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

129     Toxicokinetics

129.1     Absorption and distribution

129.1.1     Inhalation

In male volunteers (six individuals) exposed for 8 hours on four different days to NMP at levels of 0, 10, 25, or 50 mg/m³, NMP was readily absorbed from the respiratory tract; a plasma half-life of about 4 (2.9-5.8) hours was found. At the end of the exposure there was a close correlation between exposures and the plasma concentration of NMP. (Åkesson & Paulsson 1997).

Rats exposed by inhalation to 620 mg/m³ of NMP for 6 hours showed an increase in the concentration of NMP in the blood from 0 to 4 hours after termination of the exposure. (Ravn-Jonsen et al. 1992 - quoted from Åkesson 1994 and from IUCLID 2000).

129.1.2     Oral intake

In rats, NMP is readily absorbed from the gastrointestinal tract. The plasma radioactivity concentration reached peak values at 2 hours after oral administration (gavage, in water) of 22.5 mg ¹⁴C-NMP (112 mg/kg b.w.). Radioactivity concentrations declined thereafter with a terminal half-life of 27 and 29 hours for females and males, respectively, and concentrations were still measurable 5 days after dosing. The parent compound accounted for more than 80% of the plasma radioactivity until 8 hours post-administration, indicating little first-pass metabolism. Biotransformation rapidly became more evident thereafter, and by 12 hours virtually all of the plasma radioactivity was in the form of polar metabolites. (Midgley et al. 1992).

129.1.3     Dermal contact

After application of ¹⁴C-NMP to the skin of rats (2.5 mg in isopropanol to an area of 9 cm² of shaved skin on the back), the plasma radioactivity levels changed little during 1 to 6 hours and reached peak values at 6 and 2 hours for males and females, respectively. Radioactivity concentrations declined thereafter and were still measurable 5 days after dosing. The urinary excretion profiles suggested a percutaneous uptake of about three-quarters of the applied dose. The parent compound accounted for more than 80% of the plasma radioactivity until 8 hours post-administra­tion, thereafter biotransformation rapidly became more evident and at 12 hours virtually all of the plasma radioactivity was in the form of polar metabolites. (Midgley et al. 1992).

In male rats administered ¹⁴C-NMP dermally at doses of 0.2, 2.0, or 20 mg/cm², 50% of the 0.2 or 2.0 mg/cm² doses and 75% of the 20 mg/cm² dose was absorbed (Research Triangle Institute 1991 - quoted from IUCLID 2000).

The uptake of NMP through human skin in vitro is about 4 times lower than through rat skin (Priborsky & Mühlbachova 1990 - quoted from Åkesson 1994).

129.1.4     Other routes

The disposition of NMP was studied in male rats given a single intravenous dose (45 mg/kg b.w.) of [4-³H]-NMP, [methyl-¹⁴C]-NMP and [ring-¹⁴C]-NMP in single-labelled studies or double-labelled studies. Plasma levels of NMP measured at 6 hours after dosing suggest a rapid distribution phase followed by a slow elimination phase; the half-life for the elimination from plasma was about 7 hours for both ¹⁴C-isomers and about 10 hours for the ³H-isomer. Metabolites were not detected in plasma in any appreciable quantities until 4 hours after administration and unmetabolised NMP still accounted for more than 80% of the radioactivity in plasma after 6 hours. Six hours after administration of NMP, the highest concentration of radioactivity occurred in the liver, small and large intestine, testes, stomach, and kidneys. After 24 hours, only the liver and intestines contained appreciable amounts of radioactivity. (Wells & Digenis 1988).

NMP passes the placenta and after exposure for 6 hours (by inhalation to 620 mg/m³) foetal blood concentrations were similar to maternal blood concentrations (Ravn-Jonsen et al. 1992 - quoted from Åkesson 1994 and from IUCLID 2000).

129.2     Elimination

129.2.1     Inhalation

In male volunteers (six individuals) exposed for 8 hours on four different days to NMP at levels of 0, 10, 25, or 50 mg/m³, NMP was readily eliminated from the body, mainly by biotransformation to other compounds. The elimination curve suggested a non-linear pattern and at the end of exposure showed a mean (range) half-life of NMP in the urine of about 4.5 (3.5-6.6) hours. The parent compound found in urine samples collected during exposure and at the subsequent 44 hours corresponded to about 2% of the calculated absorbed dose. At the end of the exposure, there was a close correlation between exposures and the urinary excretion of NMP. (Åkesson & Paulsson 1997).

129.2.2     Oral intake

Three healthy male volunteers were administered 100 mg NMP orally and all urine was collected during 9 consecutive days. The mean excreted fractions in the urine were 0.8% for NMP, 44% for 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP), 0.4% for N-methylsuccinimide (MSI), and 20% for 2-hydroxy-N-methylsuccinimide (2-HMSI); one-third of the dose was not recovered in urine as any of these four metabolites. There was no conjugation with glucuronic acid or sulphate. The half-lives for 5-NHMP, MSI, and 2-HMSI in urine was approximately 4, 8, and 17 hours, respectively. (Åkesson & Jonsson 1997 - quoted from TOXLINE PLUS 1999-2000/01).

Following oral administration (gavage, in water) of 22.5 mg ¹⁴C-NMP (112 mg/kg b.w.) to rats, about 95% of the radioactivity was excreted during 5 days mainly through the urine (85-88% of the dose within 24 hours after dosing). Faecal excretion and exhalation were of minor importance accounting for 1-2% and 6-7% of the dose in the faeces and in exhaled air (as [¹⁴C]CO₂), respectively. (Midgley et al. 1992).

In male rats given ¹⁴C-NMP orally at doses of 5 or 500 mg/kg b.w., 84 and 75% of the dose, respectively, was excreted in the urine within 24 hours. In the urine, 4 metabolites were found with 5-hydroxy-N-methyl-2-pyrrolidone accounting for 60% of the administered dose; NMP was not identified in the urine. (Research Triangle Institute 1991 - quoted from IUCLID 2000).

129.2.3     Dermal contact

Following topical administration of ¹⁴C-NMP to the skin of rats (2.5 mg in isopropanol to an area of 9 cm² of shaved skin on the back), 69 to 78% of the radioactivity was excreted during 5 days mainly through the urine (61-70% of the dose within 24 hours after dosing). Faecal excretion and exhalation were of minor importance accounting for 1-2% and 6-7% of the dose in the faeces and in exhaled air (as [¹⁴C]CO₂), respectively. (Midgley et al. 1992).

Following dermal application (doses of 0.2, 2.0, or 20 mg/cm²), the primary route of excretion was in the urine; four metabolites were found with 5-hydroxy-N-methyl-2-pyrrolidone accounting for 60% of the administered dose, NMP was not identified in the urine (Research Triangle Institute 1991 - quoted from IUCLID 2000).

129.2.4     Other routes

The disposition of NMP was studied in male rats given a single intravenous dose (45 mg/kg b.w.) of [4-³H]-NMP, [methyl-¹⁴C]-NMP and [ring-¹⁴C]-NMP in single-labelled studies or double-labelled studies. The major route of excretion of radioactivity was via the urine and accounted for about 70% of the dose within 12 hours. After 24 hours, cumulative excretion in the urine represented about 80% of the dose. Cumulative excretion of total radioactivity into faeces and exhaled air was minor, with only 2.4% of the dose recovered in faeces after 72 hours and about 1% (as [¹⁴C]CO₂) in exhaled air after 24 hours. There was a minor biliary excretion of about 2% of the administered dose.

Analyses of urine revealed the presence of one major metabolite accounting for 72% of the excreted radioactivity and two minor metabolites accounting for 9 to 21% and 9-15% of the excreted radioactivity, respectively. Acidic hydrolysis of the major metabolite yielded a substance, which was identified as 4-(methyl­amino)-butenoic acid; the identity of the intact major metabolite remained to be identified. Only a minor part (<1%) was excreted in the urine as the parent compound. (Wells & Digenis 1988).

129.3     Mode of action

No data have been found.

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