1H-Imidazole-1-ethanol, 4,5-dihydro-, 2-nortall-oil alkyl derivs.

Endpoint summary

Description of key information

The acute oral median lethal dose, (LD50) of the test material, in the Sprague-Dawley CD strain rat, was estimated as being greater than 2500 mg/kg bodyweight.
Under the conditions of the study, the acute dermal LD50 of the test material is considered to be greater than 2000 mg/kg body weight.

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:

The study was performed between 23 march 2000 and 11 April 2000.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class 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 (Cri : CD ® (SD) IGS BR) strain rats supplied by Charles River (UK) Ltd, Margate, Kent, UK were used. At the start
of the study the males weighed 201 to 211 g, and the females 223 to 231 g, and were eight to twelve weeks old. After an acclimatisation period of at least five days the animals were selected at random and given a number unique within the cage by taiI marking.

The animals were housed in groups of three by sex in solid-floor polypropylene cages furnished with woodflakes. With the exception of an overnight fast immediately before dosing and for approximately three to four 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 temperature and relative humidity were set to achieve limits of 19 to 25°C and 30 to 70% respectively. Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study. The rate of air exchange was approximately fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light and twelve hours darkness.

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 2.15 mL/kg

CLASS METHOD
- Rationale for the selection of the starting dose: The information available suggested a starting dose of 2000 mg/kg.

Doses:

2000 mg/kg

No. of animals per sex per dose:

3 animals of each sex per dose

Control animals:

no

Details on study design:

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 bodyweight at the time of dosing. Treatment of animals was sequential. Sufficient time was allowed between each sex to confirm the survival of the previously dosed animals.

The animals were observed for deaths or overt signs of toxicity 1/2, 1, 2 and 4 hours after dosing and subsequently once daiIy for up to fourteen days.

Individual bodyweights were recorded prior to dosing and seven and fourteen days after treatment or at death.

At the end of the observation period the surviving animals were killed by cervical dislocation. All animals were 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:

Not applicable.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 500 mg/kg bw

Remarks on result:

other: Mortalities were noted at 2000 mg/kg bodyweight.

Mortality:

Individual mortality data are given in Table 1 (attached background material).
One female was killed in extremis two days after dosing.

Clinical signs:

other: Individual clinical observations are given in Tables 2 and 3 (see attached background material). Clinical signs of toxicity commonly noted were hunched posture, lethargy, pi lo-erection and decreased respiratory rate with additional incidents of emaciatio

Gross pathology:

Individual necropsy findings are given in Tables 6 and 7 (see atttached background material).
Abnormalities noted at necropsy of the female that died during the study were haemorrhage and sloughing of the gastric mucosa, sloughing of the nonglandular epithelium of the stomach and haemorrhage of the small and large intestines. Abnormalities noted at necropsy of males that were killed at the end of the study were stomach adhered to the liver and/or white foci present over all of the non-glandular epithelium of the stomach. No abnormalities were noted at necropsy of females that were killed at the end of the study.

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 estimated to be greater than 2500 mg/kg bodyweight.
Mortalities were noted at 2000 mg/kg bodyweight.

Executive summary:

A study was performed to assess the acute oral toxicity of the test material following a single oral administration to the Sprague-Dawley CD strain rat. The method followed that in the OECD Guidelines for Testing of Chemicals No. 423 "Acute Oral Toxicity - Acute Toxic Class Method" (adopted 22 March 1996) and Method B1 tris of Commission Directive 96/54/EC (which constitutes Annex V of Council Directive 67/548/EEC) .

Using all available information, 2000 mg/kg bodyweight was selected as the starting dose.

A group of three fasted females was treated with the starting dose. This was followed by a group of three fasted animals of the other sex at the same dose level.

The undiluted test material was administered orally. The animals were observed ¹/₂, 1, 2 and 4 hours after dosing and then once daily for up to fourteen days. Bodyweights were recorded on Day 0 (day of dosing) and on Days 7 and 14, or at death. At the end of the observation period the surviving animals were killed by cervical dislocation and all animals were subjected to gross necropsy.

One female was killed in extremis two days after dosing.

Clinical signs of toxicity commonly noted were hunched posture, lethargy, piloerection and decreased respiratory rate with additional incidents of emaciation, diarrhoea, dehydration, ptosis, gasping, laboured and noisy respiration and staining around the eyes, mouth and snout. Surviving animals recovered four to seven days after dosing.

The surviving animals showed expected gains in bodyweight over the study period except for one female which showed slight bodyweight loss during the first week and expected gain in bodyweight during the second week of the study.

Abnormalities noted at necropsy of the female that died during the study were haemorrhage and sloughing of the gastric mucosa, sloughing of the non-glandular epithelium of the stomach and haemorrhage of the small and large intestines. Abnormalities noted at necropsy of males that were killed at the end of the study were stomach adhered to the liver and/or white foci present over all of the non-glandular epithelium of the stomach. No abnormalities were noted at necropsy of females that were killed at the end of the study.

The acute oral median lethal dose, (LD₅₀) of the test material, in the Sprague-Dawley CD strain rat, was estimated as being greater than 2500 mg/kg bodyweight. Mortalities were noted at a dose level of 2000 mg/kg bodyweight.

No symbol and risk phrase are required according to EU labelling regulations.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

2 500 mg/kg bw

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 August 1990 to 13 September 1990

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.

Qualifier:

according to guideline

Guideline:

EPA OPP 81-2 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hazelton Research Products, Inc., Denver PA
- Age at study initiation: Young adult
- Weight at study initiation: 2-3 kg
- Fasting period before study:
- Housing: Each animal was housed in a wire mesh cage.
- Diet: ad libitum; Agway ® ProLab Rabbit Formula (Agway, Inc., Syracuse, NY)
- Water: ad libitum; fresh tap water
- Acclimation period: five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not stated
- Humidity (%): Not stated
- Air changes (per hr): Not stated
- Photoperiod (hrs dark / hrs light): 12 hour light-dark cycle

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

EXPOSURE CALCULATION
The approximate area dosed on each rabbit was 130cm2. Based on an average body weight of 2.13 kg times the dose level of 2000 mg/kg, the average dose was determined to be 4260 mg. Therefore, the approximate amount of test material applied per unit of exposed skin was calculated to be 32.8 mg/cm2.

TEST SITE
The fur on the back of each rabbit was clipped with electric clippers on the day prior to dose administration. The test article was applied topically to the clipped area at a dose level of 2000 mg/kg body weight. Each test site was covered with gauze and then occluded with a layer of plastic wrap and a stockinette sleeve held in place with tape.

REMOVAL OF TEST SUBSTANCE
The binders were removed 24 hours after dose administration and the exposure sites gently wiped with a clean water-moistened gauze to remove as much non-absorbed test article as possible.

Duration of exposure:

24 hours

Doses:

2000 mg /kg body weight

No. of animals per sex per dose:

five male and five female

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed for pharmacotoxic signs and mortality three times on the day of dose administration and twice daily thereafter. Individual bodyweights were recorded prior to dose administration on study day 1 and on days 4, 8 and 15 (study termination).
- Necropsy of survivors performed: yes; All animals were euthanized with an injection of sodium pentobarbitol on study day 15 and subjected to gross necropsy examination. The external body surface and orifices, major visceral organs, body cavities and the carcass were examined and the results recorded. No tissues were saved.

Statistics:

No statistical analysis was performed.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 95% confidence limits not reported.

Mortality:

All animals survived to study termination.

Clinical signs:

other: A gel-like substance in the waste tray and soft stools.

Gross pathology:

No internal abnormalities were noted during gross necropsy examination of the animals. Gross necropsy confirmed eschar sloughing.

Other findings:

All animals appeared normal from study days 8-15. Test article application caused severe dermal irritation characterised by edema and eschar formation.

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this study, the acute dermal LD50 of the test material is considered to be greater than 2000 mg/kg body weight.

Executive summary:

The test material was applied topically to five male and five female New Zealand White Rabbits at a dose level of 2000 mg/kg body weight for a period of 24 hours. The animals were observed for pharmacotoxic signs and mortality during a 15 day observation period.

All animals survived to study termination (day 15). Under the conditions of this study, the acute dermal LD₅₀ of the test material is considered to be greater than 2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

Acute Oral:

A study was performed to assess the acute oral toxicity of the test material following a single oral administration to the Sprague-Dawley CD strain rat.

Using all available information, 2000 mg/kg bodyweight was selected as the starting dose.

The undiluted test material was administered orally. The animals were observed 0.5, 1, 2 and 4 hours after dosing and then once daily for up to fourteen days. Bodyweights were recorded on Day 0 (day of dosing) and on Days 7 and 14, or at death. At the end of the observation period the surviving animals were killed by cervical dislocation and all animals were subjected to gross necropsy.

One female was killed in extremis two days after dosing.

Clinical signs of toxicity commonly noted were hunched posture, lethargy, piloerection and decreased respiratory rate with additional incidents of emaciation, diarrhoea, dehydration, ptosis, gasping, laboured and noisy respiration and staining around the eyes, mouth and snout. Surviving animals recovered four to seven days after dosing.

Abnormalities noted at necropsy of the female that died during the study were haemorrhage and sloughing of the gastric mucosa, sloughing of the non-glandular epithelium of the stomach and haemorrhage of the small and large intestines. Abnormalities noted at necropsy of males that were killed at the end of the study were stomach adhered to the liver and/or white foci present over all of the non-glandular epithelium of the stomach. No abnormalities were noted at necropsy of females that were killed at the end of the study.

The acute oral median lethal dose, (LD₅₀) of the test material, in the Sprague-Dawley CD strain rat, was estimated as being greater than 2500 mg/kg bodyweight. Mortalities were noted at a dose level of 2000 mg/kg bodyweight.

No symbol and risk phrase are required according to EU labelling regulations.

Acute Dermal:

The test material was applied topically to five male and five female New Zealand White Rabbits at a dose level of 2000 mg/kg body weight for a period of 24 hours. The animals were observed for pharmacotoxic signs and mortality during a 15 day observation period.

All animals survived to study termination (day 15). Under the conditions of this study, the acute dermal LD₅₀ of the test material is considered to be greater than 2000 mg/kg body weight.

Justification for classification or non-classification

Based on the results of these studies (LD50 oral >2500 mg/kg bw and LD50 dermal >2000 mg/kg bw) the test material can be considered to be non-classified for acute oral toxicity and acute dermal toxicity.