Registration Dossier

Administrative data

Description of key information

Oral acute toxicity:
LD50= 2976 mg/kg bw , key study with 5 rats per sex and per dose according to OECD Test Guideline 401.
Dermal acute toxicity:
LD50 > 2000 mg/kg, key study with 5 rats per sex and per dose according to OECD Test Guideline 402.

Inhalation: Data waiving: In accordance with column 2 of REACH Annex VIII, the study does not need to be conducted since exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size.

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:
From February 18 to February 28, 1991
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Necropsy of animals was not conducted. However, this deviation was not considered to have affected the scientific validity and interpretation of the results. No GLP.
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
(Necropsy of animals was not conducted. However, this deviation was not considered to have affected the scientific validity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River U.K. Ltd.
- Age at study initiation: 9-11 weeks
- Weight at study initiation: males: 190-269 g; females: 128-161 g
- Fasting period before study: fasted overnight
- Housing: Single sex groups of up to three rats in cages with stainless steel wire-mesh walls, floors and tops (33 cm x 22 cm x 16 cm). Paper-lined trays for excreta were placed beneath each cage and changes three times weekly.
- Diet (e.g. ad libitum): Pelleted diet (LAD1, Special Diet Services Ltd.), ad libitum.
- Water (e.g. ad libitum): from the public supply, ad libitum.
- Acclimation period: The animals were quarantined for a minimum of four days in a non-barrier animal room with access restricted to essential personnel. At least five days before dosing the animals were rehoused.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23 ºC
- Humidity (%): 30-70%
- Air changes (per hr): not documented.
- Photoperiod (hrs dark / hrs light): 12 hour day and 12 hour night


IN-LIFE DATES: From February 18 to February 28, 1991
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Animals were fasted overnight, weighed and given a single dose of the undiluted test material by gavage, using a ball pointed cannula and syringe.
Doses:
Animals were dosed at 1000, 1710, 2924 and 5000 mg/kg. The undiluted test material was administered at dose volumes of 1.06, 1.82, 3.11 and 5.32 ml/kg.
No. of animals per sex per dose:
Five animals per sex per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: A detailed clinical examination was made six times on the day of dosing and twice daily thereafter for the remainder of the 14 day observation period. The initial (Day 1), Day 8 and Day 15 bodyweights were recorded and changes in bodyweight calculated.
- Necropsy performed: no
Statistics:
The 14 day LD50, 95% confidence interval and the dose-mortality slope were calculated using a method based on probit analysis (Finney, 1977).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 976 mg/kg bw
Based on:
test mat.
95% CL:
2 667 - 3 551
Mortality:
Mortalities occurred on Days 2, 3 and 4 among rats dosed at 2924 and 5000 mg/kg. No rat survived treatment at the highest of these dose-levels.
Clinical signs:
The principal clinical signs observed among rats dosed with the test substance were piloerection, lachrymation, hunched posture, abasia/ataxia and/or prostration, diarrhoea, yellow staining of the anogenital fur and an unkempt appearance. There were additional cases of tachypnoea or bradypnoea, twitching and coma preceding death among those treated at the high dose-level. Other isolated clinical signs included salivation, periorbital encrustation and eye closure.
Onset of hunched posture, abasia and diarrhoea among rats treated at the intermediate or high dose levels was common within one-half hour of dosing and at the low dose level occurred within 3 hours of dosing. Other principal signs of reaction were established by Day 2. Recovery, as judged by external appearance and behaviour, was advanced by Day 3 but incomplete until Day 4 (1000 mg/kg) or Day 11 (1710 and 2924 mg/kg).
Body weight:
Low bodyweight gains or losses of bodyweight during the first week of the study were apparent among rats treated at 1710 or 2924 mg/kg. Despite this, all surviving rats had gained weight relative to their Day 1 bodyweights by the end of the 14 day observation period.

Table 7.2.1:      Summary of Acute Oral Toxicity

Males

Females

Dose

Mortality

Time of death

Dose

Mortality

Time of death

1000 mg/kg

0/5

--

1000 mg/kg

0/5

--

1710 mg/kg

0/5

--

1710 mg/kg

0/5

--

2924 mg/kg

1/5

Day 4

2924 mg/kg

3/5

Day 2

5000 mg/kg

5/5

Days 2-3

5000 mg/kg

5/5

Days 2 -3

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral LD50 for the test substance is 2976 mg/kg.
Executive summary:

Groups of five rats per sex were dosed at 1000, 1710, 2924 and 5000 mg/kg. A detailed clinical examination was made six times on the day of dosing and twice daily thereafter for the remainder of the 14 day observation period. The initial (Day 1), Day 8 and Day 15 bodyweights were recorded and changes in bodyweight calculated. Animals surviving to the end of the study were killed by carbon dioxide asphyxiation. Mortalities occurred on Days 2, 3 and 4 among rats dosed at 2924 and 5000 mg/kg. No rat survived treatment at the highest of these dose-levels. The acute oral LD50 for the test substance is 2976 mg/kg.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 976 mg/kg bw
Quality of whole database:
Klimisch 2. Non-GLP study.

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:
From February 18 to March 5, 1991
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: There are no deviations from the OECD Guideline 402 (Acute Dermal Toxicity). No GLP.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River U.K. Ltd.
- Age at study initiation: 9-11 weeks
- Weight at study initiation: males: 219-262 g; females: 142-166 g
- Housing: Single sex groups of up to three rats in cages with stainless steel wire-mesh walls, floors and tops (33 cm x 22 cm x 16 cm). Paper-lined trays for excreta were placed beneath each cage and changes three times weekly.
- Diet (e.g. ad libitum): Pelleted diet (LAD1, Special Diet Services Ltd.), ad libitum.
- Water (e.g. ad libitum): from the public supply, ad libitum.
- Acclimation period: The animals were quarantined for a minimum of four days in a non-barrier animal room with access restricted to essential personnel. At least five days before dosing the animals were rehoused.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23 ºC
- Humidity (%): 30-70%
- Air changes (per hr): not documented.
- Photoperiod (hrs dark / hrs light): 12 hour day and 12 hour night


IN-LIFE DATES: From February 18 to March 5, 1991
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
On the day before dosing the dorsal fur was removed from the animals using electric clippers. A single dose of the undiluted test material was applied to the skin. The test material was held in place with a gauze dressing (approx 6 x 8 cm) covered with waterproof adhesive tape.
Duration of exposure:
Following a 24 hour exposure the dressings were removed, the skin washed with warm dilute detergent solution and dried.
Doses:
Animals received a single dermal application at 2000 mg/kg. The undiluted test material was administered at a dose volume of 2.13 ml/kg.
No. of animals per sex per dose:
Five animals per sex per dose
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: A detailed clinical examination was made five times on the day of dosing and twice daily thereafter for the remainder of the 14 day observation period. The initial (Day 1), Day 8 and Day 15 bodyweights were recorded and changes in bodyweight calculated.
- Necropsy performed: no
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
None of the rats died.
Clinical signs:
There were no signs of systemic reaction to treatment. Sites of application of the test material showed erythema and, in one case, oedema from Day 2 and yellow discolouration from Day 3. The inflammatory reaction resolved by Day 5 and the treated skin was overtly normal from Day 11.
Body weight:
All rats had gained weight relative to their Day 1 bodyweights by the end of the 14 day observation period.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute dermal LD50 for the test substance is greater than 2000 mg/kg.
Executive summary:

Five rats per sex were dosed at 2000 mg/kg. Following a 24 hour exposure the dressings were removed. A detailed clinical examination was made five times on the day of dosing and twice daily thereafter for the remainder of the 14 day observation period. The initial (Day 1), Day 8 and Day 15 bodyweights were recorded and changes in bodyweight calculated. Animals surviving to the end of the study were killed by carbon dioxide asphyxiation. None of the rats died. The acute dermal LD50 for the test substance is greater than 2000 mg/kg.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
2 000 mg/kg bw
Quality of whole database:
Klimisch 2. Non-GLP study.

Additional information

Oral acute toxicity:

Key study. Study with 5 rats per sex and per dose according to OECD test guideline 401.

The result was as follows: LD50 =2976 mg/kg bw.

Dermal acute toxicity:

Key study. Study with 5 rats per sex and per dose according to OECD test guideline 402.

The result was as follows: LD50 >2000 mg/kg bw.

Inhalation: Data waiving: In accordance with column 2 of REACH Annex VIII, the study does not need to be conducted since exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size.


Justification for selection of acute toxicity – oral endpoint
Only one reliable study available.

Justification for selection of acute toxicity – inhalation endpoint
In accordance with column 2 of REACH Annex VIII, the study does not need to be conducted since exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size.

Justification for selection of acute toxicity – dermal endpoint
Only one reliable study available.

Justification for classification or non-classification

Oral acute toxicity:

LD50 =2976 mg/kg bw : not classified

Dermal acute toxicity:

LD50> 2000 mg/kg bw: not classified