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

H. NEUROTOXICITY
Summary: Possible adverse effects of nerve fiber degeneration and spinal cord degeneration were
observed in chickens treated with DDVP. No acute delayed neurotoxicity in hens was reported,
except at lethal doses. An acute neurotoxicity study in the rat given DDVP by gavage resulted in
cholinergic effects which included gait alteration, constricted pupils, tremors, and salivation.
Gavage - Chicken
DDVP (97.87% pure; 0, 0.3, 1.0, or 3.0 mg/kg-day) was given to domestic hens (21/group) by gavage
for 28 days (Huntingdon Research Centre Ltd., 1994). Hens were observed for a total of 49 or 77
days after the onset of dosing. There was an overall trend for decreased body weight gain from days
1-28 (@ 7%); however, recovery of body weigh gain occurred from days 28-77. Clinical signs of
neurotoxicity was observed at 1.0 mg/kg (unsteady gait and an inability to stand), and 3.0 mg/kg
(wings outstretched, being pecked, limping, inability to stand, quiet/subdued, unsteadiness, and
death). Histological examination showed axonal degeneration in the cerebellum, spinal cord, sciatic
nerve and tibial nerve, as well as splitting/thickened and/or densely staining material within the myelin
in all doses. The NOEL for neurotoxicity was @ 0.3 mg/kg based on clinical and histological findings.
On day 4, brain ChE was inhibited 44% at 1.0 mg/kg and 65% at 3.0 mg/kg. By day 30, brain ChE
activities were inhibited: 26, 34, and 54%, respectively, for 3.0, 1.5, and 0.3 mg/kg. However, brain
neurotoxic esterase and spinal cord neurotoxic esterase were not affected. This study was
considered acceptable according to FIFRA guidelines.
Acute delayed neurotoxicity of DDVP was studied in atropinized chickens (10/group) after oral
administration of 16.5 mg/kg DDVP (96.5% purity, LD50 of 16.15 mg/kg) on day 1 and again on day
22 (Beavers et al., 1988). At sacrifice on day 43, a possible adverse effect was noted in one of 10
treated chickens. Histopathological examinations of the sciatic nerve showed nerve fiber
degeneration in the proximal right sciatic nerve, and axonal swelling in proximal and distal parts of that
nerve. This study was considered acceptable to DPR according to FIFRA guidelines.
No delayed neurotoxicity was observed in two studies where hens (15/group) were treated with 2.5
mg/kg DDVP (93% purity) daily, 5 days per week for 3 weeks (The Kettering Lab., 1964), and with
22.9 mg/kg (purity not specified) in a single administration (Shell Chemical Co., 1971). These studies
were considered unacceptable to DPR according to FIFRA guidelines (protocol and results were not
adequately described).
Delayed neurotoxicity at a dose in excess of the lethal dose was studied in hens (6/group) 2 weeks
after being treated with a single dose of DDVP (purity not stated, 100 mg/kg) (Caroldi and Lotti, 1981).
Fifteen minutes before DDVP dosing, hens were given eserine (0.1 mg), atropine sulfate (20 mg), and
2-PAM (100 mg/kg) to block the ChE effects of DDVP. At 24 hours after dosing, neurotoxic esterase
activity (NTE) in the brain, spinal cord, and peripheral nerve was reduced more than 78% in the
treated hens. The hens showed mild signs of ataxia at 12-14 days after exposure. This was a
published study and not reviewed for acceptability.
Using a similar protocol as Caroldi and Lotti (1981), hens were not ataxic until a second dose was
given 1-3 days after the first dose (Johnson, 1978). The investigator suggested that ataxia was
associated with spinal cord NTE. The second dose resulted in significant level of spinal cord NTE
inhibition to induce ataxia in the hens. This was a published study and not reviewed for acceptability.
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