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

29   Summary

29.1   Description

Hexamethylenetetramine occurs as hygroscopic and colourless crystals or as a white crystalline powder with no or mild ammonia odour. It has a low vapour pressure (0.004 mmHg) and a high water solubility (449 g/l).

29.2   Toxicokinetics

Hexamethylenetetramine is rapidly absorbed in humans following oral administration. It is distributed to various tissues and is detectable in e.g. amniotic fluid and milk. In slightly acidic environments such as in sweat, gastric fluid or urine, hexamethylenetetramine partially degrades to formaldehyde and ammonia. Upon contact with the skin, hexamethylenetetramine has also been reported to produce formic acid. In the gastric fluid, about 10-30 % of an orally administered dose of hexamethylenetetramine is degraded. The half-life for a formulation of hexamethylenetetramine in humans is about 4 hours. In the same study, more than 80 % of the oral dose of hexamethylenetetramine was excreted unchanged in the urine during the first 24 hours following administration.

29.3   Human toxicity

29.3.1   Single dose toxicity

Inflammation of the bladder and an increased concentration of nitrogen in the blood have been reported following an accidental ingestion of an overdose of hexamethylenetetramine-mandelate.

29.3.2   Repeated dose toxicity

Pulmonary or nasal symptoms (e.g. wheezy breathing, chest tightness, shortness of breath, couching, sneezing, rhinorrhoea, obstruction) have been reported in workers exposed to hexamethylenetetramine in a production plant, in the lacquer and plastics industries, in a tire manufacturing plant and in a foundry. In all of the workplaces, the workers were exposed to other chemicals (e.g. formaldehyde, ammonia, resorcinol, phenol, furfuryl alcohol, cyanides, epoxy resins, curatives) as well. Lung function measurements in one of the studies revealed significant reductions in expiratory flow rates at low lung volumes. In another study, an intracutaneous skin test with hexamethylenetetramine gave positive reactions in all workers and a provocative inhalation test with an aerosol of a lacquer product revealed allergic reactions from either the lungs, the nose or the skin.

Hexamethylenetetramine has been reported to cause allergic eczema and irritation of the skin and eyes in e.g. workers in the rubber, lacquer and plastics industry but also in people in contact with finished rubber objects. No signs of sensitisation were observed in a maximization test, which was performed in 25 adults with mascara, which contained 0.1 % hexamethylenetetramine. However, several patients have tested positive in allergic patch tests to 2 % hexamethylenetetramine. In the same studies three to four times as many patients tested positive to 1-2 % formaldehyde. Positive patch test reactions for hexamethylenetetramine have occurred in persons who were sensitised to formaldehyde or ethylenediamine. Case reports also exist of workers who had positive patch tests to hexamethylenetetramine but who tested negative to formaldehyde.

Adverse effects have been reported in less than 3.5 % of patients receiving hexamethylenetetramine and its salts orally as a drug. The most frequent adverse effect is gastrointestinal disturbances. Rarely, hypersensitivity reactions have occurred. Other adverse effects reported rarely are headache, dyspnoea, generalized oedema, tinnitus, muscle cramps, dysuria, and microscopic or gross haematuria.

29.3.3   Toxicity to reproduction

Only the expected number of congenital abnormalities was observed in more than 200 newborns that had been exposed to hexamethylenetetramine during the first trimester.

29.3.4   Mutagenic and genotoxic effects

Hexamethylenetetramine was not mutagenic in Ames test and in a microtitre fluctuation test with urine concentrates from 72 men who worked in a tire plant where hexamethylenetetramine was a workplace pollutant.

29.3.5   Carcinogenic effects

An increase in certain types of cancer has been reported among workers in a rubber making company and among Danish moulders. Both groups of workers have been exposed to hexamethylenetetramine but also to a mixture of other chemicals including some with suspected and/or confirmed carcinogenic properties.

29.4   Animal toxicity

29.4.1   Single dose toxicity

The oral LD₅₀-values reported for hexamethylenetetramine range from 9200 to higher than 20000 mg/kg b.w. for rats and 1853 mg/kg b.w. for mice.

29.4.2   Repeated dose toxicity

No adverse effects were noted in mice (CTM and C3Hf/Dp), rats (Wistar and BD II) and cats dosed with up to 2500, 1500 or 1250 mg/kg b.w., respectively, of hexamethylenetetramine in their drinking water, in their feed or by gavage for 13-104 weeks. A yellow discoloration of the fur of treated rats (but not of treated mice and cats) was observed. The discolouration has been explained as a result of a reaction between formaldehyde present in the urine from treated rats and kynurenine, which is a normal constituent of rat hair. SWR/Dp mice that received 2500 mg/kg b.w. and CTM mice that received 12500 mg/kg b.w. had a slight retardation of growth. A slight reduction in survival was also observed for CTM mice dosed with 12500 mg/kg b.w. A dose of 7500 mg/kg b.w. caused 50 % mortality in the rats.

No to mild skin irritation was observed in rabbits and guinea pigs exposed dermally to hexamethylenetetramine in concentrations of 0.2-2 %. A 0.2 % solution of hexamethylenetetramine was non-irritant to the rabbit eye while a mascara containing 0.1 % hexamethylenetetramine was mildly irritant for unrinsed rabbit eyes.

Hexamethylenetetramine caused skin sensitisation in 17/20 of guinea pigs induced with a 30 % solution and challenged with a 50 % solution in a maximisation test. No skin sensitisation was observed in another maximisation test where hexamethylenetetramine was used in a concentration of 0.2 %.

29.4.3   Toxicity to reproduction

No substance-related reproductive or developmental effects were seen in 4 studies where rats were fed or given hexamethylenetetramine in their drinking water in doses up to about 2000 mg/kg b.w. However, a significant lower body weight was found in pups, which were born of dams treated during pregnancy and lactation with 2000 mg/kg b.w. of hexamethylenetetramine and, which in addition were treated with the same dose of the chemical for the first 20 weeks of age.

In dogs fed about 15 mg/kg b.w. of hexamethylenetetramine, no substance-related reproductive or developmental effects were noted. In dogs fed about 31 mg/kg b.w. of hexamethylenetetramine, the percentage of stillborn pups was slightly increased, and the weight gain and the survival to weaning of the pups were slightly impaired. In another study where dogs were fed about 94 mg/kg b.w. of hexamethylenetetramine, a few pups were born with abnormalities.

29.4.4   Mutagenic and genotoxic effects

In most studies, hexamethylenetetramine was not mutagenic in Ames test with and without metabolic activation systems. It was negative in a mouse lymphoma assay and for chromosomal aberrations in human leucocytes. Hexamethylenetetramine was positive for chromosomal aberrations in HeLa cells, for DNA-damage in a recombination assay with spores of Bacillus subtilis, for inhibition of growth of a mutant of Escherichia coli, and for an increased number of transformations in the Styles‘ cell transformation assay with baby hamster kidney cells. In the cell transformation assay an equal number of transformations and equivalent toxicity was observed with a 50 times smaller dose of formaldehyde.

Hexamethylenetetramine was negative in vivo for clastogenic activity in the bone marrow in a micronucleus assay in C3H mouse. It was positive for dominant lethal mutations in C3H mice orally administered a very high dose but negative at doses below 10000 mg/kg b.w. Hexamethylenetetramine caused mutations in larval spermatocytes of Drosophila melanogaster at concentrations, which were higher than those used in medical therapy.

29.4.5   Carcinogenic effects

No evidence of substance-related carcinogenicity was found in 4 different studies where mice or rats were fed or given hexamethylenetetramine in their drinking water in doses up to about 2500 mg/kg b.w. for up to 2 years or in 2 studies where mice or rats were exposed dermally to hexamethylenetetramine in a concentration of up to 30 % for up to 2 years. In rats injected subcutaneously with a 40 % solution of hexamethylenetetramine for 1½ year, more tumours were found than in the control group. 

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