Ibuprofen

Endpoint summary

Description of key information

The oral LD50 was determined to be 800 - 1600 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1984-04-10 to 1984-05-08

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study, study with GLP.

Principles of method if other than guideline:

HRC Standard Protocol, detailed documentation of the protocol included in the report

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS: 2-day old rats
- Source: Charles River UK Limited, Manston, Kent
- Age at study initiation: 2 days
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: co-housing with mothers, dams housed individually
- Diet (e.g. ad libitum): nursed by dams
- Water (e.g. ad libitum): nursed by dams
- Acclimation period: 2 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 3°C
- Humidity (%): 55 +/- 15%
- Air changes (per hr): 13
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 1984-04-06 (arrival of time-pregnant females) To: 1984-04-30

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TEST ANIMALS: 28-day old rats
- Source: Charles River UK Limited, Manston, Kent
- Age at study initiation: 28 days
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: 5 per cage
- Diet (ad libitum): S.F. Laboratory diet
- Water (ad libitum): tap water
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 3°C
- Humidity (%): 55 +/- 15%
- Air changes (per hr): 13
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 1984-04-11 To: 1984-04-30

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TEST ANIMALS
- Source: Charles River UK Limited, Manston, Kent
- Age at study initiation: 50 days
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: 5 per cage
- Diet (ad libitum): S.F. Laboratory diet
- Water (ad libitum): tap water
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 3°C
- Humidity (%): 55 +/- 15%
- Air changes (per hr): 13
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 1984-04-04 To: 1984-04-30

Route of administration:

oral: gavage

Vehicle:

other: 00.4% aqueous Cellosize (hydroxyethyl cellulose)

Details on oral exposure:

VEHICLE
vehicle: 0.4% (w/v) solution of Cellosize (hydroxyethyl cellulose, PQ 15000) in deionized water
- Concentration in vehicle: 1, 2, 4, 8 % (w/v)
- Amount of vehicle (if gavage): 2 ml/100 g bw, i.e. 20 ml/kg bw
- Justification for choice of vehicle: for consistency with previous work on the formulated material, the sponsor (The Boots Company plc) also provided the Cellosize (hydroxyethyl cellulose) used as a vehicle in this study.
- Lot/batch no. (if required): no data
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED:
20 ml/kg bw

DOSAGE PREPARATION (if unusual):
Addition of the Cellosize (powder) to the heated water (almost at the boiling point) under stirring.

Doses:

0, 200, 400, 800, 1600 mg/kg bw

No. of animals per sex per dose:

5 males and 5 females per group

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, macroscopic pathological changes

Statistics:

no data

Sex:

male/female

Dose descriptor:

LDLo

Effect level:

200 mg/kg bw

Remarks on result:

other: 2-day old rats

Sex:

male/female

Dose descriptor:

LDLo

Effect level:

200 mg/kg bw

Remarks on result:

other: 28-day old rats

Sex:

male/female

Dose descriptor:

LDLo

Effect level:

200 mg/kg bw

Remarks on result:

other: 50-day old rats

Mortality:

In rats of all three ages, a single oral dose of 800 and 1600 mg/kg bw elicited profound toxicity. In terms of mortality, the test substance appeared to be slightly more toxic to 2-day old rats than to 28- or 50-day old rats at the same dose level. The older age group animals showed essentially similar, but unexpected patterns of response at these doses (800 and 1600 mg/kg bw). At 400 mg/kg bw, effects were minimal while treatment with 200 mg/kg bw did no elicit any noticeable effect in any age group.
For details, see table below.

Clinical signs:

other: No conclusive signs of toxicity were observed in pups but in the 28- and 50-day age groups marked signs of reaction were observed at 1600 and 800 mg/kg. Signs were not confined to decedents, all animals shoved a similar pattern of response during the firs

Gross pathology:

No conclusive macroscopic changes were detected in pups which died but in older animals all decedents showed gastro-intestinal changes typical of this class of compound, for example, free serous fluid in the abdominal cavity, intestinal adhesions, and pallor of the kidneys and liver. Terminal sacrifice of animals dosed at 1600 and 800 mg/kg revealed macroscopic changes in same animals - particularly males - which were also considered to be related to treatment.
There were no unusual findings at termination in any animals treated at 200 at 400 mg/kg.

Table: mortality rates (accidental deaths excluded) 

	males			females
	age at dosing			age at dosing
	2 d	28 d	50 d	2 d	28 d	50 d
dose level [mg/kg bw]
0	0/5	0/5	0/5	0/5	0/5	0/5
200	1/5	0/5	0/5	1/4	0/5	0/5
400	0/5	0/5	0/5	0/4	0/5	0/5
800	2/5	0/5	0/5	1/5	0/5	0/5
1600	5/5	4/5	4/5	4/4	2/5	3/5

 

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

800 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute toxicity: oral

In a GLP-compliant study five Sprague Dawley rats per sex per dose were exposed to the test substance via oral gavage (BASFSE, 1984). Three age groups (2, 28 and 50 days old) were exposed to 0, 200, 400, 800 and 1600 mg/kg bw. After an observation period of 14 days animals were necropsied. In rats of all three ages, a single oral dose of 800 and 1600 mg/kg bw elicited profound toxicity. 1 out of 5 males and 1 out of 4 females, that were 2 days old (pups), exposed to 200 mg/kg bw died. 2 out of 5 male pups and 1 out of 5 female pups exposed to 800 mg/kg bw died. All pups exposed to 1600 mg/kg bw died. 4 out of 5 males and 2 out of 5 females, in the 28-day age group, exposed to 1600 mg/kg bw died. 4 out of 5 males and 3 out of 5 females, in the 50-day age group, exposed to 1600 mg/kg bw died. No animals died in the control group, aged 28 or 50 days and exposed to 200, 400 or 800 mg/kg bw, and pups exposed to 400 mg/kg bw. No conclusive signs of toxicity were observed in pups but in the 28- and 50-day age groups marked signs of reaction were observed at 1600 and 800 mg/kg. Signs were not confined to decedents, all animals shoved a similar pattern of response during the first few days after dosing typified by lethargy associated with lose of body tone, inactivity, unsteady and sluggish movement, piloerection, walking on tip-toe, hunched posture, pale extremities, staining of the fur in the urogenital region, and pale eyes. Among animals which survived, gradual remission of symptoms occurred and animals appeared to have recovered well by termination. In general, animals treated with 800 mg/kg recovered faster than those at 1600 mg/kg and females recovered faster than males. At 400 mg/kg only transient signs were observed while at 200 mg/kg treatment did not elicit any noticeable response. Amongst animals dosed at 28 or 50 days old, mean bodyweight of both males and females at 1600 mg/kg was characterised by abrupt weight loss during Day 2; males were more noticeably affected than females both in terms of the degree and duration of the weight loss sustained. A similar but less pronounced pattern of response occurred at 800 mg/kg, a noticeable retardation of growth rate also being recorded in pups at this dosage. Amongst rats dosed at 28 or 50 days of age, a marginal initial retardation of weight gain was observed at 400 mg/kg whereas the weight gain of rats 2 days old at dosing in this treatment group was essentially comparable with control. At 200 mg/kg there was no conclusive evidence of any adverse reaction to treatment. No conclusive macroscopic changes were detected in pups which died but in older animals all decedents showed gastro-intestinal changes typical of this class of compound, for example, free serous fluid in the abdominal cavity, intestinal adhesions, and pallor of the kidneys and liver. Terminal sacrifice of animals dosed at 1600 and 800 mg/kg revealed macroscopic changes in same animals - particularly males - which were also considered to be related to treatment. The LD50 was determined to be between 800 and 1600 mg/kg bw.

In another study, ten male Wistar rats per dose were exposed to the test substance via oral gavage. No information is available on the concentration of the doses used. After an observation period of 14 days animals were necropsied. Deaths occurred within 3 days from intestinal ulceration. No information was presented on the mortality rate. Clinical signs of toxicity comprised of sedation, prostration, loss of righting reflex and labored respiration. Intestinal ulceration was reported upon necropsy. The approximate LD50 was determined to be 1600 mg/kg bw.

Justification for classification or non-classification

Based on the available information the test substance needs to be classified as Acute Tox Cat 4, H302: Harmful if swallowed in accordance with EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation No. 1272/2008.

Based on the available information classification for acute inhalation toxicity and acute dermal toxicity is not possible in accordance with EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation No. 1272/2008.