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Description of key information

Oral (OECD 401), rat: LD50: > 2000 mg/kg bw (limit test)

Dermal (OECD 402), rat: LD50: > 2000 mg/kg bw (limit test)

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:
12 Nov - 3 Dec 1996
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
adopted 24 Feb 1987
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Version / remarks:
Commission Directive 92/69/EEC
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
THE DEPARTMENT OF HEALTH OF THE GOVERNMENT OF THE UNITED KINGDOM
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Remarks:
Crl: CD®BR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Ltd., Margate, UK
- Females nulliparous and non-pregnant: not specified
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: 221 - 239 g (males) and 213 - 233 g (females)
- Fasting period before study: Animals were fasted overnight prior to dosing and approx. 4 h after dosing.
- Housing: in groups of up to 5 animals by sex in solid-floor polypropylene cages, wood flakes bedding
- Diet: Rat and Mouse Expanded Diet No. 1 (Special Diets Services Limited, Witham, Essex, UK), ad libitum
- Water: mains drinking water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 21
- Humidity (%): 46 - 55
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
oral: gavage
Vehicle:
DMSO
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle: 10 mL/kg bw

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
Range-finding study: 1 male and 1 female
Main study: 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: 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 body weights were recorded prior to dosing on Day 0 and on Days 7 and 14 or at death.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, gross pathology
Preliminary study:
In the range-finding study, no deaths were reported. Clinical signs of toxicity noted were ataxia, hunched posture, lethargy, pilo-erection, ptosis, decreased respiratory rate, laboured respiration and splayed gait. Based on this information, a dose level of 2000 mg/kg body weight 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:
2/5 males were found dead 2 days after dosing.
Clinical signs:
Common signs of systemic toxicity noted for were ataxia, hunched posture, lethargy, decreased respiratory rate and laboured respiration with additional signs of ptosis, increased salivation and red/brown stains around the mouth or snout. lncidents of systemic toxicity noted were pilo-erection, gasping and noisy respiration, loss of righting reflex and splayed gait. Surviving animals recovered 3 - 6 days after dosing.
Body weight:
Surviving animals showed expected gain in body weight during the study except for one female which showed body weight loss during the first week and expected gain in bodyweight during the second week.
Gross pathology:
Abnormalities noted at necropsy of the males that died during the study were haemorrhagic lungs, dark liver and dark kidneys. No abnormalities were noted at necropsy of animals that were killed at the end of the study.

Table 1. Results of the acute oral toxicity study.

Dose level

(mg/kg bw)

Mortalities

Clinical signs

 

n

n

males

2000

2/5

5/5

females

2000

0/5

5/5

Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008
Conclusions:
In this acute oral toxicity study in rats an LD50 value of > 2000 mg/kg bw was found.
Executive summary:

A study was performed to assess the acute oral toxicity of the test material in the Sprague-Dawley CD strain rat according to OECD Guideline 401. A group of ten fasted animals (five males and five females) was given a single oral dose of test material as a solution in dimethyl sulphoxide 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. Two males were found dead two days after dosing. Common signs of systemic toxicity noted were ataxia, hunched posture, lethargy, decreased respiratory rate and laboured respiration with additional signs or incidents of pilo-erection, ptosis, gasping and noisy respiration, loss of righting reflex, increased salivation, red/brown stains around the mouth or snout and splayed gait. Surviving animals recovered three to six days alter dosing. The LD50 was > 2000 mg/kg.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Quality of whole database:
The available information comprises an adequate, reliable (Klimisch score 1) and consistent study, and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

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:
19 Nov - 3 Dec 1996
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
adopted 24 Feb 1987
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
Commission Directive 92/69/EEC
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
THE DEPARTMENT OF HEALTH OF THE GOVERNMENT OF THE UNITED KINGDOM
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Remarks:
Crl:CD®BR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Ltd, Margate, UK
- Females nulliparous and non-pregnant: not specified
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: 209 - 227 g (males) and 204 - 214 g (females)
- Housing: individually during 24 h exposure period and in groups of 5 by sex for the remainder of the study in polypropylene cages, woodflake bedding
- Diet: Rat and Mouse Expanded Diet No.1 (Special Diets Services Limited, Witham, Essex, UK), ad libitum
- Water: mains drinking water, ad libitum
- Acclimation period: minimum of 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 21, On one occasion the temperature was below the limit specified in the protocol (19 °C). This deviation was considered not to affect the purpose or integrity of the study.
- Humidity (%): 50 - 56
- Air changes (per hr): approx. 15
- Photoperiod (hrs dark / hrs light): 12 / 12
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Remarks:
moistened with distilled water
Details on dermal exposure:
TEST SITE
- Area of exposure: clipped area on back and flanks
- % coverage: approx. 10%
- Type of wrap if used: A piece of surgical gauze was placed over the treatment area and semioccluded with a piece of self-adhesive bandage. The bandage was further secured with a piece of BLENDERM wrapped around each end.

REMOVAL OF TEST SUBSTANCE
- Washing: Treated skin and surrounding hair was wiped with cotton wool moistened with distilled water to remove any residual test material.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount applied: 2000 mg/kg bw
- Concentration: 100%
- Constant volume or concentration used: yes
- For solids, paste formed: yes, moinstened with distilled water

Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
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 deaths or overt signs of toxicity 1/2, 1, 2 and 4 h 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 evidente of primary irritation and scored according to Draize Score. Individual body weights were recorded prior to application of the test material on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during the study period.

Clinical signs:
No clinical signs of toxicity were observed up to the end of the 14-day observation period.
Body weight:
All animals showed expected gain in body weight during the whole study period.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
- Other observations: No signs of skin irritation were noted during the study.
Interpretation of results:
GHS criteria not met
Conclusions:
In this acute dermal toxicity study in rats an LD50 value of > 2000 mg/kg bw was found.
Executive summary:

A group of ten animals (five males and five females) was given a single oral dose of test material as a solution in dimethyl sulphoxide at a dose level of 2000 mg/kg bodyweight. The study was performed according to OECD guideline 402 and GLP. The animals were observed for fourteen days and were then killed and subjected to gross pathological examination. 2/5 males were found dead. Signs of systemic toxicity noted were ataxia, hunched posture, lethargy, decreased respiratory rate and laboured respiration with additional signs or incidents of pilo-erection, ptosis, gasping and noisy respiration, loss of righting reflex, increased salivation, red/brown stains around the mouth or snout and splayed gait. Surviving animals recovered three to six days alter dosing. Abnormalities noted at necropsy of the males that died during the study were haemorrhagic lungs, dark liver and dark kidneys. No abnormalities were noted at necropsy of animals that were killed at the end of the study. The LD50 >2000 mg/kg.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate, reliable (Klimisch score 1) and consistent study, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

Oral

The acute oral toxicity of the test substance was assessed in a study according to OECD Guideline 401 and in compliance with GLP (1996). Based on a preliminary study, groups of 5 male and female rats were given a test substance dose of 2000 mg/kg bw (limit test) via gavage. 2/5 males and 0/5 females died. All animals revealed signs of toxicity within 24 h, surviving animals recovered on Day 3 - 6. Thus, an oral LD50 > 2000 mg/kg bw was determined.

Dermal

The acute dermal toxicity of the test substance was assessed in a study according to OECD Guideline 402 and in compliance with GLP (1996). Groups of 5 male and 5 female rats were treated with the test substance for 24 hrs at a concentration of 2000 mg/kg bw under semiocclusive conditions. No mortality or signs of toxicity occurred during the study period. Thus, a dermal LD50 > 2000 mg/kg bw was determined.

Justification for classification or non-classification

The available data on acute oral and dermal toxicity of the test substance do not meet the criteria for classification according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.