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

134 Evaluation

Air saturated with NMP at 20°C has an NMP concentration of around 1400 to 1600 mg/m³; thus, higher airborne exposure levels consist of a mixture of vapour and aerosol. When comparing the results of the inhalation studies, some discrepancies are observed; these may be due to a different vapour/aerosol ratio as well as particle size distribution between the reported studies.

NMP is readily absorbed following inhalation, oral administration and dermal application, and distributed widely to organs and tissues; in humans, a close correlation between inhalation exposures and the plasma concentration of NMP has been observed. NMP is rapidly metabolised and excreted with the major route of excretion being the urine (85-88%). Four metabolites have been identified in the urine with 5-hydroxy-N-methyl-2-pyrrolidone being the major one.

Volunteers did not report any discomfort to eyes or upper airways following exposure to NMP at concentrations up to 50 mg/m³ for 8 hours on four different days, whereas 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). This discrepancy may be due to NMP work processes performed at temperatures above the boiling point of NMP (202°C) in the microelectronics industry (in relation to operations with ovens at temperatures up to 240°C) and thus, the 8-hour TWA concentration may have contained periods of high peak exposures or the warm NMP vapour may have condensed to an aerosol, which is irritating to the eyes. Individuals have reported an odour of acetone following exposure to NMP around 50 mg/m³, the odour was reported as “not uncomfortable”. Workers have experienced skin irritation and acute irritant contact dermatitis of the hands has been reported.

NMP is of low acute toxicity in the rat with the 4-hour LC₅₀-values reported being greater than 5100 mg/m³ or in the range of 3100-8800 mg/m³. The available studies do not suggest that NMP is a skin irritant or sensitiser, whereas NMP has shown eye irritancy in rabbits.

In one study of rats, mortality occurred within 9 days following inhalation exposure to NMP (aerosol-vapour mixture) at 1000 mg/m³; marked pulmonary oedema and congestion, bone marrow effects, and prominent atrophy and necrosis in the lymphoid tissue in the thymus, spleen and lymph nodes were observed in dead animals. In all the other studies on rats exposed repeatedly to NMP by inhalation (most studies: 6 hours a day, 5 days per week), histopathological lesions (including testicular damage) were observed only at very high exposure levels (above 3000 mg/m³). Other signs of exposure (mild secretion from the nose and lethargy and irregular respiration for 3 to 4 hours from start of exposure) have been noted at lower exposure levels (predominantly as an aerosol). Exposure of rats to NMP at 620 mg/m³ (6 hours a day, 7 days per week for 90 days) did not cause neurotoxic effects in the central nervous system. In a 2-year inhalation study, the highest dose level (400 mg/m³, 6 hours a day, 5 days per week to the vapour predominantly) did not cause any adverse effects and no clinical signs of exposure were reported; thus 400 mg/m³ is considered as being a NOAEL in the rat for NMP as a vapour with respect to clinical effects as well as to chronic toxicity.

A very common observation is a discoloration of the urine (inhalation from around 400 mg/m³); however, this effect, although not been further investigated, is not considered as being an adverse effect as no renal lesions have been detected except for a chronic progressive nephropathy observed in a 2-year study on rats, which is a very common naturally occurring lesion in the kidneys of ageing rats.

No reproductive effects were noted in a two-generation study on rats exposed by inhalation to 480 mg/m³; in a multigeneration study on rats, oral administration (500 mg/kg b.w. per day for 13 months) affected reproduction and parental effects were noted.

Several teratology studies have investigated the developmental toxicity of NMP in rats (most studies) and in rabbits; generally, no malformations were observed at dose levels, which did not induce maternal toxicity. Foetotoxic effects in form of a lower foetal body weight have been observed in some studies on rats at dose levels (480-620 mg/m³ (inhalation); 400-500 mg/kg b.w./day (oral administration); 750 mg/kg b.w./day (dermal administration)) that 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. A number of studies have reported foetotoxic effects only at dose levels, which also affected the maternal animals (predominantly evidenced as a reduced body weight and/or body weight gain); however, if a correction for the gravid uterine weight is done, no difference in body weight and/or body weight gain is observed between exposed animals and the controls.

Based on the available data, it is considered that developmental effects (lower foetal body weight, neurobehavioral effects) may occur at dose levels, which do not affect the maternal animals.

The mutagenicity and genotoxicity tests available indicate that NMP is not a mutagenic or genotoxic substance. No carcinogenic effects were observed in rats exposed by inhalation (up to 400 mg/m³, 6 hours a day, 5 days per week for 2 years).

134.1.1 Conclusion

Based on the available data, the critical effect in humans following exposure to airborne NMP is considered to be the irritative effects on the eyes and the respiratory tract; the critical effect in humans following dermal contact is considered to be skin irritation. Data obtained from studies on experimental animals do not indicate that other effects, including neurotoxic effects, than the irritative ones should be expected to occur following exposure to the levels of NMP eliciting these irritative effects.