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Key value for chemical safety assessment

Additional information

Butyl benzyl phthalate showed weak positive responses in two key in vivo studies (reliability 2) conducted under the auspices of the National Toxicology Program (NTP, 1997f). Both studies involved a single intraperitoneal injection of up to 5 g/kg bw in mice. In the chromosome aberration assay, examination of the bone marrow cells 17 hours later revealed a weak (but statistically significant) increase in aberrations at the top dose of 5 g/kg bw, while no such increase was observed at the delayed 36-hour sampling time. In this assay the mitotic index was not determined as an indicator of cytotoxicity. In the sister-chromatid exchange (SCE) assay, in which the bone marrow cells were examined 23 or 42 hours after treatment, there was a weak increase in numbers of SCEs; this showed a significant trend at 42 hours, and also at 23 hours after disregarding the top dose level (which had shown a reduced response).

 

Two other in vivo studies of lower reliability provide no evidence of genotoxic potential. Thus, in a study available in abstract form only (reliability 4), butyl benzyl phthalate did not induce dominant lethal mutations in the foetuses when two strains of male mice were given three subcutaneous injections of up to 4.6 g/kg bw and mated with untreated females of the same strain. A slight, dose-related reduction in total implants was observed after the first mating period, indicating that the compound was tested at a high enough dose to produce signs of toxicity (a slight reduction in fertility) (Bishop et al., 1987). Another study assigned a reliability code of 3 (not reliable) due to the low test dose used (0.18 mg/kg bw/day) found no evidence of micronucleus induction in the bone marrow of female rats that were treated via the drinking water throughout pregnancy and lactation (Ashby et al., 1997).

In two reliable studies, butyl benzyl phthalate did not induce chromosome aberrations and showed no convincing evidence of sister-chromatid exchange (SCE) induction when tested in vitro with Chinese hamster ovary cells, both in the presence and absence of a rat liver metabolic activation (S9) fraction (NTP, 1997e). Although an equivocal result was obtained in the first SCE assay in the absence of S9 (a significant trend (P=0.004) without any significant increase in SCEs at any of the dose levels), the subsequent study without S9 using a higher top dose and the assay with S9 were clearly negative.

 

Butyl benzyl phthalate (or Santicizer 160) also showed no convincing evidence of mutagenicity at the thymidine kinase locus in two reliable mouse lymphoma assays, when tested up to a cytotoxic concentration in the presence and absence of a rodent liver metabolic activation fraction (Litton Bionetics, 1977; NTP, 1997c). The NTP study reported increased mutant frequencies in the absence of S9, but only at concentrations that produced precipitation. No increase in mutant frequency was observed in the presence of S9 (NTP, 1997c).

 

When tested at concentrations of 10 mg/plate or higher in the Ames bacterial test, in the presence and absence of a liver metabolic activation fraction, butyl benzyl phthalate (or Santicizer 160) has shown no evidence of mutagenic potential in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538. Three such studies are reported, two reliability 2 (Litton Bionetics, 1976; NTP, 1997d) and the other reliability 4, not assignable (Flowers, 1976).


Short description of key information:
Butyl benzyl phthalate has shown only weak genotoxic potential in vivo, in chromosome aberration and sister-chromatid exchange (SCE) assays, following a single intraperitoneal injection of up to 5 g/kg bw in mice. Other, less reliable, in vivo assays in mice, for dominant lethal mutations or micronucleus induction, gave negative results. The compound has shown no convincing evidence of genotoxic activity in vitro, in chromosome aberration or SCE tests in Chinese hamster ovary cells, in the mouse lymphoma assay, or in Ames bacterial tests.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

The available studies on the in vivo and in vitro genotoxicity of butyl benzyl phthalate are considered adequate for concluding that the compound does not need to be classified for mutagenicity, under the EU CLP Regulations.