Dichlorvos (DDVP) Risk Characterization Document - California ...

D. CHRONIC TOXICITY AND ONCOGENICITY
Summary: DDVP caused the inhibition of plasma, erythrocyte, and brain ChE activities. Other nononcogenic
effects included hepatocellular lesions (vacuoles in the cytoplasm, cell swelling,
prominence of cell membranes), reduced body weight, emesis, salivation, and ataxia. Oncogenic
effects observed in rats and mice were pancreatic adenoma; mononuclear leukemia; mammary gland
carcinomas, fibroadenomas, and adenomas; forestomach papillomas and carcinomas; and pituitary
adenomas. DDVP also increased tumor growth rate in rats given leukemia transplant. The chronic
toxicity of DDVP was studied in rats, mice, and dogs and is summarized in Table 9.
Dietary - Rat
Osborne-Mendel rats (10/sex/control, 50/sex/treated group) were fed DDVP (94% purity; 0, 150, or
1000 ppm) in the diet daily for 80 weeks (NCI, 1977a). After 3 weeks on the 1000 ppm diet, the
dosage of DDVP in this group was reduced to 300 ppm because of toxicity (tremors, rough coats, and
diarrhea). The estimated dosages for 150 and 300 ppm were 7.5 and 15 mg/kg-day, respectively,
based on the assumed consumption rate of 5% body weight. In the second year of the study, clinical
signs (rough coat, epistaxis, hematuria, alopecia, dark urine, palpable masses, bloating or abdominal
distention) were observed in both the control and treated groups. The average body weights of the
high-dose (300 ppm) rats were lower than those of the other groups, an approximate difference of 50
grams throughout the study (estimated from graphed data). The NOEL for reduced body weight was
150 ppm (7.5 mg/kg-day). The possible treatment-related findings were increased incidences of
macrophage accumulation in the lungs, myocardial fibrosis, and thyroid follicular cell hyperplasia.
There was no evidence of oncogenicity. This study was unacceptable to DPR according to FIFRA
guidelines (no analysis of diet, no individual data, inadequate number of concurrent controls, and
staggered start for low and high doses with 4-week interval). The EPA classification of this study was
supplementary.
CD rats (25/sex/group) were fed DDVP (93% purity; 0, 0.1, 1, 10, 100 or 500 ppm) in the diet daily for
2 years (Witherup et al., 1967). There was a 22-80% loss of the test material due to volatilization and
hydrolysis. The average dosages were 0, 0.0013, 0.013, 0.13, 1.2, and 8.0 mg/kg-day based on the
body weight and food consumption rates for both sexes at week 104, and the average concentrations
of DDVP in the diet 12-16 hours after preparation of the diet. In the 100 ppm group, there were
statistically significant (p @ 0.05) decreases of 79% (of control values) for both plasma and
erythrocyte ChE activities in the males, and of 95% for plasma and 82% for erythrocyte ChE in
females. The reduction in brain ChE activity to 85% of control values in the 500 ppm group was not
statistically significant. Histopathological examination of tissues from rats fed 500 ppm showed liver
cells with diffused fine vacuoles in the cytoplasm, occasionally fat vacuoles, and swelling of the cell.
The NOELs were 100 ppm (1.2 mg/kg-day) for liver effects and 10 ppm for plasma and erythrocyte
ChE inhibition, and greater than 500 ppm (> 8.0 mg/kg-day) for brain ChE inhibition. This study was
considered unacceptable to DPR according to FIFRA guidelines (inadequate numbers of animals at
risk, weekly instead of daily preparation of diet, inadequate histopathology, as only major organs were
examined, and blood chemistry). The EPA classification of the study was supplementary.
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