[1,2,4]Triazolo[1,5-a]pyrimidine-2-sulfonamide, N-(2,6-difluorophenyl)-5-methyl-

Toxicity to reproduction

Administrative data

Endpoint:

two-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

23 June 1988 to 1 November 1990

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

EPA OPP 83-4 (Reproduction and Fertility Effects)

GLP compliance:

yes

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

N-(2,6-difluorophenyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonamide

EC Number:

619-383-6

Cas Number:

98967-40-9

Molecular formula:

C12H9F2N5O2S

IUPAC Name:

N-(2,6-difluorophenyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonamide

Constituent 2

Reference substance name:

N-(2',6'-difluorophenyl)-5-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonamide

IUPAC Name:

N-(2',6'-difluorophenyl)-5-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonamide

Details on test material:

- Name of test material (as cited in study report): XRD-498

- Molecular weight:253.3 Daltons

- Physical state:White, very fine crystals
- Analytical purity:99.7%


- Purity test date: 10 January 1989
- Lot/batch No.: AGR 240043

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: rodent chow

Details on mating procedure:

- M/F ratio per cage:1:1
- Length of cohabitation: 7 days
- Proof of pregnancy: vaginal plug and sperm in vaginal smear considered day 1 of pregnancy
- After 7 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: a third 7-day cohabitation period was used for females as necessary
- After successful mating each pregnant female was caged (how): singly in stainless steel cages with wire mesh floors

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

F0 generation was dosed for for 10 weeks.
F1 adults were dosed for 12 weeks.

Frequency of treatment:

Daily

Details on study schedule:

- F1 parental animals not mated until 12 weeks after selected from the F1 litters.

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0 - control
Basis:
actual ingested

Doses / concentrations 2

Remarks:

Doses / Concentrations:
100 mg/kg body weight/day
Basis:
actual ingested

Doses / concentrations 3

Remarks:

Doses / Concentrations:
500 mg/kg body weight/day
Basis:
actual ingested

Doses / concentrations 4

Remarks:

Doses / Concentrations:
1000 mg/kg body weight/day
Basis:
actual ingested

No. of animals per sex per dose:

30 animals per sex per dose group

Control animals:

yes

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

Dose descriptor:

NOEL

Effect level:

1 000 other: mg/kg bw/day (actual ingested)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Remarks on result:

other: Generation: F0, F1a, F1b, F2 (migrated information)

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

The F1a pups, which served as parental generation for the F2 animals, matured and successfully produced litters with no evidence of treatment-related effects.

Applicant's summary and conclusion

Conclusions:

Based on the results of this study, the no-observable-effect-level for reproductive effects was 1000 mg/kg bw/day. No paternal or maternal toxicity was demonstrated at any dose level tested including the high dose level of 1000 mg/kg bw/day.

Executive summary:

Fischer-344 rats were fed XRD-498 at dose levels of 0, 100, 500, or 1000 mg/kg bw/day in the diet. Following 10 weeks of exposure, the F0 rats were mated to produce F1a and F1b litters. At weaning, 30 F1a pups/sex/dose level were randomly selected to become the F1 adults. After 12 weeks of exposure to XRD-498, the F1 adults were mated to produce the F2 litters. Reproductive performance and neonatal survival and development were evaluated to assess the reproductive effects of treatment. Body weights, body weight gains, feed consumption, clinical observations, kidney weights, and gross pathologic and results of histopathologic examinations were evaluated for evidence of toxicity. Reproductive performance of the F0 and F1 adult rats was not affected by XRD-498 treatment. No effects attributable to XRD-498 treatment were found in the growth and development of the F1a, F1b, and F2 pups. The F1a pups, which served as parental generation for the F2 animals, matured and successfully produced litters with no evidence of treatment-related effects. No parental toxicity was demonstrated in the F0 or F1 adult rats, even at the high dose level of 1000 mg/kg bw/day. Based on the results of this study, the no-observable-effect-level for reproductive effects was 1000 mg/kg bw/day (limit test). No paternal or maternal toxicity was observed at any dose level tested.