| Front page | | Contents | | Previous | | Next |

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

26   Human toxicity

26.1   Single dose toxicity

An accidental overdose of 8 g of hexamethylenetetramine-mandelate (corresponding to a dose of 384 mg/kg b.w. of hexamethylenetetramine in a 10 kg child), which was ingested by a 2½-year-old boy, caused haemorrhagic cystitis (inflammation of the bladder) and mild azotaemia (increased concentration of nitrogen in the blood). The boy recovered without specific treatment. (Ross & Conway 1970 – quoted from Loeper & Berzins 1995).

26.2   Repeated dose toxicity

26.2.1   Inhalation

A cross-sectional study was performed with 33 employees of a hexamethylenetetramine producing plant to assess the health effects of hexamethylenetetramine on the airways and the skin of the workers. Sixteen of the employees (blue and white collar workers) with no or occasional low exposure to hexamethylenetetramine served as controls while 17 employees (baggers, shiftleaders, and executive staff) with exposure to far higher concentrations served as the exposed group. In addition, 4 out of 5 employees that had left the production for medical reasons during the last 10 years were included in the study. For each worker, anamnestic data were recorded and a physical examination of the skin and lungs was performed. In addition, total and specific IgE to four environmental allergens was measured, lung function and bronchial hyperresponsiveness was assessed, and skin prick tests and patch tests with known sensitising substances as well as with hexamethylenetetramine were performed. Measurements were made at different sites in the plant and/or in personal air space of inhalable dust, respirable dust, hexamethylenetetramine, formaldehyde, and ammonia to assess the exposure level.

All measured concentrations of dust and chemicals were in the range of 0.2 – 2.6 mg/m³. Geometric mean hexamethylenetetramine concentrations as assessed by personal sampling were 0.3 mg/m³ in shiftleaders and 0.6 mg/m³ in baggers.
Irritant dermatitis of the hands, predominantly on the palmar parts, was observed in all highly exposed subjects, but also (to a lower extent) in two controls. No other differences were found between the exposed and the control group. Two workers in the exposed group and one in the control group had work-related symptoms. Of the two exposed workers, one person reported shortness of breath, rhinoconjunctivitis and dermatitis of the hands, face and neck that occurred after “accidents with high formaldehyde exposure”. The second worker had pre-existing hay fever and seasonal asthma and gave a history of work-related shortness of breath and rhinitis but he had a normal lung function and no bronchial hyperresponsiveness. One control worker reported work-related conjunctivitis, probably due to long-lasting computer work. No sensitisation to hexamethylenetetramine as assessed by skin prick and patch tests were found in exposed or control workers.
Two out of the four ex-workers (both former baggers) had a positive patch test (but a negative skin prick test) to hexamethylenetetramine. These two former workers had a negative patch test to formaldehyde and no airway symptoms. They reported eczema (located at exposed skin areas in one person and generalised in the other) and conjunctivitis during exposure after 2 weeks or 7 months but were free of symptoms after removal from exposure. The two former workers that tested negative in the patch tests, experienced eczema of the neck “shortly” after exposure and recurrent swelling of eyelids and wrists after one year, respectively. At the time of the study they both presented with eczema, although improved. (Merget et al. 1999).

Seven workers in the lacquer or plastics industries that had worked around epoxy resins, plastics, or paint developed asthma and other allergic symptoms (allergic coryza (nasal catarrh), contact dermatitis, allergic conjunctivitis). An intracutaneous skin test with 0.02 ml of a 1:100 dilution of hexamethylenetetramine gave positive reactions in all workers. The positive reaction was characterised by immediate wheal formation. In a provocative test the workers were inhaling the lacquer product in aerosol form and showed either 1) wheezing and heaviness on the chest or severe asthma, 2) allergic coryza, or 3) skin manifestations of allergy. Some of the workers also had positive reactions to ethylenediamine in both tests. It is unclear from the article which other chemicals the workers might have been exposed to. (Gelfand 1963).

Workers in a tire manufacturing plant were exposed daily to a hexamethylenetetramine-resorcinol mixture (which comprised 2-3 % of the total rubber mix) as well as to their reaction products which were thought to include formaldehyde, ammonia, cyanides and curatives. Fifty-two exposed workers completed a questionnaire and had their lung function measured. The workers suffered from acute symptoms such as itching, skin rashes, coughing, chest tightness, burning eyes and impaired breathing. The excess of symptoms (in comparison with a non-exposed group of workers) persisted when the effects of smoking and drinking were accounted for. Significant reductions in expiratory flow rates at low lung volumes were reported, indicating increased resistance in the small airways. (Gamble et al. 1976).

Workers in foundry where a moulding process utilizes a phenol-formaldehyde resin and hexamethylenetetramine as catalyst, suffered from nasal symptoms such as sneezing, rhinorrhoea, and obstruction as well as wheezy breathing. Twenty of 46 workers in the core shop or casting areas reported asthma or wheezy breathing. Of these, 11 developed the symptoms after starting work at the foundry. Workers involved in other working processes less frequently reported these symptoms. Most environmental measurements of chemical contaminant were below the threshold limits. However, the concentration of furfuryl alcohol (50 ppm in air) and formaldehyde (4 ppm in air) was above the limits in the general foundry. The authors suggest that both irritant and hypersensitivity mechanisms are present because of the onset of symptoms in relation to exposure to fumes and vapours. (Low & Mitchell 1985 – quoted from Loeper & Berzins 1995).

26.2.2   Oral intake

When hexamethylenetetramine is given orally at doses greater than 500 mg four times per day, gastrointestinal distress occur. Bladder irritation, painful and frequent micturition (urination), albuminuria, haematuria, and various rashes may result from doses of 4-8 g a day for longer than 3-4 weeks. (Goodman & Gilman 1975 – quoted from Loeper & Berzins 1995).Adverse effects have been reported in less than 3.5 % of patients receiving hexamethylenetetramine and its salts as a drug. The most frequent adverse effect is gastrointestinal disturbances, including nausea, vomiting, diarrhoea, abdominal cramps, and anorexia. Rarely, hypersensitivity reactions including rash, pruritus, urticaria, and stomatitis have occurred. Other adverse effects reported rarely are headache, dyspnoea, generalized oedema, tinnitus, muscle cramps, dysuria, and microscopic or gross haematuria. (McEvoy 1997 – quoted from HSDB 2000).

26.2.3   Dermal contact

A maximization test has been performed using 25 adults, 8 men and 17 women, to assess the potential for contact sensitisation of a mascara, which contained 0.1 % hexamethylenetetramine. A pre-test using 25 adults who got an occlusive patch of test material applied to the volar aspect of the forearm for 48 hours showed that the test material was non-irritating. For induction, 0.3 g of test material was applied under an occlusive patch to the volar aspect of the forearm and was covered with a 15 mm aluminium chamber for five 48-hour periods. Sodium lauryl sulphate, 1 %, was used during the induction because the test material was found to be non-irritating during the pre-test. Following a 10-day non-treatment period a challenge was performed by applying an occlusive patch to a new site for 48 hours using the same procedure as for the induction. However, this time a 5 % aqueous solution of sodium lauryl sulphate was used. Observations were made upon removal of the patch and after 24 hours. No signs of sensitisation were observed following the challenge. (Ivy Research Laboratories Inc. 1980 – quoted from CIR 1992).

Hexamethylenetetramine has been reported to cause allergic eczema in rubber workers. After exposure to hot rubber containing 0.1 % hexamethylenetetramine, 60 workers suffered from acute dermatitis with itching and redness of exposed skin. Removal of the chemical from all rubber stock prevented further cases. (Cronin 1924 – quoted from IUCLID 2000).

Seven (2.0 %) out of 357 tested patients remitted to an occupational dermatology clinic in Finland during a 6-year period had a positive allergic patch test reaction to 2 % hexamethylenetetramine. In the same period 5.8 % (82/1414) were positive to 1 % formaldehyde. The study is not stating whether any cross-reaction between hexamethylenetetramine and formaldehyde was observed. (Kanerva et al. 1999).

A similar result was reported in another study where 1.9 % of 309 tested patients had a positive reaction to 2 % hexamethylenetetramine and 6.2-8.7 % of tested patients had a positive reaction to 1-2 % formaldehyde (Holness & Nethercott 1997).

One case report exists of a worker who had a positive patch test to hexamethylenetetramine but who tested negative to formaldehyde. The worker developed itchy eruptions, which were aggravated by sweating, on his hands, neck, and shoulders. When tested, negative results were obtained for a range of chemicals tested in open patch tests on the upper arm for 20 minutes. In closed patch tests, chemicals were applied for 24 hours and readings were taken 1 and 24 hours after removal. Only 1 % hexamethylenetetramine in petrolatum produced a positive reaction with erythema and papules. For 2 % aqueous formaldehyde a questionable positive result was observed at the 48-hour reading but at the 72-hour reading the result was negative. Eight months later a retest was performed using hexamethylenetetramine and formaldehyde. At this test a negative result was obtained for formaldehyde. As a negative control, hexamethylenetetramine tested negative in 9 colleagues. Positive controls for formaldehyde were performed using formaldehyde-sensitised patients. (Hayakawa et al. 1988 – quoted from CIR 1992, and Loeper & Berzins 1995).

Hexamethylenetetramine has been reported as allergenic not only in occupational use but also in contact with finished rubber objects (Fregert 1981 – quoted from Loeper & Berzins 1995).

Patients sensitised by external exposure to formaldehyde have experienced dermatitis when exposed dermally to hexamethylenetetramine in rubber dress shields or when ingesting it as a drug (Fisher 1978, Sulzberger 1940 – both quoted from CIR 1992).
Positive patch test reactions have occurred in persons who were sensitised to formaldehyde when they were tested with hexamethylenetetramine (Fisher 1986 – quoted from Loeper and Berzins 1995).
Contact dermatitis was also observed when ethylenediamine sensitive persons were patch tested with hexamethylenetetramine (Balato et al. 1986 – quoted from Loeper & Berzins 1995).

See also the study performed by Merget et al. (1999) described in section 3.2.1 Inhalation.

26.2.4   Other routes

No data have been found.

26.3   Toxicity to reproduction

In a surveillance study conducted between 1985 and 1992 of Michigan Medicaid recipients involving 229,101 completed pregnancies, 209 newborns had been exposed to hexamethylenetetramine during the first trimester. Eight (3.8 %) major birth defects were observed. Nine major birth defects were expected. (Briggs et al. 1994 – quoted from HSDB 2000).

No congenital abnormalities were observed in the children of 3 women who had taken hexamethylenetetramine as well as 5 other drugs (choleinic sodium, phenolphthalein, papaverine HCL, methylhomatropine, and menthol) during the first two weeks of pregnancy (Siffel & Czeizel 1995).

26.4   Mutagenic and genotoxic effects

Urine samples were collected from 72 men, 44 of whom smoked, who worked in a tire plant where hexamethylenetetramine was a workplace pollutant. Twenty-three clerks, 16 of whom smoked, were used as controls. Urine concentrates equivalent to 10 ml of urine were tested for mutagenicity in the Ames test with metabolic activation in Salmonella typhimurium strains TA 98, TA100, and TA1535, and in a microtitre fluctuation test. A smoking related increase in mutagenicity was observed in strain TA98. Hexamethylenetetramine was not mutagenic in this study. (Crebelli et al. 1984, 1985 – quoted from CIR 1992 and Loeper & Berzins 1995).

26.5   Carcinogenic effects

An increase in intestinal, lung, bladder, and skin cancer as well as leukaemia has been reported among 13570 men who had worked for at least 5 years at one company in rubber making, especially in areas where the rubber ingredients were mixed and compounded. Hexamethylenetetramine was used as an accelerator in the process in this plant. However, the mixture consisted of several antioxidants and other accelerators with suspected carcinogenic properties. (Monson & Fine 1978 – quoted from IUCLID 2000 and Loeper & Berzins 1995).

The mortality from cancer was increased in a cohort of 632 Danish moulders, mainly because of excess deaths from bladder cancer. Hexamethylenetetramine is added as a catalyst to some synthetic resin moulds. However, the workers have been exposed to a mixture of chemicals including carbon monoxide, nitrogen oxides, hydrogen cyanide, ammonia, amines, aldehydes, phenols, benzene, benzoic acid, toluene, cresols, methane, ethylene, acetylene, and various polycyclic aromatic hydrocarbons (of which some are carcinogenic). (Hansen 1991).

| Front page | | Contents | | Previous | | Next | | Top |