Fenpropimorph was first evaluated by the 1994 Joint Meeting, which established an ADI of 0–0.003 mg/kg bw on the basis of a NOAEL of 10 ppm, equal to 0.3 mg/kg bw per day, in a 2-year study of toxicity and carcinogenicity in rats (Annex 1, reference 71). At its Thirty-third Session, the Codex Committee on Pesticide Residues considered the evaluations of residues and dietary intake of fenpropimorph by the 1999 Joint Meeting and noted that the absence of an acute RfD had precluded completion of an assessment of acute dietary risk. The present Meeting was asked to consider the need to establish an acute reference dose (RfD).

The JMPR in 1994 noted that the LD₅₀ of fenpropimorph after oral administration ranged from 1500 to 3500 mg/kg bw in rats, and that the values in rats after dermal application or inhalation were also low (dermal LD₅₀, 4300 mg/kg bw; inhalation LC₅₀, > 3.6 to > 8.5 mg/l of air).

WHO (1999) has classified fenpropimorph as ‘unlikely to present acute hazard in normal use’.

Studies evaluated by the 1994 JMPR did not show any remarkable early signs of toxicity after repeated doses, even at high levels that eventually elicited signs of liver toxicity, anaemia and growth retardation. In short-term studies in rats (but not dogs) treated in the diet, inhibition of plasma and erythrocyte cholinesterase activity was occasionally seen, but there were no consistent dose– or time–response relationship, nor were the sexes equally susceptible. In the 2-year study in rats treated in the diet, inhibition of brain acetylcholinesterase was seen, males being more severely affected than females. However, these effects were difficult to interpret because brain cholinesterase activity was also depressed in controls at terminal sacrifice and there were no effects on erythrocyte cholinesterase activity at any time. In rabbits treated by gavage on days 6–18 of gestation, embryotoxicity, fetotoxicity and developmental anomalies were seen only at doses that were clearly toxic to the does (NOAEL, 12 mg/kg bw per day; LOAEL, 36 mg/kg bw per day). Similar findings were made in studies of developmental toxicity in rats, in which the NOAEL was 10 mg/kg bw per day and the LOAEL was 40 mg/kg bw per day. The 1994 JMPR concluded that fenpropimorph is not genotoxic.

In a study of behaviour and neuromorphology performed in accordance with USA’s Environmental Protection Agency test guideline 81-8 and complying with good laboratry practice, technical-grade fenpropimorph (purity, 94.3%) was administered by gavage in an aqueous Cremophor suspension to 49-day-old male and female Wistar rats (Chbb:THOM SPF). The rats were assigned randomly to groups of 10 of each sex and housed singly in steel-wire cages in an air-conditioned environment. The dose administered was 0, 100, 500 or 1500 mg/kg bw. Functional observational testing and motor activity measurements (carried out in separate polycarbonate cages) were conducted 7 days before dosing, on the day of administration and then 7 and 14 days after dosing. Function was measured within the 2–6-h period that was expected to encompass the peak effect. At the end of the study, five rats from each group were killed by perfusion fixation under pentobarbital anaesthesia for histological examination of the central and peripheral nervous systems.

Body-weight gain was significantly depressed (by 6.6%) when compared with that of controls after 7 days in males given 1500 mg/kg bw (p < 0.05). The clinical and behavioural signs observed in males and females at 500 and 1500 mg/kg bw included piloerection and decreased rearing activity. Decreased motor activity was observed in males and females at 1500 mg/kg bw, but only in females at 500 mg/kg bw. The effects on rearing and motor activity did not persist beyond the day of dosing, while the piloerection persisted for a few days only in the group at 1500 mg/kg bw. No treatment-related effects were seen in sensorimotor or reflex function. Statistically significant increases in hindlimb grip strength were seen in females at the highest dose on day 14 only and in landing foot-splay tests in males at the intermediate dose on day 7 only, but these findings were considered to be incidental owing to the weakness of the dose– and time–response relationships. No gross neuroanatomical or histopathological lesions of the central or peripheral nervous systems were found that could be attributed to treatment. The NOAEL was 100 mg/kg bw (Mellert et al., 1997).

Additional studies in mice and dogs treated with fenpropimorph in the diet for 4–6 weeks were submitted. Although the Meeting considered that they were not relevant to the setting of an acute RfD, they were evaluated as part of this monograph addendum.

Groups of eight male and eight female CD-1 mice received diets containing fenpropimorph (purity, 92.5%) at a concentration of 0, 500, 1000, 2000 or 4000 ppm, equal to 0, 80, 170, 340 and 670 mg/kg bw per day for males and 0, 83, 200, 380 and 790 mg/kg bw per day for females, for 4 weeks. The highest dose resulted in significant toxicity (piloerection, salivation, hunched posture and lethargy), one animal of each sex died and the deterioration in general health was considered sufficient to justify termination of this dose at 23–24 days. Markedly reduced body-weight gain was seen at this dose, although statistically significantly reduced weight gain was also seen in males at 2000 ppm. The relative and absolute weights of the liver were significantly increased at all doses except females at 1000 ppm. There were no consistent or dose-related changes in cholinesterase activity in plasma, erythrocyte or brain. No NOAEL could be identified (Hunter et al., 1980).

Groups of eight male and eight female CD-1 mice received diets containing fenpropimorph (purity, 92.5%) at a concentration of 0, 25, 50, 100 or 200 ppm, equal to 3.3, 6.6, 13 and 24 mg/kg bw per day for males and 0, 4, 8, 15 and 32 mg/kg bw per day for females, for 6 weeks. After 3 weeks, the dietary concentration of the rats at 25 ppm was increased to 400 ppm (equal to 47 mg/kg bw per day for males and 60 mg/kg bw per day for females). There were no deaths, morbidity or effects on weight gain, food consumption or appearance in any group. There were no remarkable findings at autopsy, except that the relative liver weights were increased in both males and females at doses > 100 ppm, and the relative spleen and kidney weights were increased in some treated groups, with no clear consistency by dose or sex. Minimal centrilobular hepatocytic enlargement was seen at 400 ppm. The NOAEL was 100 ppm, equal to 13 mg/kg bw per day, on the basis of the liver changes (Hunter et al., 1979).

Groups of four male and four female beagle dogs received diets containing fenpropimorph (purity, 99.1%) at a concentration of 0, 200, 400, 800 or 1000 ppm, equal to 0, 7, 12, 27 and 51 mg/kg bw per day for males and 0, 8, 15, 29 and 62 mg/kg bw per day for females, for 4 weeks. The effects on growth were minimal and not clearly dose-related, although the failure of females at the highest dose to gain weight from a low initial base may have been treatment-related. The absolute weight of the liver was clearly increased in males at 1600 ppm and the relative weight at concentrations > 800 pm, but not in females. The testis weight was reduced in males at the highest dose. The relative weight of the spleen was increased in females, but not in males, at concentrations > 800 ppm. No histopathological changes were found that were attributable to treatment. The NOAEL was 400 ppm, equal to 12 mg/kg bw (Kirsch et al., 1978).

In a study submitted to the current Meeting, of behaviour and neuromorphology in male and female Wistar rats, a single dose of fenpropimorph administered by gavage at 0, 100, 500 or 1500 mg/kg bw caused a small but significant, depression of body-weight gain only in males at the highest dose. The clinical and behavioural signs in animals of each sex at 500 and 1500 mg/kg bw included piloerection and decreased rearing activity. Decreased motor activity was observed in both males and females at the highest dose and in females at 500 mg/kg bw. The effects on rearing and motor activity did not persist beyond the day of dosing, while the piloerection persisted for a few days in animals at the highest dose. No treatment-related effects on sensorimotor or reflex functions were seen. Statistically significant increases in hindlimb grip strength were seen in females at the highest dose on day 14 only and in landing foot-splay tests in males at the intermediate dose on day 7 only. However, these findings were probably incidental, in view of the weakness of the dose– and time–response relationships. No gross neuroanatomical or histopathological lesions of the central or peripheral nervous system were seen that could be attributed to treatment. The NOAEL was 100 mg/kg bw.

The Meeting considered that the above study was appropriate for assessing the acute hazard of fenpropimorph and used it as the basis for establishing an acute RfD of 1 mg/kg bw, which incorporates a safety factor of 100.

Hunter, B., Jordan, J., Gopinath, C., Harrington, S. & Gibson, W.A. (1979) Preliminary assessment of Reg. No. 108 406 toxicity to mice by dietary administration for 6 weeks. Unpublished report dated 31 August 1979 from Huntingdon Research Centre, Huntingdon, Cambridgeshire, England. Submitted to WHO by BASF Aktiengellschaft, Limburgerhof, Germany.

Hunter, B., Jordan, J., Heywood, R., Street, A.E. & Gibson, W.A. (1980) Preliminary assessment of Reg. No. 108 406 toxicity to mice by dietary administration for 4 weeks. Unpublished report dated 16 May 1980 from Huntingdon Research Centre, Huntingdon, Cambridgeshire, England. Submitted to WHO by BASF Aktiengellschaft, Limburgerhof, Germany.

Kirsch, P., Deckardt, K., Freisberg, K.O., Mirea, D., Schulz, V. & Byrt, B.B. (1978) Study of the toxicity of Reg. No. 108 406 to dogs in a 4-week feeding study. Unpublished report dated 5 December 1978 from BASF Aktiengellschaft, Ludwigshafen, Germany.

Mellert, W., Kaufman, W. & Hildebrand, B. (1997) Fenpropimorph—Acute neurotoxicity study in Wistar rats. Unpublished report No. 2C0047/93061 from BASF Department of Toxicology. Submitted to WHO by BASF Crop Protection Division, Limburgerhof, Germany.

WHO (1999) Recommended Classification of Pesticides by Hazard and Guidelines to Classification 1998–1999 (WHO/PCS/98.21/Rev. 1), Geneva, International Programme on Chemical Safety.

    See Also:
       Toxicological Abbreviations
       Fenpropimorph (Pesticide residues in food: 1994 evaluations Part II Toxicology)