Appendices 1-18 to: Report on the Health Effects of Selected Pesticide Coformulants

Appendices 1-18 to: Report on the Health Effects of Selected Pesticide Coformulants

30 Evaluation

The critical effect of hexamethylenetetramine is the sensitisation it may cause following exposure by inhalation or skin contact. Skin sensitisation has been observed in a guinea pig maximisation test as well as in humans in several patch tests. Several workers with mixed exposures, including exposure to hexamethylenetetramine, have reported allergic eczema and/or asthma-like symptoms. In one study, reductions in expiratory flow rates at low lung volumes was reported. In another study, intracutaneous skin tests with hexamethylenetetramine gave positive reactions in all workers and a provocative inhalation test with an aerosol of a lacquer product showed allergic reactions from either the lungs, the nose or the skin.
It is a cause of concern that no inhalation studies with hexamethylenetetramine have been performed in animals since it because of the mixed exposures is unclear from the human studies whether the symptoms from the lungs are caused by hexamethylenetetramine.

No systemic effects following inhalation of hexamethylenetetramine have been reported in humans. No toxicokinetic inhalation studies have been performed. However, due to the high water solubility of hexamethylenetetramine it is most likely absorbed following inhalation.

A low order of acute oral toxicity has been observed in experimental animals.

Irritation of the skin and eyes has been reported in workers with mixed exposures, including exposure to hexamethylenetetramine, as well as in laboratory animals.

Only few adverse effects (of which the most frequent is gastrointestinal disturbances) have been reported in patients receiving hexamethylenetetramine and its salts orally as a drug.
In laboratory animals exposed orally to high doses of hexamethylenetetramine, only slight growth retardation and survival was observed.

No substance-related reproductive or developmental effects were observed in rats exposed to high doses (up to 2000 mg/kg b.w.) of hexamethylenetetramine in their drinking water. Dogs seemed more sensitive since some developmental effects (increased percentage of stillborn pups, decreased weight gain and survival to weaning of pups) were observed in dogs fed about 31 mg/kg b.w. of hexamethylenetetramine. However, at 15 mg/kg b.w. no developmental effects were noted.
In humans, only the expected number of congenital abnormalities was observed in more than 200 newborns that had been exposed to hexamethylenetetramine during the first trimester.

Both positive and negative results were obtained in assays for mutagenicity and genotoxicity of hexamethylenetetramine. However, in the in vivo assays, positive results were only observed when the administered doses were very high.

Oral and dermal carcinogenicity studies in rats and mice exposed to high doses of hexamethylenetetramine revealed no evidence of substance-related tumours.

Some of the effects observed following exposure to hexamethylenetetramine may be due to its degradation products, e.g. formaldehyde, ammonia, and formic acid, which may be formed in slightly acidic environments. Formaldehyde is known to be a strong sensitising agent to the skin and is, according to the EU classification criteria, classified as such (R43).