Methenamine

Endpoint summary

Description of key information

Methenamine is not a local irritant by contact with skin and eyes of rabbits. In contrast to available animal data, occupational dermal exposure of methenamine in humans provides some evidence that methenamine may cause local skin irritancy although a clear discrimination between skin irritation andsensitisationis not possible based on these studies. After contact to human skin and sweat, methenamine may be hydrolyzed forming formaldehyde and ammonia. It is therefore possible that the reported adverse effects are rather caused by the metabolites formaldehyde and ammonia and not bymethenamineas such. Furthermore, the effects noted might be linked to the skin sensitising properties of methenmaine, as the studies do not allowa discriminationbetween skin irritating and skinsensitisingeffects.

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Additional information

Skin:

Key study:

In a primary dermal irritation study (Zechel, 1984), 5 months old White Russian rabbits (male and female) were dermally exposed to 0.5 g of methenamine moistened with 0.12 ml water for 4 hours to the rabbits neck. Animals then were observed for 72 h. Irritation was scored by the method of Draize. No erythema and edema was observed during the observation period (Scores 0).

In this study, methenamine is not a dermal irritant.

Supporting study:

Methenamine was topically applied to the flanks of 6 male rabbits (Zondlo, 1992). The test compound was administered in distilled water at a concentration of 0.20 %; a volume of 0.5 mL was applied under an occlusive patch. Both intact and abraded sites were used. The test solution was kept in contact with the skin for 24 h; the time of observation was 72 h. Long lasting (24 hours) occlusive skin contact resulted in slight irritation in 6 male rabbits with a 0.2 % aqueous solution of the substance. This effect may be due to the formation of formaldehyde and ammonia under the given significantly more stringent test conditions. These results, however do not indicate that the substance needs to classified as irritant according to 67/548/EC and CLP criteria.

Eye:

Key study:

In a primary eye irritation study (Zechel, 1984) 0.1 g methenamine was instilled into the conjunctival sac of the eye of 6-7 months old White Russian rabbits (male and female).Animals then were observed for 72 hrs. Irritation was scored by the method of Draize. No irritation was observed during the observation period (Cornea, iris, conjunctiva and chemosis scores 0). Only a very weak secretion was observed after 1 h. In this study, methenamine is not an eye irritant.

Human data:

In a case study reported by Merget et al. (1999), irritant dermatitis of the hands, predominantly of the palmar parts was observed in all highly exposed workers. However, it should be recognized that the number of persons included in the study was rather low (17 workers). Since high and low-dose exposure groups were defined on the basis of the type of occupational function only, assessment of quantitative dermal exposure of persons affected is difficult. This evaluation is supported by the fact, that positive cases were also reported in the low exposure group. In addition the study does not allow a discrimination between skin irritation and skin sensitising effects.

Methenamine caused acute dermatitis in 60 male employees in a local rubber factory. On the head (forehead, cheeks and sides of the neck) as well as the exposed parts of the arm (entire forearm, back of the hand, area between the fingers) the initial symptom was redness, followed by fine, watery vesicles, and later edema. Extreme itching was the principle symptom reported. Later, many of the persons affected had indolent, deep infections that proved resistant towards treatment. Removal of methenamine from the entire rubber stock prevented further cases. Systemic toxicity was not observed (Cronin, 1924). These findings also do not aloow a causal link between methenamine exposure and the observed effects, as the findings noted could be linked to other chemicals or to exposure of formaldehyde and/or ammonia, potential hydrolysis products or impurities in methenamine. Furthermore a discrimination between irritating and sensitising effects is not possible.

Rubber workers exposed to methenamine-resorcinol-mixtures reported an excess of acute symptoms. Symptoms associated with handling the mixtures included itching and skin rash. However, no direct causal relationship could be drawn between the observed adverse effects and any specific responsible agent (Gamble, 1976).

The data on irritation caused by fumes containing methenamine and its decomposition products ammonia and formaldehyde may reflect mainly the well known irritative properties of these decomposition products (Dreyfors et al., 1989). Hydrolysis of methenamine may also occur upon contact to skin.

Justification for selection of skin irritation / corrosion endpoint:
Guideline study, but no GLP study.

Justification for selection of eye irritation endpoint:
Only key study available.

Justification for classification or non-classification

Methenamine is not a local irritant by contact with skin and eyes of rabbits. Occupational dermal exposure of methenamine in humans provides some evidence that methenamine might causes local skin irritancy. After contact to human skin and sweat, methenamine may be hydrolyzed forming formaldehyde and ammonia. It is therefore possible that the reported adverse effects are caused by the metabolites formaldehyde and ammonia. In addition, these studies do not allow a clear discrimination between irritant and sensitising effects. Due to the low quality of available human data classification as “irritating” (Xi) and labelling with R38 according to 67/548/EEC or classification as skin irritant category 2 according to CLP (GHS) is not justified.

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.