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Administrative data

Description of key information

oral: LD50 > 5000 mg/kg bw (rat), OECD Guideline Study.

dermal: LD50 > 2000 mg/kg bw (rat), OECD Guideline Study (Read Across to structurally related substance)

inhalation: no reliable data available, study is however not required according to Annex VIII (8.5) of the Official Journal of the European Union since two other routes are provided.

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:
September 1, 1982 - September 14, 1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
predating GLP, QAU statement included
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
no
Remarks:
but QUA statement included in report
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Tif:RAIf (SPF), F3-crosses of RII 1/Tif x RII 2/Tif
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: CIBA-GEIGY LTD. Tierfarm, 4334 Sisseln, Switzerland
- Age at study initiation: 7 - 8 weeks
- Weight at study initiation: 183 - 202 g
- Fasting period before study: overnight
- Housing: groups of five in Macrolon cages type 3 with standardized soft wood bedding
- Diet: Rat food, NAFAG No. 890, ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 55 ± 15
- Air changes (per hr): approx. 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: Distilled water containing 0.5% carboxymethylcellulose and 0.1% polysorbate 80
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg bw

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 or until all symptoms have disappeared, whichever lasts longer
- Frequency of observations and weighing: Mortality: daily, a.m. and p.m. on working days; Signs and Symptoms: daily; Body weight: on days 1, 7, 14 and at death
- Necropsy of survivors performed: yes
Statistics:
From the body weights, the group means and their standard deviations were calculated.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: no mortality occured
Mortality:
No deaths occured.
Clinical signs:
Following clinical signs were observed: dyspnoea: 1 hour after exposure until day 11, exophthalmus: 1 hour after exposure until day 12, ruffled fur: one hour after exposure until day 11, curved body position: one hour after exposure until day 4.
The animals recovered within 14 days.
Body weight:
Normal body weight gain.
Gross pathology:
No compound related gross organ changes were observed.
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 oral toxicity performed under GLP-like quality control and following OECD guideline 401, 5 male and 5 female rats (Tif:RAIf) were treated with the test substance by oral gavage administration at a dosage of 5000 mg/kg body weight. Distilled water containing 0.5% carboxymethylcellulose and 0.1% polysorbate 80 served as vehicle. All animals were observed daily for 14 days for mortality, toxicity and clinical effects. Body weights were recorded on days 1, 7, 14 and at termination of the study. All animals were necropsied and examined macroscopically. All animals survived until the end of the study period. The following clinical signs were observed: dyspnoea: 1 hour after exposure until day 11, exophthalmus: 1 hour after exposure until day 12, ruffled fur: one hour after exposure until day 11, curved body position: one hour after exposure until day 4. The animals recovered within 14 days. No compound related gross organ changes were observed. Therefore, based on the results of this study, the LD50 in the rat 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:
Apr. 1, 1992 to Jun. 22, 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Tif: RAIf (SPF)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: CIBA-GEIGY Limited (Animal Production) 4332 stein, Switzerland
- Weight at study initiation: 202 to 229 g
- Housing: Individually housed, in Macrolon cages type 3, with standarized soft wood bedding
- Diet (e.g. ad libitum): ad libitum, NAFAG 890 TOX
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2 °C
- Humidity (%): 55 +/- 10%
- Photoperiod (hrs dark / hrs light): 12 hrs dark/ 12 hrs light
Type of coverage:
semiocclusive
Vehicle:
CMC (carboxymethyl cellulose)
Details on dermal exposure:
TEST SITE
- Area of exposure: back
- % coverage: 10%
- Type of wrap if used: guaze-lined semiocclusive dressing


REMOVAL OF TEST SUBSTANCE
- Washing (if done): cleaned with lukewarm water
- Time after start of exposure: 24 hour

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg body weight
- Constant volume or concentration used: yes (4 mL/kg body weight)

VEHICLE
- Amount(s) applied (volume or weight with unit): 0.5% carboxymethylcellulose in 0.1% aqueous polysorbate 80

Duration of exposure:
24 hours
Doses:
2,000 mg/kg body weight
No. of animals per sex per dose:
5 animals/sex/dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily observations and weighing on Day 0, 7 and 14
- Necropsy of survivors performed: yes
Statistics:
None
Preliminary study:
Limit Test
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No mortality
Clinical signs:
Piloerection was seen, that is a common unspecific clinical sign in acute dermal tests. The animals recovered within 2 to 3 days. At autopsy, no deviations from normal morphology were found.
Body weight:
normal body weight gain
Gross pathology:
None
Other findings:
Other Observations: No deviation from normal morphology were found upon necropsy
Interpretation of results:
GHS criteria not met
Remarks:
Migrated information
Executive summary:

Upon an acute dermal administration of 24 hours and a 14 day post-treatment observation period, the following LD50 (with 95% confidence limits calculated, where possible) was determined for the test item:

LD50 in male rats: greater than 2000 mg/kg body weight

LD50 in female rats: greater than 2000 mg/kg body weight

LD50 in rats of both sexes: greater than 2000 mg/kg body weight

Piloerection was seen, being a common symptom in acute dermal tests. The animals recovered within 2 to 3 days. At autopsy, no deviations from normal morphology were found.

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

Additional information

Acute oral toxicity

In an acute oral toxicity study groups of 7 to 8 week old fasted rats (Tif:RAIf, 5 per sex) were given a single oral dose of the test substance in distilled water containing 0.5% carboxymethylcellulose and 0.1% polysorbate 80 at a dose level of 5000 mg/kg body weight followed by a 14 days observation period. No deaths occurred. Dyspnoea, exophthalmus, ruffled fur and curved body positions were observed. After 12 days no clinical signs were observed anymore. Overall, under the chosen test conditions, the test substance was not toxic after single oral administration: Oral LD50 > 5000 mg/kg bw

Similar results were observed in a supporting study performed with rats. In this study, male and female rats were treated with the test substance at a dose level of 5000 mg/kg by single gavage application. No mortalities occurred, somnolence and dyspnoe were observed (no data how long). The LD50 in this study was 5000 mg/kg body weight. In two supporting studies performed with mice, oral LD50 values of greater than 5000 mg/kg were reported as well.

In addition, two studies are available from IBT which revealed LD50 values of 4556 mg/kg and > 10000 mg/kg in mice and rats, respectively. Considering the history of IBT (reporting of fake data), the reliability of these studies is uncertain and an accurate Klimisch rating is impossible. Consequently, the study is rated with Klimisch 4. However, since falsified data were predominantly reported for studies with repeated exposure, the data from these studies were taken into careful consideration. The data presented are in line with the reliable reports and provide additional support of the very low acute oral toxicity of the test article.

Acute dermal toxicity

Two studies assessing the acute dermal toxicity of the test article are available from IBT (different batches used, 1975). In both studies, one male New Zealand White rabbit per dose group was treated with test material for 24 hours under occlusive conditions. Dose levels were 300, 1000 and 3000 mg/kg body weight. No mortalities occurred and as a result the LD50 was determined to exceed 3000 mg/kg body weight. However, both studies can only be rated with Klimisch 4 (see above).

For further assessment, a study performed with a structurally related compound is considered (see attached read across justification document). In this acute dermal toxicity study, groups of Tif: RAIf (SPF) rats (5 per sex) were given a single dermal dose of the test substance in carboxymethyl cellulose at a dose level of 2000 mg/kg body weight. No deaths occurred. Piloerection was seen, being a common unspecific clinical sign in acute dermal tests. The animals recovered within 2 to 3 days. At autopsy, no deviations from normal morphology were found. Overall, under the chosen test conditions, the test substance does not have toxic properties in case of single dermal exposure: Dermal LD50 > 2000 mg/kg bw.

Based on the data obtained with structural analogue together with the results from the IBT studies, it is concluded that the test article is of low acute dermal toxicity. In view of the extremely low oral toxicity, the low skin penetration potential and for animal welfare reasons, it is considered inappropriate to conduct an additional dermal toxicity study for the test substance.

Acute inhalation toxicity

Three studies conducted by IBT are available. In each study, five Charles River rats per sex were exposed to an atmosphere containing the test article for 4 hours followed by a 14 day observation period. No mortalities occurred in any of the studies. The reported maximum concentrations of test material were 3410, 3480 and 6300 mg/m3. Based on the history of IBT, these studies can only be rated with Klimisch 4 (see above). Since no further testing is necessary according to Annex VIII (8.5) of Regulation (EC) No 1907/2006 (reliable data on two other routes are provided) these inhalation studies are disregarded.

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, the test substance is not classified for acute toxicity.