Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
11 April, 1985 - 29 April 1985
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study in compliance with GLP and similar to OECD 401.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1985
Report Date:
1985

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Cashmeran
- Molecular formula: C14H22O
- Molecular weight: 206.3
- Physical state: pink semi-solid
- Stability under test conditions: There was no apparent change in the physical state of the test article during administration.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Labs, Wilmington, Massachusetts
- Weight at study initiation: 150 - 280 grams
- Fasting period before study: 18 hours
- Housing: Individually in stainless steel wire mesh cages.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 C +/- 3 C
- Humidity (%): 30 - 70%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12h light, 12h dark

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.25% methylcellulose
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 5000 mg/kg

DOSAGE PREPARATION (if unusual):
Dose level 2000 mg/kg: 6.0 grams test substance in final volume of 15 ml
Dose level 3200 mg/kg: 9.6 grams test substance in final volume of 15 ml
Dose level 4000 mg/kg: dosed as received
Dose level 5000 mg/kg: dosed as received
Doses:
2000, 3200, 4000, and 5000 mg/kg bw
No. of animals per sex per dose:
5 animals per sex per dose (10 animals per dose group)
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: fourteen days
- Frequency of observations and weighing: Immediately, one and four hours after dosing, and twice daily for 14 days thereafter
- Necropsy of survivors performed: yes, gross necropsy
- Other examinations performed: clinical signs, body weight, central nervous sytem (CNS) effects, mortality, gross necropsy
Statistics:
By the method of Litchfield and Wilcoxon, JPET 966: 99-114 (1949)

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 901 mg/kg bw
Based on:
test mat.
95% CL:
> 2 325 - < 3 619
Mortality:
2000 mg/kg: 0/5 males died and 1/5 females died
3200 mg/kg: 2/5 males died and 3/5 females died
4000 mg/kg: 4/5 males died and 5/5 females died
5000 mg/kg: 5/5 males died and 5/5 females died

Mortality occured at day 1, day 2 and day 3.
Clinical signs:
Decreased activity, diarrhea, salivation, lacrimation, ptosis, poor grooming, piloerection, decreased or increased muscle tone, abnormal stance, abnormal gait, dyspnea, tremors, convulsions, wet pelage (ventral surface), red discoloration (ventral surface), writhing and prostration were observed. Clinical symptoms occurred during the first hours and days. At 2000 mg/kg there were no clinical symptoms from day 3 to day 14. For the higher dosages, clinical symptoms also decreased over time.
Body weight:
At dose level 2000 mg/kg bw, an increase in body weight was observed from day 1 to day 14.
The other dose levels showed a (slight) decrease in body weight from day 1 to day 14.
Gross pathology:
Necropsy of animals dying on study revealed: hemorrhagic lungs, discolored and fluid-filled intestines, distended stomachs and multiple lesions in the stomachs.
Other findings:
Necropsy showed non-descended testes in one animal.
No visible lesions were observed at terminal necropsy.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of this test, the LD50 of the test substance was in both male and female rats > 2000 mg/kg bw. According to the criteria outlined in Annex I of 67/548/EEC and Annex VI of 1272/2008/EC, cashmeran does not have to be classified as acute toxic by the oral route.
Executive summary:

In an acute oral toxicity study, four groups of ten rats (five males and five females) were administered cashmeran (test article 85-206-02) at dose levels of 2000, 3200, 4000 and 5000 mg/kg bw. The rats showed decreased activity, diarrhea, salivation, lacrimation, ptosis, poor grooming, piloerection, decreased or increased muscle tone, abnormal stance, abnormal gait, dyspnea, tremors, convulsions, wet pelage (ventral surface), red discoloration, writhing and prostration. 1 of 10 rats died at 2000 mg/kg, 5 of 10 died at 3200 mg/kg, 9 of 10 died at 4000 mg/kg and 10 of 10 died at 5000 mg/kg. Necropsy of the animals dying on the study revealed hemorrhagic lungs, discolored and fluid-filled intestines, distended stomachs and multiple lesions in the stomachs.

The acute oral LD50 for cashmeran in male and female rats was determined to be 2901 mg/kg bw with 95% CI of 2325 - 3619 mg/kg bw. The calculated LD50 for males was 3380 mg/kg bw (95% CI: 2907 - 3930 mg/kg bw). The calculated oral LD50 for females was 2685 mg/kg bw (95% CI: 2043 - 3529 mg/kg bw).

According to the criteria outlined in Annex I of 67/548/EEC and Annex VI of 1272/2008/EC, cashmeran does not have to be classified as acute toxic by the oral route.