15687271

I U C L I D
D a t a s e t
Existing Chemical
CAS No.
EINECS Name
EINECS No.
Molecular Formula
Substance ID: 15687271

15687271
ibuprofen
2397846
C13H18O2
Dataset created by:
EUROPEAN COMMISSION European Chemicals Bureau
This dossier is a compilation based on data reported by the European

Chemicals Industry following Council Regulation (EEC) No. 793/93
on the Evaluation and Control of the Risks of Existing Substances.
All (nonconfidential) information from the single datasets, submitted
in the IUCLID/HEDSET format by individual companies, was integrated
to create this document.
The data have not undergone any evaluation by the European Commission.
Creation date:
18FEB2000
Number of Pages:
44
Chapters:
all
Edition:
Year 2000 CDROM edition
Flags:
nonconfidential
(C) 2000 EUROPEAN COMMISSION

European Chemicals Bureau
date: 18FEB2000
1. General Information
______________________________________________________________________________
1.0.1 OECD and Company Information
1.0.2 Location of Production Site
1.0.3 Identity of Recipients
1.1 General Substance Information

Substance type:
Physical status:
organic
solid
1.1.1 Spectra
1.2 Synonyms
2(4Isobutylphenyl)propionic acid
Source:
ALBEMARLE S.A. Brussels
2(4isobutylphenyl) propanoic acid
Source:
Boots Chemicals, The Boots Company PLC
Knoll Pharmaceuticals Nottingham
Nottingham
4isobutylhydratropic acid
Source:
Nottingham
alphamethyl4(2methyl propyl) benzeneacetic acid

Source:
Nottingham
ibuprofen
Source:

pisobutylhydratropic acid
Source:
ALBEMARLE S.A.
Brussels
1.3 Impurities
1.4 Additives
1/44
Nottingham
date: 18FEB2000
______________________________________________________________________________
1.5 Quantity
Quantity
10 000
50 000 tonnes
1.6.1 Labelling
1.6.2 Classification
1.7 Use Pattern

Type:
Category:
type
Non dispersive use
Type:
Category:
type
Wide dispersive use
Type:
Category:
industrial
Chemical industry: used in synthesis
Type:
Category:
industrial
Personal and domestic use
Type:
Category:
use
Pharmaceuticals
1.7.1 Technology Production/Use
1.8 Occupational Exposure Limit Values

Type of limit:
Limit value:
Short term expos.
Limit value:
Schedule:
Frequency:
Source:
other
5 mg/m3
15 mg/m3
15 minute(s)
3 times
ALBEMARLE S.A.
Brussels
2/44
date: 18FEB2000
______________________________________________________________________________
Type of limit:
Limit value:
Short term expos.
Limit value:
Schedule:
Frequency:
Remark:
Source:
Type of limit:
Limit value:
Short term expos.
Limit value:
Schedule:
Frequency:
Remark:
Source:
other
5 mg/m3
15 mg/m3
15 minute(s)
3 times
Personal protective equipment:
Respiratory protectionapproved particulate respirator
Hand protectionPVC or rubber gloves
Eye protectionchemical safety goggles
Skin protectionoverall or disposable coverall
Type of occupational exposure limitin house workplace
exposure level.
Boots Chemicals, The Boots Company PLC Nottingham
other
5 mg/m3
15 mg/m3
15 minute(s)
3 times
Personal protective equipment:
Respiratory protectionapproved particulate respirator
Hand protectionPVC or rubber gloves
Eye protectionchemical safety goggles
Skin protectionoverall or disposable coverall
Type of occupational exposure limitin house workplace
exposure level.
1.9 Source of Exposure

Remark:
Production Process
Isobutylbenzene is acetylated with acetyl chloride in the
presence of aluminium chloride and in carbon tetrachloride
solvent.After quenching into dilute hydrochloric acid, the
organic layer is washed with water, stripped of its
solvent with steam, and 2(4isobutylphenyl) ethanone
isolated by vacuum distillation. Sodium isopropoxide
solution, made by dissolving sodium in refluxing isopropyl
alcohol, is mixed with the 2(4isobutylphenyl) ethanone
and isopropyl chloroacetate. After distilling off the
isopropyl alcohol the residue is hydrolysed by heating
with diluted caustic soda solution. Aqueous isopropyl
alcohol is then removed by steam distillation. The organic
layer is separated, and may be combined with a toluene
wash of the aqueous phase.Toluene is removed and
2(4isobutylphenyl) propanal isolated by vacuum
distillation. 2(4isobutylphenyl) propanal is converted
to its oxime by reaction with an aqueous solution of
hydroxylamine sulphate and caustic soda solution, in the
presence of acetic acid.After separating off the aqueous
layer, the oxime is rearranged and hydrolysed with a
solution of caustic soda in water or sodium chloride
solution.Some of the water is distilled off and the
3/44
date: 18FEB2000
______________________________________________________________________________
Source:
remaining mixture refluxed under pressure to give

ibuprofen as a solution of its sodium salt.After
acidification with hydrochloric acid, the ibuprofen is
purified by extraction into hot hexane, back extraction
into caustic soda solution, and another extraction into
hot hexane after reacidification with hydrochloric
acid.After filtration of the hot extract, the ibuprofen
crystallises on cooling and is collected, washed at least
twice with hexane, and dried.
Sources of potential human exposure
This material is a pharmaceutical and has been tested and
approved by international regulatory authorities for oral
and dermal applications.
There is one site of maufacture and it is classed as
closed in that the process takes place in enclosed vessels
and associated pipework.
1.10.1 Recommendations/Precautionary Measures
1.10.2 Emergency Measures
1.11 Packaging
1.12 Possib. of Rendering Subst. Harmless
1.13 Statements Concerning Waste
1.14.1 Water Pollution
1.14.2 Major Accident Hazards
1.14.3 Air Pollution
4/44
date: 18FEB2000
______________________________________________________________________________
1.15 Additional Remarks

Remark:
Source:
Disposal in accordance with current legislation using

high temperature incineration. Contaminated empty
packaging materials should be treated in a similar manner.
Transport:
UNSI number not applicable
UN hazard class not applicable
UN packing group not applicable
1.16 Last Literature Search
1.17 Reviews
1.18 Listings e.g. Chemical Inventories
5/44
date: 18FEB2000
2. Physicochemical Data
______________________________________________________________________________
2.1 Melting Point

Value:
GLP:
Source:
75 77.5 degree C
no data
Nottingham
(1)
Value:
Decomposition:
Sublimation:
Method:
GLP:
Source:
75 78 degree C
no
no
other: in house study using Mettler FP80 Central Processor and
FP81 MBC cell
no
2.2 Boiling Point
2.3 Density
Type:
Value:
Method:
GLP:
Remark:
Source:
Test condition:
bulk density
.2 .6 g/cm3
other: see TC
no data
Method: In house
Testcylinders raised and fall back under gravity
Test believed to have been carried out at ambient
temperature
2.3.1 Granulometry
2.4 Vapour Pressure

Value:
Method:
GLP:
Source:
Test condition:
= .000012 hPa at 25 degree C

other (measured): see TC
no data
Method: Knudson effusion techniquesee journal reference
(2)
6/44
date: 18FEB2000
______________________________________________________________________________
2.5 Partition Coefficient

log Pow:
Method:
Year:
GLP:
Remark:
Source:
Test condition:
log Pow:
Method:
Year:
GLP:
Source:
.23 3.3 at 25 degree C

other (measured): see TC
no
Results
S.D.= standard deviation
At pH 5, ibuprofen at 1mM, log Pow = 3.3, S.D.of 28.9
At pH 7, ibuprofen at 0.1mM, log Pow = 1.47, S.D.of 2.43
At pH 7, ibuprofen at 10mm, log Pow = 0.24, S.D.of 0.05
MethodIn house
Shake flask method followed by 1 hour equilibration to
give initial phase separation.Phase separation completed
by centrifugation and then assay for drug content was by
HPLC. Assay of samples was carried out after approximately
20 hours shaking, and then after further 4 hour intervals
until the results suggested that equilibrium had been
achieved.
= 3.94 at 37 degree C
no data
Nottingham
(3)
log Pow:
Method:
Year:
GLP:
Remark:
Source:
= 3.94
no data
Value given in the average of 3 experiments
(4)
2.6.1 Water Solubility

Value:
GLP:
Source:
= .043 other: mg/mL at 37 degree C

no data
Nottingham
(5)
7/44
date: 18FEB2000
______________________________________________________________________________
Qualitative:
Source:
not soluble
Nottingham
(6)
pKa:
pH:
Method:
GLP:
Source:
Test condition:
4.54 at 25 degree C
= 4.4 at 40 other: ug/ml
other: in house test
no data
pKa value temperature not known
Nottingham
2.6.2 Surface Tension
2.7 Flash Point
2.8 Auto Flammability
2.9 Flammability
Result:
Remark:
Source:
non flammable
Stable at normal temperature. Will burn if exposed to heat
or flame.
2.10 Explosive Properties

Result:
Source:
other: Moderate dust explosion hazard

2.11 Oxidizing Properties
8/44
Nottingham
date: 18FEB2000
3. Environmental Fate and Pathways
______________________________________________________________________________
3.1.1 Photodegradation
3.1.2 Stability in Water
3.1.3 Stability in Soil
3.2 Monitoring Data (Environment)
3.3.1 Transport between Environmental Compartments
3.3.2 Distribution
3.4 Mode of Degradation in Actual Use
3.5 Biodegradation
Type:
Inoculum:
Concentration:
Degradation:
Result:
Method:
Year:
Test substance:
Source:
Test condition:
aerobic
activated sludge
20 mg/l related to Test substance
= 10 60 % after 28 day
other
OECD Guideline 301 B "Ready Biodegradability: Modified Sturm
Test (CO2 evolution)"
GLP: no data
as prescribed by 1.1 1.4
The test carried out was the Sturm Test (OECD 301B). The
test substance at approximately 20 mg/l in an inorganic
medium was inoculated with 100000 1000000 per ml
microorganisms in the form of activated sluge from a
water reclamation works and aerated at 2025 degrees C.
The amount of carbon dioxide produced was compared to the
theoretical yield calculated from the carbon content of the
test substance. A standard, Dglucose, was also included.
The test substance is considered to have passed the Sturm
Test if >60% theoretical carbon dioxide is evolved in 28
days providing that this occurs within 10 days of the
sample liberating 10% carbon dioxide.
The standard, Dglucose, met the criteria of the test. The
test substcne, ibuprofen, showed >10% but <60% carbon
dioxide evolution over the 28 day test period. This
indicates that the test substance did not meet the criteria
9/44
date: 18FEB2000
3. Environmental Fate and Pathways
______________________________________________________________________________
to be termed biodegradable by this method.

Type:
Inoculum:
Kinetic:
Method:
Year:
Test substance:
Remark:
Source:
Test condition:
Type:
Inoculum:
Result:
Method:
Year:
Test substance:
Source:
28 day
= 31.1 %
OECD Guideline 301 D "Ready Biodegradability: Closed Bottle
Test"
GLP: yes
no data
The closed bottle test gave an approximate 30%
biodegredation
MethodClosed bottle test
inherently biodegradable
other: no data
GLP: no data
no data
(7)
3.6 BOD5, COD or BOD5/COD Ratio
3.7 Bioaccumulation
10/44
date: 18FEB2000
4. Ecotoxicity
______________________________________________________________________________
AQUATIC ORGANISMS
4.1 Acute/Prolonged Toxicity to Fish
Type:
Species:
Exposure period:
Unit:
NOEC:
LC50:
Method:
Year:
Test substance:
Remark:
Source:
Type:
Species:
Exposure period:
Unit:
NOEC:
LC50:
Method:
Year:
Test substance:
Remark:
Source:
static
Cyprinodon variegatus (Fish, estuary, marine)
96 hour(s)
mg/l
Analytical monitoring: no data
= 300
> 300
other: 96 hour static toxicity test
GLP: no data
no data
Due to apparent presence of undissolved test material in
the containers at 100 and 300 mg/L the actual LC50 may be
less than 300 mg/L and closer to 100 mg/L
static
Lepomis macrochirus (Fish, fresh water)
96 hour(s)
mg/l
= 10
= 173
GLP: no data
no data
LC50 calculated with 95% confidence limits of 117 and 257
mg/l
4.2 Acute Toxicity to Aquatic Invertebrates

Species:
Exposure period:
Unit:
NOEC:
EC50:
Method:
Year:
Test substance:
Source:
Daphnia magna (Crustacea)

48 hour(s)
mg/l
= 3.37
= 9.06
GLP: yes
no data
11/44
date: 18FEB2000
4. Ecotoxicity
______________________________________________________________________________
Species:
Exposure period:
Unit:
NOEC:
LC50 :
Method:
Year:
Test substance:
Remark:
Source:
Daphnia magna (Crustacea)

48 hour(s)
mg/l
= 3
= 11.5
GLP: no data
no data
LC50 calculated with 95% confidence limits of 3 and 30 mg/L
Species:
Exposure period:
Unit:
NOEC:
LC50 :
Method:
Year:
Test substance:
Source:
Mysidopsis bahia (Crustacea)

96 hour(s)
mg/l
= 30
> 100
GLP: no data
no data
4.3 Toxicity to Aquatic Plants e.g. Algae

Species:
Endpoint:
Exposure period:
Unit:
IC50 :
Method:
Year:
Test substance:
Remark:
Source:
Test condition:
Selenastrum capricornutum (Algae)

other: see RM
96 hour(s)
mg/l
> 30
other: see TC
GLP: no data
no data
Endpoint was determined from cell density by direct cell
counts using a haemocytometer counting chamber and a
compound microscope.
96 hour static toxicity test
12/44
date: 18FEB2000
4. Ecotoxicity
______________________________________________________________________________
Species:
Endpoint:
Exposure period:
Unit:
IC50 :
Method:
Year:
Test substance:
Remark:
Source:
Test condition:
Species:
Endpoint:
Exposure period:
Unit:
NOEC:
EC50:
Method:
Year:
Test substance:
Source:
Test condition:
Skeletonema costatum
other: see RM
96 hour(s)
mg/l
= 7.1
other: see TC
(Algae)
GLP: no data
no data
Endpoint was determined from cell density by direct
counts using a haemocytometer counting chamber and a
compound microscope
IC50 calculated with 95% confidence limits of 3.0 and 10.0
mg/l
96 hour static toxicity test
Skeletonema costatum
5 day
mg/l
= 20.5
= 39.9
other: see TC
(Algae)
GLP: yes
no data
Static test, 5 days exposure and 9 days recovery
4.4 Toxicity to Microorganisms e.g. Bacteria

Type:
Species:
Exposure period:
Unit:
EC50:
Method:
Year:
Test substance:
Source:
Test condition:
aquatic
Photobacterium phosphoreum (Bacteria)
5 minute(s)
mg/l
Analytical monitoring: no
= 12.3
other
GLP: no
MICROTOX TOXICITY TEST
The test sample was dissolved in a suitable solvent at
suitable test concentrations and inoculated with the test
culture, Photobacterium phosphorium. A control consisting
of the test system without the test substance was also
included. After the required incubation times the amount
of bioluminescence of the control and test substance were
measured, and the EC50 values calculated by the system
software.
13/44
date: 18FEB2000
4. Ecotoxicity
______________________________________________________________________________
Type:
Species:
Exposure period:
Unit:
EC50:
Method:
Year:
Test substance:
Source:
Test condition:
aquatic
15 minute(s)
mg/l
= 13.12
other
GLP: no
Test as for 5 minute incubation time
Type:
Species:
Exposure period:
Unit:
EC50:
Method:
Year:
Test substance:
Source:
Test condition:
aquatic
30 minute(s)
mg/l
= 13.82
other
GLP: no
Test as for 5 minutes incubation time
4.5 Chronic Toxicity to Aquatic Organisms

4.5.1 Chronic Toxicity to Fish
4.5.2 Chronic Toxicity to Aquatic Invertebrates
14/44
date: 18FEB2000
4. Ecotoxicity
______________________________________________________________________________
TERRESTRIAL ORGANISMS
4.6.1 Toxicity to Soil Dwelling Organisms
4.6.2 Toxicity to Terrestrial Plants
4.6.3 Toxicity to other NonMamm. Terrestrial Species
4.7 Biological Effects Monitoring
4.8 Biotransformation and Kinetics
15/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
5.1 Acute Toxicity

5.1.1 Acute Oral Toxicity
Type:
Species:
Sex:
Number of
Animals:
Vehicle:
Value:
Method:
Year:
Test substance:
Remark:
Source:
Test substance:
Type:
Species:
Sex:
Number of
Animals:
Vehicle:
Value:
Method:
Year:
Test substance:
Source:
LD50
rat
ca. 1600 mg/kg bw

other: in house method
GLP: no data
other TS: see TS
Results
Toxic doses caused depression of the central nervous system.
Death resulted from perforation of the lower intestine.
Maximium noeffect level = 400 mg/kg
Lowest dose causing overt signs = 800 mg/kg
Highest nonlethal dose = 800 mg/kg
Lowest dose causing death = 1600 mg/kg
Highest dose with survivors = 1600 mg/kg
Study conducted prior to GLP requirements
Ibuprofen suspended in 10% acacia
(8)
LD50
rat
= 969 mg/kg bw
other: no detail given
GLP: no data
other TS: ibuprofen ester with guaiacol
(9)
Type:
Species:
Sex:
Number of
Animals:
Vehicle:
Value:
Method:
Year:
Test substance:
Remark:
other
rat
= 400 mg/kg bw
other: see RM
GLP: yes
no data
Method
5 male and 5 female rats were given single oral doses of
ibuprofen at 400, 800, 1200 and 1600 mg/kg. 15 male and 15
female controls received the vehicle, 0.4% aqueous
Cellosize solution. The rats were observed for a 14 day
16/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
period.
Source:
Type:
Species:
Sex:
Number of
Animals:
Vehicle:
Value:
Method:
Year:
Test substance:
Remark:
Source:
Test substance:
Type:
Species:
Sex:
Number of
Animals:
Vehicle:
Value:
Method:
Year:
Test substance:
Source:
Results
The animals given 400mg/kg ibuprofen showed no overt signs
of toxicity.Animals given 800mg/kg or more lost condition,
had a wasted appearance and distened abdomen. There were
no deaths after 400mg/kg treatment. Six rats given
800mg/kg ibuprofen and all the animals given 1200 and
1600mg/kg became moribund and were killed between one and
five days. Gastrointestinal irritation and adhesions, and
pale livers, kidneys and spleens were seen in the treated
groups, except for the 400mg/kg group where no treatment
related findings were made.
Type of test NOEL
LD50
mouse
ca. 800 mg/kg bw

GLP: no data
other TS: see TS
Results
Toxic doses caused depression of the central nervous system.
Death resulted from gastric ulceration.
Maximum noeffect level = 200 mg/kg
Ibuprofen suspended in 10% acacia
(10)
LD50
mouse
= 897 mg/kg bw
other: no detail given
GLP: no data
other TS: ibuprofen ester with guaiacol
(9)
17/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
Type:
Species:
Sex:
Number of
Animals:
Vehicle:
Value:
Method:
Year:
Test substance:
Remark:
Source:
Type:
Species:
Sex:
Number of
Animals:
Vehicle:
Value:
Method:
Year:
Test substance:
Remark:
other
dog
other: see RM
GLP: no data
other TS: ibuprofen in gelatin capsules
Method
Single oral doses of 20 to 320 mg/kg were given after
overnight fasting.Examination of blood, urine and faeces
was carried out before and after dosing. Some of the dogs
were killed after 1 day, others after 7 days.
Results
Doses of 20 and 50 mg/kg were non toxic. Doses of 125, 200
and 320 mg/kg all caused gastric damage, feacal blood loss
and albuminuria. The maximun no effect level was between
50 and 125 mg/kg.
Type of test in house test, effect of single oral dose
other: see RM
primate
other: see RM
GLP: no data
no data
Method
One male and one female baboon were each given a single
oral dose of 100 mg/kg of ibuprofen. Signs of toxicity,
food consumption and water intake were recorded daily.
Comprehensive haematology, blood biochemistry and
urinalysis were carried out at least once before dosing
and 24 hours and 6 days after dosing. Faecal examination
for occult blood was carried out daily before and after
dosing. Both baboons were killed one week after dosing,
organ weights determined and organs examined
histologically.
Results
A single dose of 100 mg/kg of ibuprofen had no adverse
effect in the baboon
Both animals had minor fluctuations in body weight after
dosing and were slightly below initial weight when killed.
Food and water intake was unaffected.
Haematological and blood biochenical values were not
altered significantly.
Urine analysis normal.
Trace of blood detected in faeces of male 6 days after
18/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
Source:
dosing.
All organ weights were within normal limits and on gross
and microscopic examination there were no findings
attributable to dosing.
Type of Test investigation of effect of single oral dose
of 100 mg/kg on baboons.
5.1.2 Acute Inhalation Toxicity
5.1.3 Acute Dermal Toxicity
5.1.4 Acute Toxicity, other Routes

Type:
Species:
Sex:
Number of
Animals:
Vehicle:
Route of admin.:
Value:
Method:
Year:
Test substance:
Remark:
Source:
LD50
mouse
i.p.
ca. 320 mg/kg bw
in house method
GLP: no data
other TS: ibuprofen in 10% acacia
Results
Toxic doses caused depression of the central nervous
system.
Death resulted from gastric ulceration.
(11)
19/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
Type:
Species:
Sex:
Number of
Animals:
Vehicle:
Route of admin.:
Value:
Method:
Year:
Test substance:
Remark:
Source:
LD50
rat
s.c.
ca. 1300 mg/kg bw
in house method
GLP: no data
Results
Toxic doses caused depression of the central nervous
system.
Death resulted from perforation of the lower intestine.
Lowset dose causing overt signs = 1600 mg/kg
(11)
5.2 Corrosiveness and Irritation

5.2.1 Skin Irritation
Species:
Concentration:
Exposure:
Exposure Time:
Number of
Animals:
PDII:
Result:
EC classificat.:
Method:
Year:
Test substance:
Remark:
Source:
GLP:
Recorded on the company Safety Data Sheet as "May be
irritating to skin". This is based on worker anecdotal
evidence which suggests that any potential for skin
irritancy may be slight.
20/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
5.2.2 Eye Irritation

Species:
Concentration:
Dose:
Exposure Time:
Comment:
Number of
Animals:
Result:
EC classificat.:
Method:
Year:
Test substance:
Remark:
Source:
GLP:
Recorded on the company Safety Data Sheet as "Irritating
to eyes". This is based on worker anecdotal evidence.
5.3 Sensitization
Type:
Species:
Number of
Animals:
Vehicle:
Result:
Classification:
Method:
Year:
Test substance:
Source:
Guinea pig maximization test

guinea pig
not sensitizing
OECD Guideline 406 "Skin Sensitization"
1981
GLP: yes
other TS: 10% ibuprofen gel
21/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
5.4 Repeated Dose Toxicity

Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
Method:
Year:
Test substance:
Remark:
Result:
Source:
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
Method:
Year:
Test substance:
Remark:
Result:
rat
other: AshWistar
oral feed
2 years
Sex: male/female
7days per week
0, 20, 60, and 120 mg/kg/day, 80 rats per dose level (40 male
and 40 female)
yes, concurrent no treatment
other: see RM
GLP: no data
no data
Method In house study conducted 1975
Detailed macroscopic and microscopic examination was
carried out on animals which died or were killed.
See also section 5.7. as the studies in that section are
combined carcinogenicity and chronic toxicity studies.
The only pathological findings considered to be related to
treatment were RENAL PAPILLARY changes in the groups given
60 or 120 g/kg/day and GASTROINTESTINAL DAMAGE that was
most prevalant in animals receiving the highest dose.
No evidence of CARCINOGENICITY was seen.
INCREASED URINE FLOW rate at the highest dose. PULMONARY
and LIVER LESIONS were prevalant at 120 mg/kg/day which
were probably stress related.
rat
Wistar
other: oral intubation
13 weeks
Sex: male/female
7 days per week

half animals killed at 13 weeks, other half kept undosed for a
further three weeks.
20, 60, 180 and 540 mg/kg/day (20 animals per treatment
group,10 male and 10 female)
yes, concurrent vehicle
other: in house test by oral intubation
GLP: no data
other TS: ibuprofen suspended in 0.4% cellosize solution
Control group consisted of 20 males and 20 females
Study conducted proir to GLP requirements
All rats dosed with 540 mg/kg/day either DIED or were
KILLED IN EXTREMIS after 4 days. Most of these animals had
ULCERATION of the ILIUM or CAECUM with PERITONITIS and
SLIGHT DILATION of the RENAL TUBULES.
Females on all three lowest doses had ENLARGEMENT of the
KIDNEYS which was dose related.ENLARGEMENT of the LIVER
22/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
Source:
and OVARIES occurred at 180 mg/kg/day and of the SPLEEN

and OVARIES at 60 mg/kg/day.
Males at 180mg/kg/day had ENLARGED KIDNEYS, SPLEEN and
TESTES. Non of the enlarged organs was histologically
abnormal.
3 weeks after withdrawal of treatment the organ to body
weight ratios had almost completely returned to normal.
At 180 mg/kg/day 2/10 males killed at 10 and 11 weeks,
and 2/10 females killed at 13 weeks had INTESTINAL DAMAGE
(11)
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
NOAEL:
Method:
Year:
Test substance:
Remark:
Result:
Source:
rat
Wistar
6 months
Sex: male/female
daily
7.5, 20, 60 and 180 mg/kg/day (20 animals per treatment, 10

male and 10 female)
7.5 20 mg/kg bw
other: in house test by oral intubation
GLP: no data
other TS: ibuprofen suspended in 0.4% cellosize
180mg/kg/day dose:
Males significant LESS WEIGHT GAIN than controls
1/10 males treatment related DEATH (INTESTINAL LESIONS)
All males and females in final week of dosing were
ANAEMIC (LOW ERYTHROCYTE COUNT and HAEMOGLOBIN LEVELS)
In nearly all males ORGAN TO BODY WEIGHT RATIOS were
greater than in the controls.ENLARGED LIVER, KIDNEY
and SPLEEN.
Same organs enlarged in females although body weight
similar to controls
Males, COMBINED SEMINAL VESICLE and PROSTATE WEIGHT
SUBNORMAL
Females, UTERINE WEIGHT INCREASED
1/10 males and 3/10 females, significant HISTOLOGICAL
CHANGESINTESTINAL ULCERS
Daily doses of 60 and 20 mg/kg were not ulcerogenic but

caused small changes in organ weights, some of which were
reversible.The lowest dose of 7.5 mg/kg/day was without
effect.
(12)
23/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
Method:
Year:
Test substance:
Remark:
Result:
Source:
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
NOAEL:
Method:
Year:
Test substance:
Remark:
Result:
rat
Wistar
28 days
Sex: male
daily
Non reported
25, 50 and 100 mg/kg/day (5 male rats per dose level)
yes
other: see RM
GLP: no data
Method this was a preliminary test only.
Groups of 5 male rats were given 0, 25, 50 and 100
mg/kg/day ibuprofen in 10% acacia for 28 days. The rats
were killed and examined for gross damage. Histopathology
tests were not carried out.
No DEATHS were observed in any of the groups and the
WEIGHT GAINS of the dosed groups were similar to those of
the controls.
At autopsy NO GROSS ABNORMALITIES were observed in any of
the animals.
mouse
other
oral feed
13 weeks
Sex: male/female
daily
approximately 300, 75 and 19 mg/kg/day (20 animals per dose,

10 male and 10 female)
> 75 mg/kg bw
GLP: no data
no data
Strain of mouse Schofield
300mg/kg/day LIVER ENLARGEMENT, greater in males than
females.HISTOLOGICALLY LIVERS of dosed animals no
different to controls, and PLASMA GPT activities within
NORMAL range.
300mg/kg/day caused GASTROINTESTINAL DAMAGE in a small
proportion of mice, but no effect on KIDNEY WEIGHT or
HISTOLOGY.
Source:
75 and 19 mg/kg/day NO SIGNIFICANT TOXIC EFFECTS

24/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
NOAEL:
Method:
Year:
Test substance:
Remark:
Result:
Source:
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
NOAEL:
Method:
Year:
Test substance:
Remark:
Result:
Source:
cat
no data
other: see RM
30days
Sex: no data
daily
4, 8 and 50 mg/kg/day (2, 4 and 2 cats respectively)

no
< 4 mg/kg bw
GLP: no data
Route of Administration gelatin capsules and fed shortly
afterwards.
All three dose levels caused GASTRIC UPSET and EROSION or
ULCERATION of the STOMACH.Highest dose more toxic than
other two dose levels.
1/2 animals on 50 mg/kg/day moribund after receiving six
doses and were killed.
Apart from STOMACH no other organ showed histological
abnormalities.
ULCEROGENIC at 4 mg/kg/day
dog
Beagle
other: see RM
30 days
Sex: male/female
Daily
16, 8 and 4 mg/kg/day (4 animals per group)

4 8 mg/kg bw
GLP: no data
Route of Administration
Orally in gelatin capsules at 10.00 and 16.00 hours each
day, shortly before food.
16 mg/kg/day NO GROSS or CLINICAL SIGNS of TOXICITY
16 and 8 mg/kg/day postmortem examination revealed GASTRIC
ULCERS or EROSIONS and INTESTINAL INFLAMMATION.
4 mg/kg/day LESIONS NOT OBSERVED
(12)
25/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
NOAEL:
Method:
Year:
Test substance:
Remark:
Result:
Source:
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
Method:
Year:
Test substance:
Remark:
Result:
Source:
dog
Beagle
other: see RM
26 weeks
Sex: male/female
Daily
16, 4 and 2 mg/kg/day (4 animals per dose level, 2 male and 2

female)
4 16 mg/kg bw
GLP: no data
Route of Administration
Daily oral dosing with gelatin capsules
GASROINTESTINAL TRACT ULCERATIVE LESIONS in all animals
given 16 mg/kg/day
OCCULT BLOOD irregularly detected in faecal samples in all
four dogs at the highest dose level.
Dogs on 4 and 2 mg/kg/day NO ADVERSE REACTIONS or
GASTROINTESTINAL DAMAGE.
In all animals HAEMATOLOGICAL and BIOCHEMICAL VALUES DID
NOT ALTER SIGNIFICANTLY.
dog
Beagle
other: oral in gelatin capsules
15 weeks
Sex: male
daily
none
4 mg/kg/day for 2 weeks, then 4 mg/kg twice daily for a
further 13 weeks.
no data specified
other: 3 dogs treated as above , the drug being administered
in gelatin capsules. Faeces regularly tested for occult blood,
blood and urine analyses carried out and histological
examination of various tissues after death
GLP: no data
With the dose of 4 mg/kg/day for 2 weeks there was NO SIGN
of GASTRIC DAMAGE.After increasing the dose to 4 mg/kg
twice daily OCCASIONAL FAECAL BLOOD LOSS was observed and
one dog developed PELVIC PERITONITIS.
26/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
Method:
Year:
Test substance:
Remark:
Result:
Source:
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
NOAEL:
LOAEL:
Method:
Year:
Test substance:
Remark:
primate
Sex: male/female
other: baboon
other: ibuprofen in gelatin capsules given orally
30 days
Twice daily
40 and 100 mg/kg daily

other: received lactose only
other: see RM
GLP: no data
Method
Groups of 3 male and 3 female baboons were given twice
daily doses of 20 and 50 mg/kg ibuprofen in gelatin
capsules. Food and water intake and signs of toxicity
were recorded daily. Bodyweight was recorded weekly. All
animals observed ophthalmoscopically predosing and on day
29 of dosing. Various haematological, blood biochemistry
and urine analyses were carrried out along with faecal
observation for occult blood. All animals were killed on
day 30, organ weights determined and the organs observed
histologically.
Results
NO OVERT SIGNS of TOXICITY seen in baboons of either sex
given 40 or 100 mg/kg daily, but post mortem examination
revealed MINIMAL SUPERFICIAL EROSION of the GASTRIC ANTRAL
MUCOSA in some males.
primate
Sex: male/female
other: baboon (Papio hamadryas)
other: orally in gelatine capsules
52 weeks
twice daily at approximately 10.00 and 16.00 hours
none
16, 40 and 100 mg/kg/day. 10 animals per dose level, 5 male
and 5 female. Control group also contained 5 male and 5 female
animals.
= 16 mg/kg bw
= 40 mg/kg bw
other: see RM
GLP: yes
Method
During the course of the study the animals were observed
for overt signs of toxicity, bodyweight and food and water
consumption. The eyes of all the animals were observed
with an ophthalmoscope before dosing and at 6, 13, 26, 39
and 50 weeks.
A wide variety of investigations were carried out at
27/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
Result:
various times including: haematology, biochemistry,

urinalysis, occult blood in faeces and bone marrow
examination.
On completion of the 52 weeks dosing all the animals were
killed and a full macroscopic examination was carried out,
organ weights determined and microscopic examination of a
wide range of tissues carried out.
Results
OVERT SIGN OF TOXICITY 1/10 animals given 100 mg/kg/day
showed subdued behaviour during week 17. This may have
been related to treatment.
Small LOSSES IN BODY WEIGHT observed in the first week of
dosing in a number of males receiving 100 mg/kg/day.
NO DOSE RELATED EFFECTS observed in food and water
consumption.
NO ABNORMALITIES related to dosing observed using the
opthalmoscope.
No significant dose related abnormal results observed from
HAEMATOLOGY, BIOCHEMISTRY or URINALYSIS.
No evidence of PERSISTANT GASTROINTESTINAL BLEEDING in
any of the animals.
No BONE MARROW ABNORMALITIES related to dosing were
observed.
Terminal studies:
Source:
Areas of CORTICAL PITTING in the KIDNEYS observed in 2/10

animals receiving 40 mg/kg/day and in 9/10 animals
receiving 100 mg/kg/day.
ORGAN WEIGHTS normal with the exception of KIDNEY WEIGHTS
in animals receiving 100 mg/kg/day where they were
statistically higher.
In animals receiving 100 mg/kg/day there was an increased
incidence of RENAL CORTICAL SCARRING and in 3/10 animals
receiving this dose MINOR FOCAL PAPILLARY CHANGES were
observed.
28/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
Method:
Year:
Test substance:
Remark:
Result:
Source:
primate
other: baboon
oral unspecified
37 days
Sex: male/female
Twice daily
None recorded
16, 40 and 100 mg/kg/day (2 baboons per dose level, one male
and one female)
other: given lactose only
other
GLP: no data
Method
Groups of one male and one female baboons were given twice
daily (at 10.00 and 16.00 hours) doses of ibuprofen in
gelatin capsules. Total doses per day were 16, 40 and 100
mg/kg.The control group, one male and one female received
lactose only.
No OVERT REACTIONS to treatment were observed.
HAEMATOLOGY, BLOOD BIOCHEMISTRY, URINE ANALYSIS and FAECAL
BLOOD LOSS were not adversely affected by treatment.
At 100 mg/kg/day SUPERFICIAL EROSIONS in the GASTRIC
ANTRUM and the UPPER DUODENUM were observed.
5.5 Genetic Toxicity in Vitro

Type:
System of
testing:
Concentration:
Metabolic
activation:
Result:
Method:
Year:
Test substance:
Remark:
Source:
Ames test
Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and
TA1538
1, 10, 100, 500, 750 and 1000 ug per plate
with and without
negative
other: see RM
GLP: no data
no data
Method similar to OECD 471, although there appears to be
no replication of the test.
(13)
29/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
5.6 Genetic Toxicity in Vivo

Type:
Species:
Strain:
Route of admin.:
Exposure period:
Doses:
Result:
Method:
Year:
Test substance:
Remark:
Result:
Source:
Cytogenetic assay
human
Sex: no data
no data
unspecified
Not specified
Daily dose of 0.8 to 1.2 g in adults, and 0.2 to 0.6 g in
children, overall course doses of 5 to 32.4 and 5.6 to 16.8 g
respectively
other: see RM
GLP: no data
no data
Method
11 adults and 10 children receiving antirheumatic therapy
were given daily doses of Brufen. Chromosome sets in the
lymphoid cells of peripheral blood were analysed
using the methodology of Hungerford, D.A. Stain
Technology 40, 333 (1965)
Results
The use of Brufen in both adults and children resulted in
no significant increases in the numbers of chromosomal
aberrations.
(14)
Type:
Species:
Strain:
Route of admin.:
Exposure period:
Doses:
Result:
Method:
Year:
Test substance:
Remark:
Result:
Source:
Sister chromatid exchange assay

human
no data
unspecified
2 weeks
1200 mg/day BrufenR
Sex: male/female
other: see RM
GLP: no data
other TS: BrufenR
Method
4 male and 3 female, non smoking patients aged 34 to 61,
all with degenerative rheumatic diseases received 1200
mg/day BrufenR. There was a control group of 34 females,
aged 22 to 30, who were healthy, non smoking and
untreated.All investigations were carried out in two
separate tests. Sister chromatid exchange rates were
carried out with reference to the methods of Perry, P.
and Wolfe, S. (1974), New Giemsa Method for Differential
Staining of Sister Chromatids, Nature (London) 251,
156158.
No significant alteration in the Sister Chromatid Exchange
Rates was observed in lymphocytes under in vivo conditions
at this dosage over a 2 week period.
(15)
30/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
5.7 Carcinogenicity
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Result:
Control Group:
Method:
Year:
Test substance:
Remark:
Result:
Source:
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Result:
Control Group:
Method:
Year:
Test substance:
Remark:
rat
other: AshWistar
oral feed
2 years
Sex: male/female
daily
20, 60 and 120 mg/kg (80 animals per dose level, 40 male and
40 female. Control group same number of animals and sex
distribution)
GLP: no data
no data
This was a combined carcinogenicity and chronic toxicity
study and the data are therefore also relevant to section
5.4.
The only specific pathological effect observed in treated
animals was an increased incidence of RENAL PAPILLARY
LESIONS, i.e.NECROBIOSIS in rats of both sexes given 60
and 120 mg/kg daily and PAPILLARY NECROSIS in one rat
given 60 mg/kg daily and in five rats given 120 mg/kg
daily.There was a variable degree of GASTROINTESTINAL
DAMAGE that was more in evidence in the high dose group.
Distribution, type and time of appearance of tumours in
treated and control animals were similar, and there was no
significant difference in the incidence of animals bearing
tumours whether malignant or of all types.
It is concluded that ibuprofen was NOT CARCINOGENIC in the
AshWistar rat.
rat
Wistar
oral feed
2 years
Sex: male/female
daily
None reported
180 mg/kg/day for the first 55 weeks, then 60 mg/kg/day
thereafter. 30 male and 30 female rats treated.
GLP: no data
no data
5.4.
31/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
Result:
Source:
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Result:
Control Group:
Method:
Year:
Test substance:
Remark:
Result:
Source:
GROWTH and FOOD CONSUMPTION unaffected

Only specific PATHOLOGICAL EFFECT observed was INTESTINAL
ULCERATION before and after adjustment in dose.
No significant difference in WEIGHT GAIN between the
controls and treated animals.
No evidence of TUMOUR INDUCTION.
It was concluded that ibuprofen was NOT CARCINOGENIC in
the rat.
mouse
other
oral feed
80 weeks
Sex: male/female
daily
300 mg/kg daily for first 43 weeks, then 100mg/kg daily for
the remainder of experiment. 100 animals per dose level (50
male and 50 female). Same number of animals and sex
distribution in control group.
GLP: no data
no data
Strain of mouse was Schofield
5.4.
In treated mice GROWTH was DEPRESSED but FOOD CONSUMPTION
was NOT ADVERSELY AFFECTED. The only specific pathological
effect observed was GASTROINTESTINAL DAMAGE, the males
appearing more susceptible than the females before
adjustment in dose level. A VARIETY of TUMOURS developed
which were similar in disribution pattern, incidence and
time of appearance to that occurring in undosed control
mice, with one exception. MAMMARY TUMOURS were less common
among the mice on ibuprofen.
It is concluded that ibuprofen is NOT CARCINOGENIC in the
mouse.
32/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
5.8 Toxicity to Reproduction

Type:
Fertility
Species:
rat
Sex: male/female
Strain:
no data
Route of admin.: oral feed
Exposure Period: 14 days after mating
Frequency of
treatment:
daily
Premating Exposure Period
male:
60 days (age unknown)
female:
60 days (age unknown)
Duration of test: see RM method
Doses:
approximately 20 mg/kg/day, 10 males and 20 females
Control Group:
Method:
other: see RM
Year:
GLP: no data
Test substance:
no data
Remark:
Method
10 male and 20 female rats were given 20 mg/kg/day
ibuprofen in their diet for 60 days, after which the
females were mated with the males. A control group was
similarily treated but received plain diet. 14 days later
the females were separated from the males and those
animals receiving ibuprofen returned to normal diet. The
rats were allowed to deliver their young normally and
suckle them for 21 days when the young were killed.
See also section 5.9 as studies there included information
on toxicity to reproduction.
Result:
Treatment with approximately 20 mg/kg/day ibuprofen for 60
days before mating did not affect libido or fertility.
Source:
Type:
Species:
Strain:
Route of admin.:
Exposure Period:
other: effect on general reproductive performance

rat
Sex: male/female
Wistar
All females dosed from 14 days before mating until killed.
10/24 females from each group killed on day 14 of pregnancy,
remainder killed when young 21 days old.
Frequency of
treatment:
once daily by oral intubation
male:
at least 63 days
female:
14 days
Duration of test:
Doses:
120 or 20 mg/kg once daily, 12 male and 24 female rats per
dose level
Control Group:
Method:
other: see RM
Year:
GLP: no data
Test substance:
no data
Remark:
Method
Using the protocol recommended by the FDA
Groups of 12 male and 24 female BootsWistar rats were
33/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
Result:
Source:
treated with 120 or 20 mg/kg ibuprofen as a suspension in

0.4% Cellosize solution (dose volume 1ml/100g body weight)
by oral intubation once daily.The control group received
a similar volume of 0.4% Cellosize solution. Males were
dosed for at least 63 days and females 14 days before
mating.Each male was then caged with 2 females from the
same group for 14 days, after which the females were
housed individually.Both sexes were dosed throughout this
period and afterwards the females, but not the males, were
dosed until they were killed.Ten females from each group
were killed on day 14 of pregnancy. The remainder were
allowed to litter normally and rear their young to 21
days of age and were then killed along with the young.
See also section 5.9 as studies there were combined
reproductive and teratogenic studies
A dose of 120 mg/kg daily of ibuprofen was TOXIC to the
females as judged by the effect on BODYWEIGHT and, at
parturition, by EXCESSIVE HAEMORRHAGE, WEAKNESS, PROLONGED
and INCOMPLETE DELIVERY and DEATH of both dams and young
in utero.The dams that survived produced LITTERS of LESS
THAN NORMAL SIZE, but VIABILITY and BODYWEIGHT were
unaffected in those given 20 mg/kg daily.NO CONGENITAL
ABNORMALITIES related to treatment were observed. It was
therefore confirmed that ibuprofen had NO ANTIFERTILITY
ACTION and NO EMBRYOTOXIC or TERATOGENIC ACTION and does
NOT INFLUENCE LACTATION and the CARE OF THEIR YOUNG in the
rat.
Type:
other: general effect on reproduction
Species:
rat
Sex: female
Strain:
no data
Route of admin.: oral unspecified
Exposure Period: from day 6 of pregnancy
Frequency of
treatment:
daily
male:
none
female:
none
Duration of test: see RM
Doses:
5, 20 and 100 mg/kg/day (40 rats per dose level)
Control Group:
yes
Method:
other: see RM
Year:
GLP: no data
Test substance:
no data
Remark:
Method
Groups of 40 rats were dosed with 5, 20 and 100 mg/kg/day
ibuprofen from day 6 of pregnancy. 20 rats per dose level
were killed at day 19 of pregnanacy, the remainder
continuing to term. The control group consisted of 80
animals.
This was a combined reproductive and teratogenic study and
the results are therfore also relevant to section 5.9.
Result:
LITTER SIZE, FOETAL WEIGHT and FOETAL VIABILITY were not
34/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
Source:
affected.
NO MALFORMATIONS or CONSTITUTIONAL ABNORMALITIES occurred
in either the young or the foetuses.
It was concluded that ibuprofen has NO EXPERIMENTAL
TERATOGENIC ACTIVITY.
Type:
Species:
mouse
Sex: female
Strain:
no data
Exposure Period: from day 6 of pregnancy
Frequency of
treatment:
daily
male:
none
female:
none
Doses:
5, 20 and 100 mg/kg/day (50 mice per dose level)
Control Group:
yes
Method:
other: see RM
Year:
GLP: no data
Test substance:
no data
Remark:
Method
Groups of 50 mice were treated with 5, 20 and 100
mg/kg/day ibuprofen from the 6th day of pregnancy. 20 mice
from each group were killed at day 17, and the remainder
went to term.The control group consisted of 150 mice.
therefore the results are also relevant to section 5.9.
Result:
affected.
No MALFORMATIONS or CONSTITUTIONAL ABNORMALITIES occurred
in either the YOUNG or the FOETUSES.
Source:
35/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
Type:
Species:
rabbit
Sex: female
Strain:
no data
Exposure Period:
Frequency of
treatment:
from day 6 of pregnanacy
male:
none
female:
none
Doses:
5, 15 and 50 mg/kg/day ( 30 rabbits per dose level)
Control Group:
yes
Method:
other: see RM
Year:
GLP: no data
Test substance:
no data
Remark:
Method
Groups of 30 rabbits were dosed with 5, 15 and 50
mg/kg/day ibuprofen from day 6 of pregnancy. 12 rabbits
at the lowest dose and 10 at the two highest doses were
killed at day 29 of pregnancy. The control group contained
60 animals.
the data are therefore also relevant to section 5.9.
Result:
affected.
NO MALFORMATIONS or CONSTITUTIONAL ABNORMALITIES occurred
in either the young or the foetuses.
Source:
36/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
5.9 Developmental Toxicity/Teratogenicity

Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Duration of test:
rabbit
Sex: female
New Zealand white
gavage
days 1 to 29 of pregnancy, where day 0 was the day of mating
Daily
females killed on day 30 of pregnancy (day 0 was the day of
mating) and uterine contents examined
Doses:
60, 20 and 7.5 mg/kg/day (17, 19 and 22 animals per group
respectively). Control group contained 23 animals
Control Group:
NOAEL Maternalt.: < 7.5 mg/kg bw
NOAEL Teratogen.: > 60 mg/kg bw
Method:
other
Year:
GLP: no data
Test substance:
other TS: aqueous solution of the sodium salt of ibuprofen
Remark:
Method
Newly mated female rabbits were given ibuprofen in doses
of 60, 20 and 7.5 mg/kg/day from day 1 to 29 of
pregnancy.Control females received 1 ml/kg daily of
water.All females were killed on day 30 of pregnancy and
their uterine contents examined.
Result:
LESS GROWTH than controls plus STOMACH ULCERS observed in
females given 60 mg/kg/day. A few also had PNEUMONIA and
a mild degree of FOCAL HEPATITIS.
Females given 20 mg/kg/day were similarily though less
affected.
Females given 7.5 mg/kg/day GREW NORMALLY, but had some
GASTRIC ULCERS or EROSIONS
Minimal GASTRIC DAMAGE was observed in 2/23 controls
PREMATURE BIRTHS on days 26 and 28 of pregnancy observed
(NORMAL YOUNG) in 2/17 females given 60 mg/kg/day
In females given 60 mg/kg/day there was a REDUCTION IN
THE NUMBER OF LIVE FOETUSES per litter plus a
corresponding REDUCTION IN THE RATIO OF IMPLANTS TO
CORPORA LUTEA
In females given 20 and 7.5 mg/kg/day LITTER SIZE was
UNAFFECTED
There was no significant differences between the groups
in the numbers of dead and resorbed foetuses
Average FOETAL WEIGHT normal in all groups
CONGENITAL MALFORMATIONS of various kinds occurred in the
foetuses of treated and control animals.
Source:
Ibuprofen was determined to be NOT TERATOGENIC

(11)
37/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Duration of test:
Doses:
Control Group:
Method:
Year:
Test substance:
Remark:
Result:
rabbit
Sex: female
New Zealand white
gavage
days 1 to 28 of gestation where day 0 was the day of mating
daily
females killed on day 29 of pregnancy (day o was day of
mating) , litter values determined and foetuses examined for
structural abnormalities
60, 20 and 7.5 mg/kg/day (21 animals per level)
yes
other
GLP: no data
other TS: aqueous solution of ibuprofen
Method
Animals killed on day 29, litter values determined and
foetuses subsequently examined for structural
abnormalities of the skeleton and viscera.
Treatment did not appear to adversely affect the
following:
1)Parent animals body weight change, pregnany rate and
macroscopic changes.
2)Litter values as assessed by number of implantations,
viable young, pre and post implantation loss, litter and
mean foetal weights.
3)Embryonic and foetal development incidences of major
malformations, minor visceral or skeletal anomalies and
skeletal variance.3 malformations of the same type
(umbilical hernia) at 60 mg/kg/day was considered likely to
be a coincidental event, albeit rare.
Source:
It was concluded that the oral administration of all doses

throughout pregnancy ellicited NO ADVERSE EFFECT on the
developing progeny.
38/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
Species:
Strain:
Route of admin.:
Exposure period:
rat
Sex: female
Wistar
days 1 to 20 where presence of spermatozoa in vaginal smear
was taken as first day of pregnancy
Frequency of
treatment:
daily
Duration of test: uterine contents examined on day 21 of pregnancy (day 1 was
first day of pregnancy)
Doses:
180, 60, 20 and 7.5 mg/kg/day (4, 15, 13 and 11 animals
respectively per dose level). Control group contained 11
animals
Control Group:
NOAEL Maternalt.: = 7.5 mg/kg bw
Method:
other
Year:
GLP: no data
Test substance:
other TS: aqueous solution of the sodium salt of ibuprofen
Remark:
Method
Newly mated female rats were given ibuprofen in doses of
180, 60, 20 and 7.5 mg/kg/day from day 1 to day 20 of
pregnancy. Control females received 10 ml/kg of water
daily. The uterine contents were examined on day 21 of
pregnancy and the foetuses examined for external,
visceral and skeletal abnormalities.
Result:
Females receiving 180, 60 or 20 mg/kg of ibuprofen on
days 1 to 20 of pregnancy were found to have
GASTROINTESTINAL LESIONS graded in severity according to
dose.
NO LESIONS observed in animals on 7.5 mg/kg/day or in the
controls.
Females on 180 mg/kg/day had a DIMINISHED RATE OF GROWTH.
LITTER SIZE NORMAL, FOETAL WEIGHT and SURVIVAL RATE NORMAL
in all groups.
It is concluded that ibuprofen is NOT TERATOGENIC in the
rat.
Source:
(16)
39/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
Species:
Strain:
Route of admin.:
Exposure period:
rat
Sex: female
Wistar
days 1 to parturition, where presence of spermatozoa in
vaginal smear was taken as first day of pregnancy.
Frequency of
treatment:
daily
Duration of test: mothers and young killed when young were 21 days old.
Doses:
20 and 7.5 mg/kg/day (10 and 6 animals per dose level
respectively). Control group contained 15 animals.
Control Group:
yes
NOAEL Maternalt.: = 7.5 mg/kg bw
Method:
other
Year:
GLP: no data
Test substance:
no data
Remark:
Method
Newly mated female rats were given ibuprofen in doses of
0, 7.5 and 20 mg/kg/day from day 1 of pregnancy to
parturition. The rats were allowed to deliver and rear
their young normally until the young were 21 days old
when both mothers and young were killed and examined.
Result:
Rats given 20 mg/kg/day GAINED LESS WEIGHT than the
controls during pregnancy.
All groups had UNEVENTFUL PREGNANCIES and the young were
DELIVERED WITHOUT DIFFICULTY.
In all groups there was no significant effect on the
NUMBER OF LIVE YOUNG PER LITTER, VIABILITY INDEX and
WEANING WEIGHT.
Source:
It is concluded that ibuprofen is NOT TERATOGENIC in the

rat.
(17)
5.10 Other Relevant Information

Type:
Remark:
Source:
adsorption
Ibuprofen administered orally was rapidly absorbed in
rats, rabbits and dogs. Absorption in rats was shown to
occur mainly from the intestine and to a lesser, though
significant, extent from the stomach.Four metabolites of
ibuprofen were detected in rabbit plasma, 3 of these also
in rat plasma, but none in dog plasma. Distribution
studies with ibuprofen14C revealed that repreated oral
dosing of rats led to some accumulation of radioactivity
in the adrenals, ovaries, thyroid, skin and fat, without
structure or function being affected. Dogs, however had
high levels only in bile.
(11)
40/44
date: 18FEB2000
5. Toxicity
______________________________________________________________________________
Type:
Remark:
Source:
Distribution
See information under absorption (page 1)
Type:
Remark:
Source:
Metabolism
See information under absorption (page 1)
5.11 Experience with Human Exposure

Remark:
If inhaled ibuprofen can cause epistaxes (nosebleeds)

Occupational Exposure
Summary of Dust Exposure Monitoring for Primary Production
Plant 1990 to February 1994
Ibuprofen was sampled as total inhalable dust using
sampling methodology as outlined in Methods of Detection
of Hazardous Substances 14. The ibuprofen on the sample
filters was quantified using HPLC.
Total number of results = 62
Source:
Range as Time Weighted Average over the period of

monitoring (typically approximately 1 hour) = None
detected (<0.01) to 32 mg per cubic metre
All of the results calculated to below 5 mg per cubic
metre when expressed as 8 hour time weighted averages
assuming zero exposure over the remainder of the shift.
The assumption of zero exposure would be expected to be
essentially valid in nearly all cases.
Recorded on the company Safety Data Sheet as "Irritating
to eyes and respiratory system. May be irritating to
skin." This is based on worker anecdotal evidence.
The respiratory irritancy included a tingling sensation
in the nose and sternutatory (sneeze inducing) properties.
The degree of irritancy was fairly mild.
The anecdotal evidence suggests that any potential for
skin irritancy may be slight.
41/44
date: 18FEB2000
6. References
______________________________________________________________________________
(1) Martindale The Extra Pharmacopoeia 28th Edition 1982

(2) Journal of Pharmaceutical Sciences Vol. 79, No.6,
June 1990 Page 552. Determination of Ibuprofen vapour
pressure at temperatures of pharmaceutical interest.
Ertel,K.D. et al.
(3) J. Pharm. Pharmacol. 1992. 44: 634639
Prediction of Skin Permeability of Drugs: comparison of
Human and Hairless Rat Skin by Yasunori Morimoto et al
(4) International Journal of Pharmaceutics, 79 (1992) 2128
Prediction of skin permeability of drugs. II. Development
of composite memebrane as a skin alternative by Tomomi
Hatanaka et al
(5) J. Pharm. Pharmacol. 1992, 44: 634639
Prediction of Skin Permeability of Drugs: Comparison of
Human and Hairless Rat Skin by Yasunori Marimoto et el.
(6) Martindale The Extra Pharmacopoeia 28th edition quotes
"Practically insoluble in water"
(7) J. Pharm. Pharmacol. 1985, 37: 112
ReviewThe Fate of Pharmaceutical Chemicals in the
Aquatic Enviroment by Mervyn,L et al.
Biodegradation studies carried out on ibuprofen using
methods for testing recommended by the Department of
Enviroment(UK), Standing Committee of Analysts
(1981),Assessment of Biodegradability 1981, in Methods
for the Examination of Waters and Associated Materials,
HMSO, and by King,E.F.(1981) Notes on Water Research
No.28 Biodegradability Testing, Water Research Centre,
Medmemham (August 1981).
Actual tests and results not detailed, overall result
was that ibuprofen is inherently biodegradable.
(8) Toxicology and Applied Pharmacology 15, 310330 (1969)
Adam, S.S. et al
(9) Drugs of the Future Vol 5, No.11, 539540 (1980)
by L. de Angelis
Adams, S.S. et al
Absorption, Distribution and Toxicity of Ibuprofen by
Adams, S.S. et al
Adams,S.S. et al
42/44
date: 18FEB2000
6. References
______________________________________________________________________________
(13) Journal of Applied Toxicology Vol 6(4), 237243 (1986)

Mutagenicity Testing of Selected Analgesics in Ames
Salmonella Strains by Oldham,J.W. et al
(14) Vopr. Revm. 1980 Vol 4, 6263
Karaseva,N.M., Kostrova,A.A. and Sigidin,Y.A.
Institute of Rheumatism (Prof. V.A. Nanosova, Assoc.
Member, Acadamy of Medical Sciences of the USSR, Director)
Acadamy of Medical Sciences of the USSR.
A Comparative Study of the Cytogenetic Activity of
Acetylsalicylic Acid and Brufen.
(15) Mutation Research 174 (1986) 131134
Investigation of the Influence of Nonsteroidal
Antirheumatic Drugs on the Rates of Sister Chromatid
Exchange by Kullich, W. and Klein, G.
Adams,S.S. et al.
Absorption, Distribution and Toxicity of ibuprofen by
Adams, S.S. et al
43/44
date: 18FEB2000
7. Risk Assessment
______________________________________________________________________________
7.1 Risk Assessment
44/44

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Substance ID: 15687271

Dataset created by:

EUROPEAN COMMISSION European Chemicals Bureau

This dossier is a compilation based on data reported by the European

Year 2000 CDROM edition

(C) 2000 EUROPEAN COMMISSION

1.0.1 OECD and Company Information

1.0.2 Location of Production Site

1.0.3 Identity of Recipients

1.1 General Substance Information

alphamethyl4(2methyl propyl) benzeneacetic acid

Boots Chemicals, The Boots Company PLC

1.7 Use Pattern

1.7.1 Technology Production/Use

1.8 Occupational Exposure Limit Values

1.9 Source of Exposure

remaining mixture refluxed under pressure to give

1.10.1 Recommendations/Precautionary Measures

1.10.2 Emergency Measures

1.12 Possib. of Rendering Subst. Harmless

1.13 Statements Concerning Waste

1.14.1 Water Pollution

1.14.2 Major Accident Hazards

1.14.3 Air Pollution

1.15 Additional Remarks

Disposal in accordance with current legislation using

1.16 Last Literature Search

1.18 Listings e.g. Chemical Inventories

2.1 Melting Point

2.2 Boiling Point

2.4 Vapour Pressure

= .000012 hPa at 25 degree C

2.5 Partition Coefficient

.23 3.3 at 25 degree C

2.6.1 Water Solubility

= .043 other: mg/mL at 37 degree C

2.6.2 Surface Tension

2.7 Flash Point

2.8 Auto Flammability

2.10 Explosive Properties

other: Moderate dust explosion hazard

2.11 Oxidizing Properties

2.12 Additional Remarks

3.1.2 Stability in Water

3.1.3 Stability in Soil

3.2 Monitoring Data (Environment)

3.3.1 Transport between Environmental Compartments

3.4 Mode of Degradation in Actual Use

to be termed biodegradable by this method.

3.6 BOD5, COD or BOD5/COD Ratio

3.8 Additional Remarks

4.2 Acute Toxicity to Aquatic Invertebrates

Daphnia magna (Crustacea)

Daphnia magna (Crustacea)

Mysidopsis bahia (Crustacea)

4.3 Toxicity to Aquatic Plants e.g. Algae

Selenastrum capricornutum (Algae)

Analytical monitoring: no data

Analytical monitoring: no data

4.4 Toxicity to Microorganisms e.g. Bacteria

4.5 Chronic Toxicity to Aquatic Organisms

4.5.2 Chronic Toxicity to Aquatic Invertebrates

4.6.2 Toxicity to Terrestrial Plants