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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: See read-across justification attached.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2007

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

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

Test animals

Species:
rat
Strain:
other: Crl:CD(SD) BR
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5 % (wt/vol)
Duration of treatment / exposure:
Six month treatment with three month interim sacrifice and one month recovery groups (control and high dose group)
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 250, 500, 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
10/sex/group for control and treatment groups and 5/sex/recovery group
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
Repeat-dose toxicity was evaluated based on mortality; clinical observations; body weight; food consumption; ophthalmology; clinical pathology, including hematology, coagulation, and chemistry; and/or macroscopic and microscopic pathology.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food efficiency:
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Details on results:
In the 6-month repeat-dose toxicity study with 3-month interim sacrifice in rats, six rats in total were found dead (one control male, two males dosed at 500 mg/kg/day, and two females dosed at 1,000 mg/kg/day) or sacrificed for humane reasons (one male dosed at 1,000 mg/kg/day). Except for one male dosed at 500 mg/kg/day that was found dead on day 161 and whose cause of death was undetermined, the cause of death for the remaining four rats was considered to be gavage related. The male dosed at 1,000 mg/kg/day that was sacrificed for humane reasons on study day 133 was diagnosed with widespread lymphoma, a common spontaneous tumor. None of these deaths was attributed to the test item. Treatment had no adverse effects on food consumption, but some dosed rats had intervals of increased food intake. This transient increased appetite was not considered evidence for toxicity from the test item. Ophthalmic examinations of rats in all dose groups did not identify any treatment-related changes; there were some age-related changes. Hematology data did not indicate toxicity from the test item after 92 days (3 months), 176 days (6 months), or 204 days (1-month recovery). There were no conclusive findings from the clinical chemistry data to indicate evidence for toxicity at any interval. Mean absolute and relative organ weights were somewhat variable but failed to demonstrate a clear pattern for toxicity from the test item. No macroscopic or microscopic morphological changes were associated with test item exposure. The NOAEL was reported to be 1,000 mg/kg/day.

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No treatment related adverse effects observed up to the highest dose (limit dose) tested.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
No treatment related adverse effects were noted in this 6-month repeat-dose toxicity study with 3-month interim sacrifice in rats, including recovery groups. The NOAEL for males and females was determined to be 1000 mg/kg bw/day (limit dose).
Executive summary:

A study was carried out similar or equivalent to OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents) using L-Thymidine. The read-across approach to the L-isomer of the nucleoside is justified.

A total of 10 males and 10 females was dosed at 0, 250, 500 and 1000 mg/kg bw/day (up to the limit dose) for six month with three month interim sacrifice and one month recovery groups (control and high dose group). Repeat-dose toxicity was evaluated based on mortality; clinical observations; body weight; food consumption; ophthalmology; clinical pathology, including hematology, coagulation, and chemistry; and/or macroscopic and microscopic pathology.

In the 6-month repeat-dose toxicity study with 3-month interim sacrifice in rats, none of the observed deaths was attributed to the test item. Treatment had no adverse effects on food consumption, but some dosed rats had intervals of increased food intake. Ophthalmic examinations of rats in all dose groups did not identify any treatment-related changes. Hematology data did not indicate toxicity from the test item after 92 days (3 months), 176 days (6 months), or 204 days (1-month recovery). There were no conclusive findings from the clinical chemistry data to indicate evidence for toxicity at any interval. Mean absolute and relative organ weights were somewhat variable but failed to demonstrate a clear pattern for toxicity from the test item. No macroscopic or microscopic morphological changes were associated with test item exposure. The NOAEL was determined to be 1000 mg/kg/day.

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