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Description of key information

In the first acute oral toxicity test conducted according to OECD 401 guideline and without GLP principles, the test substance is slightly toxic in Chinese hamster  and the LD50 was determined to be 2739 mg/kg bw.
In the second acute oral toxicity test conducted according to OECD 401 guideline and without GLP principles, the test substance is harmful in Mouse and the LD50 was determined to be 1413 mg/kg bw.
In the third acute oral toxicity test conducted according to OECD 401 guideline and without GLP principles, the test substance is slightly toxic in rats and the LD50 was determined to be 1037 mg/kg bw.
In the acute dermal toxicity test conducted according to OECD 402 guideline and without GLP principles, the test substance is practically nontoxic in rats and the LD50 was determined to be greater tahn 4000 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:
key study
Study period:
April 9 - April 30, 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well-documented pre-guideline study without GLP, testing protocol similar to OECD 401
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
Pre-guideline and pre-GLP study.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: T1f: RAIf (SPF)
Sex:
male/female
Details on test animals and environmental conditions:
Healthy random bred rats of 7-8 weeks age were raised on the premises and kept at room temperature of 22 + 2 deg. C, at relatie humidity of 55 + 10% and on a 10 hour light cylce day. They received ad libitum rat food (supplier: NAFAG, Gossau, Switzerland) and water.
They were adapted to the laboratory for a minimum of 4 days before treatment. During treatment and observation period the animals were housed in groups of 5 animals in Macrolon cages type 3. Animals were individually marked with picric acid.
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG 400, Fluka AG, Art. 81170
Details on oral exposure:
Animals fasted overnight were treated by single oral intubation.
Doses:
400 - 1000 - 2000 - 3000 mg/kg bw
No. of animals per sex per dose:
5 males and 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations: 1 / hour for the first 5 hours, thereafter at least 1 / day. Body weight determination 1 / week
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
LD50 including 95% confidence intervals were calculated by the logit model
Sex:
male/female
Dose descriptor:
LD50
Effect level:
ca. 1 037 mg/kg bw
Based on:
test mat.
95% CL:
> 668 - < 1 403
Mortality:
Males: 3000 mg/kg 2 (3 hours), 1 (5 hours), 2 (24 hours) : 5/5
Males: 2000 mg/kg 1 (24 hours), 1 (day 2), 1 (day 4), 1 (day 6) : 4/5
Males: 1000 mg/kg 2 (24 hours): 2/5
Males: 400 mg/kg : 0/5

Females: 3000 mg/kg 1 (2 hours), 3 (5 hours), 1 ( 24 hours) : 5/5
Females: 2000 mg/kg 1 (24 hours), 1 (day 3), 1 (day 4), 1 (day 6) : 4/5
Females: 1000 mg/kg 3 (24 hours), 1 (day 6) : 4/5
Females: 400 mg/kg : 0/5
Clinical signs:
Animals treated with 3000 mg/kg bw showed a moderate effect on ruffled fur for the first 5days and slight effects as sedation, dyspnea, exophthalmos, diarrhea and curved body position (all on on the first 5 hours).

Animals treated with 2000 mg/kg bw showed a moderate effect on ruffled fur (2 hours - day 7) and dyspnea (days 4-6). Slight effects recorded were sedation (2 hours - day 6), ruffled fur (1 hour plus days 7-11), dyspnea (1 hour - day 3 plus day 7 - day 10), exophthalmos (1 hour - day 7), diarrhea (24 hours - day 6) and curved body position (1 hour - day 10).

Animals treated with 1000 mg/kg bw showed a moderate effect on ruffled fur (3 hours - day 6). Slight effects recorded were sedation (2 hours - 5 hours), ruffled fur (1 hour - 2 hours plus days 7 and 8), dyspnea (1 hour - day 6), exophthalmos (1 hour - day 7), diarrhea (24 hours - day 3) and curved body position (1 hour - day 6).

Animals treated with 400 mg/kg bw showed slight effects on dyspnea (1 hour - day 6), exophthalmos (24 hours - day 4), ruffled fur (1 hour - day 8) and curved body position (1 hour - day 6).
Body weight:
Dose sex bw changes bw changes

400 mg/kg bw males: First week: 24% 2nd week: 20%
1000 mg/kg bw males: First week: -19% 2nd week: 40%
2000 mg/kg bw males: First week: -17% 2nd week: 24%
3000 mg/kg bw males: First week: --- 2nd week: ---

400 mg/kg bw females: First week: 11% 2nd week: 14%
1000 mg/kg bw females: First week: -12% 2nd week: 26%
2000 mg/kg bw females: First week: -27% 2nd week: 4%
3000 mg/kg bw females: First week: --- 2nd week: ---

The bw changes in both weeks could not be calculated for both males and females treated with a dose of 3000 mg/kg.
Interpretation of results:
sligthly toxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute toxicity is similar for males and females. The LD50 is 1037 (668-1403) mg/kg bw.
Executive summary:

The acute toxicity has been investiagated in a pre-guideline and pre-GLP study performed and recorded similarly to the later standards. The doses selected were 3000 -2000 -1000 and 400 mg/kg bw. Each 5 male and 5 female animals were treated by gavage application with the test substance suspended in PEG 400. Mortality was 100% at the top dose in both sexes. Mortality at the lower dose was 80% in both sexes, 40% in males and 80% in females at 1000 mg/kg bw. The low dose was without mortality in both sexes. At all doses there were the usual clinical symptoms in animals of both sexes. Mortality occurred within 6 days after treatment. The LD50 calculated is 1037 mg/kg bw (95% confidence limits are 668 -1403 mg/kg).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 037 mg/kg bw
Quality of whole database:
Data from rat, mouse and chinese hamster are available. The rat is the most sensitive species.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

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
Study period:
May 21 - June 10, 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well-documented pre-guideline study without GLP, testing protocol similar to OECD 402
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
pre-guideline and pre-GLP study
Principles of method if other than guideline:
According to: Noakes, D.N. and Sanderson, D.M. (1969). A method for determining the dermal toxicity of pesticides. Brit. J. Indust. Med. 26, pp 59-64.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Tif:RAIf (SPF)
Sex:
male/female
Details on test animals and environmental conditions:
Healthy random bred Rats of 8-9 weeks age were raised on the premises and kept at room temperature of 22 + 2 deg. C, at relatie humidity of 55 +/- 10% and on a 10 hour light cylce day. They received ad libitum rat food (supplier: NAFAG, Gossau, Switzerland) and water. They were adapted to the laboratory for a minimum of 4 days before treatment. During treatment and observation period the animals were housed individually in Macrolon cages type 2.
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
Approximately 24 hours before treatement an area of approximately 60 square centimeters was shaved with an electric clipper. For the treatment the test material was evenly dispersed on the skin with a syringe and was covered with an occlusive dressing which was fastened around the trunk with an adhesive elastic bandage. After 24 hours the dressing was removed, the skin was cleaned with lukewarm water and the reaction of the skin was appraised.
Duration of exposure:
24 hours
Doses:
0 - 3000 - 3500 - 4000 mg/kg bw Treatment with higher doses was not possible

No. of animals per sex per dose:
5 males and 5 females

Control animals:
yes, concurrent no treatment
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations: 1 / hour for the first 5 hours, thereafter at least 1 / day. Body weight determination 1 / week
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:
not required
Sex:
male/female
Dose descriptor:
LD0
Effect level:
> 4 000 mg/kg bw
Based on:
test mat.
Mortality:
no mortality observed during the observation period of 14 days following treatment
Clinical signs:
Animals treated with 4000 mg/kg bw showed a moderate skin erithema (days 2-8) and a slight skin erythema on day 9.
Slight effects recorded are sedation (days 1-5), dyspnea (days 1-6), exophthalmos (days 1-7), ruffled fur (days 1-8) and curved body position (days 1-6).

Animals treated with 3500 mg/kg bw showed a moderate skin erithema (days 2-7) and a slight skin erythem(days 8-9).
Slight effects recorded are sedation (days 1-5), dyspnea (days 1-6), exophthalmos (days 1-7), ruffled fur (days 1-8) and curved body position (days 1-6).

Animals treated with 3000 mg/kg bw showed a moderate skin erithema (days 2-7) and a slight skin erythema (days 8-9).
Slight effects recorded are sedation (days 1-2), dyspnea (days 1-6), exophthalmos (days 1-7), ruffled fur (days 1-8) and curved body position (days 1-6).
Body weight:
The following body weight changes were recorded :

Control 3000 mg/kg 3500 mg/kg 4000 mg/kg
males 1st week 12% 4% 5% -1%
2nd week 19% 9% 21% 21%

Control 3000 mg/kg 3500 mg/kg 4000 mg/kg
females 1st week 3% -1% -1% -4%
2nd week 7% 13% 10% 11%
Gross pathology:
No substance related gross organ changes were seen.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute toxicity is similar for males and females. The acute dermal toxicity is >4000 mg/kg bw.
Executive summary:

The acute dermal toxicity has been investigated in a pre-guideline and pre-GLP study performed and recorded similarly to the later standards. The doses selected were 4000, 3500 and 3000 mg/kg bw. Each 5 male and 5 female animals were treated on the shaved skin (60 cm2) and received an occlusive patch . There was no mortality in all dose groups. At all doses there were the usual clinical symptoms in animals of both sexes. The LD50 derived is >4000 mg/kg.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
4 000 mg/kg bw

Additional information

Oral:

The acute toxicity of p-(2,3-epoxypropoxy)-N,N-bis(2,3-epoxypropyl)aniline was assessed on three different species: Chinese hamster, mouse and rats which is the most sensitive species.

In the first experiment, in Chinese hamsters, the acute oral LD50 of the test material was determined in both sexes and animals were

observed over a period of 14 days. The LD50 is found to be 2739 (2276-3429) mg/kg. The test material has therefore a slight acute toxicity to Chinese hamsters by this route of administration.

In the second experiment, the acute toxicity has been investigated in mouse. Each 5 male and 5 female were trated by gavage application with the test substance suspended in PEG 400 at doses seleceted: 3000 -2500 -1500 -1000 and 600 mg/kg bw.

Mortality was 100% at the top dose in females and 80% in the top dose in males. Mortality at the lower dose was 80% in both sexes, 80% in males and 60% in females of the middle group. Mortality was 20% in males and 0% in females at 1000 mg/kg bw. The low dose was without mortality in males and 20% in females. At all doses there were the usual clinical symptoms in animals of both sexes. Mortality occurred within 4 days after treatment. The LD50 calculated is 1413 mg/kg bw (95% confidence limits are 1024 -1873 mg/kg).

In the third experiment which is the Key study, the acute toxicity has been investigated in rats, 5 male and 5 female were used in each group. The doses selected were 3000 -2000 -1000 and 400 mg/kg bw. The test system was supsended in PEG 400.

Mortality was 100% at the top dose in both sexes. Mortality at the lower dose was 80% in both sexes, 40% in males and 80% in females at 1000 mg/kg bw. The low dose was without mortality in both sexes. At all doses there were the usual clinical symptoms in animals of both sexes. Mortality occurred within 6 days after treatment. The LD50 calculated is 1037 mg/kg bw (95% confidence limits are 668 -1403 mg/kg).

Dermal:

The acute dermal toxicity has been investigated in rats. The doses selected were 4000, 3500 and 3000 mg/kg bw. Each 5 male and 5 female animals were treated on the shaved skin (60 cm2) and received an occlusive patch . There was no mortality in all dose groups. At all doses there were the usual clinical symptoms in animals of both sexes. The LD50 derived is >4000 mg/kg.


Justification for selection of acute toxicity – dermal endpoint
The acute dermal toxicity has been investigated in a pre-guideline and pre-GLP study performed and recorded similarly to the later standards. The doses selected were 4000, 3500 and 3000 mg/kg bw. Each 5 male and 5 female animals were treated on the shaved skin (60 cm2) and received an occlusive patch . There was no mortality in all dose groups. At all doses there were the usual clinical symptoms in animals of both sexes. The LD50 derived is >4000 mg/kg.

Justification for classification or non-classification

According to Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures, p-(2,3-epoxypropoxy)-N,N-bis(2,3-epoxypropyl)aniline should be classified for acute oral toxicity as Category 4 and should be labeled as H302: Harmful if swallowed.

p-(2,3-epoxypropoxy)-N,N-bis(2,3-epoxypropyl)aniline does not have to be classified for acute dermal toxicity to Regulation (EC) No 1272/2008.