Registration Dossier

Administrative data

Description of key information

Information available from acute oral toxicity test showed adverse effects to female mice at highest dose of 2000 mg/kg bw. LD50 for oral acute toxicity was not determined.

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:
23 Nov 1987 - 1 Feb 1988
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Remarks:
non-guideline study equivalent to OECD TG 420
Reference:
Composition 1
Qualifier:
no guideline followed
Version / remarks:
No guideline was followed for the study, but it is considered equivalent to OECD TG 420
Principles of method if other than guideline:
Non-GLP, non-guideline study equivalent to OECD TG 420
GLP compliance:
no
Test type:
fixed dose procedure
Limit test:
yes
Test material information:
Composition 1
Specific details on test material used for the study:
GR46580X batch number: RKN/656/1
Species:
mouse
Strain:
other: CR/H
Sex:
male/female
Details on test animals and environmental conditions:
Male and female mice weighing approximately 20g on arrival from the in-house Rodent Breeding Unit were used. They were housed in groups of up to five to a cage. Diet and water from the local domestic supply were provided ad libitum. Each animal was uniquely identified by ear marking and by one of a block of serial numbers. Ambient temperature was maintained between 20 and 22C. Relative humidity was maintained between 56% and 76%.
Route of administration:
oral: gavage
Vehicle:
other: 0.5% Methocel K15M Premium (hydroxypropyl methyl cellulose, viscosity type 15000) in Water for Irrigation USP.
Details on oral exposure:
The test materials were used as suspensions in 0.5% Methocel K15M Premium (hydroxypropyl methyl cellulose, viscosity type 15000) in Water for Irrigation USP. Mice were given a single oral dose of the appropriate material at a constant dose volume of 20mL/kg.
Doses:
The animals were randomly allocated to groups of 5 males and 5 females (up to 5 animals to a cage) using computer-generated tables. The animals were given the following treatments:
Treatment
Vehicle

GR46580X 2000mg/kg
GR46580X 200mg/kg
GR46580X 200mg/kg (retest)
No. of animals per sex per dose:
5/sex/group
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were examined for signs of ill health and reaction to treatment at least four times during the first 6 hours after dosing, then daily for up to 14 days after dosing. Additional observations were carried out when considered necessary. Body weights were recorded on the day of dosing, 7 or 8, and 14 days after dosing.
- Autopsy: Surviving animals were autopsied on the last day of the study. The abdomen and thorax were opened and the contents examined macroscopically. Macroscopic examination was also carried out on animals that died or were killed before the end of the study.
Statistics:
No information
Preliminary study:
Not relevant
Key result
Sex:
male/female
Dose descriptor:
discriminating dose
Effect level:
ca. 200 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Clinical signs of toxicity were noted in both sexes on the day of dosing with 2000mg/kg GR465 80X, and one female was killed in extremis one day after dosing.
Mortality:
Vehicle Control
There were no deaths.
CCl11400, 2000mg/kg
There were no deaths.
CCl22363, 2000mg/kg
There were no deaths.
GR46580X, 2000mg/kg
On the day of dosing, all females showed a decrease in motor activity, and three males showed hunched posture. On the day after dosing, one female was subdued, preferring to be inactive, and showed laboured respiration, closed eyes, and low posture. This animal showed no improvement and was killed later the same day.
GR46580X, 200mg/kg (retest)
There were no deaths in any animal.

The 200 mg/kg dose had to be retested after suspicions of dosing damage. The initial 200 mg/kg test results were thus disregarded and the substance was retested at 200 mg/kg dose.
Clinical signs:
Vehicle Control
There were no clinical signs of toxicity.
GR46580X, 2000mg/kg
On the day of dosing, all females showed a decrease in motor activity, and three males showed hunched posture. On the day after dosing, one female was subdued, preferring to be inactive, and showed laboured respiration, closed eyes, and low posture. This animal showed no improvement and was killed later the same day.
GR46580X, 200mg/kg
No clinical signs of toxicity were noted in any animal on the day of dosing. On the day after dosing, one female showed a swelling behind the right forelimb and was killed. This animal showed evidence of dosing damage. Hunched posture and/or staring coat were noted in one female 4 to 8 days after dosing, and hunched posture was noted in one female 8 days after dosing. These animals appeared normal for the remainder of the observation period. There were no deaths or clinical signs of toxicity in any male. ยท
GR46580X, 200mg/kg (retest)
There were no clinical signs of toxicity in any animal.
Body weight:
All surviving test animals showed comparable weight gains to the vehicle controls over the study period.
See attachment 'Mice body weights'
Gross pathology:
Vehicle Control
No abnormalities were noted at necropsy.
GR46580X, 2000mg/kg
At autopsy, the stomach of the animal that was found dead was found to be impacted and the intestinal contents were very dark. All other animals appeared normal for the remainder of the observation period. Pale kidneys and pronounced liver lobules were noted in one male killed at the end of the study. The remaining animals appeared normal.
GR46580X, 200mg/kg (retest)
No abnormalities were noted at necropsy.

The 200 mg/kg dose had to be retested after suspicions of dosing damage. The initial 200 mg/kg test results were thus disregarded and the substance was retested at 200 mg/kg dose.
Other findings:
Nothing mentioned.
Interpretation of results:
other: Harmful, according to the study' scheme
Remarks:
This indicates that mortality and/or clinical signs were observed. The LD50 value is above 2000 mg/kg which was the highest dosing level
Conclusions:
The toxicity rating of GR46580X was: Harmful
Criteria used for interpretation of results: EU
Executive summary:

From the results of the study, the toxicity rating for GR46580X (Thio-acid) was harmful.

The acute oral toxicity of GR46580X was evaluated in CR/H mice. The test material was administered by gavage as suspensions in 0.5% aqueous Methocel K15M Premium (hydroxypropyl methyl cellulose, viscosity type 15000). Groups of 10 mice (5 male, 5 female) were used. The animals were observed for up to 14 days after dosing. The acute oral toxicity of the test material was assessed on the basis of clinical signs.

Clinical signs of toxicity were noted in both sexes on the day of dosing with 2000 mg/kg GR46580X and one female was killed in extremis one day after dosing. There were no clinical signs of toxicity at a dose level of 200 mg/kg GR46580X and the material was classified as harmful.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating dose
2 000 mg/kg bw

Additional information

Justification for classification or non-classification

Available test results not sufficient for classification for acute toxicity.