Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Report date:
2012

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
Toxi-Coop ZRT.
Test type:
acute toxic class method
Limit test:
yes

Test material

Constituent 1
Test material form:
solid: crystalline
Details on test material:
- Name of test material: Thymidine

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: Young adult rat, 8 weeks old in first and second step
- Weight at study initiation: Body weight range at starting (first step): 203 - 211 g, body weight range at starting (second step): 195 - 199 g
- Fasting period before study: The day before treatment the animals were fasted. The food, but not water was withheld overnight.
- Housing: Group caging (3 animals/cage), type II polypropylene/polycarbonate cages, laboratory bedding
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: 12 days in first step and 13 days in second step

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): 8-12 air exchanges/hour by central air-condition system
- Photoperiod (hrs dark / hrs light): Artificial light, from 6 a.m. to 6 p.m.

IN-LIFE DATES:
- From: 18 Sept. 2012
- To: 03 Oct. 2012

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5 %
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw
- Lot/batch no.: N83746634

MAXIMUM DOSE VOLUME APPLIED:
- Maximum dose volume: 10 mL/kg bw

DOSAGE PREPARATION:
-Formulations were prepared just before the administration and stirred continuously during the treatment.

CLASS METHOD
- Rationale for the selection of the starting dose: Starting dose was selected on the basis of the available information about the test item.
Doses:
The acute toxic class method was carried out involving a stepwise procedure with the use of 2000 mg/kg bw as the starting dose in three female rats. No animal died in the first step at 2000 mg/kg bw dose level, so treatment with 2000 mg/kg bw was repeated on further three female rats. No animal died in the second step, too. Thus, the study was terminated.
No. of animals per sex per dose:
Three female rats per treatment group.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed individually after dosing at least once during the first 30 minutes, then 1 h, 2 h, 3 h, 4 h after the treatment and twice each day for 14 days thereafter. The body weights were recorded on day 0 (just before the treatment), on day 7 and on day 14 with a precision of 1 g.
- Necropsy of survivors performed: Yes
- Other examinations performed: Individual observations were performed on the skin and fur, eyes and mucous membranes and also respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
Statistics:
Not applicable.

Results and discussion

Effect levelsopen allclose all
Sex:
female
Dose descriptor:
LD0
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortalities occurred at 2000 mg/kg bw single oral dose (limit dose). All female rats in step 1 and also step 2 survived until the end of the 14-day observation period.
Clinical signs:
No treatment related symptoms were observed throughout the 14-day post-treatment period in any of the female animals.
Body weight:
The mean body weight of the animals corresponded to their species and age throughout the study.
Gross pathology:
All animals survived until the scheduled necropsy on Day 14. Slight hydrometra was observed in one treatment group female and moderate hydrometra was recorded in a second treatment group female. The hydrometra is physiological finding and connected to the cycle of the animal. No pathological changes were found related to the effect of the test item during the macroscopic examination of animals.

Applicant's summary and conclusion

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
No mortalities occurred after a single 2000 mg/kg bw oral dose (limit dose). There were no treatment related clinical or behavioral signs and no effect on body weights and body weight gains during the study. Autopsy revealed no treatment related pathological changes. Based on the results observed the LD50 was determined to be > 2000 mg/kg bw/day. The LD0 was determined to be 2000 mg/kg bw/day.
Executive summary:

A study following the acute toxic class method was carried out according to EU Method B.1 tris, OECD Guideline 401 (Acute Oral Toxicity) and OPPTS 870.1100. In a stepwise experimental procedure animals were treated with a starting dose of 2000 mg/kg bw (limit dose). The test item was administered to three female rats per oral gavage. Over a period of 14 days there were no mortalities observed at the 2000 mg/kg bw dose level. Therefore, treatment with 2000 mg/kg bw was repeated on further three female rats. Again, no mortalities were observed over a period of 14 days. All animals were periodically weighed, observed for clinical and behavioral symptoms. Gross pathological examination was carried out on the 14th day after the treatment.

No lethality was noted at single oral dose (gavage) of 2000 mg/kg bw (limit dose). No clinical symptoms were observed on the day of the treatment and during the 14-day observation period, the general state and behavior of experimental animals were normal. The body weight development was undisturbed in all animals. All animals survived until the scheduled autopsy on day 14. All organs of all experimental animals proved to be free of treatment related gross pathological changes.

Based on the results observed the LD50 was determined to be > 2000 mg/kg bw/day (limit dose). The LD0 was determined to be 2000 mg/kg bw/day (limit dose).