Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1982
Report Date:
1982

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
adopted May 1981
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Initiator 654
- Physical state: liquid
- Purity: > 97%
- Expiration date of the lot/batch: Feb. 1983

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Acclimatization period: at least one week.
Age of animals at beginning of study: About 12 weeks
Type of cage: Type DK-III stainless steel wire mesh cages
Number of animals per cage: 5
Animal identification: Identification of groups using cage cards
Room temperature: 20 - 26°C
Relative humidity: 45 - 75%
Air changes: 15 - 20 /hour
Day/night rhythm: 12 h/12 h (6.00 - 18.00 hours/18.00 - 6.00 hours)
Drinking water: Fully demineralized water each workday, ad libitum; tap water on public holidays, ad libitum
Diet: SSNIFF R; Ssniff Versuchstierdiäten, Soest, FRG
Fasting period: 16 hours before administration, water available ad libitum

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5% in water
Details on oral exposure:
Preparation with 0.5% aqueous carboxymethyl cellulose
Reason for the vehicle: Aqueous formulation corresponds to the physiological medium
Form of administration: Emulsion
Concentrations used: 26.1, 38.3, 50% (w/v)
Application volume: 10 ml/kg
Doses:
2610, 3830, 5000 mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Observation period: 14 days
Weight check: Animals of comparable weights (± 20 g) in one cage.
Cageside observation: Recording of signs and symptoms < 15', 15', 30', 1 h, 2 h, 4 h, and 5 h after administration of test substance and then once each workday. Check for moribund and dead animals twice each workday and once daily at weekends and on public holidays.
Pathology: Withdrawal of feed 16 hours before sacrifice with CO2, followed by necropsy and gross-pathological examination. All animals that die are necropsied as early as possible.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Remarks on result:
other: Mortality occurred at all dose levels (2160, 3830 and 5000 mg/kg )
Mortality:
Males: 5000 mg/kg 1/5 after 1 day, no mortality at other dose levels
Females: 5000 and 2610 mg/kg: 2/5 after 1 day, 3830 mg/kg: 1/5 after 1 day
Clinical signs:
Male animals:
All dose groups showed dyspnea, apathy, staggering, twitching, piloerection (not observed for high dose males), and poor general state.
Abnormal position, tonus with bending, tonic-clonic convulsions, salivation, and fasciculation were observed in high dose males only.

Female animals:
The following symptoms were observed in all dose groups, unless noted otherwise: Dyspnea, apathy, abnormal position (not in mid dose females), staggering, paresis hind leg (only low dose), twitching, spastic gait (only low dose), tonus with bending, , tonic convulsions (not in mid dose females), clonic convulsions (only low dose), piloerection, erythema (only low dose), fasciculation (not in mid dose femaes), cachexia (only low dose), and poor general state
Additionally high dose females showed opisthotonos, loss of hair, exsiccosis, and salivation.

Most symptoms were only observed for app. 1 day (2 days in high dose animals), but low dose females exhibited dyspnea, apathy, staggering, and poor general state up to day 12 or 13.
Body weight:
Mean body weight male animals: 193 at study start, 282 g after 13 days
Mean body weight female animals: 190 g at study start, 224 g after 13 days
Gross pathology:
Animals that died (female): Stomach: Bloody erosions in the region of the glandular stomach in 1 animal; liver: grayish-white to clay-colored periphery involving a minimum part of the acinus.
Sacrificed animals (male & female): Organs: No abnormalities detected.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of the study, the acute oral LD50 of the registered substance was found to be >5000 mg/kg bw in the rat.
Executive summary:

Males were less sensitive than females. Doses of 2160, 3830 and 5000 mg/kg bw were tested. In females, 2 of 5 animals each died at 2160 and 5000 mg/kg bw within the first day of dosing. In the mid dose, one female died. One high dose male died, but no mortality was observed in the remaining dose groups. In the females that died, bloody erosions in the region of the glandular stomach occurred in 1 animal. In the liver, grayish-white to clay-colored periphery involving a minimum part of the acinus was observed. No findings were observed in surviving animals.