Methenamine

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1987

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: public available literature (non GLP, non guideline)

Data source

Reference

Reference Type:

publication

Title:

The Chernoff-Kavlock Assay: Its Validation and Application in Rats.

Author:

Wickramaratne, G.A. de S.

Year:

1987

Bibliographic source:

Teratogenesis, Carcinogenesis, and Mutagenesis 7, 73-83

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Public available literature. No guideline indicated. For details on method see IUCLID5 materials and methods section.

GLP compliance:

not specified

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Methenamine

EC Number:

202-905-8

EC Name:

Methenamine

Cas Number:

100-97-0

Molecular formula:

C6H12N4

IUPAC Name:

1,3,5,7-tetraazatricyclo[3.3.1.1³,⁷]decane

Test material form:

solid: crystalline

Test animals

Species:

rat

Strain:

other: Alpk:AP (Wistar -derived)

Details on test animals or test system and environmental conditions:

Housing was under SPF conditions, the dams being singly housed in mesh cages with potable water and food available ad libitum. From day 18 of gestation, the cages were fitted with solid bottoms, and the dams were provided with nesting material.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

Administration by gavage, the volume being adjusted to administer 10 mL/kg bodyweight on the daily bodyweight.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

no data on analytical verification of doses

Details on mating procedure:

Day 1 of gestation was defined as the day on which a sperm-positive vaginal smear was observed.

Duration of treatment / exposure:

Dosing was done over the period days 7-17 inclusive gestation.

Frequency of treatment:

daily

Duration of test:

Dams: 22 days (gestation)
Litters: 5 days

No. of animals per sex per dose:

9 female rats

Control animals:

yes, concurrent vehicle

Details on study design:

During validation of a Screening Assay (Chernoff-Kavlock Assay) modified for studies on rats methenamine was investigated with a group of 9 female rats treated orally (gavage) during gestation day 7 to 17 with daily doses of 1000 mg/kg bw.

Examinations

Maternal examinations:

- vaginal smear
- observation of body weight on day 1, 7-17 and 22
- Number of pregnant rats
- mortality

Ovaries and uterine content:

not examined.

Fetal examinations:

- mean litter size
- total and mean number of live pups on day 1 and 5
- percentage survival
- Mean pup weight on day 1 and 5
- Mean weight gain per litter (days 1-5)

Statistics:

standard deviation
Criteria for Assessment of results:
A set of three rules was drawn up on an empirical basis to assess the results. The rules are based on both the results of the validation phase and the background data on reproductive parameters for the strain. The rules are:
1) no effect on litter size, survival, or postnatal weight gain - negative
2) reduced litter size at birth (mean less than 8) or reduced postnatal survival (less than 80%)- potential teratogen
3) reduced postnatal weight gain (less than 30%) with no reduction in survival - potential foetotoxin

Indices:

not calculated.

Historical control data:

No data available (validation of study).

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
In comparison to the concurrent control group a reduced weight gain was observed in treated maternal animals, indicating some toxicity or at least adverse effects of the treatment.

Effect levels (maternal animals)

Key result

Dose descriptor:

NOAEL

Basis for effect level:

mortality

Remarks on result:

other: no data

Maternal abnormalities

Key result

Abnormalities:

no effects observed

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Details on embryotoxic / teratogenic effects:
Compared with the controls, the 5 pregnant dams of the treated group showed no difference in mean litter size, survival of pups and pup postnatal weight gain. However, the number of dams for which offspring could be evaluated is poor, and it is not discussed and no information is given in this study to explain, why only 5 out of 9 sperm-positive dams produced litters in the test group.

Effect levels (fetuses)

1

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Basis for effect level:

other: teratogenicity

2

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Basis for effect level:

other: fetotoxicity

Fetal abnormalities

Key result

Abnormalities:

no effects observed

Overall developmental toxicity

Key result

Developmental effects observed:

no

Applicant's summary and conclusion

Conclusions:

In a Chernoff-Kavlock assay in rats methenamine was shown to be not teratogenic and not fetotoxic at a limit concentration of 1000 mg/kg bw/day, revealed some indication for systemic toxicity under the given test conditions in the dams.

Executive summary:

During validation of a Screening Assay (Chernoff-Kavlock Assay) modified for studies on rats methenamine was investigated with a group of 9 female rats treated orally (gavage) during g.d. 7 to 17 with daily doses of 1000 mg/kg bw.

In comparison to the concurrent control group a reduced weight gain was observed in treated dams.

Compared with the controls, the 5 pregnant dams of the treated group showed no difference in mean litter size, survival of pups and pup postnatal weight gain. However, the number of dams for which offspring could be evaluated is poor, and it is not discussed and no information is given in this study to explain, why only 5 out of 9 sperm-positive dams produced litters.