Registration Dossier

Administrative data

Description of key information

Acute oral toxicity in rat, gavage, LD50 > 5000 mg/kg bw (OECD 401)

Acute dermal toxicity in rat, LD50 > 2000 mg/kg bw (OECD 402)

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:
1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
GLP compliance:
yes
Remarks:
Research & Consulting Company AG
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Kleintierfarm Madoerin AG, CH 4414 Fuellinsdorf/Switzerland
- Age at study initiation: 9 to 11 weeks
- Weight at study initiation: Males 192 to 210 g, Females 173 to 181 g
- Fasting period before study: 12 to 18 hours
- Housing: Housed in groups of 5 in Makrolon type-3 cages
- Diet (e.g. ad libitum): Pelleted standard Kliba 343
- Water (e.g. ad libitum): Community tap mater
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 40 to 70
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: Jun 5, 1986 To: Jun 26, 1986
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
4% solution in distilled water
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 20 mL/kg body weight
Doses:
5000 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: Each animal was examined for changes in appearance, behavior four times during test Day 1, and daily during Days 2 to 15, body weight on Days 1, 8, and 15, and mortality/viability 4 times during test Day 1, and daily during Days 2 to 15.
- Necropsy of survivors performed: Yes. Necropsies were performed for all animals.
Statistics:
The toxicity was estimated without use of a statistical model.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Remarks on result:
other: 20% of animals died.
Mortality:
One male and one female rat died on Day 3 of the test period.
Clinical signs:
The symptoms observed were sedation, dyspnea, ataxia (males), curved body position, and ruffled fur, which disappeared within 7 days.
Body weight:
There was increase in the body weight during the observation period. The mean body weight in males was 201, 208 and 246 g at day 1, 8 and 15 of the study, respectively. The mean body weight in females was 179, 188 and 200 g at day 1, 8 and 15 of the study, respectively.
Gross pathology:
In the 2 animals that died on Day 3, the following macroscopic organ changes were observed:
lung: dark-red mottled, not collapsed
intestines/stomach: meteorism severe, yellowish contents
In the animals that were terminated at the end of the test period, the following macroscopic organ changes were observed:
lung: dark-red mottled
Interpretation of results:
GHS criteria not met
Conclusions:
Based on the results of this study, the oral LD50 in rats is greater than 5000 mg/kg.
Executive summary:

In a GLP compliant OECD guideline study, 5 male and 5 female Wistar rats were treated with the test substance by oral gavage administration. The test item was diluted in 4% carboxymethyl cellulose and applied at a dose level of 5000 mg/kg body weight. All animals were observed for toxicity and mortality four times during test day 1 and once daily thereafter during the post-dose observation period of 14 days. Body weights were recorded on days 1, 8 and 15. All animals were necropsied and examined macroscopically. One male and one female animal died on test day 3. The surviving animals showed symptoms of sedation, dyspnea, ataxia (males), curved body position, and ruffled fur, which disappeared within 7 days. All surviving animals gained weight normally. In the 2 animals that died, the following macroscopic organ changes were observed: dark-red mottled lungs, not collapsed, severe meteorism in intestines/stomach with yellowish content. In the animals that were terminated at the end of the test period, the following macroscopic organ changes were observed: dark red mottled lung. Based on the result of this study, the LD50 was determined to exceed 5000 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 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:
1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
GLP compliance:
yes
Remarks:
Research & Consulting Company AG
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Kleintierfarm Madoerin AG CH 4414 Fuellinsdorf/Switzerland
- Age at study initiation: 9 to 11 weeks
- Weight at study initiation: males 211 to 229 g, females 193 to 212 g
- Fasting period before study: no data
- Housing: housed individually in Makrolon type-2 cages with standard softwood bedding
- Diet (e.g. ad libitum): Pelleted standard Kliba 343, ad libitum
- Water (e.g. ad libitum): Community tap water, ad libitum
- Acclimation period: at least 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 40 to 70
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: Jun 5, 1986 To: Jun 26, 1986
Type of coverage:
occlusive
Vehicle:
other: 4% solution of carboxymethylcellulose sodium salt in distilled water
Details on dermal exposure:
TEST SITE
- % coverage: 10 %
- Type of wrap if used: Test article was applied evenly on the skin with a syringe and covered with an occlusive dressing. The dressing was wrapped around the abdomen and fixed with an elastic adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The treated skin was washed with luke-warm tap water and dried with disposable paper towels.
- Time after start of exposure: 24 hours after application

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 4 mL/kg bw.
Duration of exposure:
24 hours
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: Each animal had an examination for changes in appearance and behavior four times during Day 1, and daily during Days 2 to 15. Individual body weight measurements were recorded on Days 1, 8, and 15.
- Necropsy of survivors performed: yes
Statistics:
Statistical analysis was not performed.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Remarks on result:
other: An LD50 could not be established as no deaths were observed from the single dose administration.
Mortality:
No deaths were observed.
Clinical signs:
Erythema was observed in both sexes. The male rats had recovered within 5 days, whereas the females showed erythema until termination of observation. No systemic symptoms mere observed.
Body weight:
Body weight gain was unaffected during the observation period (see table 1 for details).
Gross pathology:
No pathological changes were observed.

Table 1. Body weights and standard deviations

Dose (mg/kg bw)

Males

Females

Day 1

Day 7

Day 14

Day 1

Day 7

Day 14

2000

219 ± 6.9 g

246 ± 12.0 g

265 ± 12.0 g

199 ± 7.7 g

204 ± 6.4 g

212 ± 9.0 g

 

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the results of this experiment, the LD50 after dermal application to rats was determined to be greater than 2000 mg/kg bw.
Executive summary:

In a dermal acute toxicity study according to OECD guideline 402 and in compliance with GLP, five male and five female Wistar rats were treated occlusively with the test article in a 4% solution of Carboxymethylcellulose sodium salt for 24 hours and observed for 14 days thereafter. There were no deaths. Erythema formation was observed in all animals. The male rats had recovered within 5 days, whereas the females showed erythema until termination of observation. No systemic symptoms were observed. Body weight gain was unaffected during the observation period. All animals appeared normal at necropsy. Under the conditions of this study, the LD50 is greater than 2000 mg/kg bw in male and female rats when topically applied.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

Acute oral toxicity

The acute oral toxicity of the test substance was assessed in rats following OECD guideline 401 and in compliance with GLP. In the limit test, a single dose of 5000 mg/kg body weight in distilled water containing 4% was applied once by gavage to five male and five female Wistar rats following an observation period of 14 days. One male and one female animal died on test day 3. The surviving animals showed symptoms of sedation, dyspnea, ataxia (males), curved body position, and ruffled fur, which disappeared within 7 days. All surviving animals gained weight normally. In the 2 animals that died, the following macroscopic organ changes were observed: dark-red mottled lungs, not collapsed, severe meteorism in intestines/stomach with yellowish content. In the animals that were terminated at the end of the test period, the following macroscopic organ changes were observed: dark red mottled lung. Based on the result of this study, the LD50 was determined to exceed 5000 mg/kg body weight.

This result was confirmed in a second acute toxicity study following OECD guideline study 401. Again, the test substance in distilled water containing 0.5% carboxymethylcellulose and 0.1% polysorbate 80 was applied once by gavage to 5 male and 5 female rats at a dosage of 5000 mg/kg body weight. All animals survived until the end of the study period. Dyspnea, ruffled fur, and curved body position were seen, being common symptoms in acute tests. In addition, sedation was observed on the application day. The animals recovered within 11 days. Body weights increased during the observation period. No deviations from normal morphology were found. Based on the results of this study, the LD50 in the rat was determined to exceed 5000 mg/kg body weight.

 

Acute dermal toxicity

In a dermal acute toxicity study according to OECD guideline 402 and in compliance with GLP, five male and five female Wistar rats were treated occlusively with the test article in a 4% solution of Carboxymethylcellulose sodium salt for 24 hours and observed for 14 days thereafter. There were no deaths. Erythema formation was observed in all animals. The male rats had recovered within 5 days, whereas the females showed erythema until termination of observation. No systemic symptoms were observed. Body weight gain was unaffected during the observation period. All animals appeared normal at necropsy. Under the conditions of this study, the LD50 is greater than 2000 mg/kg bw in male and female rats when topically applied.

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for the purpose of classification under Regulation (EC) No.1272/2008. Based on the data, classification for acute toxicity is not warranted under Regulation (EC) No.1272/2008.