FENAMIPHOS EXPLANATION Fenamiphos was examined for toxicological evaluation by the JMPR in 1974 and 1985 (Annex 1, FAO/WHO, 1975a and 1986a). The 1974 Meeting estimated an ADI of 0.0006 mg/kg bw. In 1985, following a direct request for reevaluation received from a Member State and a review of additional data, the JMPR converted and reduced the ADI to a temporary ADI of 0.0003 mg/kg bw because of concern for foetotoxicity demonstrated in a rabbit teratology study. The 1985 JMPR required submission of the results of an on-going rat oncogenicity study, of a full legible report and raw data for the rat teratology study and a new rabbit teratology study to clarify the foetotoxicity observed at low dietary levels. These studies have been submitted and are reviewed in this monograph addendum. EVALUATION FOR ACCEPTABLE INTAKE BIOLOGICAL DATA Toxicological studies Special Studies on Carcinogenicity Rats Groups of 50 male and 50 female Fischer 344 rats were fed diets containing mean effective concentrations of 0, 1.7, 7.8 or 37 ppm (equal to approximately 0, 0.1, 0.50.6 and 2.5-3.4 mg/kg bw/day) technical fenamiphos (89.3% pure) for two years. Clinical observation, mortality, food and test article consumption, hematology, blood chemistry, urinalysis and body weight were monitored throughout the study. Additional groups of 10 animals/sex/group were given 0 or 37 ppm fenamiphos for one year. At this time they were terminated and brain cholinesterase activity was determined. All rats, including those found dead or sacrificed in extremis during the study and those terminated at 12 or 24 months, underwent gross macroscopic observation, organ weight measurement and microscopic evaluation of more than forty tissues. Ophthalmological examination was done on 10 rats/sex/group prior to initiation and termination of the study. Percent of survival at termination was not treatment-related and ranged from 58-88% in males and 62-84% in females. Clinical observation showed a possibly treatment-related higher incidence of rough coat and alopecia in females of the high dose group when compared to controls. A statistically significant decrease of body weight was noted throughout the study for both male and female rats of the high dose group. Although no treatment-related effect on feed consumption was noted, there was a dose-related statistically significant decrease of plasma cholinesterase activity in rats of both sexes in all dose groups throughout the study. Plasma cholinesterase inhibition in male rats was 7 to 38% at 1.7 ppm, 24 to 69% at 2.8 ppm and 56 to 88% at 37 ppm. In females plasma cholinesterase inhibition ranged from 22 to 96% throughout the study. Erythrocyte cholinesterase activity (EChE) was also statistically significantly inhibited in both sexes at all dose levels when compared with controls. EChE inhibition was 5 to 7% at 1.7 ppm, 12 to 25% at 7.8 ppm and 56 to 81% at 37 ppm in males and 3 to 11% at 1.7 ppm, 21 to 43% at 7.8 ppm and 62 to 81% at 37 ppm in females. A statistically significant decrease of brain cholinesterase activity was observed in male rats of the high dose level at termination (-14%) and in both sexes (-25% in males and -24% in females) at the interim sacrifices after 1 year of treatment. There was a statistically significant increase in relative brain, heart and lung to body weight for both males and females of the high dose group at termination. In high dose females, the relative kidney to body weight was also significantly increased when compared to controls. At interim sacrifices females also showed a statistically significant increase of relative organ to body weights for adrenals, brain, heart, kidneys and ovaries. These changes were considered to be related to the decrease in body weight observed in rats of both sexes at the 37 ppm dose level. The only statistically significant change in absolute organ weight at termination was a decrease in liver weight and an increase in lung weight in both sexes at 37 ppm. Hematological examination showed several statistically significant differences in treated animals when compared to controls in both sexes at 3, 6 and 12 month examinations. These differences were randomly distributed and were not dose-related and therefore they were not considered to be treatment-related. No treatment-related changes were observed during ophthalmological examination or in food consumption, clinical chemistry, urinalysis, gross pathology and tissue masses in fenamiphos-treated rats when compared to controls. No treatment-related neoplastic lesions were observed during histopathological examination. No increase in the incidence of any tumor, total tumors, or total number of animals with tumors was observed at any dose level in either sex in fenamiphos-treated rats at termination or interim sacrifice when compared to controls. A statistically significant higher incidence of non-neoplastic inflammatory lesions were observed in the nasal,, laryngeal and lung tissue of rats receiving 37 ppm fenamiphos in the diet when compared to controls. These changes were attributed by the author of the study to the marked cholinesterase inhibition present in these animals. No treatment-related non-neoplastic changes were noted at 1.7 and 7.8 ppm. The authors of the study concluded that under the conditions of the study fenamiphos was not oncogenic to male or female Fischer 344 rats. Based on the serum and erythrocyte cholinesterase activity inhibition present at all dose levels tested a NOAEL was not found in this study (Hayes, 1986a). Special Studies on Embryotoxicity and Teratogenicity Rats Four groups of 25 female FB30 rats mated overnight with untreated males (in the ratio of 1 male to 2 females) were given by gavage a daily dose of 0, 0.3, 1 and 3 mg/kg bw/day fenamiphos (92.5% pure) in a aqueous Cremophor emulsion from day 6 to day 15 of gestation (presence of sperm in the smear obtained in the morning after mating). Control females received the same volumes (10 ml/kg bw) of the aqueous emulsion. On day 20 of gestation the dams were narcotized with CO2 and the fetuses were removed by Caesarian section and examined for litter size, average fetus weight per litter, sex, external and visceral abnormalities and skeletal malformations and development. Eighteen out of 25 dams receiving 3 mg/kg bw/day fenamiphos showed signs of toxicity (trembling and laying on one side) and 2 died. Time of death was not given and cause of death could not be established. No treatment-related signs of toxicity or deaths were observed in rats receiving 0, 0.3 or 1 mg/kg bw/day fenamiphos. A 15% reduction of average weight gain during the treatment period was found in dams receiving 3 mg/kg bw/day fenamiphos when compared to controls. The difference was reported to be not statistically significant by the author of the study. A total of 6 females were not fertilized in this study (1, 2, 2 and 1 in the 0, 0.3, 1 and 3 mg/kg bw/day dose group, respectively). The average placenta weight of the high dose group was statistically significantly (p < 0.05) lower than that of the control group. There were no treatment-related effects on the number of fertilized or pregnant females, litter size, number of resorptions, number of studied fetuses, average fetus weight, sex ratio, incidence of alterations of development, type or number of malformations. The most frequent manifestations observed were nodulations on ribs which were present in 2 fetuses from one litter of the 0.3 mg/kg bw/day group and in 4 fetuses from 3 litters of the 1 mg/kg bw/day dose group. The other malformations observed were general edema, abdominal fissure and anophthalmia in one fetus of the 0.3 mg/kg bw/day dose group. No malformation was observed in fetuses of the high dose group. The lower placenta weight observed in the high dose group was not considered to be toxicologically significant because it was considered to be still within the normal range and because no effects on embryonic and fetal development were seen in the study. It was concluded that fenamiphos at doses up to and including 3 mg/kg bw/day was not embryotoxic or teratogenic to FB30 rats. It was, however, toxic to mothers at the dose level of 3 mg/kg bw/day (Schulter, 1981). Rabbits In a dose finding embryotoxicity (including teratogenicity) study, groups of 3 mated (1:1) female Chinchilla rabbits were given single daily doses of 0, 0.1, 0.8, or 3 mg/kg bw/day fenamiphos (91% pure) in distilled water with 0.5% Cremophor EL by gavage from day 6 through day 18 post coitum. Cholinesterase activity was measured in plasma and erythrocytes before the first dose and just after the last dose administration. On day 28 post coitum all females were terminated and the fetuses removed by Caesarian section, sexed, weighed and examined for gross external and internal abnormalities. One female of the high dose group had body weight loss from day 10 and died on day 12 post coitum. A mean body weight loss of 3.7% and a reduction of food consumption (-33.1%) were noted during the treatment period in high dose animals when compared to controls. A statistically significant inhibition of both plasma and erythrocyte cholinesterase activity of 89 and 90%, respectively, was noted in rabbits of the high dose group on day 18 post coitum. Five pre-implantation losses and 1 fetal resorption were observed in the high dose group but not in the 2 lower dose groups or in controls. No treatment-related differences were noted in number of corpora lutea, implantations, live and dead fetuses or fetal weight in treated groups when compared to controls. It was concluded by the authors of the study that fenamiphos orally administered to mated female Chinchilla rabbits was toxic to the mothers at dose levels of 0.8 and 3 mg/kg bw/day but not at the dose level of 0.1 mg/kg bw/day. Based on these results, dose levels of 0.1, 0.5 and 2.5 mg/kg bw/day were proposed for the main study (Becker et al., 1986). In the main study 4 groups of 16 single-mated female Chinchilla rabbits were administered by gavage single daily doses of 0, 0.1, 0.5 and 2.5 mg/kg bw/day fenamiphos (91% pure) in distilled water from day 6 through day 18 post coitum. On day 28 post coitum the dams were killed and fetuses were removed by Caesarian section. Only dams with at least one living fetus were used for calculation of body weight gain, food consumption and reproduction data. Dams were examined for position of fetuses in the uterus, number of corpora lutea, implantations, resorptions, live and dead fetuses. Fetuses were weighed and examined for sex, external and internal malformations, skeletal abnormalities and development. Three females (one in each of the 0, 0.1 and 0.5 mg/kg bw/day dose group) were not pregnant. Four females of the 2.5 mg/kg bw/day dose group died as a result of fenamiphos treatment, after 3, 5 and 10 days of treatment and on day 21 post coitum. Treatment-related signs of toxicity (salivation and dyspnoea) were observed in these 4 females and in 5 other females of the high dose group from the second till the last day of treatment (day 7 and 18 post coitum, respectively). In 2 females which died, ataxia was noted and in another, diarrhea was observed. No signs of toxicity were noted in any female of the 0, 0.1 and 0.5 mg/kg bw/day dose group. A treatment-related statistically significant decrease of mean food consumption (29.4%) and a treatment-related reduction of body weight gain (56%) was observed during the treatment period in dams of the high dose group when compared to controls. Food consumption was significantly increased in this group from day 24 to day 28. No treatment-related or statistically significant differences were observed in the mean number of implantations, corpora lutea, live or dead fetuses and resorptions. In fetuses no effect which could be attributed to the administration of fenamiphos was seen in sex ratio, body weight, external or internal malformations, skeletal abnormalities or development. In one fetus of the high dose group, encephalocele with reduced size of the brain was noted. This finding was not considered to be treatment-related. A number of treatment-unrelated skeletal changes was noted in fetuses of all groups. Based on the maternal toxicity observed at the high dose level the NOAEL for the females under the conditions of this study was 0.5 mg/kg bw/day. Under the conditions of the study fenamiphos was not considered to be embryotoxic or teratogenic when administered to mated female Chinchilla rabbits (Becker, 1986). Short term studies Rats Groups of 209 male and female Fischer 344 rats were given diets containing 0, 0.37, 0.57, or 0.91 ppm fenamiphos (89% pure) for 14 weeks. Rats were monitored for clinical signs of toxicity, mortality, abnormality, masses, food consumption and body weight throughout the study. Cholinesterase activity was determined in 10 rats/sex/group in plasma and erythrocytes at 5, 9, 12 and 14 weeks and in brain at termination of the study. No effects attributable to the administration of fenamiphos were noted during clinical observation nor in food consumption and body weight measurements. Statistically but not toxicologically significant decreases of both plasma and erythrocyte cholinesterase activity were observed in fenamiphos-treated rats of both sexes when compared to controls. Maximum plasma cholinesterase inhibition as compared to controls was 17% at week 14 in males of the 0.37 ppm dose group and 24% at week 9 in females of the high dose group. Erythrocyte cholinesterase inhibition was in all cases < 10%. No toxicologically significant treatment-related change was noted for brain cholinesterase activity. It was concluded that no biologically significant cholinesterase activity inhibition was found in this study. The NOAEL for fenamiphos in this study was 0.9 ppm equal to 0.07 and 0.08 mg/kg bw/day for male and female rats, respectively (Hayes, 1986b). COMMENTS The oncogenicity study in rats, the full report of the teratology study in rats and the new teratology study in rabbits required by the 1985 JMPR have been submitted and evaluated. Fenamiphos was not oncogenic to Fischer 344 rats in a combined chronic toxicity/oncogenicity study. Erythrocyte cholinesterase activity was inhibited in both sexes at all dose levels tested. No biologically significant cholinesterase inhibition was seen, however, in a 90-day rat study at doses up to and including 0.9 ppm, equal to 0.07-0.08 mg/kg bw/day. Despite some inconsistences noted in the full report of the rat embryotoxicity/teratogenicity study required by the 1985 JMPR, this study was considered to be adequate. The compound was not teratogenic to Long Evans FB 30 rats, but it was toxic to the dams at the highest dose of 3 mg/kg bw/day. In the required new teratology study (JMPR, 1985), which was performed in Chinchilla rabbits, fenamiphos was toxic to mothers but it was not embryotoxic or teratogenic. This was in contrast to the results of a previous teratology study in New Zealand rabbits, where fenamiphos administered at similar or lower doses was found to be both fetotoxic and teratogenic. A re-evaluation and comparison of data from all these studies indicate that fenamiphos is toxic to female rats and rabbits. However, the concern of the 1985 Meeting about the fetotoxicity and teratogenicity observed in New Zealand rabbits (Mackenzie, 1982) was partially alleviated by the results of two new studies. A 3-generation reproduction study previously evaluated by the JMPR was negative. On the basis of the results of the oncogenicity study in rats and on the species- and strain-dependent results of the fetotoxicity/ teratogenicity studies, an ADI was estimated. TOXICOLOGICAL EVALUATION LEVEL CAUSING NO TOXICOLOGICAL EFFECT Rat: 0.9 ppm in the diet, equal to 0.07 mg/kg bw/day in males and 0.08 mg/kg bw/day in females Dog: 2 ppm in the diet, equivalent to 0.05 mg/kg bw/day ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN 0-0.0005 mg/kg bw. STUDIES WHICH WiLL PROVIDE INFORMATION VALUABLE IN THE CONTINUED EVALUATION OF THE COMPOUND Observations in man. REFERENCES Becker, H., Mueller, E., Luetkemeir, H. & Sachsse, K., 1986. Dose-finding embryotoxicity (including teratogenicity) study with SRA 3886 in the rabbit. Unpublished report No. 065250 from Research & Consulting Co. AG, Itingen, Switzerland. Submitted to WHO by Bayer AG. Leverkusen, FRG. Becker, H., 1986. Embryotoxicity (including teratogenicity) study with SRA 3886 in the rabbit. Unpublished report No. R 3917 from Research & Consulting Co. AG, Itingen, Switzerland. Submitted to WHO by Bayer AG. Leverkusen, FRG. Hayes, R.H., 1986a. Combined chronic toxicity/oncogenicity study of technical fenamiphos (Nemacur) with rats. Unpublished report No. 721 from Corporate Toxicology Dept., Mobay Chemical Co., Stilwell, KA, USA. Submitted to WHO by Bayer AG. Hayes, R.H., 1986b. Ninety-day cholinesterase study on rats with technical fenamiphos (Nemacur) in diet. Unpublished report No. 717 from Corporate Toxicology Dept., Mobay Chemical Co., Stilwell, KA, USA. Submitted to WHO by Bayer AG. Leverkusen, FRG. Mac Kenzie, K.M., 1982. Teratology study with Nemacur in rabbits. Unpublished report No. 308 from Hazelton Raltech, Inc. Submitted to WHO by Bayer AG. Leverkusen, FRG. Schulter, G., 1981. SRA 3886 (Nemacur): Evaluation for embryotoxicity and teratogenic effects in orally dosed rats. Unpublished report No. 9785 from Institute for Toxicology, Bayer AG. Submitted to WHO by Bayer AG. Leverkusen, FRG.
See Also: Toxicological Abbreviations Fenamiphos (ICSC) Fenamiphos (WHO Pesticide Residues Series 4) Fenamiphos (Pesticide residues in food: 1977 evaluations) Fenamiphos (Pesticide residues in food: 1978 evaluations) Fenamiphos (Pesticide residues in food: 1980 evaluations) Fenamiphos (Pesticide residues in food: 1985 evaluations Part II Toxicology) Fenamiphos (Pesticide residues in food: 1997 evaluations Part II Toxicological & Environmental) Fenamiphos (JMPR Evaluations 2002 Part II Toxicological)