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

Endpoint summary

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:

24.04.1995 - 15.05.1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Male and female Sprague-Dawley CD strain rats supplied by Charles River (UK) Ltd., Margate, Kent, UK were used. At the start of the main study the males weighed 140 to 150 g, and the females 128 to 136 g, and were five to eight weeks of age. After an acclimatisation period of at least 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 groups of up to five by sex in solid-floor polypropylene cages furnished with woodflakes. With the exception of an overnight fast immediately before dosing and for approximately two hours after dosing, 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 23 °C and relative humidity of 45 to 55%. 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.

Route of administration:

oral: gavage

Vehicle:

arachis oil

Details on oral exposure:

For the purpose of the study the test material was freshly prepared, as required, as a suspension at the appropriate concentration in arachis oil B. P.. Determination by analysis of the concentration, homogeneity and stability of the test material preparations was not appropriate because it was not specified in the Study Plan and is not a requirement of the Test Guideline.
All animals were dosed once only by gavage using a metal cnnula attached to a graduate syringe. The volume administered to each animal was calculated according to its fasted bodyweight at the time of dosing.

Doses:

2000 mg/kg bodyweight

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

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.
Individual bodyweights were recorded prior to dosing on Day 0 and on Day 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 for examination of major organs. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Preliminary study:

A range-finding study was performed to establish a dosing regime as follows:
Dose level: 2000 mg/kg bw; concentration: 200 mg/ml; 1 male and 1 female rat
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 5 days.
Individual bodyweights were recorded on the day of dosing to allow calculation of individual treatment volumes. No necropsies were performed.
There were no deaths. Clinical signs of toxicity noted were hunched posture, lethargy, decreased respiratory rate and laboured and noisy respiration up to three days after dosing.
Based on this information, a dose level of 2000 mg/kg bodyweight was selected for the main study.

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 levels:
No death occured. Hunched posture, lethargy and decreased respiratory rate were observed up to two days after dosing.

Body weight:

3-0 Male: Day 0 (141 g); Day 7 (196 g); Day 14 (239 g)
3-1 Male: Day 0 (148 g); Day 7 (212 g); Day 14 (271 g)
3-2 Male: Day 0 (150 g); Day 7 (228 g); Day 14 (285 g)
3-3 Male: Day 0 (145 g); Day 7 (206 g); Day 14 (264 g)
3-4 Male: Day 0 (140 g); Day 7 (199 g); Day 14 (254 g)
4-0 Female: Day 0 (128 g); Day 7 (170 g); Day 14 (190 g)
4-1 Female: Day 0 (136 g); Day 7 (189 g); Day 14 (216 g)
4-2 Female: Day 0 (135 g); Day 7 (196 g); Day 14 (230 g)
4-3 Female: Day 0 (130 g); Day 7 (178 g); Day 14 (196 g)
4-4 Female: Day 0 (128 g); Day 7 (178 g); Day 14 (191 g)

Gross pathology:

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

Interpretation of results:

GHS criteria not met

Conclusions:

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

Executive summary:

A study was performed to assess the acute oral toxicity of the test material in the Sprague-Dawley CD strain rat. The method followed that in the OECD Guidelines for Testing of Chemicals No. 401 "Acute Oral Toxicity" (adopted 24 February 1987) and Method B1 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.

Following a range-finding study, a group of ten fasted animals (five males and five females) was given a single oral dose of test material as a suspension in arachis oil B.P. at a dose level of 2000 mg/kg bodyweight. The animals were observed for fourteen days after the day of dosing and were then killed and subjected to gross pathological examination.

There were no deaths. Hunched posture, lethargy and decreased respiratory rate were noted during the study.

All animals showed an expected increase in bodyweight during the study.

No abnormalities were noted at necropsy.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

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:

30.05.1995 - 13.06.1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

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.

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.

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.

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50