Methenamine

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Remarks:

combined repeated dose and carcinogenicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1968

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: public available literature (non GLP, non guideline) but good documentation

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Non-carcinogenicity of Methenamine in Mice and Rats.

Author:

Della Porta, G., Colnaghi, M.I., Parmiani, G.

Year:

1968

Bibliographic source:

Fd. Cosmet. Toxicol. 6, 707-715

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:

yes

Remarks:

only one single dose, limited number of parameters investigated

Principles of method if other than guideline:

Public avaialble literature. No guideline indicated. For details on method see 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:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

10 weeks old, outbread Wistar rats

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Details on oral exposure:

Groups of 48 male and 48 female outbred Wistar rats (10 weeks old) received 0, or 1.0% methenamine in the drinking water for 104 weeks (calculated intake 2.0-1.5 g/kg bw/d in males and 2.5-2.0 g/kg bw/d in females).

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

no analytical measurement

Duration of treatment / exposure:

104 weeks

Frequency of treatment:

continuous (drinking water ad libitum)

Doses / concentrations

Remarks:

Doses / Concentrations:
0, or 1.0% methenamine (calculated intake 2.0-1.5 g/kg bw/d in males and 2.5-2.0 g/kg bw/d in females)
Basis:
nominal in water

No. of animals per sex per dose:

48

Control animals:

yes, plain diet

Details on study design:

Groups of 48 male and 48 female outbred Wistar rats (10 weeks old) received 0, or 1.0% methenamine in the drinking water for 104 weeks (calculated intake 2.0-1.5 g/kg bw/d in males and 2.5-2.0 g/kg bw/d in females). After the termination of treatment rats were observed for a subsequent treatment-free period of up to 3 years of age.

Positive control:

no positive control.

Examinations

Observations and examinations performed and frequency:

Animals were inspected daily and weighted every two weeks. Water intake was determined periodically (no further information). There were no data on hematology and clinical biochemistry.

Sacrifice and pathology:

Necropsy and microscopic examination of organ samples were carried on animals dying during the study or were killed at the end of the study.

Other examinations:

no other examinations.

Statistics:

not indicated.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

Water intake was comparable in both control and methenamine treated test groups throughout the study. Body weights showed no significant differences between controls and methenamine treated groups. At the end of the second year 84% of survivors were noted in methenamine-treated and untreated animals. In all methenamine treated rats a yellow coloration of the coat was observed. At necropsy and microscopic examination no specific pathological lesions related to methenamine treatment were observed in rats which died during the study or were sacrificed at the end of the test.

Effect levels

1

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 500 - 2 000 mg/kg bw/day (nominal)

Sex:

male

Basis for effect level:

other: no treatment related effects observed.

2

Key result

Dose descriptor:

NOAEL

Effect level:

>= 2 000 - 2 500 mg/kg bw/day (nominal)

Sex:

female

Basis for effect level:

other: no treatment related effects observed.

Target system / organ toxicity

Key result

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

Based on the results of the study, >= 1.0% (calculated intake >= 2.0-1.5 g/kg bw/d in males and >= 2.5- 2.0 g/kg bw/d in females) methenamine was established as no-toxic-effect-level (NOAELsys) for outbred Wistar rats.

Executive summary:

Groups of 48 male and 48 female outbred Wistar rats (10 weeks old) received 0, or 1.0% methenamine in the drinking water for 104 weeks (calculated intake 2.0-1.5 g/kg bw/d in males and 2.5-2.0 g/kg bw/d in females). After the termination of treatment rats were observed for a subsequent treatment-free period of up to 3 years of age. Animals were inspected daily and weighted every two weeks. Water intake was determined periodically (no further information). There were no data on hematology and clinical biochemistry. Necropsy and microscopic examination of organ samples were carried on animals dying during the study or were killed at the end of the study. Water intake was comparable in both control and methenamine treated test groups throughout the study. Body weights showed no significant differences between controls and methenamine treated groups. At the end of the second year 84% of survivors were noted in methenamine-treated and untreated animals. In all methenamine treated rats a yellow coloration of the coat was observed. At necropsy and microscopic examination no specific pathological lesions related to methenamine treatment were observed in rats which died during the study or were sacrificed at the end of the test. Based on the results of the study, >=1.0% (calculated intake >=2.0-1.5 g/kg bw/d in males and >= 2.5- 2.0 g/kg bw/d in females) methenamine was established as no-toxic-effect-level (NOAELsys) for outbred Wistar rats.