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EC number: 202-297-4
CAS number: 94-04-2
The purpose of this study was to evaluate the toxicity of the Test Item, vinyl2-ethylhexanoate (VEHA), when administered daily via oral gavage to rats for at least13 weeks.Male and female Sprague Dawley (Hsd:Sprague Dawley SD) rats were assigned tofour groups, and doses were administered as indicated in the following table. Animalswere dosed via oral gavage once daily for 13 weeks at a volume of 5 mL/kg. The vehiclecontrol item was corn oil.
Dose Levelb Dose Concentrationb Number of AnimalsGroupa (mg/kg/day) (mg/mL) Males Females1 (Control) 0 0 10 102 (Low) 250 50 10 103 (Intermediate) 500 100 10 104 (High) 1000 200 10 10a Group 1 was administered vehicle control item onlyb Animals were dosed at a volume of 5 mL/kg
Assessment of toxicity was based on mortality, clinical observations, body weights, bodyweight changes, food consumption, ophthalmic observations, functional observationalbattery (FOB), locomotor activity, estrous cycle determinations, and clinical andanatomic pathology. Blood samples were collected for thyroid hormone and serum bileacids analyses.All animals survived to their scheduled sacrifice.No VEHA-related ophthalmic observations were noted.Vinyl 2-ethylhexanoate-related ataxia was noted for animals administered1000 mg/kg/day; ataxia was confined to one male on Days 6 and 8, and three females(one on Days 3 and 4, one on Days 3-5, and one on Day 4. Ataxia was not observed afterDay 8 and was deemed nonadverse. Lower, but not significant, mean body weight (9%)in males and decreased body weight gain in males and females was noted for animalsadministered 1000 mg/kg/day, compared with controls. Mean body weight gain over the13-week dosing phase were lower than controls by 24 and 33% for males and femalesadministered 1000 mg/kg, respectively. Although decreased body weight gain wassignificantly lower, the transient nature, lack of additional correlating observations (suchas decreased body condition), and lack of a need for intervention decreased body weightgain was considered nonadverse.A VEHA-related neurobehavioral observation and locomotor activity finding ofdecreased activity was noted. An increased incidence of mildly decreased activity formales administered 1000 mg/kg/day, compared with controls was reported during theFOB testing on Day 81. Animals administered 1000 mg/kg/day were noted withdecreased activity for all four locomotor measured activities (x + y ambulations,fine movements, basic movements, and rearing). Decreased activity was independent ofsex and was noted as an overall effect and as a treatment by interval interaction. Animalsadministered 500 mg/kg/day were also noted with decreased activity in fine and basicmovements, compared with controls. Due to the magnitude of the decreased activity(31 to 63%) in animals administered 1000 mg/kg/day, it was considered adverse.Vinyl 2-ethylhexanoate-related effects in clinical pathology test results were minimal tomild in magnitude, dose-dependent, and noted for animals administered ≥250 mg/kg/day,but more pronounced in animals administered 1000 mg/kg/day. Clear mechanisms forthese effects were not identified; however, may have been related to lower body weightgain and potentially decreased anabolic processes and/or altered lipid metabolism.Hematology effects consisted of minimally lower red cell mass (i.e., lower red blood cellcount, hemoglobin concentration, and hematocrit) - (males only), minimally lower totalwhite blood cell count (due to lower absolute neutrophil and/or lymphocyte counts), andminimally lower platelet count noted for animals administered 1000 mg/kg/day. Clinicalchemistry effects were minimal to mild in magnitude and consisted of decreased totalprotein concentration, due to decreased albumin and globulin concentrations noted forboth sexes administered 1000 mg/kg/day; higher cholesterol, high density lipoprotein,and triglyceride, and glucose (females only) concentrations noted for both sexesadministered ≥500 mg/kg/day; and lower low density lipoprotein concentration noted formales administered ≥250 mg/kg/day. No VEHA-related effects were identified incoagulation, thyroid hormone, or urinalysis test results.Vinyl 2-ethylhexanoate-related microscopic findings were noted in the liver, thymus,mesenteric lymph node, testes, and epididymis, and these microscopic findings differedby sex.Minimal or slight centrilobular hepatocyte hypertrophy (correlated with increased liverweights) was noted for males administered ≥500 mg/kg/day, and minimal to moderatetubular degeneration/atrophy of the testes and luminal cell debris of the left epididymiswere observed in males administered ≥500 mg/kg/day. Tubular degeneration/atrophy inthe testes and luminal cell debris in the left epididymis correlated with decreasedepididymis, prostate, and prostate/seminal vesicle organ weights for males administered1000 mg/kg/day.Decreased lymphocytes were noted in females administered 1000 mg/kg/day andoccurred at a slight or moderate severity in the thymus (correlated with decreased thymusweight parameters for females administered 1000 mg/kg/day) and at a moderate severityin the mesenteric lymph node.Vinyl 2-ethylhexanoate-related, increased kidney weights were noted for animalsadministered ≥500 mg/kg/day but were noted without a microscopic correlate. Liverweights were also increased for females administered 1000 mg/kg/day without amicroscopic correlate.VEHA-related decrease in sperm motility, total sperm count, and sperm concentration(density) was noted for males administered 1000 mg/kg/day. No VEHA-related effects onmorphology were noted at any dose level.Male and female rats were administered vehicle control item or 250, 500, or1000 mg/kg/day VEHA via oral gavage once daily. Vinyl 2-ethylhexanoate-relatedobservations in animals administered 1000 mg/kg/day included: nonadverse increasedincidence of ataxia in the first week; nonadverse decreased body weight gain; adversereduction in activity at Week 12; pronounced alterations in clinical chemistry andhematology endpoints of minimally lower total white blood cell count, minimally lowerplatelet count, decreased total protein concentration, higher cholesterol, higher highdensitylipoprotein, and higher triglyceride; microscopic findings of centrilobularhepatocyte hypertrophy (males), decreased lymphocytes (females), tubulardegeneration/atrophy of testes and luminal cell debris of the epididymis (males) withcorrelated decreased organ weights; and a significant decrease in sperm motility, spermcount, and nonsignificant decreases in sperm density (males). For these reasons1000 mg/kg/day was considered adverse when administered for 13 weeks. Vinyl2-ethylhexanoate-related observations in animals administered 500 mg/kg/day included:nonadverse reduction in activity at Week 12, alterations in clinical chemistry andhematology endpoints seen at 1000 mg/kg/day but at a lower magnitude, centrilobularhepatocyte hypertrophy in males, tubular degeneration/atrophy of the testes and luminalcell debris of the epididymis with no correlating organ weight changes. Due to the mildseverity of findings and the lack of an impact on the health and wellbeing of animalsadministered 500 mg/kg/day, effects for this dose were considered nonadverse whenadministered for 13 weeks. Thus, the no observed adverse effect level (NOAEL) is500 mg/kg/day.
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