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Description of key information

Information available for diisobutyl phthalate indicates that the male reproductive system is a potential target for effects following repeated oral exposure. This is supported by information available for the homologue dibutyl phthalate which, in addiiton, produced changes in liver consistent with peroxisome proliferation.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
70 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

In a pre-guideline investigation reported by Hodge (1954; not available for review but summarized by ECHA, 2009), groups of rats (5/sex/group; strain not known) were fed diet containing 0, 0.1, 1.0 or 5.0% DIBP for 4 month; this was equivalent to approx. 0, 70, 700 or 3500 mglkg bw/d in both sexes (ECHA, 2009). Slower growth was noted in animals fed 1% DIBP and above, with marked reductions in body weight seen in both sexes fed 5% DIBP (-43% for males; -13% for females). Animals from the high dose group also exhibited slight reductions in red blood cell counts (males) and haemoglobin (both sexes). Absolute (-30%) and relative (-50%) testes weights were clearly decreased in animals receiving 5.0% DIBP via the diet, with absolute and relative liver weights markedly increased in high dose animals of both sexes (+5% and +80%, respectively, for males; +40% and +60% for females). The results of histopathological assessment of liver and kidney tissue were unremarkable. The findings are compatible with a NOAEL of 70 mg/kg bw/d for effects on growth, with effects on organ weights (including decreased testis weight and increased liver weight) and haematological parameters recorded following higher exposures.

With regard to DIBP-related changes in the male reproductive system, other investigations have demonstrated significant reductions in zinc concentrations in testes (and liver), increased testicular testosterone concentration (but no effect on levels in serum), significantly reduced absolute and relative testicular weights as well as decreased spermatogenesis and desquamation of spermatocytes in rats fed 2.0% DIBP in the diet (Oishi and Hiraga, 1980a; summarized by ECHA, 2009). Comparable findings of a significant reduction in absolute and relative testes weights, significantly decreased concentration of zinc in testes and liver and significantly increased testosterone concentrations in testes and serum have been recorded in rats fed diet containing 2.0% monoiso-butyl phthalate (MIBP) (Oishi and Hiraga, 1980b; summarized by ECHA, 2009). MIBP is the monoester formed following hydrolysis of DIBP (Mentlein and Butte, 1989).

Supporting information on other systemic effects is available for the structural analogue dibutyl phthalate (DBP) (summarized by EU, 2003). This includes results from a good quality sub-chronic feeding study (NTP, 1995) in which male and female F344/N rats were fed diets containing 0, 2500, 5000, 10000, 20000 or 40000 ppm DIB for up to 13 wk. Principle findings included haematological changes (decreased haemoglobin, red cell counts, and haematocrit; increased platelets and nucleated erythrocytes), altered serum chemistry values (decreased cholesterol and triglyceride; increased alkaline phosphatase activity, bile acid concentration and cyanide-insensitive palmitoyl-CoA oxidase activity), organ weight effects (increased relative liver and kidney weights, decreased testicular weights) and histopathological alterations in liver (cytoplasmic alterations, increased number of peroxisomes) and testis (germinal epithelial degeneration). The overall NOAEL from this study was 2500 ppm DIB in the diet (equivalent to 177 mg/kg bw/d, both sexes) based on alterations in haematological, serum chemistry and organ weight values at 0.5%. The NOAEL for effects on testis (degeneration of germinal epithelium) was 5000 ppm DBP (359 mg/kg bw/d). The NOAEL for peroxisome prolifearation-related changes (increased PCoA activity) was 2500 ppm DIB in both sexes (177 mg/kg bw/d). Other studies detailed in the risk assessment report for DBP (EU, 2003) give generally similar findings and values.

Overall, the available data indicate a NOAEL of 70 mg/kg bw/d for DIBP, based on body weight effects in the rat. Higher exposures are associated with changes in the (male) reproductive system while information for DBP indicates that the liver (peroxisome proliferation) is another target tissue in the rat.

ECHA (2009) Member State Committee support document for the identification of diisobutyl phthalate as a substance of very high concern because of its CMR properties, 27 November 2009. http://echa.europa.eu/chem_data/authorisation_process/candidate_list_table_en.asp

EU (2003) European Union Risk Assessment Report: dibutyl phthalate, volume 29. Office for Official Publications of the European Communities, Luxembourg.

Hodge, HC (1954) Preliminary acute toxicity tests and short term feeding tests of rats and dogs given di-isobutyl phthalate and dibutyl phthalate.

Oishi, S and Hiraga, K. (1980a) Testicular atrophy induced by phthalate acid esters: Effect on testosterone and zinc concentrations. Toxicol. Appl. Pharmacol. 53,35-41

Oishi, S and Hiraga, K. (1980b) Testicular atrophy induced by phthalic acid monoesters: effects of zinc and testosterone concentrations. Toxicology 15,197-202


Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; urogenital: testes

Justification for classification or non-classification

The effects seen in the rodent studies are not of sufficient severity, or sufficient relevance to man, to meet the criteria for classificationa with respect to repeat dose toxicity.