Registration Dossier

Administrative data

Description of key information

Acute toxicity:
- Oral LD50: 2901 mg/kg bw (combined M+F) (method similar to OECD 401)
- Inhalation LD50: 17400 mg/m3 (route-to-route extrapolation from acute oral toxicity study)
- Dermal LD50: 2901 mg/kg bw (route-to-route extrapolation from acute oral toxicity study)

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:
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.
Reference:
Composition 0
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 information:
Composition 1
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
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)
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.
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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 901 mg/kg bw
Quality of whole database:
This study is adequate for covering this endpoint.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
17 400 mg/m³
Quality of whole database:
This assessment is considered to be sufficient adequate for covering this endpoint.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 901 mg/kg bw
Quality of whole database:
This assessment is considered to be adequate for covering this endpoint.

Additional information

In an acute oral toxicity study, four groups of ten rats (five males and five females) were administered Cashmeran 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. Mortality was 1 of 10 rats at 2000 mg/kg, 5 of 10 at 3200 mg/kg, 9 of 10 at 4000 mg/kg and 10 of 10 at 5000 mg/kg. Necropsy of the animals dying on the study revealed hemorrhagic lungs, discoloured 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).

Based on the acute oral toxicity study, acute studies via the inhalation and dermal route are waived and acute toxicity values for these routes have been derived using route to route extrapolation.

An acute inhalation toxicity study is not needed for substances with high viscosity (the substance has a viscosity of 31.7 mP.s) and acute oral and dermal toxicity values are available. For inhalation, an LD50 of 2900 mg/kg bw can be roughly converted into 174000 mg/per person by multiplying it with a person’s weight: (60 kg 2900 x 60=174000). An inhalation volume for one person during 4 h (standard exposure time in the OECD TG for acute inhalation is 5m3 (assuming 10m3/8h for workers). This means that an LC50 concentration in 1 m3 and 4 hours exposure is 34800 mg/m3 (174000mg/5m3). Taking into account that during that the absorption during the inhalation route is twice the oral route the LC50 and therefore the LC50 for inhalation could be 17400 mg/m3. The maximum saturates vapour pressure for Cashmeran is 84.7 mg/m3 (1 Pa (Vap Pr. Cashmeran) x 206 (MW) / 8.3 (R, gas constant) x 293 (°K)). This means that Cashmeran cannot reach a concentration higher than 84.7 mg/m3. Therefore an LC50 for inhalation cannot be reached and no classification and labelling is needed for the acute inhalation route.

With respect to the acute toxicity via the dermal route, the study is scientifically unjustified because the acute oral toxicity is above 2000 mg/kg bw. Based on the toxicokinetic data the dermal availability is not expected to exceed the oral availability. Therefore the LD50 via the dermal route can be estimated to be similar to the oral LD50, because 50% absorption is assumed via both routes, resulting in an LD50 of 2901 mg/kg bw.


Justification for selection of acute toxicity – oral endpoint
One acute oral toxicity study is available, which is performed according to OECD guidelines and under GLP conditions. This study is adequate for covering this endpoint.

Justification for selection of acute toxicity – inhalation endpoint
The acute inhalation toxicity is derived using route to route extrapolation from the acute toxicity results, using 100% absorption. This assessment is considered to be sufficient adequate for covering this endpoint.

Justification for selection of acute toxicity – dermal endpoint
The acute dermal toxicity is derived using route to route extrapolation from the acute oral toxicity results using the same absorption as in the acute oral toxicity study. This assessment is considered to be adequate for covering this endpoint.

Justification for classification or non-classification

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, dermal and inhalation route.