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

133     Summary

133.1     Description

NMP is a colourless, hygroscopic liquid with a mild amine odour. NMP is miscible with water. Air saturated with NMP at 20°C has an NMP concentration of around 1400 to 1600 mg/m³; higher airborne exposure levels will thus consist of a mixture of vapour and aerosol.

133.2     Toxicokinetics

In humans, a close correlation between inhalation exposures and the plasma concentration of NMP was observed; a plasma half-life of about 4 hours was found. NMP was readily eliminated, mainly by biotransformation to other compounds (major metabolites in urine being 5-hydroxy-N-methyl-2-pyrro­lidone and 2-hydroxy-N-methyl­succinimide); the major route of excretion being the urine. The elimination curve suggested a non-linear pattern and at the end of exposure showed a main (range) half-life of NMP in the urine of about 4.5 (3.5-6.6) hours.

In the rat, NMP is readily absorbed through the respiratory and gastrointestinal tracts and through the skin. The plasma radioactivity concentration peaked at 2 or 2-6 hours following oral or topical administration, respectively. Following absorption, NMP is distributed widely to organs and tissues with the highest concentrations occurring in the liver, small and large intestine, testes, stomach, and kidneys. NMP is rapidly metabolised and excreted, the major route of excretion being the urine (85-88%). Four metabolites have been found in the urine with 5-hydroxy-N-methyl-2-pyrrolidone being the major one.

133.3     Human toxicity

133.3.1     Single dose toxicity

No data have been found.

133.3.2     Repeated dose toxicity

Volunteers exposed to NMP at levels up to 50 mg/m³ did not report any discomfort to eyes or upper airways and no changes in the spirometric data could be registered; two individuals reported an odour of acetone at 50 mg/m³, the odour was reported as “not uncomfortable”.

Workers in the microelectronics industry have reported severe eye irritation following exposure for a short time (30 minutes) to levels of about 3 mg/m³ (8-hour TWA), exposures around 66 mg/m³ were reported as being immediately uncomfortable (within 30 seconds) with minor eye irritation, and exposures above 200 mg/m³ were found unbearable follow­ing a few seconds of exposure.

Several workers have experienced skin irritation and contact dermatitis on the hands after a few days of working with NMP; no signs of contact sensitisation have been reported.

133.3.3     Toxicity to reproduction

One case of intrauterine growth retardation followed by foetal demise at 31 weeks gestation has been reported in a laboratory worker exposed to NMP throughout the first trimester of pregnancy.

133.3.4     Mutagenic and genotoxic effects

No data have been found.

133.3.5     Carcinogenic effects

No data have been found.

133.4     Animal toxicity

133.4.1     Single dose toxicity

In the rat, the 4-hour LC₅₀-value has been reported as being greater than 5100 mg/m³ or in the range of 3100-8800 mg/m³. The reported oral and dermal LD₅₀-values ranged from 3600-7900 mg/kg and from 2500-10000 mg/kg, respectively, in the rat.

Skin irritation tests in rabbits indicated a low potential for skin irritation, whereas NMP is an eye irritant in this species; NMP did not show any skin sensitisation when tested in the guinea pig.

133.4.2     Repeated dose toxicity

Mortality occurred within 9 days in rats exposed to NMP (aerosol-vapour mixture, respirable aerosol with >95% of the droplets being below 10 µm in diameter) at 1000 mg/m³ (6 hours a day, 5 days per week); marked pulmonary oedema and congestion, bone marrow effects (haemorrhage, hypoplasia, and necrosis in the haemopoietic cells), and prominent atrophy and necrosis in the lymphoid tissue in the thymus, spleen and lymph nodes were observed in dead animals.

No histopathological lesions have been observed in rats exposed by inhalation (6 hours a day, 5 days per week) to NMP at up to 500 mg/m³ for 2 or 4 weeks; at 1750 mg/m³ for 6 weeks; up to 1000 mg/m³ for 13 weeks; or up to 400 mg/m³ for 2 years; at levels above 4000 mg/m³ (2 weeks) lesions were observed in the lungs and in the glandular stomach.

Following oral administration (dietary), no pathological lesions were observed in rats and mice when NMP was administered at dose levels up to 420 mg/kg b.w. per day (rats) or up to 500 mg/kg b.w. per day (mice) for 90 days; centrilobular hepatocellular hypertrophy has been observed in female rats (1344 mg/kg b.w. per day) and in both sexes of mice (1931 mg/kg b.w. per day) following dietary administration for 90 days.

Mild secretion from the nose has been observed in rats exposed to 1750 mg/m³ and irritation of the respiratory tract has been reported following exposure from about 1000 mg/m³. One study has reported signs of lethargy and irregular respiration in rats after exposure to 100-1000 mg/m³ for 3 to 4 hours. Following exposure to NMP at 620 mg/m³ (6 hours a day, 7 days per week for 90 days), no indications of neurotoxic effects in the central nervous system of rats were observed.

Tremor, restlessness, piloerection, and defensive reactions have been reported in rats 2 weeks following oral administration (2066 mg/kg b.w per day by gavage).

In a 90-day dietary study, male rats showed an increase in mean foot splay values (from 433 mg/kg b.w. per day) and a higher incidence of low arousal and slight palpebral closure (at 1057 mg/kg b.w. per day).

Increased organ weights have been observed in rats (increased thyroid weight in males at 420 mg/kg b.w. per day (dietary) for 13 weeks; increased absolute and relative liver (females only) and kidney weights at 1057 (males) / 1344 (females) mg/kg b.w. per day for 90 days) and in mice (increased liver, kidney, thyroid, and pituitary weights in males from 200 mg/kg b.w. per day (dietary) for 13 weeks).

Reduced body weight gain has been observed following oral administration to rats (from 1800 mg/kg b.w. per day (dietary) for 4 weeks, from 517 mg/kg b.w. per day (gavage) for 4 weeks, from 433/565 mg/kg b.w. per day (dietary, males/females) for 90 days), to mice (from 200 mg/kg b.w. per day (dietary) for 13 weeks), and in dogs (apparently from 25 mg/kg b.w. per day (dietary) for 13 weeks), and in rats following inhalation of 400 mg/m³ for 2 years.

A very common observation following exposure to NMP is a discoloration of the urine (dark yellow to orange to red-brown (depending on exposure level) from around 400 mg/m³ following inhalation and from around 170 mg/kg b.w. per day following oral administration).

133.4.3     Toxicity to reproduction

Testicular effects (reduced weight and damage) were observed in rats following exposure to NMP by inhalation (3000 mg/m³ for 90 days) or by oral administration (ca. 2000 mg/kg b.w. per day for 4 weeks).

No reproductive effects were noted in rats exposed by inhalation (480 mg/m³ for up to 100 days; 2-generation study), but a slight decrease in foetal weight was detected among F1 offspring; following oral administration (500 mg/kg b.w. per day for 13 months; multi-generation study), reproduction was affected and parental effects (reduced body weight and feed consumption) were noted.

In teratology studies, no developmental effects were observed in rats or rabbits exposed by inhalation (rats: 350 mg/m³; rabbits: 1000 mg/m³; 6 hours/day on days 6-15 and 6-20 (rat), or 7-19 (rabbit)), following oral administration (rats: 330 mg/kg b.w./day on gestation days 6-15; rabbits: up to 175 mg/kg b.w./day on gestation days 6-18), or following dermal administration (rats: 500 mg/kg b.w./day on gestation days 6-15; rabbits: 1000 mg/kg b.w./day on gestation days 17-19). At higher dose levels (480-620 mg/m³ (inhalation); 400-500 mg/kg b.w./day (oral administration); 750 mg/kg b.w./day (dermal administration)), foetotoxic effects (a lower foetal body weight) have been observed in rats in the absence of maternal toxicity. Generally, no malformations have been observed at dose levels, which did not induce maternal toxicity. A neurobehavioral teratology study has shown an impairment of higher cognitive functions related to solving difficult tasks in rats exposed at 620 mg/m³ on gestation days 7-20, a dose level that did not induce maternal toxicity.

133.4.4     Mutagenic and genotoxic effects

NMP has been tested in several short-term tests with negative result in every of these in vitro and in vivo tests, both with and without metabolic activation, except for a positive result for aneuploidy in yeast when tested under special circumstances.

133.4.5     Carcinogenic effects

NMP was not carcinogenic in rats when tested for carcinogenicity by inhalation (up to 400 mg/m³) for 2 years. A two-year carcinogenicity study (feeding) has been performed in rats; however, the results of the study have apparently not been published.

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