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

131     Animal toxicity

131.1     Single dose toxicity

131.1.1     Inhalation

In a study (OECD Guideline 403), the LC₅₀-value (4-hour exposure) was reported as being greater than 5.1 mg/l (>5100 mg/m³) in the rat (BASF 1988 - quoted from IUCLID 2000). In another study in the rat, the LC₅₀-value (4-hour exposure) was reported as being in the range of 3.1 to 8.8 mg/l (3100-8800 mg/m³) (Du Pont 1988 - quoted from IUCLID 2000).

In rats exposed to a saturated atmosphere (NMP heated to 110°C) for 6 hours, no mortality was observed and the animals did not show any signs of toxicity during the 2-week observation period (GAF 1986 - quoted from IUCLID 2000).

When rats were exposed to a saturated atmosphere (NMP at 20°C) for 8 hours, no mortality occurred but animals showed a mild irritation of mucous membranes (BASF 1963 - quoted from IUCLID 2000).

In mice exposed to NMP at concentrations around 0.2 mg/l (200 mg/m³) (NMP heated to 100-120°C) for 2 hours, no mortality was observed, but irritation of eyes and the upper respiratory tract was observed. No histopathological changes were observed. (Stasenkow & Kotschekov 1965 - quoted from IUCLID 2000).

131.1.2     Oral intake

The reported oral LD₅₀-values for NMP ranged from 3600 to 7900 mg/kg in rats (13 values reported), from 4100 to 7700 mg/kg in mice (7 values reported), and of 3500 mg/kg and 4400 mg/kg in rabbits and guinea pigs, respectively (2 values reported for each species) (Studies quoted in IUCLID 2000).

131.1.3     Dermal contact

The reported dermal LD₅₀-values for NMP ranged from 2500 to 10000 mg/kg in rats (4 values reported), and from 2000 to 8000 mg/kg in rabbits (5 values reported) (Studies quoted in IUCLID 2000).

Skin irritation tests in rabbits using a modified Draize procedure indicated a low potential for skin irritation. (International Speciality Products - quoted from Åkesson 1994).

Skin irritation tests in rabbits (7 references) indicate that NMP is slightly irritating in this species; no irritation was reported in 2 other references (Studies quoted in IUCLID 2000).

Aqueous solutions of NMP caused skin irritation in guinea pigs at 50% but not at 5% (International Speciality Products - quoted from Åkesson 1994; GAF 1974 - quoted from IUCLID 2000).

131.1.4     Other routes

Eye irritation tests in rabbits (8 references) indicate that NMP is an eye irritant in this species; no eye irritation was noted (one reference) when NMP was tested as a 10 or 25% aqueous solution (Studies quoted in IUCLID 2000).

131.2     Repeated dose toxicity

131.2.1     Inhalation

In Wistar rats (10 animals) exposed (head-nose only) to NMP (mixture of vapour and aerosol) at 1000 mg/m³ 8 hours a day, 5 days per week for 2 weeks, no pathological lesions were observed. The urine was dark yellow. (BASF 1989 - quoted from IUCLID 2000).

Wistar rats (5 animals of each sex per group) were exposed (head-nose only, OECD-guideline 412) to NMP aerosol at 4000, 7000, or 10000 mg/m³ 6 hours a day, 5 days per week for 14 days. High-dose animals as well as some mid-dose animals died within 5 days. The urine was dark yellow in all animals. A dose-related reduced body weight gain and respiratory tract irritation were observed. Pathological lesions were observed in the lungs of mid- and high-dose males and in the glandular stomach in all high-dose males and in all exposed females. (BASF 1993 - quoted from IUCLID 2000).

Rats (Charles River CD, 15 animals of each sex per group) were exposed to an aerosol-vapour mixture of NMP at levels of 100, 500, or 1000 mg/m³ for 6 hours a day, 5 days per week for 4 weeks. The control group was exposed to air only. Each test level of NMP was generated as a respirable aerosol (>95% of the droplets below 10 µm in diameter). (Lee et al. 1987).

All exposed rats showed signs of lethargy and irregular respiration after about 3 to 4 hours of exposure; these signs usually persisted until the end of each exposure. Low- and mid-dose rats recovered within 30 to 45 minutes post-exposure whereas high-dose rats generally did not recover by 18 hours post-exposure.

In high-dose rats, excessive mortality occurred (8 died and 5 were sacrificed of 30 animals) within the first 9 days of exposure and exposure was discontinued after 10 days; the surviving rats were placed on 2 weeks of recovery. In dead rats, marked pulmonary oedema and congestion were observed; the bone marrow showed haemorrhage, hypoplasia, and necrosis in the haemopoietic cells; and prominent atrophy and necrosis were observed in the lymphoid tissue in the thymus, spleen, and lymph nodes. Rats sacrificed after 10 days of exposure revealed slight bone marrow hypoplasia and atrophy of lymphoid tissue in the thymus, spleen, and lymph nodes; minimal necrotic changes were observed in the haemopoietic cells of the bone marrow and lymphoid cells in the thymus, spleen, and lymph nodes. The histopathological changes were almost reversible within the 2-week recovery period.

No significant histopathological lesions were observed in low- and mid-dose animals.

In Wistar rats exposed (head-nose only, OECD-guideline 412) to NMP aerosol at 10, 30, or 100 mg/m³ 6 hours a day, 5 days per week for 4 weeks, no pathological lesions were observed. In high-dose animals, the urine was dark yellow. (BASF 1993 - quoted from IUCLID 2000).

Sprague-Dawley rats (10 animals of each sex) were exposed to NMP vapour at 1750 mg/m³ 6 hours a day, 5 days per week for 6 weeks. From the 8th day of exposure, rats exhibited a mild secretion from the nose. The urine was dark yellow in all animals. No pathological lesions were observed. (BASF 1983 - quoted from IUCLID 2000).

Wistar rats were exposed (head-nose only, OECD-guideline 413) to NMP (aerosol or vapour not stated) at 500, 1000, or 3000 mg/m³ 6 hours a day, 5 days per week for 90 days. The urine was dark yellow in all animals. Irritation of the respiratory tract and reduced body weight (males) were observed in mid- and high-dose animals. Signs of mild hepatic effects were observed in high-dose animals. No histopathological lesions or signs of toxicity were observed in the mid- and low-dose groups. Testicular effects are given in 4.3. (BASF 1994 - quoted from IUCLID 2000).

In Wistar rats exposed to 150 ppm (620 mg/m³, the highest possible concentrations of NMP vapour) NMP 6 hours a day, 7 days per week for 90 days, examination of evoked potentials in the brain at the termination of exposure showed no indications of neurotoxic effects in the central nervous system (Fries et al. 1992).

Rats (Charles River CD, 120 animals of each sex per group) were exposed to a mixture of NMP aerosol and vapour (only trace amounts of aerosol was detected when chamber atmosphere was analysed) at levels of 40 or 400 mg/m³ for 6 hours a day, 5 days per week for 2 years. The control group (120 animals of each sex) was exposed to air only. (Lee et al. 1987).

No significant differences in either morbidity or mortality were observed between exposed and control rats. Low-dose females and high-dose rats showed a greater incidence of stained wet perinea than the respective controls. High-dose rats discharged dark yellow urine and the male rats had a greater urine volume. High-dose male rats had after 2 years exposure gained approximately 6% less body weight than the controls.

Histopathological examinations were performed on most organs and tissues. There were no differences in either the incidence or severity of neoplastic or nonneoplastic lesions between exposed and control rats except for a slightly higher incidence of chronic progressive nephropathy in low-dose male rats at 12 months.

131.2.2     Oral intake

NMP was administered in the diet to rats (Crl:CD BR; 5 animals of each sex per group) at dose levels of 0, 2000, 6000, 18000, or 30000 ppm (equivalent to 0, 200, 600, 1800, 3000 mg/kg b.w. per day according to WHO standard assumptions) for 28 days. Abnormal urine coloration was observed at dose levels from 18000 ppm. Reduced body weight gain and food consumption were observed in the 18000 ppm (males) and 30000 ppm dose groups. Histopathological alterations (hypocellular bone marrow, testicular degeneration and atrophy, and thymic atrophy) observed in high-dose animals were judged to be secondary to nutritional and body weight effects in these rats. (Malek et al. 1997 - quoted fromTOXLINE PLUS 1999-2000/01).

Sprague-Dawley rats (10 animals of each sex per group) were given NMP by gavage at 0, 258, 517, 1033, or 2066 mg/kg b.w. 5 days per week for 4 weeks. High-dose animals exhibited tremor, restlessness, piloerection, and defensive reactions after two weeks of exposure. The urine was dark yellow in all animals after one week of exposure. A reduced body weight gain was observed in male rats of the three highest dose groups (from 517 mg/kg b.w.). (BASF 1978 - quoted from IUCLID 2000).

In Wistar rats (25 animals of each sex per group) given NMP in the diet at 0, 800, 2000, or 5000 ppm (NMP levels in diet equivalent to 70, 170, 420 mg/kg b.w. according to IUCLID) for 90 days, no pathological lesions were observed. In high-dose males, the thyroid weight was increased when compared to the control group. (GAF Corp. 1976 - quoted from IUCLID 2000).

Rats (20-26 male and females per group) were administered NMP at dietary levels of 0, 3000, 7500, or 18000 ppm (equal to 0, 169/217, 433/565, or 1057/1344 mg/kg b.w./day for males/females, respectively) for 90 days. A change in urine coloration was observed at all dose levels in both sexes. Decreased body weight and body weight gain were observed in mid- and high-dose groups. Increased absolute and relative kidney weights were observed in high-dose animals. In high-dose females, absolute and relative liver weights were increased and were associated with an increased incidence of centrilobular hepatocellular hypertrophy. Of 36 neurobehavioral parameters investigated, mid- and high-dose male rats showed increases in mean foot splay values and high-dose males had a higher incidence of low arousal and slight palpebral closure. There were no compound-related gross or microscopic lesions in neural or muscular tissues at any dietary concentration. The NOAEL was considered to be 3000 ppm (equal to 169/217 mg/kg b.w./day for males/females, respectively). (Malley et al. 1999).

NMP was administered for 28 days in the diet to mice (B6C3F1; 5 animals of each sex per group) at dose levels of 0, 500, 2500, 7500, or 10000 ppm (equivalent to 0, 75, 375, 1125, 1500 mg/kg b.w. per day according to WHO standard assumptions). Abnormal urine coloration was observed at dose levels from 2500 ppm. Histopathological alterations (cloudy swelling of the epithelia of the distal parts of the renal tubuli) were observed in some animals of the two highest dose levels. (Malek et al. 1997 - quoted from Toxline 1995-1998).

CD-1 mice (30 animals of each sex per group) were given NMP in the diet at 0, 400, 1000, or 2500 ppm (NMP levels in diet equivalent to 80, 200, 500 mg/kg b.w. according to IUCLID) for 90 days. A dose-related decreased body weight gain and increased relative liver weight, kidney weight, thyroid weight and pituitary weight were observed in male animals, a NOAEL of 400 ppm was stated. No effects were noted in female animals. (GAF Corp. 1977 - quoted from IUCLID 2000).

Mice (10 male and females per group) were administered NMP at dietary levels of 0, 1000, 2500, or 7500 ppm (equal to 0, 277, 619, or 1931 mg/kg b.w./day over the 90-day period) for 28 or 90 days. A change in urine coloration was observed in mid- and high-dose animals. Absolute and relative liver weights were elevated in mid- and high-dose males and centrilobular hepatocellular hypertrophy was seen in both sexes fed 7500 ppm. The NOAEL was considered to be 1000 ppm (equal to 1931 mg/kg b.w./day). (Malley et al. 1999).

In Beagle dogs given NMP in the diet at 0, 25, 79 or 250 mg/kg b.w. per day for 90 days, a dose-dependent decrease in body weight gain and a reduced serum cholesterol level in high-dose males were observed (Becci et al. 1983 - quoted from IUCLID 2000 and from Åkesson 1994).

131.2.3     Dermal contact

When NMP was applied to intact or damage skin of rabbits at concentrations of 0.4, 0.8, or 1.6 ml/kg (411, 822, 1645 mg/kg b.w.) once daily for 20 days, mild irritation of the skin but no systemic effects were noted in low- and mid-dose animals. Among high-dose animals, 1/4 died when NMP was applied to damaged skin. (GAF 1986 - quoted from IUCLID 2000).

NMP did not show any skin sensitisation when tested in guinea pig using the Draize test or an intracutaneous test (Studies quoted in IUCLID 2000).

In the intracutaneous test, male guinea pigs received 4 injections (one per week, 0.1 ml 1% v/v aqueous solution); after a 2-week rest period they were challenged by dermal application of a 5 or 50% solution. No sensitisation was observed. (DuPont 1976 - quoted from IUCLID 2000).

131.2.4     Other routes

No data have been found.

131.3     Toxicity to reproduction

131.3.1     Inhalation

In Wistar rats exposed (head-nose only, OECD-guideline 413) to NMP (aerosol or vapour not stated) at 500, 1000, or 3000 mg/m³ 6 hours a day, 5 days per week for 90 days, reduced testicular weight and testicular damage were observed in high-dose animals; the testicular damage was not reversible within a 4-week post-treatment period. Non-testicular effects are given in 4.2. (BASF 1994 - quoted from IUCLID 2000).

In Wistar rats exposed to 150 ppm (620 mg/m³, the highest possible concentrations of NMP vapour) NMP 6 hours a day, 7 days per week for 90 days, examination at the termination of exposure and 90 days later showed no macroscopically pathological findings and no differences in testes weights between the control and exposed group. By histopathological examination of the testes no abnormal changes were found and by the examination of the semen, sperm cell morphology and sperm cell concentration, no abnormalities were observed. (Fries et al. 1992).

A two-generation reproduction study with a developmental toxicity component was conducted on rats. For the reproduction phase, male and female rats were exposed to NMP at levels of 0, 10, 51, or 116 ppm (0, 42, 210, or 480 mg/m³) 6 hours a day, 7 days per week from 34 days of age to the end of the mating period for the males (100 exposure days) and till weaning for the females (about 143 exposure days, but interrupted from day 20 of gestation to day 4 postpartum). For the developmental phase, rats of both sexes were exposed to 0 or 116 ppm. The indices of reproductive performance for exposed rats did not differ significantly from those obtained for the control rats. High-dose rats had a detectable decrease in response to sound; no other signs of NMP-related toxicity were detected among the parental rats. An exposure-related but slight decrease in foetal weight was detected only among the F1 offspring whose parents were exposed to 116 ppm; this slight effect also appeared at birth among the pups of the reproductive phase where it persisted till 21 days after birth when NMP inhalation by the mother ceased. Thereafter, the body weight of the offspring was comparable to the control values. No developmental effects appeared in the 10 or 51 ppm groups. (Solomon et al. 1995 - quoted from Toxline 1995-1998).

Female rats (Charles River CD, 25 animals per group) were exposed to NMP (aerosol) at levels of 100 or 350 mg/m³ for 6 hours a day on gestation days 6 to 15. The control group was exposed to air only. Sporadic lethargy and irregular respiration were observed in several animals at both exposure levels during the first 3 days of exposure. Exposed rats did not show any significant pathological changes in any vital organs or tissues. Exposure did not affect the outcome of pregnancy or embryonal growth rate. No abnormal development was detected in vital organs and skeletons of the foetuses. (Lee et al. 1987).

In Wistar rats exposed to 150 ppm (620 mg/m³) NMP 6 hours a day, 7 days per week on gestation days 4 to 20, increased preimplantation loss, lower foetal body weights, and delayed ossification were observed; these effects were induced at a dose that did not induce maternal toxicity. No increase in malformations was found. (Hass et al. 1995).

In a behavioural teratology study, Wistar rats were exposed to 150 ppm (620 mg/m³) NMP 6 hours a day on gestation days 7 to 20. No clinical signs of maternal toxicity were observed and no differences between the exposed and the control group concerning maternal weight gain during the gestation period, pregnancy length, number of implants per dam, number of pups and sex distribution in the litters, and neonatal deaths were found. The only difference observed in the gestation period was that the urine of the females in the exposed group was coloured bright yellow. In the pre-weaning period, the exposed offspring had a lower body weight and their physical development was delayed. Neurobehavioral evaluation of the male pups revealed no effects on basal functions of the central nervous system. The animals appeared normal and motor function (rotarod), activity level (open field), and performance in learning tasks with a low grade of complexity were similar in the two groups. However, in more difficult tasks such as the reversal procedure in Morris water maze and operant delayed spatial alternation (Skinner boxes), performance was impaired in exposed offspring. (Hass et al. 1994).

Female rats (Wistar, 9-10 animals per group) were exposed (head-nose only) to NMP (aerosol) at levels of 1000, 2000, or 3000 mg/m³ for 6 hours a day, 5 days per week on gestation days 5 to 16. In maternal animals, body weight and uterine weight were reduced in a dose-related manner and the urine was yellow to red coloured in all exposed groups. In the mid- and high-dose groups, vaginal bleeding at days 14 and 15 post-conception, increased post-implantation loss, and reduced percentage of live foetuses per litter were observed. (BASF 1992 - quoted from IUCLID 2000).

In Sprague-Dawley rats (20 animals) exposed to 800 ppm (3300 mg/m³) NMP for 6 hours a day on gestation days 4 to 8, or on gestation days 11 to 15, no differences were observed between exposed animals and controls in the outcome of pregnancy, embryonal growth rate, weight of placenta, and number of malformations. No maternal toxicity was observed. (BASF 1976 - quoted from IUCLID 2000). However, according to Trochimowicz et al. (1994) “slight embryo and maternal toxicity was observed”.

Sprague-Dawley rats (20-25 pregnant rats per group) were exposed whole-body to NMP vapours at concentrations of 0, 30, 60, or 120 ppm (0, 124, 248, or 495 mg/m³) 6 hours/day on gestational days (GD) 6 through 20. Maternal body weight gain was significantly decreased in the mid- and high-dose groups on GD 6 to 13 and maternal food consumption was reduced in the high-dose group on GD 13 to 21. No significant difference in the gestational weight change corrected for the weight of the gravid uterus was observed. There were no adverse effects on embryo/foetal viability as the mean numbers of implantation sites and of live foetuses and the incidences of non-live implants and resorptions were comparable across groups. Foetal toxicity indicated by reduced foetal weight was observed at 120 ppm. There was no evidence of teratogenicity at any concentration tested. (Saillenfait et al. 2003).

In rabbits (5 animals per group) exposed to NMP at levels of 300, 1000, or 2000 mg/m³ for 6 hours a day on gestation days 7 to 19, maternal toxicity (increased liver weight, decreased uterine weight, and a number of haematological parameters) were observed in mid- and high-dose animals and the number of resorptions was increased in the high-dose group (BASF 1991 - quoted from IUCLID 2000).

Rabbits (15 animals per group) were exposed to NMP at levels of 200 (vapour), and 500 or 1000 (mixture of vapour and aerosol) mg/m³ for 6 hours a day on gestation days 7 to 19 (OECD-guideline 414). No signs of maternal toxicity were observed; the urine was dark yellow to orange coloured in all exposed groups. The only effect observed in the foetuses was a skeletal variation in rib number 13 in the high-dose group. (BASF 1993 - quoted from IUCLID 2000).

131.3.2     Oral intake

In Sprague-Dawley rats (10 animals of each sex per group) given NMP by gavage at 0, 258, 517, 1033, or 2066 mg/kg b.w. 5 days per week for 4 weeks, the absolute and relative testicular weights were significantly reduced and testicular damage was observed in high-dose male rats. (BASF 1978 - quoted from IUCLID 2000).

In a multi-generation study (OECD-guideline 416), Sprague-Dawley rats (30 animals of each sex per group) were given NMP at levels of 0, 50, 160, or 500 mg/kg b.w. per day in the diet for 13 months. The highest dose level caused reduced parental body weight and feed consumption, and affected reproduction with a concomitant reduction in survival and growth rates in the offspring. (Exxon 1991 - quoted from IUCLID 2000; EPA - quoted from Åkesson 1994). It is not clear from the two citations whether effects were observed in low- and mid-dose groups. In the IUCLID citation it is stated that “no effects were observed in low- and mid-dose groups”, whereas in the citation by Åkesson it is stated that “the data from the 50 and 160 mg/kg b.w. per day experiments do not clearly demonstrate a NOAEL.

In Sprague-Dawley rats given NMP by gavage at 0, 40, 125, or 400 mg/kg b.w. on gestation days 6 to 15, a reduced body weight gain was observed in the high-dose group; however, when correction for the gravid uterine weight was done, no difference in body weight gain was observed between exposed animals and the controls. The foetal body weight was significantly reduced in the high-dose group and an increased number of stunted foetuses was reported;the incidence of foetal variations and malformations was not increased in offspring of exposed dams when compared to the control group. (TSCAT 1992 - quoted from IUCLID 2000; EPA - quoted from Åkesson 1994).

Repeated oral doses of 1000 mg/kg b.w. per day to Sprague-Dawley rats through gestation days 6 to 15 caused a very high resorption rate (95%) and malformations in 8 out of 15 surviving developed foetuses; reduction in body weight (not further specified) of the dams was observed. No adverse effects were observed at doses of 330 mg/kg b.w. per day. (BASF 1971 - quoted from IUCLID 2000; EPA 1991 - quoted from Åkesson 1994 and from Toxline 1991-1994; BASF 1987 - quoted from Trochimowicz et al. 1994).

Repeated oral doses of 2640 mg/kg b.w. per day to NMRI mice through gestation days 11 to 15 caused increased resorption rate, increased incidence of runts, decreased foetal weight and length, and increased incidence of malformations such as cleft palate; no maternal toxicity was observed. Doses of 1060 mg/kg b.w. per day caused no observable embryotoxicity. (BASF 1970 - quoted from IUCLID 2000; EPA - quoted from Åkesson 1994; Schmidt 1976 - quoted from Trochimowicz et al. 1994).

In rabbits given NMP by gavage at 0, 55, 175, or 540 mg/kg b.w. on gestation days 6 to 18 (OECD-guideline 414), maternal toxicity (reduced body weight gain and feed consumption) was evident in the high-dose group with only trends being observed in the mid-dose group. Developmental toxicity in form of increased post-implantation loss, altered foetal morphology and increased incidences of cardio-vascular and skull malformations was observed in the high-dose group; no developmental toxicity were detected in the lower dose groups. (GAF Corp. 1991 - quoted from IUCLID 2000; ISP - quoted from Åkesson 1994).

131.3.3     Dermal contact

In Sprague-Dawley rats given NMP (undiluted) topically at 0, 75, 237, or 750 mg/kg b.w. on gestation days 6 to 15, a reduced body weight gain was observed in the high-dose group; the resorption of foetuses was increased, the foetal body weight decreased, and skeletal anomalies were observed in this dose group (no correction for gravid uterine weight was done). No effects in dams or foetuses were observed in the lower dose groups.

In a preceding dose range-finding study, a dermal dose of 1100 mg/kg b.w. per day during days 6 to 15 of gestation was embryolethal (65/66 foetuses absorbed) and caused decreased body weight gain in dams; a dose of 500 mg/kg b.w. per day had no adverse effect on pregnancy, dam body weights, implantations or gestation.

(Becci et al. 1982 - quoted from Åkesson 1994, IUCLID 2000, and from Trochimowicz et al. 1994).

Rabbits (15 animals per dose group) were given NMP (40% solution in water) topically at 0, 100, 300, or 1000 mg/kg b.w. for 6 hours a day on gestation days 7 to 19 (OECD-guideline 414). No signs of maternal toxicity were observed in any dose-group; the urine was red-brown coloured in the second half of the gestation period in mid- and high-dose groups. The only effect observed in the foetuses was a skeletal variation in rib number 13 in the high-dose group. (BASF 1993 - quoted from IUCLID 2000).

131.3.4     Other routes

Various intraperitoneally administered NMP doses (14-166 mg/kg b.w.; single or repeatedly) to mice (two strains) during various phases of pregnancy, caused increased post-implantation loss and a reduced body weight of the foetuses; and morphological malformations were observed in the foetuses. No information on maternal toxicity is given in the study. (Schmidt 1976 - quoted from Åkesson 1994 and from IUCLID 2000).

Repeated intraperitoneal doses of 1570 mg/kg b.w. per day to NMRI mice through gestation days 11 to 15 caused increased resorption rate, increased incidence of runts, decreased foetal weight and length, and increased incidence of malformations such as cleft palate; no maternal toxicity was observed. Doses of 630 mg/kg b.w. per day caused no observable embryotoxicity. (BASF 1970 - quoted from IUCLID 2000; EPA - quoted from Åkesson 1994).

131.4     Mutagenic and genotoxic effects

131.4.1     In vitro studies

NMP has been tested in different test systems, the results of these tests as given below are quoted from Åkesson (1994), Trochimowicz et al. (1994), and from IUCLID (2000).

In tests for point mutations, NMP was negative in several (10) Ames tests using various strains of Salmonella typhimurium when tested up to cytotoxic concentrations both with and without metabolic activation systems.

NMP showed positive results for aneuploidy in yeast (Saccharomyces cerevisiae) in combination with cold shock (4°C or ice-bath), but not with continuous incubation at 20°C.

When tested in mammalian cells in vitro, NMP was negative for mutations in HGPRT-locus in CHO cells, in the mouse lymphoma assay, and for unscheduled DNA synthesis in rat primary hepatocytes.

131.4.2     In vivo studies

When tested in mammalian cells in vivo, NMP was negative in a cytogenetic assay (bone marrow test for structural and numerical chromosomal aberrations) in Chinese hamsters (exposed to 800 ppm (3300 mg/m³) NMP 6 hours a day, 5 days per week for 6 weeks), in the dominant lethal assay in NMRI mice (single intraperitoneal injection of 393 mg/kg b.w.), and in the micronucleus assay in NMRI mice (single oral dose of 950, 1900, or 3800 mg/kg b.w.).

131.5     Carcinogenic effects

Rats (Charles River CD, 120 animals of each sex per group) were exposed to a mixture of NMP aerosol and vapour (only trace amounts of aerosol was detected when chamber atmosphere was analysed) at levels of 40 or 400 mg/m³ for 6 hours a day, 5 days per week for 2 years. The control group (120 animals of each sex) was exposed to air only. (Lee et al. 1987).

There were no differences in the incidence or severity of neoplastic lesions between exposed and control rats. High-dose female rats exhibited a decreased incidence of mammary gland tumours and increased incidence of mammary gland hyperplasia. A slightly greater incidence of pituitary tumours was observed in low-dose but not in high-dose rats. Nonneoplastic findings are given in 4.2.

A two-year carcinogenicity study (feeding) has been performed in rats (Dupont Haskell Laboratory 1998 – cited in Toxline 2001); however, the results of the study have apparently not been published.

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