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

45     Summary

45.1     Description

Isopropyl myristate is a colourless and practically odourless liquid with a low vapour pressure (9.35 x 10^-5 mmHg). It is practically insoluble in water.

45.2     Toxicokinetics

Very little systemic absorption (0.25 %) of isopropyl myristate occurred when four monkeys were exposed for 5 seconds to the aerosols of an antiperspirant spray containing the chemical. Following dermal application, isopropyl myristate showed local penetration in rabbits and guinea pigs but no visible penetration into the skin or organs in hairless mice.

A study with subcutaneous injection in mice indicates that if absorbed, isopropyl myristate will be distributed into almost all organs.

Isopropyl myristate has been shown to enhance the penetration rate of several other chemicals through human skin. It also has been shown to enhance the in vitro dermal absorption of ethanol and butanol through hairless mouse skin.

45.3     Human toxicity

In studies with single or repeated dermal administration of undiluted isopropyl myristate, no or minimal skin irritation was seen. When applied in petrolatum under cover for 48 hours to the backs of 50 subjects, the highest non-irritant concentration of isopropyl myristate was 10%.

No evidence of phototoxicity or photo-allergic reactions was observed in two studies with human volunteers exposed dermally to isopropyl myristate and UV-light.

Several experimental studies with healthy volunteers have failed to detect any skin sensitising potential of isopropyl myristate. That was the case in e.g. a maximization test on 25 volunteers, where a pre-treatment of the forearm with an irritant was followed by five 48-hour applications of 20% isopropyl myristate in petrolatum with 24 hours between each application, and a challenge application was given 10 days later. However, one case report exists of strong positive patch test reaction to isopropyl myristate in a woman that for 6 months had used a feminine hygiene spray containing the chemical. A case report also exist of three hospital workers with hand eczema who had positive skin-prick test reactions to 20% isopropyl myristate.

No data have been found for reproductive and developmental effects, for mutagenic and genotoxic effects, or for carcinogenic effects.

45.4     Animal toxicity

45.4.1     Single dose toxicity

The acute toxicity of undiluted isopropyl myristate following oral or dermal application is low (oral LD₅₀-value >13.7 g/kg b.w. (rats), 42.4 - > 85 g/kg b.w. (mice); dermal LD₅₀-value > 5 g/kg b.w. (rabbits)).

No deaths or evidence of systemic toxicity occurred in rats exposed to aerosol antiperspirants containing 5-20% isopropyl myristate at nominal concentrations of 10-41 mg/l for 6.5 seconds/minute for an hour or for four 15-minute periods separated by 5 minutes.

Undiluted isopropyl myristate or product formulations containing it caused no to minimal irritation of rabbit skin and eyes in several studies performed according to the Draize primary skin irritation test, the Draize rabbit eye irritation test or slight modifications of them.

45.4.2     Repeated dose toxicity

Lung weights increased (but no histological changes were found) in guinea pigs exposed for an hour three times a day, seven days a week for 4 or 13 weeks to isopropyl myristate (in an aerosol antiperspirant) in concentrations from 10 mg/m³.

In monkeys exposed for 13 weeks to isopropyl myristate (in an aerosol antiperspirant) in concentrations between 0.95 and 6.7 mg/m³, histological examinations revealed a dose-related accumulation of macrophages within the alveolar and bronchiolar walls of the lungs. During the study, the treated monkeys wheezed and coughed. However, lung function tests were normal, as were the results of haematology, blood chemistry and urinalysis. No gross lesions were seen at necropsy, and organ weights were unaffected by treatment.

No toxicological significant effects were observed in rats and hamsters exposed to isopropyl myristate aerosols (in a complex fragrance mixture) at a maximal concentration of 0.16 mg/m³ for 4 hours per day for 13 weeks.

No mortality, symptoms of intoxication, or substance-related injury of organs were recorded in rats gavaged with isopropyl myristate in doses up to 1000 mg/kg b.w. per day for 28 days or in rats fed isopropyl myristate in doses up to 2000 mg/kg b.w. per day for up to 16 weeks. Transient changes in some of the organ weights were observed in rats fed 3700 mg/kg b.w., and the blood levels of two liver enzymes and the proportion of neutrophilic leucocytes were increased in rats fed 7900 mg/kg b.w. per day of isopropyl myristate.

No systemic toxicity was observed in rabbits dosed dermally with up to 800 mg/kg b.w. of isopropyl myristate for about 20 days. Skin inflammation, mild cloudy swelling of the liver and leucocytosis were observed in rabbits dosed dermally with 5100 mg/kg b.w. of isopropyl myristate for the same period.

Isopropyl myristate was moderately to severely irritating (erythema, oedema, drying, cracking, scaling and fissuring) to rabbit and mice skin in studies lasting from 3 to 28 days. The animals were exposed dermally to 16-100% of isopropyl myristate. Microscopically, the treated skin of exposed animals showed acanthosis, parakeratosis, hyperkeratosis, and mixed inflammatory cell infiltration. In mice, the skin lesions tended to regress during continued treatment while the lesions in rabbits regressed slowly after cessation of treatment.   

Comedones were observed in rabbits, which had 1% or more of isopropyl myristate in propylene glycol applied to the ears twice daily for 2 weeks.

Applications of isopropyl myristate to the eyes of rabbits daily for 3 consecutive days apparently caused no irritation or slight irritation that had vanished after 7 days.

In 2 guinea pig sensitisation tests, isopropyl myristate suspended at 0.1% in physiologic saline showed no evidence of a sensitisation potential. However, isopropyl myristate was found to be weakly positive for skin sensitisation in the local lymph node assay in mice. The authors suggested that the positive result might be a false-positive response.

45.4.3     Toxicity to reproduction

No abnormalities were found in litters (examined grossly) of mice, which had 0.1 ml of 1% isopropyl myristate in acetone applied to the skin once weekly for 18 months.

45.4.4     Mutagenic and genotoxic effects

Isopropyl myristate tested negative in an Ames test with 5 strains of Salmonella typhimurium both with and without metabolic activation.

45.4.5     Carcinogenic effects

No significant differences were observed in the incidence of skin or internal tumours between negative control animals (mice and rabbits) and animals, which were given dermal applications of undiluted (or diluted) isopropyl myristate twice a week in lifetime (or shorter) studies.

A 50% solution of isopropyl myristate in ethanol (or isopropyl alcohol?) significantly accelerated the carcinogenic activity of 0.15% of the known skin carcinogen, benzo[a]pyrene, on the skin of mice.

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