Spinosad insecticide: subchronic and chronic toxicity and lack of carcinogenicity in CD-1 mice.
The potential toxicologic and oncogenic effects of spinosad, a natural fermentation product with insecticidal properties, were investigated. The 13-week toxicity study consisted of groups of 10 CD-1 mice/sex provided diets containing 0, 0.005, 0.015, 0.045, or 0.12% spinosad (Study 1). The 0.12% group was terminated on Test Day 44 due to mortality and overt clinical signs of toxicity. An 18-month chronic oncogenicity study consisted of groups of 50 CD-1 mice/sex provided diets containing 0, 0.0025, 0.008, or 0.036% spinosad (Study 2). Two interim groups of 10 mice/sex/group were terminated after 3 and 12 months. Females given 0.036% were terminated on Day 455 due to markedly lower body weights and feed consumption, as well as excessive mortality. Because of the early termination of the female high-dose group, additional groups of 10 male and female mice (12-month interim necrospy) and 50 male and female mice (18-month necropsy) were provided diets containing 0, 0.0008, or 0.024% spinosad (Study 3) to fully assess potential chronic toxicity and oncogenicity. Standard toxicologic parameters were evaluated consistent with existing regulatory guidelines. The primary effect in the 13-week and 18-month studies was intracellular vacuolation of histiocytic and epithelial cells in numerous tissues and organs at doses of > or = 0.015%. The histological vacuolation corresponded to ultrastructural lysosomal lamellar inclusion bodies. This alteration was consistent with phospholipidosis, a condition that results from accumulation of polar lipids in lysosomes. Lesions with no apparent direct relation to vacuolation were hyperplasia of the glandular mucosa of the stomach, skeletal muscle myopathy, bone marrow necrosis, and anemia with associated splenic hematopoiesis. The incidence of tumors in mice given spinosad was not increased relative to controls at any dose level. The no observed effect level for the 13-week study was 0.005% (6 mg/kg/day) spinosad, and for the chronic toxicity/oncogenicity study was 0.008% (11 mg/kg/day) spinosad for male and female CD-1 mice.
Stebbins
K E
KE
Toxicology and Environmental Research and Consulting, The Dow Chemical Company, 1803 Building, Midland, Michigan 48674, USA. kestebbins@dow.com
Bond
D M
DM
Novilla
M N
MN
Reasor
M J
MJ
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015197:Carcinogenicity Tests; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004435:Eating / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000648:ultrastructure; D006644:Histiocytes / Q000187:drug effects / Q000473:pathology; D007306:Insecticides / Q000008:administration & dosage / Q000633:toxicity*; D008064:Lipidoses / Q000139:chemically induced / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008136:Longevity / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects / Q000648:ultrastructure; D018942:Macrolides / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009336:Necrosis; D019055:No-Observed-Adverse-Effect Level; D014617:Vacuoles / Q000187:drug effects / Q000473:pathology
D004338:Drug Combinations; D007306:Insecticides; D018942:Macrolides; C415329:spinosad