Registration Dossier

Administrative data

Description of key information

The acute oral LD50 was estimated to be in the range of 300 - 2000 mg/kg bodyweight, as determined in a reliable study conducted according to current OECD guideline and in compliance with CLP (Harlan 2012).

An acute inhalation LC50 of 1485 ppm (equivalent 5.2 mg/l) bw is reported in a reliable study conducted according to a protocol equivalent to current guideline, but not in compliance with GLP (Terrill, 1989).

An acute dermal LD50 value of >2000 mg/kg bw is reported in a reliable study conducted according to current OECD guideline and in compliance with GLP (Harlan 2013).

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:
2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Conducted according to an appropriate OECD guideline and under GLP.
Qualifier:
according to
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan laboratories, UK
- Age at study initiation: 8-12 weeks
- Weight at study initiation: not specified
- Fasting period before study: overnight and until 3-4 hours after doswing
- Housing: In groups of 4, in suspendedsolid-floor polypropylene cages, furnished with woodflakes.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: minimum five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Air changes (per hr): minimum 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

Doses:
300, 2000 mg/kg bw
No. of animals per sex per dose:
2000 mg/kg bw, 1 female
300 mg/kg bw, 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were made 0.5, 1, 2 and 4 hours after dosing and daily for up to 14 days. Morbidity and mortality checks were made twice daily. Individual body weights were recorded on day 0 and on days 7 and 14 or at death. Due to a technician error, the body weight at death was not recorded for the animal treated at a dose level of 2000 mg/kg that was humanely killed.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: Necropsy consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities were recorded. No tissues were retained.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 mg/kg bw
Based on:
test mat.
Mortality:
The animal dosed at the 2000 mg/kg dose level was killed for humane reasons thirty minutes after dosing, due to the occurrence of clinical signs of toxicity which exceeded the severity limit set forth in the UK Home Office Project License. There were no deaths at the 300 mg/kg dose level.
Clinical signs:
Signs of systemic toxicity noted thirty minutes after dosing at the 2000 mg/kg dose level were laboured respiration, decreased respiratory rate, hypothermia and pallor of the extremities. The animal was also comatose. No signs of systemic toxicity were noted during the observation period at the 300 mg/kg dose.
Body weight:
All animals showed expected gains in bodyweight over the observation period.
Gross pathology:
Haemorrhage and epithelial sloughing of the non-glandular epithelium of the stomach and clear fluid present in the stomach were noted at necropsy of the animal treated at a dose level of 2000 mg/kg. No abnormalities were noted at necropsy in the animals dosed at 300 mg/kg.
Interpretation of results:
Category 4 based on GHS criteria
Remarks:
Migrated information
Conclusions:
The acute oral LD50 was estimated to be in the range of 300 - 2000 mg/kg bodyweight, as determined in a reliable study conducted according to current OECD guideline and in compliance with CLP.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
5 231 mg/m³

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:
2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Conducted according to an appropriate OECD guideline and under GLP.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories, UK
- Weight at study initiation: minimum 200 g
- Age at study initiation: 8-12 weeks
- Fasting period before study:
- Housing: individually, during exposure period and in groups of 4, by sex, for the remainder of the study in suspended solid-floor polypropylene cages furnished with woodflakes
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: minimum 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Air changes (per hr): minimum 15
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: the back and the flanks
- % coverage: 10
- Type of wrap if used: A piece of surgical gauze was laced over the treatment area and semi-occluded with a piece of self-adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): after the exposure period, the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with distilled water to remove any residual test item.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2.35 ml/kg

Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 males, 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 0.5, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days. The test sites were also examined for evidence of primary irritation and scored according to Draize. Individual body weights were recorded prior to application of the test item on Day 0 and on days 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: The gross necropsyconsisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
There were no deaths.
Clinical signs:
There were no signs of systemic toxicity. There were no signs of dermal irritation.
Body weight:
Animals showed expected gains in bodyweight over the study period, except for one female which showed expected gain in bodyweight during the first week but no gain in bodyweight during the second week.
Gross pathology:
No abnormalities were noted at necropsy.
Interpretation of results:
study cannot be used for classification
Remarks:
Migrated information
Conclusions:
An acute dermal LD50 value of >2000 mg/kg bw is reported in a reliable study conducted according to current OECD guideline and in compliance with GLP.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50

Additional information

The key study for acute oral toxicity reports an LD50 value between 300 and 2000 mg/kg bw in rat (Harlan 2013). The one animal which was dosed at the 2000 mg/kg bw dose level was killed due to severity of clinical signs thirty minutes after dosing. These signs included laboured respiration, decreased respiratory rate, hypothermia and pallor of the extremities and the test animal was also comatose. Haemorrhage and epithelial sloughing of the non-glandular epithelium of the stomach and clear fluid present in the stomach were noted at necropsy. There were no deaths at the 300 mg/kg bw dose level. No signs of systemic toxicity were noted during the observation period. All animals showed expected gains in bodyweight over the observation period. No abnormalities were noted at necropsy in the animals dosed at 300 mg/kg bw. A reliability 4 supporting study for acute oral toxicity was also available with limited data reported (Deichmann 1969). The study reports an acute oral LD50 of 3800 mg/kg bw.

A reliability 4 study for acute inhalation toxicity is available with limited data reported (Deichmann 1969). The study reports an acute inhalation LC50 of 22 mg/l bw. No classification for acute inhalation toxicity is proposed due to the low reliability of the only inhaled study available.

The key study for acute dermal toxicity reports an LD50 value of >2000 mg/kg bw in rat. There were no deaths during the study. There were no signs of systemic toxicity or dermal irritation. All the animals showed expected gains in bodyweight over the study period, except for one female which showed expected gain in bodyweight during the first week but no gain in bodyweight during the second week. No abnormalities were noted at necropsy.

A reliability 4 supporting study for acute dermal toxicity was also available with limited data reported (Deichmann 1969). The study reports an acute dermal LD50 of 4500 mg/kg bw.

Justification for selection of acute toxicity – oral endpoint

The only reliable study available.

Justification for selection of acute toxicity – inhalation endpoint

The only reliable study available.

Justification for selection of acute toxicity – dermal endpoint

The only reliable study available.

Justification for classification or non-classification

Based on the available reliable data, classification is required for acute oral toxicity Category 4, H302: Harmful if swallowed, in accordance with current EC Regulation No. 1272/2008. No classification is required for acute dermal or inhalation toxicity based on the available data.