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B6C3F1 mice and Sprague-Dawley rats displayed the characteristic signs of pyrethroid intoxication following single oral doses ranging from 56 to 320 and 133 to 1000 mg/kg fenvalerate, respectively. The LD50s for mice and rats were 180 and 776 mg/kg, respectively, with corn oil as the vehicle. Signs of neurologic deficit such as splayed gait, tremors, ataxia, and hind limb incoordination were observed at doses of ≥ 100 mg/kg (mice) and ≥ 133 mg/kg (rats) within 1–8 hr after dosing. These signs had disappeared in most animals within 72 hr. Slight peripheral nerve fiber damage was detected in surviving mice and rats sacrificed 10 days after dosing. The incidence and severity were dose related at doses ≥ 56 and ≥ 180 mg/kg; however, even at lethal doses, evidence was lacking for the presence of nerve lesions in several animals. Thus two distinct neurologic effects were observed: a reversible ataxia/incoordination and a neuropathologic effect manifested as sparse axonal damage in peripheral nerve.

Previous investigations have demonstrated that dermal exposure to fenvalerate or other synthetic pyrethroid insecticides can produce a skin sensory response characterized by an itching/tingling sensation in humans and animals. The objective of this investigation performed in guinea pigs was to establish treatments which would be effective against pyrethroid-mediated skin sensation. Two classes of agents were tested. Barrier agents, which block penetration of substances through the skin, did not significantly reduce the fenvalerate-mediated skin sensations. Post-treatments with steroidal Dermolate®, antihistamine Delamine® or anti-inflammatory aspirin did not significantly reduce the pyrethroid-mediated skin sensation. However, Bicozene® (a local anesthetic cream) and Tashan® (a vitamin A, D, and Econtaining cream) were effective in reducing the pyrethroid-mediated skin sensations. Prior (30 min and 5h) dermal application of vitamin E was found to be effective in significantly reducing the fenvaleratemediated skin sensation; even when applied 29 h prior to fenvalerate exposure, there appeared to be a reduced skin response. Piperonyl butoxide (PBO), a pesticide Synergist, reduced the fenvalerate skin sensations when applied either directly to the skin or in conjunction with the pyrethroid.

Groups of six male and six female Beagle dogs were fed diets containing 0, 250, 500, or 1000 ppm fenvalerate for a period of 6 months. Prominent in-life observations related to treatment were emesis, head shaking, biting of the extremities, ataxia, and tremors. One high-dose male dog was sacrificed in extremis during the study period. Mean body weights of 1000-ppm female dogs were significantly lower than those of controls. Red blood cell counts and hematocrit and hemoglobin values in high-dose male and female dogs were significantly lower than those of controls at most sampling intervals. Serum cholesterol and alkaline phosphatase levels were also increased primarily in the high-dose group. Ophthalmic examination revealed changes in retinal vessel tortousity in some mid- and high-dose dogs. Hepatic multifocal microgranulomata were observed in control and treated dogs microscopically. These changes increased in incidence and severity with dose and were considered to be related to treatment. Histiocytic cell infiltrate in mesenteric lymph nodes in some 500- and 1000-ppm female and 1000-ppm male dogs was the only other treatment-related microscopic effect.

Groups of 30 male and 30 female Fischer-344 rats were fed dietary concentrations of 0, 30, 100, 300, 3000, or 10,000 ppm decarboxyfenvalerate (DC-FEN) for up to 13 wk. An interim kill of 10 rats/sex X group was performed at 7 wk. Following 7 or 13 wk of dietary treatment, groups of rats were necropsied, which included evaluation of hemocellular, hemochemical, and uretic parameters, selected absolute and relative organ weights, and macroscopic and microscopic observations. DC-FEN did not affect mortality. Body weight was decreased in male rats fed 10,000 ppm DC-FEN. Statistically and toxicologically significant differences in clinicopathologic parameters were observed at either the highest or two highest exposure levels. Some statistically significant differences were noted in some hemocellular and/or hemochemical parameters at either 100 or 300 ppm. These subtle changes were either not dose-related, inconsistent, or not of sufficient difference to be determined to have biological significance. Absolute and relative liver weights of male and female rats fed greater than or equal to 300 ppm DC-FEN were all higher than control values except for absolute weights in female rats (300 ppm) at the interim kill. Consistent significant increases in absolute or relative kidney weights were observed in male and female rats fed 3000 or 10,000 ppm DC-FEN. Other statistically significant differences in absolute and/or relative organ weights were seen primarily where the higher doses had caused decreased carcass weight. Macroscopic treatment-related liver enlargement (hepatomegaly) was observed in male and female rats fed 3000 or 10,000 ppm DC-FEN. Only one female rat fed 300 ppm DC-FEN had hepatomegaly at the terminal kill. Significant treatment-related microscopic effects were limited to glomerulonephrosis in male and female rats fed 10,000 ppm and hepatocellular hypertrophy and other associated liver changes in male and female rats fed 3000 or 10,000 ppm DC-FEN. Liver effects at doses less than 3000 ppm were indicative of a physiologic adaptive response and were not toxicologically significant. Therefore, the biologically significant no-effect level was 300 ppm.

Groups of 50 male and 50 female B6C3F1 mice were fed dietary concentrations of 10, 50, 250 or 1250 ppm Fenvalerate for 2 years. Two groups of control mice, 50 per sex per group, received basal diet only. Mortality was increased and body weight was significantly decreased in male and female mice in the 1250 ppm treatment group. Mean body weight of female mice in the 250 ppm group was also generally lower than controls after the 60th week of feeding. Decreased albumin and increased glutamic oxaloacetic transaminase levels in mice fed 1250 ppm Fenvalerate were the only effects observed in the hematology and serum chemistry parameters examined. The only treatment related non-neoplastic pathologic effect observed in the study was multifocal microgranulomata in lymph nodes, liver and spleen of 1250 ppm male mice and 250 and 1250 ppm female mice. Less severe microgranulomatous changes were present in mesenteric lymph nodes of 50 and 250 ppm male mice. No statistically significant differences were observed in either the number or type of neoplasms in mice fed Fenvalerate diets when compared to concurrent controls. Thus, Fenvalerate was found not to be carcinogenic in B6C3F1 mice under the conditions of the test.

Groups of 93 male and 93 female Sprague-Dawley rats were fed diets containing 1, 5, 25, and 250 ppm fenvalerate for up to 2 yr. The control group consisted of 183 males and 183 females. Approximately 10 treatment and 20 control rats/sex . group were killed at intervals of 3, 6, 12, and 18 mo. When body weights, food consumption, hematology, clinical chemistry and organ weights did not reveal a treatment effect, two additional groups of 50 males and 50 female rats were placed on 0 or 1000 ppm fenvalerate diets and maintained for 2 yr. Body weight was decreased and organ/body weight ratios were increased in brain, liver, spleen, kidneys (females), heart (females), and testes (males) in the 1000 ppm group. Mammary and pituitary tumors were commonly observed, along with a variety of other tumors occurring randomly among all control and treatment groups. No statistically significant differences in the number and type of neoplasms were observed except for mammary tumors in females in the main study. These effects were judged not to be toxicologically significant, since mammary tumor incidences did not exceed expected incidences in aged female Sprague-Dawley rats, time to tumor appearance was unchanged, and no shift in percent benign versus malignant tumors occurred. Sarcomas identified in the subcutis and dermis in 5/51 1000-ppm-treated males were also identified in 2% (1/50), 2% (2/102), and 0-6% of concurrent, original, and historical controls, respectively. Microscopic examination did not reveal any treatment-related lesions. The no-observable-effect level was determined to be 250 ppm.

Groups of 80 male and 80 female B6C3F1 mice were fed diets containing 17.5, 64, 320, 1600, 8000, and 16000 ppm tetrachlorvinphos (TCVP) for up to 103 weeks. Another group of 80 male and 80 female mice were fed TCVP (16000 ppm) that was used in a previous bioassay. One hundred-sixty male and 160 female mice served as the control group. Ten treated and 20 control mice/sex/group were killed at 6, 12, and 18 months. It was estimated that the study maximum-tolerated dose was exceeded by three- and sixfold in the 8000- and 16000-ppm dose groups, respectively. Consequently, these exposures produced excessive cytotoxicity and regenerative changes in the liver and kidneys which were associated with sex-hormonal imbalance and metabolic overload in liver. A significant decrease (15-40%) in body weight was observed in mice fed 8000 and 16000 ppm TCVP. These treated mice did not gain weight during the study. Reduced food consumption and caloric intake throughout the study were probably responsible for the increased survival and the decreased incidence of spontaneous neoplasia in mice fed 8000 and 16000 ppm TCVP. Classification of pathologic lesions observed in these high-dose groups differed among study and consulting pathologists. The consultant and Shell pathologists concluded that the liver and kidney changes were causally related to excessive toxicity which was manifest primarily by hepatocellular hyperplasia and renal tubular adenoma. Study pathologist in accordance with his classification found statistically significant increases in hepatocellular carcinoma, hepatocellular adenoma or carcinoma, and renal tubular carcinoma in male mice fed 16000 ppm TCVP. The incidence of hepatic neoplasms as evaluated by the study pathologist in female mice fed 8000 and 16000 ppm TCVP although statistically significant was of questionable biologic significance when compared with historical female controls. The only statistically significant finding observed by the consulting pathologist was an increased incidence of renal tubular adenoma and renal tubular adenoma or carcinoma in male mice fed 16000 ppm TCVP. Use of results from these high-dose groups is contraindicated due to the many compromising factors affecting mice fed 8000 and 16000 ppm TCVP. TCVP was found not to be oncogenic in B6C3F1 mice at dose levels not exceeding the maximum tolerated dose.

Groups of 28 male and 28 female CD-1 mice and Fischer 344 rats were exposed to a mixture of 1,3-Dichloropropene and 1,2-Dichloropropane (D-D) vapors. Exposure concentrations were 0, 5 (4.7), 15 (14.4), or 50 (53.7) ppm, 6 h/d, 5 d/wk for 6 or 12 wk. The following parameters were evaluated: pharmacotoxic signs, body weights, hematology (HGB, HCT, RBC, WBC, and diff. leukocyte count), serum chemistry (BUN, GLU, ALB, GPT, and ALP), urinalysis, gross pathology, histopathology, organ weights, and organ weight/body weight ratios of brain, heart, liver, kidneys, testes or ovaries, and adrenals. The only exposure-related clinical effects observed were increased mean liver/body weight ratios of male rats and mean kidney/body weight ratios of female rats at the 50 ppm exposure level. Slight to moderate diffuse hepatocytic enlargement in 12 of 21 of the 50-ppm male mice after 12 wk exposure was the only compound-related histopathologic change present.