Basic information OEL & PBOEL-HHC

for API & IPI

Level 1

Updated December 2010

- Information provided subject to the 'Conditions for Sharing Materials and Advice' -
Objective

 To learn about exposure limits, particularly for Active

Pharmaceutical Ingredient and Isolated Process
Intermediates (APIs and IPIs)

 To understand how exposure limits are derived

 To know where you get the information you need and

how you use it

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Hazardous substances

 Hazardous substances are substances that can have a

harmful effect on health

 Examples:
– Chemicals – organic solvents, acids, pharmaceutical
ingredients…
– Dust – metal dust, wood dust, flour…
– Fumes – welding, soldering…
– Fibres – asbestos

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Hazardous substances can enter the body

inhalation

dermal
ingestion

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Type of Health Effects

Acute effects –
immediate reaction

Chronic effects –
develop over years

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Potency of Hazardous Substances

Snake poison – < 100mg can kill

Alcohol-2000mg gives effect

ten times that amount can kill

Nicotine- 2mg gives effect

50mg can kill

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Describing the hazard

We need to know how much of a hazardous substance a worker

can breathe without harm

This is given by the

Occupational Exposure Limit

OEL

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Occupational Exposure Limits

The OEL is the concentration in the air to which

nearly all workers may be repeatedly exposed
day after day without adverse health effects to
themselves or their children.

Termed Threshold Limit Value TLV by ACGIH

(ACGIH is an American organisation for industrial hygiene)

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OELs - caution

 OELs do not provide universal protection.

 Adverse effects may occur despite adherence to the OEL

due to reasons such as:
– Individual sensitivity
– pregnancy
– pre-existing illness

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Variation of exposure with time

 Exposure patterns vary, some tasks give high exposure, others

none. Some shifts give more exposure than others
 Shift durations vary, typically between 8 and 12 hours
 To compare exposures for different situations, we need a fixed
reference period

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OEL reference periods – 8 hours

 8 hour reference period – (ACGIH descriptor TLV-TWA)

 This is the main reference period and is concerned with

chronic effects. When the worker exposure is measured, it is
calculated what concentration it would be if the exposure was
constant over 8 hours – called the 8 hour Time Weighted
Average, or daily exposure

 The 8 hour OEL is the 8 hour TWA exposure to which it is

believed that nearly all workers may be repeatedly exposed,
day after day, for a working lifetime, without adverse effect

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OEL reference periods – 15 minutes and ceiling

 15 minute reference period – called Short Term Exposure Limit (STEL)

 Ceiling (TLV-C) – the concentration that should not be exceeded during any part
of the working exposure

 These are concerned with acute effects. The worker exposure is measured over
the period when the exposure is greatest, and the 15 minute average or
maximum level is determined. These are compared with the STEL and Ceiling
limit respectively

 The 15 minute TWA exposure should not be exceeded at any time during a work
day, even if the 8 hour TWA is within the TLV-TWA. Exposures (re. 15 mins)
above the TLV-TWA but below the TLV-STEL should not occur more than 4 times
a day, with 60 minutes at least between successive exposures

 The ceiling limit should not be exceeded during any part of the working exposure.

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Who assigns Occupational Exposure Limits?

Who assigns OELs?

For common hazardous substances

1. Your national health and safety authority
2. ACGIH (called Threshold Limit Value, TLV)

For pharmaceutical ingredients

1. J&J corporate toxicologists

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ACGIH TLVs

Order from www.acgih.org

The OEL set by your health and

safety authority and ACGIH
might be different

USE THE LOWER OEL

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Examples of OELs set by ACGIH (values 2007)

Hazardous substance Threshold Limit Value

TLV
8 hour 15 minute
Isopropyl alcohol 200ppm 400ppm
Benzene 0.5ppm 2.5ppm
Ammonia 25ppm 35ppm
Acrolein - C 0.1ppm

Particles not otherwise 10 mg/m3 -

specified An instantaneous ceiling
value that should not be
Cobalt 0.02 mg/m3 - exceeded
Source: ACGIH 2007

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Concentration Units

As mass in unit volume

1 mg /m3 is 1 mg in a cubic meter

1m 1 μg /m3 is 1 μg in a cubic meter

1000 μg /m3 = 1 mg/m3

1m
As the proportion of molecules
1m
1 ppm is one part (molecule) in a million
1ppb is one part in a billion
1000 ppb = 1 ppm

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OELs for APIs and IPIs

 National and international bodies do not set OELs for

APIs and IPIs

 OELs for APIs and IPIs are set by the company that has
developed them or are manufacturing them

API : Active Pharmaceutical Ingredients

IPI: Isolated Process Intermediates

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Setting an OEL – what to consider

 Sources of information
– Animal studies
– Pharmaceutical trials
These indicate the lowest active dose, or the dose where
there is no observed adverse effect

 Things that influence the effect on the body

– Amount you breath in (10 m3 per day)
– Body weight
– How long the chemical stays in the body
– Amount absorbed by body
– Any hazardous substances formed in the body

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Setting an OEL for APIs & APIs – how it is calculated

OEL (mg/m3) = NOEL (mg/kg/day) x BW (kg)

V (m3/day) x S x UF x 

 NOEL = the no-observable-effect-level (mg/kg/day)

 BW = average human body weight (50 kg)
 V = volume of air breathed in an 8-hr work day (10 m3/day)
 S = time, in days, to achieve a plasma steady state
 UF = uncertainty factors
  (alpha) = % absorbed through inhalation

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Typical Notes given with OELs

 If carcinogenic, mutagenic or reproductive toxin

 Skin: Substances which have the capacity to penetrate
intact skin
 Sensitization: where skin or respiratory sensitization
could occur (that is, where intense response occurs to
low concentrations after a person has become
sensitised)
 BEI: if a biological exposure index has been
recommended for the substance

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Acceptable Surface Limits

 A surface limit is sometimes set. It is helpful :

– if there might be significant exposure through the skin

– if potent substances might be re-suspended and inhaled
– to indicate contamination of surfaces

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Acceptable Surface Limits

Acceptable Surface Limit

ASL

 The ASL is the acceptable mass on

a specified surface area
(typically 10 x 10 cm, the area of
palms of hand)
 Often set at 10 times the OEL for an
area of 100cm2
 Not as frequently used as OEL
 Not set by ACGIH for any substance

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What to do with the OEL …

 Compare the results from your exposure monitoring

surveys with the OEL to check if the exposure is OK

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Evaluate exposure by comparing measured TWA exposure
with OEL

140%
Exposure
exceeds OEL
130%

120% Exposure as % of OEL

110%

100%

90%
TWA as % of OEL

80%

70%

60%

50%

40%

30% Exposure well

20% below OEL
10%

0%

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What to do with the OEL …

 If you use Respiratory Protection Equipment, compare the calculated exposure inside
the mask with the OEL to check if the effective exposure is OK

 Use the protection factor of the mask to get the concentration inside the mask

Conc outside mask

Conc inside mask =
Protection factor

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What to do with the ASL…

 Compare the measured surface

concentration with the ASL to check
that surface contamination levels
are OK

 Measure surface contamination on

skin, if feasible, and compare result
with ASL

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J&J hazard classification for API & IPI

 When drugs are in an early stage of development, there

is not enough information available to set an OEL, but
controls must be implemented

 J&J uses a hazard classification system to group

pharmaceutical ingredients according to their hazard
called PbOEL-HHC (PbOEL- Health Hazard Categories)

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OEL ranges of the PbOEL-HHCs

Categories

 1A >1000 – 3000 g/m3

 1B >100 – <1000 g/m3
 2 >20 – <100 g/m3
 3A >5 - <20 g/m3
 3B >.5 g/m3– <5 g/m3
 4 < .5 g/m3

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PbOEL-HHC versus OEL

 A PbOEL-HHC is set at a very early stage in drug

development, before there is enough information to set
an OEL

 Information is compiled in the PbOEL-HHC summary

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Examples of OEL’s and PbOELs for API’s and IPI’s

Substance OEL mg/m3 PbOEL category

Ketoconazole 0.2 1B

Nicotine 0.070 2

Nebivolol 0.015 3A
hydrochloride
Risperidone 0.0025 3B

Fentanyl 0.0001 4

Remark:
These values can change - always consult the most recent global PbOEL-HHC
OEL list for actual information!

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OEL monographs

 When corporate toxicologists assign exposure

limits, they publish an OEL monograph. This
document contains useful information such as:

1. PbOEL-HHC / OEL / ASL / notations (e.g.

sensitizer)
2. Description of substance
3. Toxicology of substance
4. How the substance acts in the body
5. Relevant data from laboratory tests, field trials
or epidemiological studies
6. How the OEL was derived
7. References

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Summary

 The hazard associated with an API/IPI is quantified by a PbOEL-HHC, an OEL

and sometimes an ASL

 APIs/IPIs are assigned to one of the 6 PbOEL-HHCs, depending on how

hazardous they are. PbOEL-HHC 1A is the least hazardous, PbOEL-HHC 4 is the
most hazardous category

 An OEL is a limit for the exposure to hazardous substances by inhalation. The

reference periods are 8 hours and/or 15 minutes

 An ASL is a limit for the dermal exposure to hazardous substances. The reference
area is typically 100cm2. This is only assigned if the dermal route is a significant
exposure path

 PbOEL-HHCs/OELs /ASLs for APIs/IPIs are set by J&J

 The OEL monograph contains these limits and other useful information

 Use these limits as the input for the risk assessment to design controls and to
monitor their effectiveness
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