Application for the Reassessment of a Hazardous Substance under ...

from Charles River Laboratories (CRL) (1996) revealed that the femalefertility indices of 55% (F 2a ) and 50% (F 2b ) were below the averagehistorical control range of 60-100%. In both litters, the pregnancy index waslower at 80 ppm than in the control, suggesting that female fecundity wasreduced with treatment. The number of females with live litters was alsoreduced at 80 ppm (both litters), with an apparent increase in the stillbirthindex in the F 2b litter. The latter was outside of the historical control rangeof 0-10.2% (CRL 1996). Marginal reductions in pup survival (day 7) and thelactation index were noted in both litters but were not considered treatmentrelated.All other reproduction and lactation indices were unremarkable.Offspring (F 2a and F 2b )At 80 ppm, F 2a pup weights (males and females) were 5-15% lower than thecontrols during the entire lactation period [postnatal days 1 (5%), 4 (15%), 7(14%), 14 (12%) and 21 (9%)]. At 80 ppm, F 2b pup weights were also lowerthan the controls during the lactation period, with a greater effect seen inmales than females [at postnatal days 4 (11/14% M/F), 7 (18/7% M/F), 14(16/3% M/F) and 21 (14/2% M/F)]. Although none of the findings in F2pups were statistically significant, the consistent trend at 80 ppm in bothlitters and with the effects seen in F 1 pups means that this effect on pupweight can not be discounted. There were no treatment-related clinical signsobserved in pups during lactation. Macroscopic examination of the 10pups/sex/dose designated for necropsy revealed no treatment relatedabnormalities.• Parental NOAEL =• Parental LOAEL =5 ppm for males and females (~0.5 mg/kg bw/d);20 ppm for male and female rats based on inhibitionof plasma, RBC and brain ChE activities (~2 mg/kgbw/d).• Reproductive NOAEL = 20 ppm (~2 mg/kg bw/d);• Reproductive LOAEL = 80 ppm based on reduced fertility and pregnancyindices, increased stillbirths in the F2 generation, anda reduction in cycling concomitant with an increasein abnormal cycling in F1 maternal rats (~8 mg/kgbw/d).• Offspring NOAEL =• Offspring LOAEL =• GLP: US EPA, 40 CFR Part 160;20 ppm (~2 mg/kg bw/d);80 ppm based on lower pup weights in bothgenerations (~8 mg/kg bw/d).• Test Guideline:US EPA OPPTS 870.3800; OECD;• Reference source: Tyl RW, Myers CB & Marr MC (1992) ―Two-generationreproductive toxicity study of DDVP administered in thedrinking water to CD® (Sprague-Dawley) rats.‖ RTI IDNo. 60C-4629-170. Lab: Reproductive and DevelopmentalToxicology Laboratory, Centre for Life Sciences andDichlorvos reassessment – application Page 212 of 436