4-oxo-4-(p-tolyl)butyric acid adduct with 4-ethylmorpholine

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

30.05.1995 - 13.06.1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1995

Report date:

1995

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

419-240-6

EC Name:

-

Cas Number:

171054-89-0

Molecular formula:

Hill formula: C28H37NO7 CAS formula: (C11H12O3)2.C6H13NO

IUPAC Name:

bis(4-(4-methylphenyl)-4-oxobutanoic acid); 4-ethylmorpholine

Test material form:

solid: crystalline

Details on test material:

Sponsor's identification: TKA 40074 (CGCI 1405)
cream coloured
2:1 adduct of Benzenebutanoic acid, 4-methyl-gamma-oxo and 4-ethylmorpholine
batch No.: 1/94

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Five male and five female Sprague-Dawley strain rats were supplied by Charles River (UK) Ltd. Margate, Kent. At the start of the study the males weighed 231 to 257 g, and the females 227 to 240 g, and were approximately ten to fourteen weeks old. After a minimum acclimatisation period of five days the animals were selected at random and given a number unique within the study by indelible ink-marking on the tail and a number written on a cage card.
The animals were housed in suspended polypropylene cages furnished with woodflakes. The animals were housed individually during the 24-hour exposure period and in groups of five, by sex, for the remainder of the study. Free access to mains drinking water and food (Rat and Mouse Expanded Diet No. 1, Special Diets Services Limited, Witham, Essex, UK) was allowed throughout the study.
The animal room was maintained at a temperature of 19 to 25 °C and relative humidity of 44 to 60%. The rate of air exchange was approximately 15 changes per hour and the lighting was controlled by a time switch to give 12 hours continuous light and 12 hours darkness.

Administration / exposure

Type of coverage:

semiocclusive

Vehicle:

arachis oil

Remarks:

shorn skin was moisted with arachis oil

Details on dermal exposure:

On the day before treatment the back and flanks of each animal were clipped free of hair using veterinary clippers.
A group of five male and five female rats were treated with the test material at a dose level of 2000 mg/kg.
The appropriate amount of the test material, as received, was applied uniformly to an area of shorn skin (approximating to 10% of the total body surface area) which had previously been moistened with arachis oil B. P.. A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage (HYPERTIE). The bandage was further secured with a piece of BLENDERM wrapped around each end. The animals were caged individually for the 24-hour exposure period. Shortly after dosing the dressings were examined to ensure that they were securely in place.
The animals were observed for deaths or overt signs of toxicity 1/2, 1, 2 and 4 hours after dosing and subsequently once daily for 14 days.
After the 24-hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with arachis oil B. P. to remove any residual test material. The animals were returned to group housing for the remainder of the study period.
After removal of the dressings and subsequently once daily for 14 days, the test sites were examined for evidence of primary irritation and scored according to the following scale from Draize J. H. (1977) "Dermal and Eye Toxicity Tests" In: Principles and Procedures for Evaluating the Toxicity of Household Substances, National Acedemy of Siences, Washington D. C., p. 31.

Duration of exposure:

24 h

Doses:

2000 mg/kg

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

On the day before treatment the back and flanks of each animal were clipped free of hair using veterinary clippers.
A group of five male and five female rats were treated with the test material at a dose level of 2000 mg/kg.
The appropriate amount of the test material, as received, was applied uniformly to an area of shorn skin (approximating to 10% of the total body surface area) which had previously been moistened with arachis oil B.P.. A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage (HYPERTIE). The bandage was further secured with a piece of BLENDERM wrapped around each end. The animals were caged individually for the 24-hour exposure period. Shortly after dosing the dressings were examined to ensure that they were securely in place.
The animals were observed for deaths or overt signs of toxicity 1/2, 1, 2 and 4 hours after dosing and subsequently once daily for 14 days.
After the 24-hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with arachis oil B.P. to remove any residual test material. The animals were returned to group housing for the remainder of the study period.
After removal of the dressings and subsequently once daily for 14 days, the test sites were examined for evidence of primary irritation and scored according to the following scale from Draize J. H. (1977) "Dermal and Eye Toxicity Tests" In: Principles and Procedures for Evaluating the Toxicity of Household Substances, National Academy of Sciences, Washington D. C., p. 31.
Any other skin reactions, if present, were also recorded.
Individual bodyweights were recorded prior to application of the test material on Day 0 and on Days 7 and 14.
At the end of the study the animals were killed by cervical dislocation and subjected to gross pathological examination. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

Male: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0

Clinical signs:

Signs of toxicity related to dose level:
No deaths occured and no signs of sytemic toxicity were observed.

Body weight:

1-0 Male: Day 0 (241 g); Day 7 (276 g); Day 14 (325 g)
1-1 Male: Day 0 (253 g); Day 7 (279 g); Day 14 (311 g)
1-2 Male: Day 0 (257 g); Day 7 (295 g); Day 14 (339 g)
1-3 Male: Day 0 (249 g); Day 7 (282 g); Day 14 (340 g)
1-4 Male: Day 0 (231 g); Day 7 (259 g); Day 14 (319 g)
2-0 Female: Day 0 (232 g); Day 7 (238 g); Day 14 (264 g)
2-1 Female: Day 0 (240 g); Day 7 (250 g); Day 14 (270 g)
2-2 Female: Day 0 (231 g); Day 7 (242 g); Day 14 (260 g)
2-3 Female: Day 0 (232 g); Day 7 (247 g); Day 14 (263 g)
2-4 Female: Day 0 (227 g); Day 7 (238 g); Day 14 (248 g)

Gross pathology:

Effects on organs:
No treatment-related macroscopic findings were observed.

Other findings:

Signs of toxicity (local):
Very slight erythema was noted in two females on day 1.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute dermal median lethal dose (LD50) of the test material in the Sprague-Dawley strain rat was found to be greater than 2000 mg/kg bodyweight.

Executive summary:

A study was performed to assess the acute dermal toxicity of the test material in the Sprague-Dawley strain rat. The method used followed that described in the OECD Guidelines for Testing of Chemicals No. 402 "Acute Dermal Toxicity" (adopted 24 February 1987) and Method B3 of Commission Directive 92/69/EEC (which constitutes Annex V of Council Directive 67/548/EEC).

The results may be used as a basis for classification and labelling under Annex VI of Council Directive 67/548/EEC (as adapted to technical progress by Commission Directive 93/21/EEC) relating to the classification, packaging and labelling of dangerous substances.

A group of ten animals (five males and five females) was given a single 24-hour, semi-occluded dermal application to intact skin at a dose level of 2000 mg/kg bodyweight. The animals were observed for fourteen days after the day of treatment and were then killed for gross pathological examination.

There were no deaths. No signs of systematic toxicity were noted during the study. Very slight erythema was noted in two females on day 1. No other signs of skin irritation were noted.

All animals showed expected gain in bodyweight during the study.

No abnormalities were noted at necropsy.

The acute dermal median lethal dose (LD₅₀) of the test material in the Sprague-Dawley strain rat was found to be greater than 2000 mg/kg bodyweight. No symbol and risk phrase are required according to EU labelling regulations.