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Description of key information

Acute oral toxicity study performed prior to implementation of official testing guidelines but comparable to OECD TG 401: 5 male rats were given single oral doses of 1000, 2150, 4640,  10000 or 21500 mg/kg bw and observed for 7 days. The LD50 value was determined to be 14700 mg/kg bw (Celanese Corporation 1956).
Acute dermal toxicity study performed prior to implementation of official testing guidelines but comparable to OECD TG 402: Groups of 4 albino rabbits were evaluated for acute dermal toxicity following single dermal application of 1000, 2150, 4640, 10000 mg/kg bw as paste for 24 hours and a post exposure observation period of 7 days. The LD50 after single application is >10000 mg/kg bw (Celanese Corporation 1956).
Acute inhalation toxicity study performed prior to implementation of official testing guidelines but similar to OECD TG 403: 20 male rats were whole body exposed to 590 mg/m³ or 850 mg/m³ (analytical) trimethylolpropane for 4 hours and observed for 14 days. No mortalities and no clinical signs of toxicity were reported up to and including the highest exposure level of 850 mg/m³ (Bayer 1965).

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:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: meets generally accepted criteria
Principles of method if other than guideline:
Method: groups of 5 male rats were given single oral doses of 1.0, 2.15, 4.64, 10.0 or 21.5 g/kg bw and observed for 7 days, gross autopsy.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 175 g
- Fasting period before study: 4 hours
- Housing: in groups
- Diet ad libitum
- Water ad libitum
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
testsubstance was given as 10 % or 20 "% or 70 % solution
Doses:
1000 mg/kg bw, 2150 mg/kg bw, 4640 mg/kg bw, 10000 mg/kg bw, 21500 mg/kg bw given as 10 % or 20 "% or 70 % solution.
No. of animals per sex per dose:
5 males
Control animals:
no
Details on study design:
Food was withheld from rats for a period of 4 hours; rats were observed for 7 days post treatment and gross signs of toxicity were noted, gross autopsy was performed upon rats that died and of the surviving rats at the end of the observation period
Statistics:
moving average method of Weil (1952)
Sex:
male
Dose descriptor:
LD50
Effect level:
ca. 14 700 mg/kg bw
Based on:
other: clinical signs of intoxication from 2150 mg/kg bw onwards and mortality rate at the highest test dose (21500 mg/kg bw) of 5/5 male rats within 24 hours
Mortality:
only at the highest test dose of 21500 mg/kg bw: 5/5 rats died within 24 hours post treatment
no other rat died
Clinical signs:
1000 mg/kg bw : rats appeared normal throughout the observation period
2150 mg/kg bw, 4640 mg/kg bw, 10000 mg/kg bw, 21500 mg/kg bw:
rats appeared depressed, exhibited lacrimation, slow and laboured respiration,
ataxia, and other effects of the limbs
21500 mg/kg bw: additionally depressed and absent placing, righting and pain reflexes
at 43 hours post dosing the surviving rats recovered
Body weight:
no data
Gross pathology:
gross autopsy of the dead rats:
hyperemic and hemorrhagic lungs
irritation of the pyloric portion of the stomach, small intestine (distended and filled with a clear yellowish colored fluid)
and peritoneum, congested kidneys and adrenal
gross autopsy of the survivors #
1000 and 2150 mg/kg bw : rats showed no gross pathothololgical changes
4600 and 10000 mg/kg bw: rats showed hyperemic zones at the periphery of the medulla in the kidneys
Other findings:
Confidence limits could not be calculated due to the "all or none" response (no further data)

Within a couple of hours after the dose, the animals that received 2.15 g/kg or more showed signs of fatigue, slow respiration and ataxia. All the animals in the highest dose group died. Autopsies revealed kidney changes in the three
highest dose groups.

Interpretation of results:
GHS criteria not met
Executive summary:

5 male rats were given single oral doses of 1000, 2150, 4640 10000 or 21500 mg/kg bw and observed for 7 days. 1000 mg/kg bw was tolerated wihout any harm. Rats of the other groups appeared depressed, exhibited lacrimation, slow and laboured respiration, ataxia, and other effects of the limbs. 21500 mg/kg bw caused the death of all animals within 24 hours. Thus the LD50 value was determined 14700 mg/kg bw (Celanese Corporation 1956).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
14 700 mg/kg bw
Quality of whole database:
Scientifically acceptable and sufficient documented for evaluation

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating conc.
Value:
850 mg/m³
Quality of whole database:
Scientifically acceptable and sufficient documented for evaluation - no mortalities and no clinical signs of toxicity were reported up to and including the highest exposure level of  850 mg/m³

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: meets gereally accepted criteria, but individual data are not shown
Reason / purpose:
reference to same study
Principles of method if other than guideline:
Groups of 4 albino rabbits were evaluated for acute dermal toxicity following single dermal application for 24 hours and a post exposure observation period of 7 days; gross autopsy
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 1.5-2.5 kg
- Housing: individually
- Diet ad libitum
- Water ad libitum:

Type of coverage:
occlusive
Vehicle:
water
Details on dermal exposure:
the material was moistened with water to form a paste; the paste was spread evenly on a non-absorbent paper backing which was applied to the closely clipped intact abdominal skin. The trunks were then wrapped securely with a gauze and adhesive tape binder for 24 hours. After removal of the binder the skin was rinsed with water in order to remove any residues. The animals were observed for 7 days
Duration of exposure:
24 hours
Doses:
1000, 2150, 4640, 10000 mg/kg bw
No. of animals per sex per dose:
4 per dose
Control animals:
not specified
Details on study design:
the material was moistened with water fo form a paste; the paste was spread evenly on a non-absorbent paper backing which was applied to the closely clipped intact abdominal skin. The trunks were then wrapped securely with a gauze and adhesive tape binder for 24 hours . After removal of the binder the skin was rinsed with water in order to remove any residues. The animals were observed for 7 days
Statistics:
no data all aninals survived
Sex:
not specified
Dose descriptor:
LD50
Effect level:
> 10 000 mg/kg bw
Based on:
other: no mortality occurred
Remarks on result:
other: no mortality
Mortality:
no
Clinical signs:
a very mild degree of dermal irritation which disappeared at the next day, no other signs were observed
Body weight:
increase over the initial body weight ( no further details given)
Gross pathology:
1000 mg/kg bw: no findings
2150, 4640, 10000 mg/kg bw::
the kidneys of the majority of the rabbits contained hyperemic zone at the cortico-medullary junction , no other findings
Other findings:
no data
Executive summary:

Groups of 4 albino rabbits were evaluated for acute dermal toxicity followling single dermal application

of 1000, 2150, 4640, 10000 mg/kg bw as paste for 24 hours and a post exposure observation period of

7 days. A very mild degree of dermal irritation which disappeared at the next day was the only clinical finding;

no animal died. Gross autopsy showed histopathological changes only in the kidneys from 2150 mg/kg bw

onwards. In the absence of any deaths, the LD50 value after single dermal administration is >10000 mg/kg bw (Celanese Corporation 1956).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Quality of whole database:
Scientifically acceptable and sufficient documented for evaluation - gross autopsy showed histopathological changes only in the kidneys from 2150 mg/kg bw onwards.

Additional information

ORAL APPLICATION

5 male rats were given single oral doses of 1000, 2150, 4640 10000 or 21500 mg/kg bw and observed for 7 days.

1000 mg/kg bw was tolerated without any harm. Rats of the other groups appeared depressed, exhibited lacrimation, slow and laboured respiration, ataxia, and other effects of the limbs. 21500 mg/kg bw caused the death of all animals within 24 hours. Gross autopsy showed pathological changes in lungs, stomach, intestine, kidneys and adrenals.

The LD50 value was determined to be 14700 mg/kg bw. (Celanese Corporation 1956). This is confirmed in other studies indicating an LD50 value >5000 mg/kg bw (Bayer 1980, BASF 1958).

DERMAL APPLICATION

Groups of 4 albino rabbits were evaluated for acute dermal toxicity following single dermal application of 1000, 2150, 4640, 10000 mg/kg bw as paste for 24 hours and a post exposure observation period of 7 days. A very mild degree of dermal irritation which disappeared at the next day was the only clinical finding; no animal died. Gross autopsy showed histopathological changes only in the kidneys from 2150 mg/kg bw onwards. In the absence of any deaths the LD50 value after single dermal administration is > 10000 mg/kg bw (Celanese Corporation 1956).

INHALATION EXPOSURE

20 male rats were exposed whole body to 590 mg/m³ or 850 mg/m³ (analytical concentrations) trimethylolpropane for 4 hours and observed for 14 days. The substance was dissolved in ethanol/lutrol (1:1) and dynamically sprayed into an inhalation apparatus. No symptoms of poisoning were observed. No mortalities and no clinical signs of toxicity were reported up to and including the highest exposure level of  850 mg/m³. The LC50 value could not be determined exactly and is supposed to be > 850 mg/m³

(Bayer 1965).

Overall, based on the available data, it can be concluded that trimethylolpropane is of low acute toxicity.


Justification for selection of acute toxicity – oral endpoint
Key study is used - clinical signs were observed at > 2000 mg/kg bw

Justification for selection of acute toxicity – inhalation endpoint
Key study is used

Justification for selection of acute toxicity – dermal endpoint
Key study is used

Justification for classification or non-classification

Directive 67/548/EEC, Annex I:

Trimethylolpropane is not classified with respect to acute toxicity.

Directive 67/548/EEC, Annex I and Regulation (EC) No. 1271/2008:

Based on the available data of trimethylolpropane a classification is not required for the oral, dermal and inhalation route.