Methenamine

Carcinogenicity

Description of key information

At present the human data did not provide any conclusive information regarding the presence of a causal association betweenmethenamineexposure and cancer in humans. There are some reports which describe findings on human health and an excess number of deaths from lung and bladder cancer on occupationally exposed workers in the steel foundry, tire and rubber industries. However, the results from these retrospective and prospective epidemiology reports did not show clear evidence of carcinogenic activity in humans due to exposure tomethenamineas one of the compounds at the workplace in production and in the working processes. Because the workers were exposed to mixtures of chemicals consisted of several compounds with suspected carcinogenicity properties. This conclusion is in line with animal data. Long-term and/or lifetime studies in experimental animals did not indicate thatmethenamineis carcinogenic in rats and mice following high oral dosages up to and including 2.5 g/kgbw/d. Taking into account the negative results from in vivogenotoxicitytesting and the negative results in carcinogenicity/long-term bioassays in mice and rats, it is concluded thatmethenaminehas not been considered to be carcinogenic in vivo.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1968

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: old public available literature (non GLP, no guideline)

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

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

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

10 weeks old, outbread Wistar rats

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

Groups of 48 male and 48 female outbred Wistar rats (10 weeks old) received 0, or 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 in drinking water for 104 weeks.

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)

Post exposure period:

After the termination of treatment rats were observed for the rest of their lives.

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, concurrent vehicle

Details on study design:

Groups of 48 male and 48 female outbred Wistar rats (10 weeks old) received 0, or 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 in drinking water for 104 weeks. After the termination of treatment rats were observed for the rest of their lives.

Positive control:

no positive control.

Observations and examinations performed and frequency:

Animals were inspected daily and weighted every two weeks. Water intake was determinated 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.
- incidences of observed tumors and the tumor types

Other examinations:

none

Statistics:

not indicated.

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.
Furthermore, the incidences of observed tumors and the tumor types observed in rats were comparable in all methenamine-treated and control groups. The percentage of tumor-free animals was higher in the methenamine treated groups than in controls.

Relevance of carcinogenic effects / potential:

Long-term administration of 1.0% methenamine in the drinking water to outbred Wistar rats did not show tumorgenic changes.

Key result

Dose descriptor:

NOAEL

Effect level:

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

Sex:

male

Basis for effect level:

other: no adverse effects.

Key result

Dose descriptor:

NOAEL

Effect level:

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

Sex:

female

Basis for effect level:

other: no adverse effects.

Dose descriptor:

NOAEL

Effect level:

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

Sex:

male

Basis for effect level:

other: Incidences of observed tumors and the tumor types observed in rats were comparable in all methenamine-treated and control groups.

Dose descriptor:

NOAEL

Effect level:

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

Sex:

female

Basis for effect level:

other: Incidences of observed tumors and the tumor types observed in rats were comparable in all methenamine-treated and control groups.

Conclusions:

Long-term administration of 1.0% methenamine in the drinking water to outbred Wistar rats did not show tumorgenic changes.

Executive summary:

Groups of 48 male and 48 female outbred Wistar rats (10 weeks old) received 0 or 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 in drinking water for 104 weeks. After the termination of treatment rats were observed for the rest of their lives. No differences between treated and control animals were observed regarding water intake and body weight gain. An 84% survival rate was noted at the end of the second year in methenamine-treated and untreated control animals which were kept under lifetime observation. The incidence, severity, and distribution of macroscopic and microscopic findings did not differ among treated rats and controls. Furthermore, the incidences of observed tumors and the tumor types observed in rats were comparable in all methenamine-treated and control groups. The percentage of tumor-free animals was higher in the methenamine treated groups than in controls. In conclusion, long-term administration of 1.0% methenamine in the drinking water to outbred Wistar rats did not show tumorgenic changes.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

1 500 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

old public available literature (non GLP, no guideline)

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Overall, a conclusion of evidence suggesting lack of carcinogenicity in humans is inevitably limited to the special conditions and levels of exposure and length of observation covered by the available health and mortality studies of occupationally exposed humans. However, studies in experimental animals involving two species (rat and mouse) are available which have shown that, within the limits of the test used, high oral doses of methenamine did not induce tumors in either rats or mice.

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result the substance is not considered to be classified under Regulation (EC) No 1272/2008, as amended for the sixth time in Regulation No 605/2014.

Additional information

In vitro data: Cell transformation assay

A transformation assay using mycoplasma-free neonatal hamster kidney (BHK) cells was used to screen for carcinogenic potential of methenamine (commercial grade purity). The assay was performed following the method of Styles. Sterile distilled water served as both the solvent and negative control. The test was performed with metabolic activation, however, the toxicity and transforming activity of methenamine was not influenced by metabolic activation. In initial experiments, a concentration dose range of 0.025-250 μg/ml methenamine was used. A dose-dependent increase in the number of transformed colonies and a negligible toxic effect was observed. The concentration range was then increased to 1- 10000 μg/ml. When the test cultures were compared to the non-exposed cultures, 80% of the cells survived the maximum concentration. A dose-dependent and significant increase in the number of transformations was observed; transforming activity was observed at a nontoxic or a very weakly toxic concentration (Plesner and Hansen, 1983 see section 7.6.1).

Summary of cell transformation tests

An increase in the transformation rate in Styles’ cell transformation assay using BHK- 21/cl.13 cells was observed after exposure to 1000 μg/ml methenamine. However, this test system is not validated and the methodology is insufficiently documented (Plesner and Hansen, 1983).In addition, the biological relevance cannot be evaluated, and animal studies (see below) demonstrate, that the effects noted are not observed in vivo.

Concern from mutagenicity data

Methenamine revealed no mutagenic effects in the Ames tests if tested up to the recommended limit concentration of 5000 µg/plate, it was weakly positive in bacterial gene mutation assays at extremely high concentrations (>= 10000 µg/plate) and in an in vitro chromosomal aberration assay in V79 cells at severely cytotoxic doses indicating some mutagenic potential in vitro test systems with bacteria and mammalian cells at very harsh test conditions. However no mutagenic effects were noted in vivo tests. Neither an in vivo chromosomal aberration test in mice nor a dominant lethal test in mice revealed any mutagenic potential in vivo. Consequently, methenamine is not considered to represent a concern with regard to mutagenicity.

Animal data

There are no carcinogenicity studies available in experimental animals according to the current criteria for the testing of carcinogenicity by oral, inhalation, or dermal application route. Some publications review long-term/lifetime studies performed to determine the effect of lifetime administration of methenamine on neoplasm development and life span of experimental animals or other selected questions. The test procedures of the presented studies are in accordance with generally accepted scientific standards, however, differ in some respects from the published guidelines. Significant study deficiencies were: size of experimental groups, only one dose level tested, range of organ weight assessment and histopathology. Nevertheless, the total data package submitted is considered useful in assessing the carcinogenic potential of methenamine. In long-term oral studies in experimental animals with different study designs and parameters investigated, there was no evidence of carcinogenic activity in rats and mice following high dosage of 2500 mg/kg bw/d methenamine (exceeded the recommended max. doses in current OECD/EU guidelines) after long-term treatment.

Several long-term studies with oral application (gavage, feed or drinking water) in rats and mice are also reported in section 7.5 (repeated dose toxicity).

Oral Gavage studies (rat) -333-day study

15 male and 15 female BD (cPah) rats were treated with a total dose of 95 g methenamine by gavage (purity unspecified) for 333 days. Assuming a mean body weight of 250 g for male rats and 180 g for female rats, the mean methenamine dose was ca. 1130 mg/kg bw/d for male and 1570 mg/kg bw/d for female rats. Except for citrus-yellow fur discolorations of varying intensities, no difference in macroscopic findings in organs or in body weight gain between experimental and control groups of both sexes were observed Neither substance-related organ changes nor tumors were reported of animals which died or were killed at the end of the study (Brendel, 1964).

Diet study (rat)-Lifetime study

To study the effects of a lifetime methenamine intake, 16 male and 16 female Wistar rats were given either 0 or 0.16% methenamine (equivalent to 0, or ca. 100 mg/kg bw/d in both sexes, based on a body weight of 420 g of male and 280 g of female rats and a mean daily consumption of 42 mg methenamine - commercial grade purity - in males and 29 mg in females) in a standard diet from weaning (two months old) to natural death. General health, behavior, and muscular activity tested in the revolving drum after 1, 3, 7 and 14 months showed no significant differences between control and test groups. Food consumption and body weight gain were similar in both control and test groups throughout the study. There were no significant differences in relative organ weight or average natural life. Causes of death of treated animals were comparable to those of the matched controls throughout the study. No methenamine-induced lesions or carcinogenic effects in males and females given about 100 mg/kg bw/d were reported. Tumor incidence in the methenamine-treated animals was not higher than that observed in control animals (Natvig et al., 1971).

Drinking water studies (rat and mouse)

Drinking water studies were performed in rats and mice of various strains. The objective of these studies was to determine the possible carcinogenic potential of methenamine when administered in drinking water for one year or longer. Methenamine (commercial grade purity) was administered to experimental animals for up to 104 weeks. Additionally, animals of both species and sexes were then observed for a subsequent treatment-free period of varying duration (e.g. until the end of the natural life).

Rat 50-week treatment period

0.1% methenamine was administered in drinking water to two groups of 15 male and 15 female 8-10 weeks old Sprague-Dawley rats. Each group received methenamine either with or without 0.2% sodium nitrite on 5 days/week for a period of 50 weeks. The animals were then observed for the rest of their lives or were killed due to moribund condition. Each animal received a total dose of 5 g methenamine over the 50 weeks treatment (equivalent to 80 mg/kg bw/d in males and 100 mg/kg bw/d in females, based on a body weight of 250 g in males and 200 g in females). There was no significant difference in the survival rate. Tumors were neither induced by methenamine alone nor in combination with nitrite (Lijinsky and Taylor, 1977).

Rat 104-week treatment period

Groups of 48 male and 48 female outbred Wistar rats (10 weeks old) received 0, or 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 in drinking water for 104 weeks. After the termination of treatment rats were observed for the rest of their lives. No differences between treated and control animals were observed regarding water intake and body weight gain. An 84% survival rate was noted at the end of the second year in methenamine-treated and untreated control animals which were kept under lifetime observation. The incidence, severity, and distribution of macroscopic and microscopic findings did not differ among treated rats and controls. Furthermore, the incidences of observed tumors and the tumor types observed in rats were comparable in all methenamine-treated and control groups. The percentage of tumor-free animals was higher in the methenamine treated groups than in controls. In conclusion, long-term administration of 1.0% methenamine in the drinking water to outbred Wistar rats did not show tumorgenic changes (Della Porta et al., 1968).

Mouse 30- or 60-week treatment period

In long-term experiments for carcinogenicity in mice, outbred 10-week-old CTM mice, inbred 5-week-old C3hf/Dp mice, and inbred 7-week-old SWR/Dp mice were used. Groups of male and female mice of these strains received 0, 0.5, 1.0, or 5.0% methenamine in the drinking water for 30 or 60 weeks. The dosage regiment for methenamine and group size for mice in these studies are taken from the study reported under 4.1.2.6 and Table 4.4. After methenamine treatment ceased, mice were further observed a subsequent treatment-free period up to 100 weeks of age. Water intake and body weight gain were similar in both controls and methenamine treated groups throughout the study. However, treatment of CTM mice with 12.5 g/kg bw/d methenamine for 30 weeks resulted in slight reductions in growth rate and survival. Slight retardation of growth was also seen in SWR mice treated with 2.5 g/kg bw/d methenamine. Similar incidences of malignant lymphomas and leukemia, mammary carcinomas, pulmonary adenomas, hepatomas, liver angioma and Harderian-gland tumors were found in both the methenamine-treated animals and control. No significant differences in total tumor incidence between methenamine-treated and untreated groups were reported. The percentage of tumor free animals varied slightly in all strain groups. Overall, in the mouse studies, there were no significant differences in the total tumor incidences between the methenamine-treated groups and control groups (Della Porta et al., 1968).

Subcutaneous injections (rat and mouse)

Groups of 39 male and 44 female infant outbred CTM mice and 20 male and 20 female outbred Wistar rats were treated by repeated subcutaneous injections with a 30% aqueous solution of methenamine (commercial grade purity) on 5 alternate days starting on day 10 of age. Each rat and mouse was treated subcutaneously with a total dose of 25 g/kg methenamine (equivalent to 50 mg/kg bw/d). After termination of dosing, all animals were then observed for the rest of their lives. No methenamine-related findings were seen regarding growth, mortality rates, average lifetime and histopathological findings. The study showed no difference with respect to type and incidence of tumors between the groups (Della Porta et al., 1968).

Summary of animal carcinogenicity data after long-term, lifetime exposure

The existing long-term/lifetime studies on methenamine are not in accordance with current testing procedures as proposed by guidelines on carcinogenicity and/or combined chronic toxicity/carcinogenicity (EEC methods, B.32, B.33). However, the carcinogenicity of methenamine has been investigated in a number of long-term oral studies, involving a variety of strains of rats and mice. The available data package is considered to be sufficient to evaluate the carcinogenic potential of methenamine. Overall, results of these studies did not indicate that methenamine is carcinogenic in experimental animals after treatment with dosages up to 2.5 g/kg bw/d (Brendel, 1964; Natvig et al., 1971; Della Porta, 1968; Lijinsky and Taylor, 1977).

Human data

There are health and mortality studies of humans exposed at their workplace to mixtures of several compounds with suspected carcinogenic potential (e.g. formaldehyde, ammonia, cyanides, carbon black, asbestos, benzene, various polycyclic aromatic hydrocarbons), which also included methenamine. Due to insufficient study quality the available studies do not allow to draw a conclusion on a causal relationship between cancer in humans and exposure to specific chemical substances. Workers, commonly employed for instance in steel or tire foundry or in rubber production, were usually exposed to methenamine contained in substance mixtures. Therefore, the observed increased incidence of tumors in workers could not be causally attributed specifically to exposure to methenamine.

In a cohort study, 13570 white male workers, who had worked in a rubber plant for at least 5 years and were exposed to methenamine combined with several other compounds were followed up to 36 years (from 1940 – 1976). Some of these compounds which are used as antioxidants and accelerators in the rubber making are suspected carcinogens. Mortality rates were compared to standardized rates of US white males. Cancer morbidity rates were also compared among persons who were employed in various work areas of the plant. Excess cases of specific cancers (observed/expected numbers) among workers in specific areas were identified and correlated to specific working areas. Expected cases were calculated on the basis of age-specific morbidity and mortality rates for employees that were not working in specifically affected areas and amounted to >10000 to 12545 individuals. The cohorts under study generally consisted of several hundred workers (ca. 250 to 2000, depending on working place, department considered, and duration of employment). No specific exposures were monitored or recorded and related to cancer frequencies. For almost all tumor types positive associations with certain working areas were identified, provided the duration of employment was at least 5 years. Among others the following results were obtained (number of cases with specific cancers among workers in specific work areas; observed/expected): stomach and intestine: rubber making (30/14.1); lung: tire curing (31/14.1); fuel cells and/or deicers (46/29.1); bladder: chemical plant (6/2.4), and tire building (16/10.7); skin cancer: tire assembly (12/1.9); brain cancer: tire assembly (8/2.0); lymphatic cancer: tire building (8/3.2); and leukemia: calendering (8/2.2), tire curing (8/2.6), tire building (12/17.5), elevators (4/1.4), tubes (4/1.6), and rubber fabrices (4/1.1). Due to the complex nature of the working environment the positive associations between the increase in cancer morbidity for workers in a rubber plants and the different working places could not be correlated to exposures to specific chemicals. Therefore, responsible compounds could not be identified (Monson and Fine, 1978).

Based on information of about 20067 personal data sheets of white male workers (up to the end of 1979) provided by the joint National Cancer Institute/Formaldehyde Institute (NCI/FI) cohort data, a retrospective evaluation was conducted. In this revision, previous key analyses were repeated by using data only for those workers whose duration of employment was one year or more. These workers represented 63.5% of the whole collective (12743 persons) and contributed 66.5% of 242 lung cancer deaths in the study. These cases were distributed over 10 plants. With a special program (OCMAP software), lung cancer rates for the white males in this cohort were calculated in consideration of plant, age, calendar time, and job type for several time-dependent formaldehyde exposures, including formaldehyde exposure in the presence of 12 selected co-exposures such as ammonia, antioxidants, asbestos, carbon black, dyelins/pigments, methenamine, melamine, particulates, phenol, plasticizers, ureal compounds, wood dust and a composite co-exposure involving antioxidants, methenamine, melamine, phenol and urea/urea compounds. Analysis of the internal cohort rates corroborates previous analyses of the NCI/FI cohort data in those significant positive associations were found between the risk of lung cancer and cumulative exposure to formaldehyde in the presence of several of the same co-exposures. However, based on the analysis of these data, it was not possible to associate a causal connection between occupational exposure to methenamine and lung cancer risk in humans (Marsh et al., 1992).

Another study was set up to investigate potential chronic health effects associated with molding in the foundry industry with mixed exposure to methenamine and other compounds including carbon monoxide, nitrogen oxides, hydrogen cyanide, ammonia, amines, aldehydes, phenols, benzene, benzoic acid, toluene, cresols, methane, ethylene, acetylene, and various polycyclic aromatic hydrocarbons (Hansen, 1991). For this purpose, a cohort of 632 male molders was followed through 10 years with regard to cause-specific mortality. Comparisons were made with another cohort of skilled workers. It was shown that the mortality from cancer was increased among the molders (standardized mortality ratio 152, 95% confidence interval 100-221), mainly because of an excess number of deaths from bladder cancer (standardized mortality ratio 896, 95% confidence interval 329-1949). It was suggested that bladder carcinogens may be formed during certain processes of molding.. In addition, phenols, cresols, and aldehydes in the foundry work atmosphere were reported to act as tumor promoters. Due to the fact that workers were usually exposed to mixtures of several agents including methenamine, the observations in workers exposed to such mixtures in the environment could not be clearly attributed to exposures to methenamine. Consequently, no conclusion can be drawn regarding a possible causal association between exposure to methenamine and/or several other compounds or particles and cancer.

Summary of epidemiological studies among workers

Data on humans occupationally exposed to methenamine alone for a long time are not available. Workers in the steel foundry and in tire and rubber industries were exposed to mixtures of chemicals including methenamine. Considering the lack of important details in the evaluation of actual occupational exposure (e.g. frequency and duration of potential exposure or contact), measurements of methenamine concentrations in the blood, urine, exhaled breath, or other biological media from exposed workers, it was not possible to link observed effects in these workers to methenamine. Consequently, the increase in mortality from cancer mainly because of an excess number of deaths from lung and bladder cancer in the steel foundry, and tire and rubber industries cannot be linked to methenamine.

In conclusion, the above-mentioned data and mortality studies available did not provide sufficient evidence for a causal association regarding an occupational methenamine exposure and cancer in humans.

Therapeutic use

From use of methenamine for long-term therapy or the prevention of recurrent urinary infections in humans it is known that dose levels of 2 to 4 g/d produced no harmful reactions or complications in humans (Goodman and Gilman, 1975; Martindale, 2005). Adverse effects have been reported in less than 3.5 % of patients receiving methenamine or its salts as a drug. Although extensively used as a drug, there is no information available on the formation of tumors in the urinary tract in humans.

Other information

Formaldehyde is formed as product of hydrolytic cleavage of methenamine, which is strongly dependent on acidic pH values. Therefore, formaldehyde formation is only relevant after oral administration as the pH of the stomach is acidic, and the amount formed will be dependent on residence time and stomach contents as well as pH. Further down the gastrointestinal tract, the pH is neutral with nearly no formation of formaldehyde. It may also be produced in the kidneys after therapeutic use of methenamine. With respect to the genotoxic potential of formaldehyde the question of a carcinogenic potential of methenamine due to formaldehyde release might be raised. Formation of tumors had been observed in the urinary tract of animals after administration of formaldehyde.

Upon oral ingestion, formaldehyde can be absorbed into the bloodstream, where it is converted to formic acid within 90 seconds. High concentrations of formic acid can rapidly necrose cells in the liver, kidneys, heart and brain. The half-life of formic acid is reported to be 90 min. Formic acid can be excreted through the kidney as sodium salt or is further oxidised to carbon dioxide and water (cf. Pandey et al., 2000).

Oral treatment of rats with formaldehyde (200 mg/kg bw) demonstrated induction of micronuclei and nuclear anomalies in stomach, duodenum, ileum and colon as compared to untreated controls (Migliore et al., 1989). The observed effects were strongest in the stomach. Other sites of the gastrointestinal tract were clearly positive but to a lesser extent with effects declining with distance from the stomach. These data suggest that formaldehyde not only causes nuclear damage at the site of application (local genotoxicity), but may also be active at more distant sites.

However, in a valid cancer study in Wistar rats with a comparable study design as required by OECD TG 453 no increased tumor incidences have been detected in any organ (Til et al., 1989). Groups of 70 males and females were administered to drinking water containing formaldehyde adjusted to achieve target intakes of 0, 5, 25 and 125 mg/kg bw/d for up to 2 years (mean doses were 1.2, 15, or 82 mg/kg bw/d for males and 1.8, 21 or 109 mg/kg/bw/d for females). More than 30 organs/tissues were examined by histopathology: data on nonneoplastic and neoplastic effects were recorded and supplemented by parameters on haematology, clinical chemistry and urinalysis. From this data it is concluded that the formation of formaldehyde due to the pH dependent cleavage of methenamine in slightly acidic body compartments should be of no concern with respect to carcinogenicity.