Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The procedures used comply with the requirements of the OECD Guideline for Testing of Chemicals No. 420, 1992, and Commission Directive 92/69/EEC, B.1 bis, 1992.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1996
Report date:
1996

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
no
GLP compliance:
yes
Test type:
fixed dose procedure

Test material

Constituent 1
Reference substance name:
reaction mass of Lycopyl salt isomers in Methanol
IUPAC Name:
reaction mass of Lycopyl salt isomers in Methanol
Details on test material:
- Name of test material (as cited in study report): (2E,4E,6E)-(3,7,11-Trimethyl-dodeca-2,4,6,10-tetraenyl)-triphenyl-phosphonium acetate
- Physical state: clear yellow liquid
- Analytical purity: not available
- Lot/batch No.: P19-39.5
- Expiration date of the lot/batch: 19 December 1996
- Storage condition of test material: In refrigerator at 2-8 °C, protected from light, covered with Nitrogen
- Other: Date of receipt 28 August 1996

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd., Margate, England
- Age at study initiation: 4-7 weeks
- Weight at study initiation:
- Fasting period before study: overnight fasting
- Housing: Animals were housed in groups of up to five, by sex, in grid-bottomed cages suspended over cardboard lined excreta trays.
- Diet (e.g. ad libitum): pelleted diet (SQC Rat and Mouse Maintenance Diet No. 1 Expanded, Special Diets Services, Witham, Essex)
- Water (e.g. ad libitum): Main drinking water in polypropylene bottles were freely available.
- Acclimation period: at least five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23
- Humidity (%): 44-61
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 50 and 100 mg/mL at dose volume of 20 mL, 50 mg/mL at dose volume of 10 mL (range finding) and 25 mg/mL at dose volume of 20 mL (main test)
Doses:
500, 1000, 2000 mg/kg bodyweight (range finding test)
500 mg/kg bodyweight (main test)
No. of animals per sex per dose:
three females (range finding test)
five females, five males (main test)
Control animals:
no
Details on study design:
In the range finding test, test article at dose levels of 500, 1000, or 2000 mg/kg bodyweight was administered once only by gavage to 3 female rats which had benn fasted overnight. All animals were weighed on the day of dosing to permit the calculation of the dose volume to be administered. Surviving animals were weighed on day 8. Dose levels were administered sequentially with at least 24 hours between the administration of one dose level and the next; the dose level selected being dependent on the results of treatment with the previous one.
Animals were observed immediately after dosing, and 30 minutes, one, 2 and 4 hours after dosing for signs of toxicity or abnormal behaviour. Observations were made daily thereafter for a furhter 7 days.
The range finding study indicated that 500 mg/kg was the highest dose that could be administered without causing mortality. The main study was therefore conducted at this level using groups of five female and five male rats.
Animals were fasted overnight before dosing. The test article was administered as a single dose by gavage. After dosing animals were returned to their cages and permitted access to food. Observations were made shortly after administration and 30 minutes, one, 2 and 4 hours after dosing. Animals were examined daily thereafter during 14 days. Bodyweights were determined before dosing and on days 2,3,4,8 and 15. All animals were weighed and than killed at the end of day 15 and a necropsy was done for all animals.

Results and discussion

Preliminary study:
The animal treated with 2000 mg/kg was found dead on day 2. Effects observed in the animal treated with 1000 mg/kg included hypoactivity, piloerection, hunched posture, perbuccal staining, unsteady on feet and a red discharge from eyes noted after 5 hours after dosing. In the animal treated with 500 mg/kg, piloerection was observed from 30 minutes after dosing until day 2, salivation was noted 30 and 60 minutes after dosing, and noisy breathing was noted on day 7 and 8.
Effect levels
Sex:
male/female
Dose descriptor:
other: maximum tolerated oral dose
Effect level:
> 500 - < 2 000 mg/kg bw
Mortality:
No deaths occurred.
Clinical signs:
One female rat exhibited noisy breathing on days 2,3,4 and 5 only. There were no clinical signs of toxicity throughout the observation period in the remaining animals.
Body weight:
There was no adverse effect on overall bodyweight gain in animals of either sex.
Gross pathology:
No treatment related findings were observed at necropsy.

Applicant's summary and conclusion

Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Treating with the test article at a dose level of 5000 mg/kg bodyweight to a group of 5 male and 5 female rats produced clinical signs of toxicity but no deaths. The result of this study indicate that the maximum tolerated oral dose lies between 500 and 2000 mg/kg bodyweight.
Executive summary:

The purpose of the study was to assess the acute oral toxicity of the test article, Ro 44 -9567/002 in the rat using the Fixed Dose Method according to OECD Guideline No. 420.

The results of a rangefinding study indicated that a dose level of 2000 mg/kg bodyweight caused death and dose levels of 500 or 1000 mg/kg produced apparent signs of toxicity but no deaths. As a dose level of 500 mg/kg bodyweight was the highest of the fixed doses that could be adminisitered without causing mortality, the main study was conducted at this dose level. The test article was administered as a single oral dose by gavage to a group of five male and five female rats which had been fasted overnight. The animals were examined frequently on the day of dosing and daily thereafter for a further 14 days at the end of which, they were killed and subjected to necropsy.

In the main study, following oral administration of a dose level of 500 mg/kg bodyweight, no deaths occurred and all animals maintained a healthy appearance with the exception of 1 female rat which exhibited noisy breathing on days 2,3,4 and 5 only. There was no adverse effect on overall bodyweight gain in animals of either sex. No treatment related findings were observed at necropsy.

Treatment with the test article, Ro 44 -9567/002, at a dose level of 500 mg/kg bodyweight to a group of five male and five female rats produced clinical signs of toxicity but no deaths. The results of this study indicate that the maximum tolerated oral dose lies between 500 and 2000 mg/kg bodyweight.