 25 weeks showed no
treatment-related effects on bodyweight gain or
histopathological findings. At a concentration of 6500
ppm, a 10% decrease in bodyweight gain was
observed. Following administration to rats for 104
weeks at ~500 to ~1000 mg.kg-1.day-1 via the drinking
water there was a statistically significant decrease in
body weight gain (~15 % and ~30 %, respectively);
no effects on the organs were reported.
Groups of mice administered drinking water
containing cyclohexanone at 13000 ppm for 13 weeks
68
showed no effects on weight gain or histopathological
findings in a range of tissues. At 25000 ppm, males
showed a 19% decrease in weight gain. At 34000
ppm, males and females, respectively, showed
decreases in weight gain of 24% and 15 %
respectively. At 47000 ppm, increased mortality
(9/20) and incidences of focal liver necrosis and
hyperplasia of the thymus were observed. Only very
limited data are available concerning the effects of
repeated contact with the skin. No effects on growth,
behaviour or structure of the eyes were observed when
cyclohexanone was applied to the skin of rabbits or
guinea pigs at up to ~160 and ~1400 mg.kg-1.day-1,
respectively, for 3 days/week for 3 weeks.
Taken together, the findings of repeated exposure
studies in experimental animals suggest that the liver
is a target organ for toxicity following long term
repeated daily exposure to relatively high
concentrations of cyclohexanone.
In relation to genotoxicity, studies in bacteria gave
negative results in the presence and absence of
exogenous metabolic activation. There are a number
of in vitro studies in mammalian cells available. The
data from these studies are mixed, although it is
possible that the apparently positive findings arose
indirectly from excessive toxicity. Reassuringly, the
better quality studies are generally negative.
Negative results were obtained from an in vivo study
of bone marrow chromosomal aberrations and a
dominant lethal test. Overall, the results of tests
conducted in vivo gives reassurance that
cyclohexanone is not mutagenic to somatic or germ
cells .
No treatment-related tumours were observed in F344
rats exposed for 2 years to cyclohexanone
administered with the drinking water at a
concentration of 3300 ppm (~500 mg.kg-1.day-1)8. At
6500 ppm (~1000 mg.kg-1.day-1) there was an
increased incidence of benign and/or malignant
tumours of the thyroid in male rats only. There is no
information to indicate the underlying mechanism of
tumour formation in these rats, hence the relevance to
human health is uncertain. However, the relevance of
this finding to the health of exposed workers is likely
to be low, particularly as the potency of
cyclohexanone to cause tumours in rats is low i.e. the
increase in tumours in rats was seen only at 1000
mg.kg-1.day-1 with no toxicologically significant
effects on the thyroid or other tissues at 500
mg.kg-1.day-1
In B6C3F1 mice exposed to cyclohexanone via the
drinking water for 2 years, a slight increase in the
incidence of liver tumours was observed in males only
at the lowest concentration tested (6500 ppm). In
view of the high background spontaneous incidence of
this lesion, and in the absence of a dose-response
relationship, it can be concluded that this study
produced no evidence of carcinogenic potential for
cyclohexanone in mice.
 REVISED OES PROPOSAL
In relation to the potential effects of cyclohexanone
on reproduction, a 2-generation inhalation study in
rats is available. In this study, Fo generation rats were
exposed to 0, 250, 500 or 1000 ppm, whereas the F1
generation rats were exposed to 0, 250, 500 or 1400
ppm, 6 hours/day, 5 days/week. Histopathological
examination revealed no effects on the testes at any
exposure level. No effect on fertility was
demonstrated at up to 500 ppm in both generations.
Rats exposed to 1000 ppm (first generation) or 1400
ppm (second generation) showed transient reductions
in maternal bodyweight. At 1000 ppm there was no
effect on male fertility in the F0 generation. However,
at 1400 ppm in male rats of the F1 generation there
were reduced indices of male fertility [not further
described in the documentation available9,10].
However, there was a persistent reduction in body
weight gain at this exposure level, and it is also noted
that at 1000 ppm there was ataxia, irregular breathing,
lacrimation and irritation of mucous membranes with
the first few exposures. Therefore at 1400 ppm such
effects may have been more severe. Hence it is
possible that generalised toxicity (including CNS
depression) may have influenced fertility outcome in
males at 1400 ppm rather than any direct effect on the
testes. Reduced survival and bodyweights in the
offspring were observed at 1400 ppm. The NOAEL
for effects on fertility is considered to be 500 ppm.
Studies of developmental toxicity in rats exposed via
inhalation show no effects on development of the
offspring with repeated daily exposures of 500 or 650
ppm during gestation. Decreases in maternal and fetal
bodyweights were observed at 1400 ppm (6 h/d, days
6-19 of gestation). In a limited study in mice exposed
to 1400 ppm (6h/d days 6-17 of gestation), decreased
maternal weight was accompanied by a reduction in
the number of corpora lutea and live fetuses. Studies
of limited quality indicate that no effects on neonate
body or organ weights occurred following maternal
dosing by oral gavage at 800 mg.kg-1.day-1 on days 8 -
12 of gestation. At 2200 mg/kg/d, decreased neonatal
body weight was observed in the presence of gross
maternal toxicity indicated by increased mortality and
decreased body weight gain. Overall, the results
indicate that cyclohexanone produces no effect on the
developing offspring at doses which are not
maternally toxic and a NOAEL of 650 ppm is
apparent from the developmental toxicity studies.
Where adverse consequences for development were
seen at higher maternally toxic doses, the contribution
made by toxicity towards the dam is unclear.
Human data
There is relatively little human data available. Case
reports of human poisonings indicate that a single
ingestion of cyclohexanone may cause
unconsciousness or excitation and metabolic acidosis.
69
Ill characterised, self-reported “irritation” to the eyes,
nose and throat at a calculated exposure level of 75
ppm (exposure duration 3 - 5 minutes) was perceived
in a group of about 10 volunteers, while the majority
of subjects did not “object” to 25 ppm(11). There have
been no reports of skin or respiratory sensitisation due
to exposure cyclohexanone.
There are no useful data describing the effects of
cyclohexanone in humans in relation to repeated
exposure or mutagenicity, carcinogenicity or
reproductive toxicity.
BASIS FOR SETTING THE LIMIT
Cyclohexanone is included in the 1st Consolidated
Indicative Limit Occupational Exposure Limit Values
Directive (2000/39/EC), with values of 10 ppm
(8-hour TWA) and 20 ppm (STEL) and a skin
notation. The following is an extract from the SCOEL
SEG SUM:
The studies indicating a LOAEL of 190 ppm
(775 mg.m-3) for systemic effects in rabbits7
and a NOAEL of 25 ppm (102 mg.m-3) for
irritation to the throat and eyes of human
volunteers11 , were considered to be the best
available basis for proposing a limit. An
uncertainty factor of 2 was applied to allow
for the limitations of the Nelson study11. The
recommended 8-hour TWA is 10 ppm (40.8
mg.m-3). This is not contradicted by the study
establishing a NOEL for systemic effects of
100 mg.kg-1.day-1 by intravenous injection. A
STEL (15 min) of 20 ppm (81.6 mg.m-3) is
proposed to limit peaks in exposure which
could result in irritation. A ‘skin’ notation is
also recommended as dermal absorption could
contribute substantially to the total body
burden.
Studies are required to determine whether the
potential conversion of cyclohexanone to
cyclohexanol is sufficient to result in testiclar
toxicity.
WATCH agreed that biological monitoring may be
useful, in view of the potential for systemic toxicity,
and that dermal exposure to cyclohexanone may
contribute to the overall body burden of
cyclohexanone. Therefore, the establishment of a
BMGV was proposed.
REFERENCES
1. NIOSH Manual of Analytical Methods, 4th Ed.,
1994, US Dept of Health and Human Services
(NIOSH) Publ No 94-113, Ketones 1, method 1300.
2. Occupational Health and Safety Administration, US
Dept of Labour, Cyclohexanone in air, method #01,
April 1979.
 REVISED OES PROPOSAL
3. Health and Safety Executive, Volatile compounds
in air...pumped solid sorbent tubes, thermal desorp-
tion, MDHS 72, HSE Books 1993, ISBN 0 11
885692 8.

4. Health and Safety Executive, Volatile compounds

in air...diffusive samplers, solvent desorption, MDHS
88, HSE Books 1997, ISBN 0 7176 2401 3.

5. Health and Safety Executive, Volatile compounds

in air...diffusive samplers, thermal desorption, MDHS
80, HSE Books 1995, ISBN 0 7176 0913 8.

6. Wright M.D. and Plant N.T. (2000). Diffusive

sampling of butyl acrylate and cyclohexanone on
Perkin-Elmer tubes, Diffusive Monitor, 11, in press,
Health & Safety Laboratory, Sheffield.

7. Treon JF, Crutchfield WE and Kitzmiller K (1943).

The physiological response of animals to
cyclohexanone, methylcyclohexane, and certain
derivatives of these compounds. The Journal of
Industrial Hygiene and Toxicology, 25, (8), 323-347.

8. Lijinsky W and Kovatch R (1986). Chronic toxicity

study of cyclohexanone in rats and mice. JNCI, 77,
(4), 941 - 949.

9. BUA (1993). BUA Report 138 (June 1993). In:

BUA Reports 136-138. Ed: GDCh-Advisory
Committee on Existing Chemicals of Environmental
Relevance (BUA),. Pub: S. 70 Stuttgart (1997).

10. DECOS (1994). Health-based recommended

occupational exposure limit for cyclohexanone. Dutch
expert committee on occupational standards.
Directorate-General of Labour. Sdu Uitgeverij
Plantijnstraat, Den Haag.

11. Nelson KW, Ege JF, Morwick R, Woodman LE

and Silverman L (1943). Sensory response to solvent
vapours. Journal of Industrial Hygiene and
Technology, 25, (7), 282 - 285.

12. Greener, Y, Martis, L and Indacochea-Redmond,

N (1982) ‘Assessment of the toxicity of
cyclohexanone administered intravenously to Wistar
and Gunn rats’, J. Toxicol. Environ. Health, 10, pp.
385 - 396

70
 REVISED OES PROPOSAL
OCCURRENCE, PRODUCTION AND USE

DIETHYL ETHER Almost all of the diethyl ether manufactured today is

Recommendation of the EC obtained as a by-product when ethanol is produced via
vapour phase hydration of ethylene over a supported
Scientific Committee on phosphorus acid catalyst. Diethyl ether is not
Occupational Exposure Limits manufactured in the UK.
8-hour TWA: 100 ppm (308 mg.m-3)
In the UK diethyl ether is mainly used in the chemical
15-minute STEL: 200 ppm (616 mg.m-3) industry as a solvent or intermediate in organic
syntheses. It is also an excellent solvent for
subject to consultation
nitrocellulose and is used in the explosives industry.
Diethyl ether has a small and still declining use in the
manufacture of diesel engine starting fluids. There is
IDENTITY AND PROPERTIES also some laboratory-scale use of this substance. In
the UK, use as an anaesthetic in human and veterinary
Chemical Name: Diethyl ether medicine has ceased.
CAS No: 60-29-7
EXPOSURE AND CONTROL
EEC No: 603-022-00-4
Empirical formula: C2H5OC2H5 The number of persons potentially exposed to diethyl
ether is unknown. HSE has no recent data on
occupational exposure to this substance and industry
Synonyms: Ether,ethyl ether,
data were limited.
1,1-oxybisethane,
ethoxyethane,
In the majority of workplaces, processes where diethyl
ethyl oxide,
ether is used are contained. At more dispersive
diethyl oxide,
processes emissions are controlled by the use of
sulphuric ether,
exhaust ventilation. Workers generally wear PPE.
anaesthetic ether.

Sat. Vap. Concentration: 68% at 25°C MEASUREMENT

Boiling point: 34.5 °C
-3
Conversion factor: 1 ppm = 3.08 mg.m at 20 C o determination of diethyl ether in workplace
Diethyl ether is a colourless, very volatile, highly
flammable liquid with a sweetish, slightly pungent,
characteristic odour. It has a vapour density 2.55 times
that of air and is explosive over the range 2 - 48% in
air. The odour threshold is approximately 9 ppm (28
mg.m-3). Diethyl ether is listed in the Approved
Supply List under the Chemicals (Hazard Information
and Packaging for Supply) [CHIP] Regulations as
harmful and extremely flammable, to be labelled with
the following risk (R) phrases:
There is a NIOSH method1 suitable for the
atmospheres. In addition, there are several detector
tubes available which may be useful for short-term
exposure measurement. Gastec tube 161, Kitagawa
tube 107S and Draeger tube Diethyl ether 100/a are
examples. Details of these are given below.
Various instrumental methods based on infra-red
spectrophotometry or semiconductors are listed in
HSE's EH 40 database of methods for sampling and
analysis, a selection is given below.
Dynamic Direct Methods

R12 Extremely flammable Detector Tubes

R19 May form explosive peroxides
Make Range(ppm) Interferences Reference
R22 Harmful if swallowed
R66 Repeated exposure may cause skin dryness or Gastec 400 -10000 Propane,other Gastec tube
organics 161
cracking Kitigawa 400-14000 Propane, Kitigawa tube
acetylene, 107S
R67 Vapours may cause drowsiness and dizziness other organics
except
halogenated
hydrocarbons

71
 REVISED OES PROPOSAL
Draeger 100-4000 Petroleum Draeger tube Diethyl ether has a low acute toxicity and induces
hydrocarbons, diethyl ether anaesthesia at concentrations in excess of 15,000 ppm
alcohols, 100/a
aromatics and (46.2 mg.m-3). The critical effect is nasal irritation. In
esters human volunteers the first indication of irritation
occurred at a calculated level of 300 ppm (924
Dynamic Indirect Methods mg.m-3). Most individuals tested felt that a
concentration of 100 ppm (308 mg.m-3) would be
Solid sorbent acceptable over an 8 hour exposure period3.

Sorbent Range Desorption Analysi Ref. No animal inhalation studies are available. A 90 day
s gavage study in rats4 established a NOEL for systemic
Charcoal 0.3 - 11 Solvent GC/FID NIOSH toxicity of 500 mg.kg-1 bw.day-1. This may
mg per
sample. correspond to an inhalation exposure concentration of
0.3 mg = 1000 ppm (3080 mg.m-3).
10 ppm
for 3 litre Diethyl ether shows no evidence of mutagenicity,
sample
either in vitro or in vivo 5,6,7. No long term animal
studies or reproduction studies are available.
Instrumental Methods
BASIS FOR THE LIMIT
Instrument Principle Lower Ref. The information in this section is taken from the
detection SCOEL summary document SEG/CDO/5A (1991)2.
limit(ppm)
MIRAN Infra-red 0.1 Quantitech
monitor, Although the Nelson study has major limitations, it
various provides the only available basis for setting exposure
models limits. A NOAEL of 100 ppm (308 mg.m-3) for nasal
Servomex Infra-red 0.08 Servomex irritancy in human volunteers was indicated by this
P404
portable IR
study. A 90 day gavage study in rats was suggestive of
analyser a NOAEL of 1000 ppm (3080 mg.m-3) for systemic
B&K Type Photoacousti Not given Bruel & effects. The volatility of diethyl ether makes the
1302 c infra-red Kjaer calculation of the effective dose administered in the
multigas
experiment difficult. However, it seems that an 8 hour
monitor
TWA of 100 ppm (308 mg.m-3), derived from
TOXICOKINETICS Nelson’s study would also provide sufficient
protection against systemic effects. To prevent short
Few data are available. Its appreciable water and lipid term exposure to irritant levels a STEL (15 min) of
solubility and its anaesthetising properties indicate 200 ppm (616 mg.m-3) is recommended.
that the vapour is readily absorbed across the
REFERENCES
respiratory tract. Absorption from the gastro-intestinal
tract or following application to the skin would be 1 US National Institute of Occupational Safety and
complicated by the volatility of diethyl ether, and no Health NIOSH (1984) Manual of Analytical Methods
actual data are available. Tissue/air partition 3rd Edition Method (3) 1610 DHHS (NIOSH)
coefficients suggest that absorbed diethyl ether will be Publication
widely distributed around the body. and there are data
in animals to show that it can cross the placenta into 2 SEG/CDO/5A (1991). CEC Criteria document for
the foetus. Information on metabolism is limited, but occupational exposure limit values. Diethyl ether.
suggests that a small percentage of absorbed diethyl Prepared by the Dept. of Environmental Technology,
ether undergoes oxidative hydrolysis to ethanol, Danish Technological Institute.
ethanal and ethanoic acid, thereby entering the carbon
pool. However, most diethyl ether appears to be 3 Nelson KW, Ege JF, Ross M, Woodman LE, and
exhaled rapidly in an unchanged form. Silverman L (1943) Sensory response to certain
industrial solvent vapours J Ind Hyg Toxicol 25 (7)
HEALTH EFFECTS 282-285
Animal studies 4 American Biogenics Corporation (1988). Study
410-2343. Ninety day gavage study in albino rats
The information in this section is taken from the using diethyl ether. Submitted to US EPA, office of
SCOEL summary document SEG/CDO/5A (1991)2. Solid Waste, Washington, DC 20460

72
 REVISED OES PROPOSAL
5 Baden, JM, and Simmon, VF, (1980). Mutagenic
activity of inhalational anaesthetics. Mutat. Res. 75,
169 - 189

6 De Flora, S, Zanacchi, P, Camoirano, A, Bennicelli,

C and Badolati, GS (1984). Genotoxic activity and
potency of 135 compounds in the Ames reversion test
and in a bacterial DNA-repair test. Mutat. Res. 133,
161 - 198.

7 Simmon, VF, Kauhanen, K and Tardiff, RG (1977).

Mutagenic activity of chemicals identified in drinking
water. Prog. Genet. Toxicol. 2, 249 - 258

73
 REVISED OES PROPOSAL
Heptan-3-one is a medium-volume solvent with a
HEPTAN-3-ONE production rate less than 1000 tonnes per annum in the
Recommendation of EC Scientific European Community. It is used as a solvent for
Committee on Occupational nitrocellulose and polyvinyl resins.
Exposure Limits
8-hour TWA: 35 ppm (166 mg.m-3) [MEASUREMENT

occupational exposure standard Heptan-3-one may be sampled by drawing air through

a charcoal tube followed by solvent desorption, or
15-minute STEL: 100 ppm (475 through porous polymer tubes (Tenax or Chromosorb
mg.m-3) 106) followed by thermal desorption. Analysis is by
Notation: Skin gas chromatography. Methods have not been fully
subject to consultation evaluated but are assumed appropriate by analogy.
With the exception of [ ] this summary is prepared Short term colorimetric detector tubes are available
from the SCOEL SEG SUM for screening measurements but react, to varying
degrees, to a number of ketones. Instrumental methods
IDENTIFICATION AND PROPERTIES are appropriate for continuous monitoring. Biological
monitoring may be useful in helping to assess
Chemical Name: Hepta-3-one
occupational exposure via dermal as well as inhalation
CAS No: 106-35-4
routes. By analogy with other ketones this may take
EEC No: 606-003-00-9 the form of monitoring the concentration of
Einecs No: 203-388-1 unchanged heptan-3-one in end of shift urine
samples.]
Formula: CH3CH2CO (CH2) 3CH3
HEALTH SIGNIFICANCE
Synonyms: 3-heptanone, ethyl butyl ketone,
EBK The SEG discussed and reviewed heptan-3-one on the
basis of the health-risk assessment carried out by the
MWt: 114.2
Dutch Expert Committee for Occupational Standards
Vapour pressure: 0.2 kPa at 25°C together with the additional information given by a
Melting-point: - 39°C member of the group.
Boiling-point: 148.5°C The SEG considered the experimental data available
Conversion factor (20°C): 4.75 mg/m3 = 1ppm to be limited, especially with respect to the almost
complete lack of human data.
The data on acute toxicity via inhalation are
Heptan-3-one is a colourless, flammable liquid with a
incomplete. However, on the basis of LC10 values for
strong fruity odour. It has a saturation concentration
rats, heptan-3-one showed greater toxicity than
in air of 0.18% by volume. Heptan-3-one is listed in
heptan-2-one (LC10 of 2 000 ppm (9 500 mg.m-3) for
the current Approved Supply List under the Chemical
four hours compared with an LC10 value of 4 000 ppm
(Hazard Information and Packaging for supply)
(19 000 mg.m-3) for four hours).
Regulations 1994 (CHIP) as Harmful, to be labelled
with the following risk (R) phrases: Although the principal non-systemic hazards reported
to be associated with exposure to ketone vapours are
irritative effects on the eyes and the upper respiratory
R10: Flammable
airways, no data for heptan-3-one are reported.
R20: Harmful by inhalation
From the three reported subchronic animal studies on
R36: Irritating to the eyes the nervous system with different routes of application
(drinking water, gavage, inhalation), the inhalation
study of Katz et al. (1980) on rats at 700 ppm (3 325
OCCURRENCE AND USE
mg.m-3), 72 hours a week for 24 weeks, is considered
74
 REVISED OES PROPOSAL
to be the key study and has neurotoxicity as the
critical effect. From these data it may be concluded
that the NOAEL in respect of the neurotoxicity of
heptan-3-one in rats is about 1258 mg/kg/day, or 700
ppm (3325 mg.m-3) based on a test for 24 weeks in
inhaled air. This is well in line with the estimated
NOAELS of 1000 mg.kg-1.day-1 by other routes of
application (Homan and Maronpot, 1978;
O’Donoghue et al., 1984).
The available data suggest that heptan-3-one is more
neurotoxic than heptan-2-one. This may be due to the
different neurotoxicity of the metabolites reported
(2,5-heptanedione from heptan-3-one and
2,6-heptanedione from heptan-2-one).
No data with respect to chronic exposure,
mutagenicity, carcinogenicity and reproductive
toxicity are available.
The only human data available showed no irritation of
heptan-3-one to human skin (25 volunteers) after 48
hours under an occlusive patch at a concentration of
4% in petrolatum.
RECOMMENDATION
Methods for the deternimation of hazardous
substances (MDHS) 72 Volatile organic compounds
in air - Laboratory method using pumped solid
sorbent tubes, thermal desorption and gas
chromatography ISBN 0 11 885692 8 HSE Books
(1992)]
Dutch Expert Committee for Occupational Standards
and Nordic Expert Group (1989) ‘Basis for an
occupational health standard 7/8-carbon chain
aliphatic monoketones’, Wibowo, A A E., Arbete och
Halsã, pp. 1-45.
Homan, E R and Maronpot R R (1978) ‘Neurotoxic
evaluation of some aliphatic ketones’, Toxicol. Appl.
Pharmacol., 45, p. 312.
Katz, G V O’Donoghue, J L Divincenzo, G D and
Terhaar, C J (1980) ‘Comparative neurotoxicity and
metabolism of ethyl n-butyl ketone and methyl n-butyl
ketone in rats’, Toxicol. Appl. Pharmacol., 52, pp.
153-158.
O’Donoghue, J L Krasavage, V J Divincenzo, G D
and Katz, G V (1984) ‘Further studies on ketone
neurotoxicity and interactions’, Toxicol. Appl.
Pharmacol., 72, pp. 201 - 209.

The subchronic inhalation study in rats reported by

Katz, establishing a NOAEL of 700 ppm, was
considered to be an adequate basis for setting the
limit. Because of the limited data, the SEG agreed
that a safety factor of 20 should be used [giving a
health based limit of 35 ppm] together with rounding
down to comply with the SEG ‘preferred value
approach’ to setting limits. The recommended 8-hour
TWA is 20 ppm (95 mg.m-3) [however the preferred
value approach has been set aside by HSE in favour of
the health based limit supported by the data].
[In view of the reported irritant effects of ketone
vapours , a STEL OES of 100 ppm is proposed. This
level is below that which structurally-related ketones
cause irritation. A skin notation is proposed.]
At the level recommended no measurement difficulties
are foreseen.

KEY BIBLIOGRAPHY
[National Institute for Occupational Safety and Health
(1984) Manual of Analytical Methods (3rd Edition)
Method 1301

75
 REVISED OES PROPOSAL
OCCURRENCE AND USE
5-METHYLHEXAN-2-ONE MIAK is a high-volume solvent with a production rate
Recommendation of the Scientific greater than 1 000 tonnes per annum in the European
Committee on Occupational Community. It is used as a solvent for
Exposure Limits cellulose-esters, acrylics and copolymers.

8-hour TWA: 20 ppm (95

mg.m-3) [MEASUREMENT
MIAK may be sampled by drawing air through a
occupational exposure standard
charcoal tube followed by solvent desorption, or
15-minute STEL: 100 ppm (475 through porous polymer tubes (Tenax or Chromosorb
mg.m-3) 106) followed by thermal desorption. Analysis is by
Notation: Skin gas chromatography. Methods have not been fully
With the exception of [ ] this summary is prepared evaluated but are assumed appropriate by analogy.
from the SCOEL SEG SUM Short term colorimetric detector tubes are available
for screening measurements but react, to varying
degrees, to a number of ketones. Instrumental methods
IDENTITY AND PROPERTIES are appropriate for continuous monitoring. Biological
Chemical Name: 5-Methylhexan-2-one monitoring may be useful in helping to assess
CAS No: 110-12-3 occupational exposure via dermal as well as inhalation
Einecs No: 203-737-8 routes. By analogy with other ketones this may take
the form of monitoring the concentration of
EEC No: 606-026-00-4;
unchanged MIAK in end of shift urine samples.]
Formula: (CH3)2CH(CH2)2 COCH3
Synonyms: Methyl isoamyl ketone,
HEALTH SIGNIFICANCE
MIAK, isopentyl methyl
The SEG reviewed and discussed the document from
ketone the Dutch Expert Committee for Occupational
MWt: 114.2 Standards. The reported experimental animal data are
Melting-point: - 73.9oC considered to be limited but sufficient for an
evaluation. As with 2-heptanone there is an almost
Boiling-point: 144oC
complete lack of human data. Methyl isoamyl ketone
Vapour pressure: 0.65 kPa at 20oC shows a relatively low acute toxicity by oral
Conversion factor : 475 mg/m3 = 1 ppm administration to animals (mice, rats, LD50: 2 540 To
(20oC, 101 kPa): 4 760 mg.kg-1). The LD50 value for dermal
application to rabbits has been estimated to be 10
g.kg-1. No LC50 values are reported, but in rats a
5-methylhexan-2-one (MIAK) is a colourless liquid
4-hour LC10 value of 2 000 ppm (9 500 mg.m-3) has
with a sharp but pleasant sweet odour. The odour
been determined.
threshold concentration is reported to be about 0.01
ppm (0.05 mg/m3). MIAK is listed in the current
Approved Supply List under the Chemical (Hazard The acute irritation potential of MIAK on the upper
Information and Packaging for supply) Regulations respiratory airway has been investigated (De Ceaurriz
1994 (CHIP) as Harmful, to be labelled with the et at., 1984). In measuring the decrease of the
following risk (R) phrases: respiratory rate an RD50 value of 1 222 ppm (5-8505
R10: Flammable mg.m-3) for 15 minutes has been determined. Using
the model of Kane et at (1979), the occupational
R20: Harmful by inhalation
exposure limit value should be between 12 and 120
ppm (57 and 570 mg.m-3) to protect from irritation.

76
 REVISED OES PROPOSAL
With methyl isoamyl ketone only one subchronic
inhalation study on rats has been reported (200, 1000
and 2000 ppm; 950, 4750 and 9500 mg.m-3, six hours
a day, five days a week for 90 days). Decrease in
aural response, lethargy and histological changes in
the liver and kidney were observed at 1000 ppm (4
750 mg.m-3) and 2000 ppm (9500 mg.m-3). From this
study (Katz et al., 1986) it may be deduced that the
critical targets are the central nervous system, kidney
and liver, and that the NOAEL is 200 ppm (950
mg.m-3).
The only observation in man is that MIAK showed no
positive reaction in a sensitization study on human
volunteers.
KEY BIBILOGRAPHY
[National Institute for Occupational Safety and Health
(1984) Manual of Analytical Methods (3rd Edition)
Method 1301
Methods for the determination of hazardous
substances (MDHS) 72 Volatile organic compounds
in air - Laboratory method using pumped solid
sorbent tubes, thermal desorption and gas
chromatography ISBN 0 11 885692 8 HSE Books
(1992)]
De Ceaurriz, J., Micillino, J. C., Marignac, B.,
Bonnet, P., Muller, J. and Guenier, J.P. (1984)
‘Quantitative evaluation of sensory irritating and
neurobehavioural properties of alphatic ketones in
mice’, Fd. Chem. Toxicol., 22, pp. 545-549.

No data are available on mutagenicity, carcinogenicity

Dutch Expert Committee for Occupational Standards
and reproduction toxicity.
and Nordic Expert Group (1989) ‘Basis for an
RECOMMENDATION
occupational health standard 7/8-carbon chain
The SEG considered the health-risk assessment as aliphatic monoketones’, in Wibowo, A. A. E., Arbete
carried out by the Dutch Expert Group for och Halsä, pp. 1-45.
Occupational Standards as adequate except for the
size of the safety factor. The Katz study was
Kane, L. E., Barrow, C. S. and Alarie, Y. (1979) ‘A
considered to be an adequate basis for setting the
short-term test to predict acceptable levels of exposure
limit. Although the Dutch Expert Group had used a
to airborne sensory irritants’, Am. Ind. Hygiene. Ass.
safety factor of 4 (with respect to the available animal
J., 40, pp. 207-229.
data and the similarities between MIAK and
2-heptanone), the SEG considered it more appropriate
to use a factor of 10 in view of the nature of the Katz, G. V., Renner, C. J. and Terhaar, C. J. (1986)
available toxicological information and in order to ‘Subchronic inhalation toxicity of methyl isoamyl
maintain consistency with the evaluation other ketone in rats’, Fund . appl. Toxicol., 6, pp 498-505.
ketones.
The recommended 8-hour TWA value is 20ppm (95
mg/m3). This value is also in line with the range of
recommended limit values of 12 to 120ppm (57 to 570
mg/m3) derived from the RD50 value to protect from
irritation.
[In view of the reported irritant effects of ketone
vapours , a STEL OES of 100 ppm is proposed. This
level is below that which structurally-related ketones
cause irritation. A skin notation is proposed.]
At the level recommended no measurement difficulties
are foreseen.

77
 REVISED OES PROPOSAL
R20: Harmful by inhalation
4-METHYLPENTAN-2-ONE R36/37: Irritating to eyes and the respiratory
Recommendation of the EC system
Scientific Committee on R66: Repeated exposure may cause skin
Occupational Exposure Limits
dryness or cracking
-3
8 hour TWA: 20 ppm (83 mg.m )
STEL (15 mins): 50 ppm (208 mg.m-3) OCCURRENCE AND USE
occupational exposure standard MIBK is a high volume industrial solvent with a
production rate in the European Community greater
Notation: Skin
than 1000 tonnes per annum. It is mainly used as a
Biological monitoring Health Guidance solvent in glues, paints, and cleaners, but also as a
Value: 20 µmol 4-methylpentan-2-one/l in solvent for some plastics and various fats, oils and
post urine shift samples waxes. Frequently, MIBK is used in combination with
subject to consultation other solvents such as toluene.

With the exception of [ ] this summary is prepared

from the SCOEL SEG SUM [MEASUREMENT
Workplace air monitoring
IDENTITY AND PROPERTIES: MIBK can be sampled by drawing air through a
Chemical Name: 4-Methylpentan-2-one charcoal tube or XE-348 tube, followed by solvent
CAS No 108-10-1 desorption, or through porous polymer tubes (Tenax
or Chromosorb 106) followed by thermal desorption.
EINECS No 203-550-1
Analysis is by gas chromatography. Samples may be
EEC No 606-004-00-4 unstable on charcoal. Short term colorimetric detector
Formula: (CH3)2CHCH2COCH3 tubes are available for screening measurements, but
Synonyms Methylisobutylketone, MIBK, react to varying degrees, to a number of ketones.
Instrumental methods are appropriate for continuous
hexone, isopropylacetone
monitoring.
MWt 100.16
Biological monitoring
Vapour pressure: 1.33kPa at 30oC
Biological monitoring may be useful in helping to
Melting point: -80oC assess occupational exposure via dermal as well as
Boiling Point: 115.8oC inhalation routes. There are analytical methods
Conversion factor: 4.16 mg/m3 = 1 ppm (20oC, available for the measurement of MIBK in blood and
101kPa) urine. Measurement of MIBK in post shift urine
samples is the preferred indicator of exposure.]
At ambient temperatures 4-methylpentan-2-one
(MIBK) is a colourless, flammable liquid with a
characteristic sweet odour. It has a saturation HEALTH SIGNIFICANCE
concentration of 40 g.m-3 at 25oC. The explosive limits The SEG reviewed a criteria document elaborated by
are 1.4% and 7.6% by volume in air. The odour the Nordic Expert Group. Although the database was
threshold is about 0.7 ppm (3 mg.m-3 ). MIBK is listed regarded as limited, the SEG came to the conclusion,
in the current Approved Supply List under the after discussing the cited reports of Armeli and Linari,
Chemical (Hazard Information and Packaging for together with the recently published paper of Hjelm,
supply) Regulations 1994 (CHIP) as Harmful , to be that a limit value could be recommended.
labelled with the following risk (R) phrases:
R11: Highly flammable

78
 REVISED OES PROPOSAL
MIBK shows a low acute toxicity by oral
administration to animals (rats, mice ; LD50 >2000M
mg.kg-1). A mouse LC50 value of 18100 ppm (75296
mg.m-3) for a 45 minute exposure period has been
determined.
Subacute (14 days) and subchronic (90 days) studies
on different species with exposure concentrations of
100 and 200 ppm (416 and 832 mg.m-3) showed
effects on the kidney at 100 ppm (416 mg.m-3) in rats
after 14 days continuous exposure (enhanced kidney
weight, reversible hyaline droplet toxic tubular
nephrosis). First indications of CNS effects (extended
reaction time) have been shown by exposing a small
number (4) of baboons to 50 ppm (208 mg.m-3 MIBK
for 7 days.
No long term animal studies, nor studies on
mutagenicity are reported. However, MIBK has been
selected for testing in Salmonella by NTP in 1989.
Tests on reproductive toxicity with rats and mice
showed no exposure -related embryotoxicity or
malformations at exposure levels up to 1000 ppm
(4160 mg.m-3 ).
Investigation of occupational exposure to MEM at
80-500 ppm (333-2080 mg.m-3), for 20 to 30
mins/day, for 3 to 12 months) was reported by Linari
with a follow up by Armeli 5 years later when
exposure had diminished to 50-105 ppm (208-437
mg.m-3). With the higher exposure, a majority of the
19 workers exposed complained of nausea (17),
vomiting (10), diarrhoea (6), irritation of eyes (17),
and airways (13). 16 workers experienced
neurasthenic symptoms. The follow up of 14 workers
5 years later with lower exposure showed a lowered,
but still existing prevalence of neurasthenia (4/14) and
irritative symptoms (2/14).
The most recent study (Hjelm, 1990) of the
toxicokinetics reported similar irritative effects and
CNS-symptoms in a small number (8) of human
volunteers during inhalation exposure to MIBC for 2
hours at 2.4, 24 and 48 ppm (10, 100 and 200 mg.m-3).
79
However, the SEG agreed that the symptoms were
subjective and decided that, in the absence of a
dose-related response, the evidence for effects at these
concentrations was not convincing. The Armali study
was therefore used as the basis for setting the limits.
From the limited data available, irritation of the eyes,
the nose, the upper respiratory tract and effects on the
CNS are regarded to be the key effects/organs.
RECOMMENDATION
The human data of Armeli, which showed effects just
below 100 ppm (410 mg.m-3), was considered to be an
adequate basis for setting the limits. The
recommended 8-hour TWA is 20 ppm (83 mg.m-3).
A STEL (15 mins) of 50 ppm (208 mg.m-3) is also
recommended.
The proposed limit values do not take account of
possible interactions with other solvents (e.g. MEK,
toluene) in combined exposure.
[Significant absorption of MIBK via the skin has
been demonstrated in guinea pigs (Hjelm et al 1991)
and therefore, a skin notation is recommended.]
At the levels recommended no measurement
difficulties are foreseen.
BIBLOGRAPHY
Methods for the determination of hazardous
substances MDHS 66 (rev) Mixed hydrocarbons (C5
to C10) in air - Laboratory method using porous
polymer diffusion samplers, thermal desorption and
gas chromatography ISBN 0 7176 0867 0 HSE
Books (1995)
Linari, F., Perelli, G. and Varese, D. (1964): Rilievi
clinici ed ematochimici in operai esposti all'azione di
un chetone superiore:
metil-isobutil-c he tone. Arch.Sci,Med., 226-239.
Armeli, G., Linari, F. and Martorano, G. (1968):
Rilievi clinici ed ematochimici in operai esposti
all'arione di un chetone superione (MIBK) ripetuti a
distanza di 5 anni. Lav.Urnano 20, 418-423.
 REVISED OES PROPOSAL
Hagberg M. (1988): Methylisobutyl Ketone.In:
Heimbürger G. and P.Lundberg (eds), Criteria
documents from the Nordic Expert Group. Arbete och
Hälsa, 33, 53-76.

Hjelm, EW, Hagberg, M., Iregren, A. and Löf, A.

(1990): Exposure to methyl isobutyl ketone:
toxicokinetics and occurrence of irritative and CNS
symptoms in man. Int. Arch. occup. Environ. Health,
62, 19-26.

[Hjelm, EW, Bowman, A, Fernstrom, P, Hagberg M,

Johanson G (1991): Percutaneous uptake and kinetics
of methyl isobutyl ketone (MIBK) in the guinea pig.
Toxicology Letters 56, 79-86]

80
 REVISED OES PROPOSAL
1994 (CHIP) as Irritant, to be labelled with the
TETRAHYDROFURAN following risk (R) phrases:

Recommendation of the Scientific R11: Highly flammable

Committee on Occupational R19: May form explosive peroxides
Exposure Limits R36/37: Irritating to eyes and the respiratory
8 hour TWA: 50 ppm (120 mg.m-3) system
-3
15-minute STEL: 100 ppm (300 mg.m ) OCCURRENCE AND USE
THF is produced mainly be catalytic hydrogenation of
Notation: Skin maleic acid anhydride or furan. It has a production
rate in the European Communities in excess of 1000
With the exception of [ ] this summary is prepared tonners per annum. It is used in industry as a solvent
from the SCOEL SEG SUM for a variety of resins, plastics and elastomers, and as
IDENTITY AND PROPERTIES an adhesive for joining plastic parts. Occupational
Chemical Name: Tetrahydrofuran exposure levels are greatest during use as a solvent
CAS No 109-99-9 adhesive with short term levels of up to 263 ppm (789
mg.m-3).
EINECS No 203-726-8
[MEASUREMENT
EEC No 603-025-00-0
Colorimetric detector tubes are available for screening
measurements. Medium and long-term monitoring of
tetrahydrofuran is by pumped sampling through a
charcoal or porous polymer tube, followed by solvent
desorption. Analysis is by gas chromatography. These
methods are suitable for concentrations between 0.2 -
100 mg.m-3, with a sample volume of 2.5 litres at a
Formula: C4H8O
flow rate of 0.005l.min-1. Continuous monitoring can
be conducted using infra-red spectrophotometry and
Synonyms Butylene oxide other methods. A biological method is reported,
measuring THF in end of shift urine samples by
Diethylene oxide
capillary gas chromatography with flame ionisation
1,4-Epoxybutane
detection.]
Hydrofuran
Mwt 72.11
HEALTH SIGNIFICANCE
Vapour pressure: 17.5kPa at 20ºC
The SEG discussed the document (SEG/CDO/2)
Melting point: - 108.5ºC which was co-produced by the Swedish Criteria Group
Boiling point: 67ºC. for Occupational Standards and the Dutch Expert
Committee for Occupational Standards.
Conversion factor: 3.00 mg/m3 = 1ppm (20ºC,
In animals, THF is rapidly absorbed by the lungs and
101kPa)
through the skin. It is distributed relatively uniformly
THF is a colourless, volatile liquid with a and a It is
in the body, with slightly higher concentrations
highly flammable and has an ether-like odour and a
observed in adipose tissues.
pungent taste. The and the odour threshold is 20-50
THF has low acute toxicity, reported LC50 values
ppm (60-150 mg/m3). THF is listed in the current
being in the region of 20,000 ppm (60,000 mg.m-3).
Approved Supply List under the Chemical (Hazard
Death is preceded by narcosis.
Information and Packaging for supply) Regulations

81
 REVISED OES PROPOSAL
Inhalation studies in animals indicate that the mucous
membranes of the eyes and respiratory tract, and the
central nervous system are the critical target tissues.
Liver and kidney damage have also been noted.
Although there are no controlled human studies,
comparable effects have been observed in reports on
workers exposed to THF vapour.
Concentration-related effects on nasal and tracheal
ciliary beating have been reported, with minimal,
transient, effects of 100 and 250 ppm (300 and 750
mg.m-3) (Ikeoka et al, 1984; Ohashi et al, 1983).
Exposure of rats to 200 ppm (600 mg.m-3) for 3 hours
also caused slight irritation of the nose and eyes
(Katahira et al, 1982a). CNS effects have been
observed following exposure of rats to 3000 ppm
(9000 mg.m-3) 3 h/day, 5 days/week for 8 weeks
(Kawata et al, 1986). Increases in serum enzymes,
indicative of liver damage, have been observed in rats
exposed to THF at 1000 ppm (3000 mg.m-3) 4h/day, 5
days/week for 12 weeks (Katahira et al, 1982b).
Similar indications have been seen in workers exposed
to THF vapour at less than 1000 ppm (3000 mg.m-3)
(Horiushi et al, 1967). A 13 week inhalation study,
conducted by Chhabra et al (1990), identified
NOAELs for systemic effects (CNS and liver
damage), of 1800 ppm (5400 mg.m-3) in rats and 600
ppm (1800 mg.m-3) in mice. Thus, 100 ppm (300
mg.m-3) may be considered as the minimal effect level.
THF may lower the threshold for epileptic seizures.
RECOMMENDATIONS
Studies showing reduction in ciliary beating (Ikeoka et
al, 1984; Ohashi et al, 1983) and irritation of the nose
and eyes of the rat (Katahari et al, 1982a) established
a lowest observed effect level of 100 ppm (300
mg.m-3) and were considered to be the best available
basis for setting exposure limits. An uncertainty
factor of 2 was considered to be appropriate in view of
the transient nature of the minimal effects observed.
The recommended 8-hour TWA is 50 ppm (150
mg.m-3). To prevent short term exposure to irritant
levels an STEL (15 mins) of 100 pm (300 mg.m-3) is
recommended.
Skin penetration may make a substantial contribution
to the total body burden so a skin notation is also
82
required. Additional information on human effects
should be obtained.
At the levels recommended, no measurement
difficulties are foreseen.
BIBLIOGRAPHY
Methods for the determination of hazardous
substances MDHS 72 Volatile organic compounds in
air - Laboratory method using pumped solid sorbent
tubes, thermal desorption and gas chromatography
ISBN 0 11 885692 8 HSE Books (1992)
Ong CN, Chia SE et al (1991) Biological monitoring
of occupational exposure to tetrahydrofuran Br J Ind
Med 48, 616-621
ACGIH (1989). Threshold Limit Values and
Biological Exposure Indices for 1989-1990.
American Conference of Government Industrial
Hygienist, Cincinnati, Ohio.
Chhabra, R S, Elwell, M R, Chou, B, Miller, R A and
Renne, R A (1990). Sub chronic toxicity of
tetrahydrofuran vapours in rats and mice. Fund.
Appl. Toxicol 14, 338-345.
DFG (1989). Maximum concentrations at the
workplace and biological tolerance values for working
materials 1989. Report XXV Commission for the
investigation of health hazards of chemical
compounds in the work area. Deutsche
Forschungsgemeinschaft. VCH, Weinheim, Germany.
Horiushi, K, Horigushi, S, Utsunomiya, T, Shinagawa,
K, Nakagawa, T, Takada, F, Deguchi, T, Okada, H,
Kawasaki, N, Murakami, Y and Kuroda, Y. (1967).
Toxicity of an organic solvent, tetrahydrofuran, on the
basis of industrial health studies at a certain factory.
Sumitomo Bulletin of Industrial Health, No 3m-49-56.
Ikeoka, H, Ohashi, Y, Maruoka, K, Nataka, J,
Masutani, H, Nakai, Y, Horigushi, S, and Teramoto,
K (1984). Effects of tetrahydrofuran exposure on the
ciliary activity and morphology of tracheal epithelium
in rabbits. Osaka City Med, J, 30, 53-67.
 REVISED OES PROPOSAL

Katahira, T, Teramoto, K and Horigushi, S. (1982a).

Experimental studies on repeated inhalation toxicity of
tetrahydrofuran in rats. Proceedings of the Tenth
Asian Conference on Occupational Health, Singapore,
2, 793-798.

Katahira, T, Teramoto, K and Horigushi, S (1982b).

Experimental studies on the acute toxicity of
tetrahydrofuran in animals. Sangyo Igaku 24,
373-378.

Kawata, F, Shimizu, T, Ozono, S. (1986).

Determination and fluorescent-histochemical
approach to catecholamines in the rat brain inhalation
of tetrahydrofuran. Nippon Hoigaku Zasshi, 40,
821-823.

Ohashi, Y., Nakai, Y., Nakata, J., Ikeoka,, H.,

Maruoka, K., Horigushi, S and Teramoto, K (1983).
Effects on the ciliary activity and morphology of
rabbit’s nasal epithelium exposed to tetrahydrofuran.
Osaka City Med, J, 29 1-14.

SEG/CDO/2 (1990). Health based recommended

occupational exposure limit for tetrahydrofuran.
Dutch Expert Committee and Swedish Criteria Group
for Occupational Standards.

83
 APPENDIX 4

EXPLANATORY NOTE - COST BENEFIT ASSESSMENT METHODOLOGY FOR

REGULATORY IMPACT ASSESSMENT AND APPLICATION TO
OCCUPATIONAL EXPOSURE LIMITS: AN OVERVIEW

1. It is Government policy that the costs of all new or revised regulation must be
assessed. Since 1982 the Health and Safety Commission (HSC) has required cost benefit
assessments (CBAs) to be undertaken for all major proposals for health and safety
regulations unless the costs resulting from their introduction are negligible. This approach has
also been extended to the consultation period for Occupational Exposure Limits (OELs).
Since October 1998, costs and benefits are discussed in the regulatory impact assessment
(RIA) framework.

2. The complexities of applying CBA/RIA methodology to occupational ill-health issues

as opposed to accident prevention mean that the results need to be considered with particular
caution. The uncertainties resulting from imperfect information on the cost of controls, and
validation of exposure compliance data can be more pronounced in relation to health issues,
so that estimates of the costs often need to be viewed as rough estimates. The extent of
uncertainty will vary according to each substance and the availability of accurate information.

3. On the other side of the scale, quantifying the benefits of an OEL also poses some
particular problems. Quantification is normally based upon how far the OEL reduces the risk
to employees exposed using dose-effect information. However, for substances such as
carcinogens the dose-effect relationship is commonly not established, and alternative ways of
deriving a monetary value to represent the benefits of setting OELs have been developed.

4. In addition, there are a number of underlying benefits that can accrue from the
introduction of an OEL and lead to more general improvements in worker protection but
cannot easily be quantified. Such benefits are often less tangible, longer term, or relate to the
general principles of introducing an OEL rather than to its specific level. They may also lead
to consequential improvements in productivity, reduction in product loss and improvements
in employee recruitment and retention, some of which are difficult to quantify. These
potential benefits include factors such as:

84
 w Defining a level playing field for all users.
w Defining adequate control.
w Providing clearer guidance on the level considered to be reasonably
practicable.
w Providing a standard for new users.
w Reducing/ limiting scope of 'discretion' by enforcing authority.
w Providing consistency with international developments.
w Reinforcing/ improving good practice.
w Encouraging/ stimulating proper reporting of ill-health.
w Promoting more effective health surveillance.
w Reducing ambient air contamination generally.

5. The Health and Safety Commission's Advisory Committee on Toxic Substances

(ACTS) takes such uncertainties and potential benefits into consideration when discussing
and agreeing proposals for OELs. It fully recognises that CBA is an aid to decision-making.
During the process of deciding on the proposal for an OEL, ACTS will consider the
CBA/RIA and the existence of the potential benefits, and will make a recommendation in the
context of its responsibilities for employee health protection, and the provision of help to
industry in risk management. The CBA/RIA provides a tool which enables HSC to make
decisions based on a knowledge of available factors including the socio-economic impact of
the proposed OEL. It is not, however, the over-riding determining factor.

85
 APPENDIX 4A

MEL PROPOSALS AND 1ST CONSOLIDATED IOELV DIRECTIVE:

SUMMARY COMPARISON OF COSTS AND BENEFITS

Substance Summary of RIA

Chlorobenzene Chlorobenzene is not manufactured in the UK. There is

some exposure in repackaging and distribution (100-200
workers). Its principal uses are as an intermediate or solvent
in chemicals manufacture (100-300 workers), as a laboratory
reagent (estimated to be 500 to 1000), and in a very few
adhesives. HSE’s enquiries suggest that fewer chemical
plants now use chlorobenzene than formerly. It was not
possible to estimate the numbers exposed in adhesive
applications. Health benefits arising from a MEL would be a
reduction in the risk of genotoxicity, however, this is not
quantifiable.
The cost to industry overall in complying with MELs of 1
ppm (8 hr TWA) and 3 ppm (STEL) are estimated to be
between £115k and £233k (over ten-years in present value
terms). Given an estimated 700 to 1500 workers are
exposed, this leads to an estimate of between £77 and £133
per employee. This is at the low end of costs per exposed
employee compared with other MELs recently set.
Although the recommended MELs are lower than the
IOELVs, the indications are that the lower levels may be
achieved without significant extra cost, and are justified in
the light of the unresolved concerns about health effects.

Dihydrogen selenide An initial compliance cost assessment indicated that

dihydrogen selenide has limited use in the semiconductor
industry as a dopant gas. Up to 30 employees may be
exposed during its use and distribution, however, dihydrogen
selenide is used in closed systems with state of the art
automated controls. Setting a MEL is unlikely to further
reduce exposure. Consequently, health benefits are likely to
be negligible, as are costs associated with compliance.
Therefore, a full RIA has not been conducted.

86
Phenol Phenol is not manufactured in Great Britain, but is used
extensively with some 70 - 80,000 people exposed in total.
The major applications (with best estimates of numbers
exposed) are: supply and transportation (250 exposed);
chemical synthesis, including resin manufacture (ca 12
companies, <200 exposed); paint stripping - aircraft (20
sites, 200 exposed); use of phenolic resins (large number of
sites, 40,000 exposed); foundry sand binders (900 foundries,
up to 33,000 exposed). Health benefits arising from a MEL
would be a reduction in the risk of mutagenic effects,
however, this is not quantifiable as there is no conclusive
evidence regarding dose and effects.
The cost to industry overall in complying with a MEL of 2
ppm (8 hr TWA) are estimated to lie in the range £606k to
£1622k (over ten-years in present value terms). The average
costs of around £15 per employee are considerably lower
than for many other substances with concerns about
genotoxicity. The foundries sector is the major contributor
to the estimated costs, however, the average cost is still
estimated to be less than £50 per employee.

Substance Summary of RIA

1st Consolidated Indicative Costs are attributable to cyclohexanone and diethyl ether.
Occupational Exposure Limit Costs are also attributable to phenol and o-xylene, m-xylene,
Values (IOELV) Directive p-xylene, xylene mixed isomers, butoxyethanol, and
5-methylheptan-3. Total one-off costs, as a result of capital
expenditure, are estimated to be about £0.4 million
(1999/2000 prices), while the ten-year present value of the
recurring costs is £8.8 million (1999/2000 prices). Recurring
costs are incurred mainly as a result of increased use of
respiratory protective equipment and increased monitoring to
check compliance with the new limit. Thus, the total cost to
society of implementing the whole Directive is £9.2 million
(1999/2000 prices) over 10 years, in present value terms. The
RIA could not quantify any of the health benefits resulting
from the introduction of this Directive. However, it was
noted that there are negative health effects associated with
exposure to the substances covered by the Directive and that
reducing exposure may lead to health benefits.

87
 APPENDIX 5

REPLYING TO THIS CONSULTATIVE DOCUMENT

1. We would like you to tell us what you think about the proposals set out in this
consultative document. The proposals are summarised below in a questionnaire which you
may wish to copy or tear out and use. You may wish to attach a separate sheet if your
comments are extensive.

2. When replying, you may also wish to bear in mind the legal advise on implementation
of the IOELV Directive. This advice is outlined in paragraphs 4 and 5 of the consultation
document.

3. The Commission tries to make its consultation procedure as thorough and open as
possible. Responses to this consultative document will be lodged with HSE’s Information
Centres after the close of the consultation period where they can be inspected by members of
the public. Please note: All views will be placed in HSE Information Centres unless you
specifically state that this response, or a part of it, should be treated as confidential.

4. Please reply to:

Carole Sullivan
Health Directorate, Chemicals Policy Division
Health and Safety Executive
6th Floor, South Wing, Rose Court
2 Southwark Bridge
London SE1 9HS
e mail: carole.sullivan@hse.gsi.gov.uk

We should like all replies to arrive no later than 1 May 2001.

88
 Health and Safety Commission

EUROPEAN COMMISSION DIRECTIVE UNDER THE

CHEMICAL AGENTS DIRECTIVE 98/24/EC TO ESTABLISH A
FIRST CONSOLIDATED LIST OF INDICATIVE
OCCUPATIONAL EXPOSURE LIMIT VALUES AT EUROPEAN
COMMUNITY LEVEL.

Reply form
(Please type, or write in block capitals)

Name of organisation or company:

Name of individual:
Address:
...............................................................................
...............................................................................
...............................................................................
...............................................................................
....
Telephone number:
E-mail address:
If you are replying on behalf of an organisation, please say what it does

....................................................................................................................................................

How many people does it employ?.............................................................................

Question Comment
1. Do you agree with the 8 hour TWA MEL
proposal for chlorobenzene?

If you disagree, please explain why.

89
2. Do you agree with the STEL MEL
proposal for chlorobenzene?

If you disagree, please explain why.

3. Do you agree with the Sk notation

proposal for chlorobenzene?

If you disagree please explain why.

4. Do you agree that the IOELV should be

adopted as an 8 hour TWA MEL for
dihydrogen selenide?

If you disagree, please explain why.

5. Do you agree that the IOELV should be

adopted as a STEL MEL for dihydrogen
selenide?

If you disagree, please explain why.

6. Do you agree that the IOELV should be

adopted as an 8 hour TWA MEL for phenol?

If you disagree, please explain why.

90
7. Do you agree that it is not necessary to
set a STEL MEL for phenol?

If you disagree, please explain why.

8. Do you agree that the Sk notation should

be retained?

If you disagree please explain why.

9. Do you agree with the 8 hour TWA OES

proposal for xylenes?

If you disagree, please explain why.

10. Do you agree with the STEL OES

proposal for xylenes?

If you disagree, please explain why.

11. Do you agree that the Sk notation

should be retained for xylenes?

If you disagree please explain why.

91
12. Do you agree with the proposal to
develop a BMGV for xylenes?

If you disagree please explain why.

13. Do you agree that the IOELV Sk

notation should be adopted for
ethylbenzene?

If you disagree please explain why.

14. Do you agree that the IOELV should be

adopted as an 8 hour TWA OES for Ortho-
phosphoric acid?

If you disagree, please explain why.

15. Do you agree that the IOELV should be

adopted as a STEL OES for
1,2,4-Trichlorobenzene?

If you disagree, please explain why.

16. Do you agree with the STEL OES

proposal for 2-Methoxy-1-methylethyl
acetate?

If you disagree please explain why.

92
17. Do you agree with the Sk notation
proposal for 2-Methoxy-1-methylethyl
acetate?

If you disagree please explain why.

18. Do you agree with the STEL OES

proposal for Cumene?

If you disagree please explain why.

19. Do you agree with the proposal to adopt

the IOELVs for Acetone, Cyclohexanone,
Diethyl ether, 5-Methyl- hexan-2-one,
4-Methylpentan-2-one and Tetrahyrofuran;
and the health based recommendation of
SCOEL for Heptan-3-one? If you disagree
with any of these proposals please state
which ones and explain why.

20. Do you have any comments on the

CBAs/RIAs for chlorobenzene, dihydrogen
selenide, phenol, piperazine and the 1st
IOELV Directive?

93
21. Do you have any further information or
views that are relevant to this consultation?

22. In your view how well does this q Very Well

q Well
consultation document represent the
q Not Well
different policy issues involved in this q Poorly
matter? [Tick one box]

23. Is there anything you particularly liked

or disliked about this consultation?
(Please add extra sheets if you wish.)

24. Would you like to receive hard copies of

proposals for piperazine when they are
published on the internet?

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 CONSULTATIVE
DOCUMENT

The full text of this and other Consultative Documents can be viewed
and downloaded from the Health and Safety Executive web site on the internet:
www.hse.gov.uk/condocs/

Consultative Documents are available from:

HSE Books, PO Box 1999
Sudbury, Suffolk CO10 2WA
Tel: 01787 881165
Fax: 01787 313995

Printed and published by the Health and Safety Executive

© Crown copyright 2001
CD166 C35 1/01