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In a reliable GLP-compliant study in which male and female rats were given benzyl butyl phthalate (BBP) in the diet at 0, 0.6, 1.2 or 2.5% for 21 days, various effects associated with peroxisome proliferation were seen at all BBP doses, and moderate peroxisome proliferation was seen at the top dose (the livers of animals in the lower dose groups were not examined for such an effect). The lowest-observed-adverse-effect level (LOAEL) was 0.6%, providing about 660 mg/kg bw/day (Ford, 1985). In two other studies using the same strain of rat, a 1-year study identified the same LOAEL (0.6%) based on peroxisome proliferation (Monsanto, 1994), while a 28-day study reported induction of palmitoyl-CoA oxidation (an index of hepatic peroxisome proliferation) at 1%, and thus established an NOAEL of 0.5% (around 540 mg/kg bw/day) (BIBRA, 1992). 

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Groups of 5 male and 5 female Fischer 344 rats were given BBP in the diet at 0.6, 1.2 or 2.5% for 21 days, providing about 660, 1300 or 2500 mg/kg bw/day. A control group received plain diet and a positive control group received DEHP at 1.2%, providing about 1100 mg/kg bw/day. The study was designed to evaluate peroxisome proliferation in the liver (by transmission electron microscopy) and other associated effects. A range of standard endpoints was also evaluated. Peroxisome numbers and size were moderately increased in the livers of males and females at the top dose (the livers of animals in the lower dose groups were not examined for such an effect), and in the positive control group. There was a range of other statistically significant effects associated with peroxisome proliferation, including increased liver weight (at all doses in both sexes), increased palmitoyl CoA, 11‑hydroxylase and 12-hydroxylase (at all doses in males and in high-dose females), decreased serum triglycerides (in mid- and high-dose males) and decreased serum cholesterol (at all doses in females). Other adverse effects included decreased body-weight gain in the mid- and high-dose groups (associated with decreased food intake), testicular atrophy (at the highest dose level) and a slight, but statistically significant, increase in kidney weight (at all doses) (Ford, 1985).

 

The EU RAR also describes a GLP-compliant 28-day study in which groups of 5 male Fischer 344 rats received BBP at 0, 0.01, 0.05, 0.1, 0.5 and 1% of the diet, or 1% DEHP (positive control). In the BBP-exposed groups there were no statistically significant effects on body weight, but relative liver weight was increased at the top dose, and there were also increases in hepatic palmitoyl-CoA oxidation activity, and whole homogenate protein content (presumably of the liver?).Testes weight was unaffected. No histopathologic changes were reported. The NOAEL observed in this study for induction of palmitoyl-CoA oxidation (as an index of hepatic peroxisome proliferation) was 0.5%, corresponding to a mean intake of 540 mg/kg bw/day (BIBRA, 1992).

 

In another study described by the EU RAR, female Fischer 344 rats were fed diets containing 0, 0.6, 1.2 or 2.4% BBP for 12 months. There was evidence of peroxisome proliferation in the liver after 1 and 12 months, from 0.6% when measured as carnitine acetyltransferase activity and from 1.2% when measured as palmitoyl-CoA oxidation. There was no evidence of cell proliferation in the liver at any of the times examined (i.e. after 1 week and 3 and 12 months of treatment), and immunotoxicity studies did not indicate any significant immune suppression or enhancement. The LOAEL for evidence of peroxisome proliferation was 0.6% BBP in the diet (Monsanto, 1994).