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

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and total ChE activities intermittently during the study in all groups except for the 5 ppm group. After 50 days of treatment, plasma and erythrocyte ChE activities of the 15 ppm group were depressed to 87 and 57%, respectively of control values. After 70 days, the erythrocyte and plasma ChE activities of the 15 ppm group were 54% and 66% of control values. The NOEL for both plasma and erythrocyte ChE inhibition was 5 ppm (adjusted 0.3 mg/kg-day). The only clinical signs (time of onset was not specified) were increased activity and urinary output in the 25 ppm and 50 ppm groups. The NOEL for clinical signs was 15 ppm (adjusted 1.0 mg/kg-day). Dietary - Cattle Two dairy cows were fed increasing amounts of DDVP (100% purity) in the feed daily for 1 to 12 days (Tracy et al., 1960). A newborn and a heifer were also exposed to DDVP from the cow milk or in the feed. When the milk cows were fed 200 ppm DDVP daily for 7 days, there was no effect on erythrocyte ChE activity. Increasing the diet concentration to 500 ppm (4.5 mg/kg) for 12 days resulted in greater than 75% depression of erythrocyte ChE activity. The oral shock dose (dose which caused cholinergic signs of salivation, diarrhea, tremors, and convulsions) determined for one of the cows was 3000 ppm (27 mg/kg). After 20 exposures, no detectable level (less than 0.17 ug/ml) of DDVP was found in the milk as determined by a bioassay with flies using death as the endpoint. Plasma and erythrocyte ChE activities in the suckling calves were not significantly affected by the treatment to the mothers. Dermal - Cattle The effect of DDVP on two cows after dermal application to the back, front shoulders, and upper back portions of the neck was studied using either a 1% DDVP aqueous solution, a 1% DDVP emulsion, or a 10% suspension (Tracy et al., 1960). The solutions were applied on the skin daily for 10-11 days. No cholinergic signs were observed, and there was no inhibition of erythrocyte ChE activity. Inhalation - Human Human subjects (60 male inmates) were housed in Army barracks for at least 10 hours and exposed to DDVP aerosols released nightly every 30 minutes per hour for about 3 hours for either 14 days (phase I) or eight 30 minutes per night, 3 to 4 nights per week for 3 weeks (phase II) to simulate aircraft environments with DDVP applications (Rasmussen et al., 1963). All the volunteers were given physical examinations, plasma and erythrocyte ChE measurements, airway resistance, and visual tests. The DDVP concentrations in the air were 0.14 to 0.33 ug/L during phase I, and 0.15 to 0.55 ug/L during phase II. No treatment-related findings were reported for phase I. The only significant finding in phase II was the inhibition of plasma ChE activity which returned to the pre-exposure level upon termination of the experiment (data as mean values were presented in a graph). The plasma and erythrocyte ChE activities of 13 workers (both sexes), who were exposed to DDVP at an average air concentration of 0.7 mg/m 3 in the production of DDVP-releasing vaporizer, were monitored for 8 months (Menz et al., 1974). The average plasma and erythrocyte ChE activities, measured weekly of the workers during production, were 35% and 60%, respectively, of the levels measured before production. The ChE activities had returned to the pre-production level one month after exposure ceased (data were presented in graphs). Medical examinations and blood chemistry performed during the study were within normal limits. DDVP, in polyvinyl resin formulation pellets, was administered to male subjects in single doses up to 32 mg/kg and repeated doses up to 16 mg/kg-day for up to 3 weeks (Slomka and Hine, 1981). Of the 107 men who received DDVP in single doses of 0.1 mg/kg to 32 mg/kg, there was a dose-related inhibition of plasma and erythrocyte ChE activities as compared to pre-treatment values. At the highest dose (32 mg/kg), the inhibition was 20-30% and 55-75% for plasma and erythrocyte ChE, of 27
pretreatment levels, respectively. The plasma and erythrocyte ChE activities were also depressed (as low as 10% of pretreatment level) in men who were exposed continuously to DDVP. For both dosing regiments, side effects (diarrhea, nausea, stomach rumbling, lassitude, restlessness, and lightheadedness) were reported by both placebo and treated men. Additional Studies Additional studies for the consideration of subchronic toxicity are described in the III.D. CHRONIC TOXICITY, III.F. REPRODUCTIVE TOXICITY, and III.G. DEVELOPMENTAL TOXICITY sections. The following is a brief discussion of the studies. Osborne-Mendel rats were fed DDVP (0 to 1000 ppm) in the diet daily for 80 weeks (NCI, 1977a). After 3 weeks on the 1000 ppm (50 mg/kg-day) 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 consumption rate of 5% body weight. Sprague-Dawley rats were given DDVP (0 to 80 ppm) in the drinking water 24 hours daily (Tyl et al., 1992). Rats of both sexes were treated for 10 and 11 weeks during the premating period, respectively, for the F0 and F1 animals and were then allowed to mate for 3 weeks. Selected F1 offspring were either necropsied or maintained to breed for the F2 generation. Cholinesterase activities of the plasma, erythrocyte, and brain were determined after mating for the males, and after lactation for the females. There were dose-related decreases in the plasma, erythrocyte, and brain ChE activities of all F0 and F1 adults, and the levels of inhibition at 20 and 80 ppm were statistically significant (p @ 0.05). The NOAEL (No-Observed-Adverse-Effect Level) for plasma, erythrocyte, and brain ChE inhibition was 5 ppm (0.5 mg/kg-day for the males and 1.1 mg/kg-day for the females). The only significant (p @ 0.05) effect observed in the pups was the reduction (91-92% of control values) in body weight of the 80 ppm F1 pups on postnatal days 14 and 21. After weaning the F2a litters, the F1 females were again exposed to DDVP and mated with untreated males for the F2b litters. There was a reduction (not statistically significant) of fertility at 80 ppm. The number of "abnormal" estrus cycles in the 80 ppm F1 females was significantly higher (68%) than in the controls (16%). The reproductive toxicity and parental NOEL for non-cholinergic endpoints was 20 ppm (2.7 mg/kg-day estimated from the premating dosage for females) based on the reduction of water consumption, body weight, fertility, and estrous cycling. In the first experiment by Thorpe et al. (1971b), female Dutch rabbits were exposed to DDVP by inhalation from day 1 of mating to gestation day 28. The DDVP nominal concentrations were 0, 0.25, 1.25, or 6.25 ug/L for 23 hours per day (equivalent to 0, 0.13, 0.65, or 3.25 mg/kg-day). Severe toxicity and mortality were observed after the 6th day of exposure in the high dose 6.25 ug/L does. Cholinergic signs observed included anorexia, lethargy, muscular tremors, mucous nasal discharges, and diarrhea. Severely affected rabbits were prone with heads turned to one side. Sixteen of 20 does died or were killed because of intoxication. The NOEL for mortality and cholinergic signs was 1.25 ug/L (adjusted dosage of 0.65 mg/kg-day). The plasma, erythrocyte, and brain ChE activities were significantly inhibited for the 1.25 ug/L and 6.25 ug/L groups. The NOEL for ChE inhibition was 0.25 ug/L (adjusted 0.13 mg/kg-day) New Zealand rabbits were given DDVP (0 to 7.0 mg/kg-day) by gavage from gestation days 7 to 19 and sacrificed on gestation day 30 (Tyl et al., 1991b). Systemic toxicity included decreased weight gain (gestation days 7 to 19) as well as mortality (2 does of the 2.5 mg/kg-day group on gestation days 12 and 15, and 4 does of 7.0 mg/kg-day group on gestation days 17 and 19). In the high dose group, cholinergic signs (ataxia, salivation, diarrhea, breathing difficulties, tremors, and excitation) were observed with the first observation of ataxia made on gestation day 10. The NOEL was 0.1 mg/kg-day for maternal toxicity. 28
Page 1 and 2: DICHLORVOS (DDVP) RISK CHARACTERIZA
Page 3 and 4: transmitter of signals from the ner
Page 5 and 6: Contributors and Acknowledgments Pr
Page 7 and 8: List of Tables Pages 1. The acute t
Page 9 and 10: hematocrit) in rats. From studies w
Page 11 and 12: II. INTRODUCTION The human health r
Page 13 and 14: food service facilities); hand-held
Page 15 and 16: G. ENVIRONMENTAL FATE Summary: DDVP
Page 17 and 18: III. TOXICOLOGY PROFILE Pharmacokin
Page 19 and 20: Inhalation - Rat Carworth Farm stra
Page 21 and 22: DIMETHYL PHOSPHATE Oral - Rat Rats
Page 23 and 24: B. ACUTE TOXICITY Summary: The acut
Page 25 and 26: Oral - Human One hundred and eight
Page 27 and 28: Table 1. The acute toxicity of DDVP
Page 29 and 30: Table 1. The acute toxicity of DDVP
Page 31 and 32: Table 2. Selected no-observed-effec
Page 33: dose-related manner. At a dosage of
Page 37 and 38: Table 3. Selected no-observed-effec
Page 39 and 40: Gavage - Rat In a study conducted b
Page 41 and 42: ate (Appendix D) and the assumption
Page 43 and 44: Gavage - Mouse In a study conducted
Page 45 and 46: Capsules - Dog DDVP (97.3-99.5% pur
Page 47 and 48: Table 9. The no-observed-effect lev
Page 49 and 50: Mice exposed to DDVP by inhalation
Page 51 and 52: F. REPRODUCTIVE TOXICITY Summary: E
Page 53 and 54: Table 11. The dosages and the inhib
Page 55 and 56: G. DEVELOPMENTAL TOXICITY Summary:
Page 57 and 58: levels not verified, too few pregna
Page 59 and 60: H. NEUROTOXICITY Summary: Possible
Page 61 and 62: IV. RISK ASSESSMENT A. HAZARD IDENT
Page 63 and 64: Acute Toxicity Inhalation The criti
Page 65 and 66: ates were not statistically signifi
Page 67 and 68: In mice, there were dose-related in
Page 69 and 70: B. EXPOSURE ASSESSMENT The exposure
Page 71 and 72: The U.S. Department of Agriculture
Page 73 and 74: Acute Exposure Estimates of potenti
Page 75 and 76: Table 19. Commodity contribution of
Page 77 and 78: C. RISK CHARACTERIZATION The potent
Page 79 and 80: Table 23. The margins of safety for
Page 81 and 82: Table 25. The margins of safety of
Page 83 and 84: label between treatment and the ava
Page 85 and 86:
VI. TOLERANCE ASSESSMENT A. BACKGRO
Page 87 and 88:
VII. CONCLUSIONS The toxicological
Page 89 and 90:
Bomhard, E., and M. Rinke, 1994. Fr
Page 91 and 92:
DPR, 1992. Sampling for pesticide r
Page 93 and 94:
Horn, K.-H., B. Teichmann, and T. S
Page 95 and 96:
NTP (National Toxicology Program),
Page 97 and 98:
TAS, 1992a. Exposure 4 . Detailed
Page 99 and 100:
Warf Institute Inc., 1977c. Acute e
Page 101 and 102:
APPENDIX A U.S. ENVIRONMENTAL PROTE
Page 103 and 104:
APPENDIX B Department of Pesticide
Page 105 and 106:
TABLE 2: Percent DDVP Dermal Absorp
Page 107 and 108:
RESIDENT EXPOSURES Environmental mo
Page 109 and 110:
post-treatment, respectively. Glove
Page 111 and 112:
Ross, J.H., H.R. Fong, , T. Thongsi
Page 113 and 114:
APPENDIX C NALED TOXICOLOGY OF NALE
Page 115 and 116:
APPENDIX D CALCULATION EQUATIONS 1.
Page 117 and 118:
APPENDIX E ONCOGENICITY POTENCY CAL
Page 119:
APPENDIX E (continued) ONCOGENICITY
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