Bis(2,3-epoxypropyl) phthalate

Endpoint summary

Description of key information

Oral Toxicity

The acute oral median lethal dose (LD₅₀) of the test item in the female Wistar strain rat was estimated to be in the range of 300 - 2000 mg/kg body weight (Globally Harmonized Classification System - Category 4).

Dermal Toxicity

The acute dermal median lethal dose (LD₅₀) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight. The test item does not meet the criteria for classification according to the Globally Harmonized System of Classification and Labelling of Chemicals.

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:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

female

Route of administration:

oral: gavage

Vehicle:

DMSO

Details on oral exposure:

A total of five animals were therefore treated at a dose level of300 mg/kg in the study. All animals were dosed once only by gavage, using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to the fasted body weight at the time of dosing. Treatment of animals was sequential. Sufficient time was allowed between each dose group to confirm the survival of the previously dosed animals.

Doses:

2000 mg/kg bw
300 mg/kg bw

No. of animals per sex per dose:

2000 mg/kg bw: 1 female
300 mg/kg bwL 5 females

Control animals:

no

Details on study design:

Clinical observations were made 30 minutes, 1, 2, and 4 hours after dosing and then daily for up to 14 days. Morbidity and mortality checks were made twice daily. Individual body weights were recorded on Day 0 (the day of dosing) and on Days 7 and 14. Due to a technician error the body weight at death was not performed on the animal treated at a dose level of 2000 mg/kg that was humanely killed 4 hours after dosing. At the end ofthe observation period the surviving animals were killed by cervical dislocation. All animals were subjected to gross necropsy. 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.

Statistics:

The following computerized system was used in the study:
Delta Controls - ORCA view

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 300 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

The animal treated at 2000 mg/kg bw was killed for humane reasons, 4 hours after dosing, due to the occurrence of clinical signs of toxicity that approached the severity limit set forth in the UK Home Office
Project Licence. There were no deaths at the 300 mg/kg dose level.

Clinical signs:

other: At the 2000 mg/kg dose level signs of systemic toxicity noted were hunched posture, pilo-erection, ataxia, ptosis, labored respiration, cyanosis, hypothermia, dehydration and prostration. No signs of systemic toxicity were noted during the observation per

Gross pathology:

At the 2000 mg/kg dose level, abnormalities noted at necropsy were dark liver, brown colored lumpy substance (feces) in the stomach and epithelial sloughing of the gastric mucosa and non-glandular epithelium of the stomach. No abnonnalities were noted at necropsy at the 300 mg/kg bw dose level.

Body weight

Dose Level mglkg	Animal Number    and Sex	Body Weight (g) at Day			Body Weight Gain (g) During Week
		0	7	14	1	2
300	1-0 Female	152	165	179	13	14
	3-0 Female	147	160	179	13	19
	3-1 Female	145	170	181	25	11
	3-2 Female	153	173	187	20	14
	3-3 Female	162	180	193	18	13

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The acute oral median lethal dose (LDso) of the test item in the female Wistar strain rat was estimated to be in the range of 300 - 2000 mg/kg body weight (Globally Harmonized Classification System - Category 4).

Executive summary:

Introduction

The study was performed to assess the acute oral toxicity of the test item in the Wistar strain rat.

Methods

Following a sighting test at dose levels of 2000 mg/kg and 300 mg/kg, a further group of four fasted females was given a single oral dose of test item, as a solution in dimethyl sulphoxide, at a dose level of 300 mg/kg body weight. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy.

Results

Mortality. The animal treated at a dose level of 2000 mg/kg was killed for humane reasons, 4 hours after dosing, due to the occurrence of clinical signs of toxicity that approached the severity limit set forth in the UK Home Office Project Licence. There were no deaths at a dose level of 300 mg/kg.

Clinical Observations. Signs of systemic toxicity noted in the animal treated at a dose level of 2000 mg/kg were hunched posture, pilo-erection, ataxia, ptosis, labored respiration, cyanosis, hypothermia, dehydration and prostration. There were no signs of systemic toxicity at a dose level of 300 mg/kg.

Body Weight. Surviving animals showed expected gains in body weight.

Necropsy. Abnormalities noted at necropsy of the animal treated at a dose level of 2000 mg/kg were dark liver, brown colored lumpy substance (feces) in the stomach and epithelial sloughing of the gastric mucosa and non-glandular epithelium of the stomach. No abnormalities were noted at necropsy of animals treated at a dose level of 300 mg/kg.

Conclusion

The acute oral median lethal dose (LD₅₀) of the test item in the female Wistar strain rat was estimated to be in the range of 300 - 2000 mg/kg body weight (Globally Harmonized Classification System - Category 4).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

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:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Five male and five female Wistar (RccHan™:WIST) strain rats were supplied by Envigo RMS (UK) Limited, Oxon, UK. On receipt the animals were randomly allocated to cages. The females were nulliparous and non-pregnant. After an acclimatization period of at least 5 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. At the start of the study the animals weighed at least 200 g, and were 8 to 12 weeks of age. The weight variation did not exceed ±20% of the mean weight for each sex.

The temperature and relative humidity were set to achieve limits of 19 to 25°C and 30 to 70% respectively. The rate of air exchange was at least fifteen 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:

unchanged (no vehicle)

Details on dermal exposure:

The calculated volume of test item, as received, was applied as evenly as possible to an area of shorn skin (approximately 10% of the total body surface area) using a graduated syringe. A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage. The animals were caged individually throughout the study. Shortly after dosing the dressings were examined to ensure that they were securely in place.

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

4

Control animals:

no

Details on study design:

After the 24-Hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with dimethyl sulphoxide followed by distilled water to remove any residual test item. As no mortalities were noted a further group of animals (four males and four females) was similarly treated with the test item at a dose level of 2000 mg/kg body weight to give a total of five males and five females. The animals were caged individually for the 24-Hour exposure period. After the 24-Hour contact period the bandages were carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with dimethyl sulphoxide followed by distilled water to remove any residual test item. These animals were returned to group housing for the remainder of the test period.

The animals were observed for deaths or overt signs of toxicity 30 minutes, 1,2 and 4 hours after dosing and subsequently once daily for 14 days.

After removal of the dressings and subsequently once daily for 14 days, the test sites were examined for evidence of primary irritation and scored.

At the end of the study the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. 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.

Statistics:

The following computerized system was used in the study:
Delta Controls - ORCA view

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths.

Clinical signs:

other: No signs of systemic toxicity were noted during the observation period.

Gross pathology:

No abnormalities were noted at necropsy.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight. The test item does not meet the criteria for classification according to the Globally Harmonized System of Classification and Labelling of Chemicals.

Executive summary:

Introduction

The study was performed to assess the acute dermal toxicity of the test item in the Wistar strain rat.

Methods

Initially, two animals (one male and one female) were given a single, 24 hour, semi-occluded dermal application of the undiluted test item to intact skin at a dose level of 2000 mg/kg body weight. Based on the results of the initial test, a further group of eight animals (four males

and four females) was similarly treated. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy.

Results

Mortality. There were no deaths.

Clinical Observations. There were no signs of systemic toxicity.

Dermal Irritation. There were no signs of dermal irritation.

Body Weight. All animals showed expected gains in body weight.

Necropsy. No abnormalities were noted at necropsy.

Conclusion

The acute dermal median lethal dose (LD₅₀) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight. The test item does not meet the criteria for classification according to the Globally Harmonized System of Classification and Labelling of Chemicals.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed