A developmental neurotoxicity screening study with technical grade Fenamiphos (Nemacur) in Wistar rats

BAYER CROPSCIENCE LP 
Document Number: M-002519-01-1
Report Number: 200696
Date: 2004-01-26

Abstract

Technical-grade fenamiphos was administered via the diet from gestation day (GD) 0 through lactation day (LD) 21 to mated female Wistar rats at nominal concentrations of 0, 2.5, 10 and 50 ppm. On postnatal day (PND) 4, litters with a minimum of eight pups, including at least three per sex, were culled to yield, as closely as possible, four males and four females. Plasma, erythrocyte and whole-brain cholinesterase (ChE) activities were measured in the offspring on PND 4 and PND 21 and in the dams on LD 21. Subsets of surviving offspring. representing at least 20 litters per level, were subjected to evaluation using the following observations and measurements-detailed clinical observations and a functional observational battery, preputial separation or vaginal patency, body weight, food consumption, automated measures of activity (figure-eight maze), acoustic startle habituation, learning and memory (passive avoidance after weaning and a water maze task on PND 60) and an ophthalmic examination. Neural tissues were collected from 10 rats/sex/dietary level (representing approximately 20 litters) on PND 21 (brain only) and at study termination (approximately 75 days of age) for microscopic examination and morphometry.

General

Based on analytical results, the mean concentrations of fenamiphos in the diet were 0,2.61, 10.2 and 51.1 ppm for nominal concentrations of 0, 2.5, 10 and 50 ppm, respectively.

The average daily intake of active ingredient at nominal dietary concentrations of 0,2.5, 10 and 50 ppm was as follows, based on the average dietary consumption for the three weeks of gestation and lactation:

Gestation: 0, 0.2, 0.9 and 4.8 mg/kg/day, respectively; and 
Lactation: 0, 0.5, 2.1 and 10.3 mg/kg/day, respectively.

Fenamiphos had no effect on reproduction parameters, including the fertility index or gestation length, at any dietary level.

Maternal

There were no deaths at any dietary level that are ascribed to treatment and no compound-related clinical signs during gestation. The only clinical sign attributed to the test substance was tremor in one high-dose animal at the end of lactation when exposure was greatest due to increased consumption of the treated diet. 

Body weight and body weight gain were not affected during gestation at any dietary level. During lactation, body weight was reduced in high-dose animals (an average 6% to 15% on lactation days 4 through 21) but not at lower dietary levels at any time.

Food consumption was not affected during gestation at any dietary level. Food consumption was reduced, relative to controls, for high-dose females during the third week of lactation, when exposure to the test substance was greatest.

Functional Observational Battery (FOB). There were no compound-related findings during gestation at any dietary level. Findings associated with the test substance (urine stain and tremor) were evident in high-dose animals on lactation day (LD) 21, when exposure was greatest, but not at lower dietary levels at any time. 

Cholinesterase activity was measured in the dams on LD 21. Inhibition of plasma ChE activity (37%) was the only effect at the 2.5 ppm dietary level. Inhibition of plasma and erythrocyte ChE activities occurred at 10 ppm (58% and 61%, respectively) and plasma, erythrocyte and brain ChE activities were inhibited at the 50 ppm dietary level (85%, 85% and 34%, respectively).

Offspring (F1 Generation)

Mortality. There were no deaths ascribed to treatment at any dietary level.

Detailed observations. No compound-related signs were apparent at any dietary level.

Litter parameters. The only compound-related effect on litter parameters involved decreased body weight and weight gain, which are described below.

Developmental landmarks (sexual maturation). There were no compound-related effects on preputial separation or vaginal patency at any dietary level.

Pupil constriction was not affected by treatment at any dietary level.

Body weight and weight gain. At birth, there were no differences in body weight at any dietary level. However, weight gain was reduced thereafter in high-dose males and females, such that they weighed an average 6% (not statistically significant) less than controls on PND 4 and significantly less than controls on days 11 (13%), 17 (18%) and 21 (17%). Body weight and weight gain were not affected by treatment at lower dietary levels.

Food consumption was not affected by treatment at any dietary level.

FOB. No compound-related effects were evident at any dietary level.

Motor and locomotor activity were not affected at any dietary level. 

Acoustic startle habituation. No compound-related effects were evident at any dietary level. 

Passive avoidance. No compound-related effects were evident at any dietary level. 

Water maze. No compound-related effects were evident at any dietary level.

Ophthalmology. No compound-related lesions were evident at any dietary level.

Cholinesterase activity. The only effect in the offspring on PND 4 was slight (19%) inhibition of plasma ChE activity at the highest dietary level. By comparison, on PND 21 the 50 ppm dietary level inhibited plasma ChE activity in both sexes (64-67%), erythrocyte ChE activity in both sexes (45-61%), and brain ChE activity in both sexes (10-12%). The only effect on PND 21 at 10 ppm was inhibition of plasma ChE activity in both sexes (21-24%) and there was no effect on any measure at the 2.5 ppm dietary level.

Gross lesions. No compound-related lesions were evident at necropsy in animals that were found dead or at scheduled sacrifice on PND 21 or at study termination.

Terminal body weight. On PND 21, terminal body weight was reduced, relative to controls, for high-dose males and females but was not affected by treatment at lower dietary levels. At study termination, body weight was not affected in perfused or non-perfused animals at any dietary level.

Brain weight. No compound-related effects were evident at any dietary level, on PND 21 or at study termination. 

Brain morphometry. There were no differences in gross or microscopic brain measurements on PND 21 or at study termination at any dietary level. 

Micropathology. There were no compound-related microscopic lesions on PND 21 (brain) or at study termination (brain, other neural tissues, and skeletal muscle).

*NOAEL and LOAEL are based on levels of dietary exposure during lactation, since effects were only evident during, or at the end of, lactation.