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Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
19 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
RL2

Additional information

A 90-day study performed according to current standards with repeated oral administration in rats revealed a NOAEL of 152 mg/kg bw. At 752 mg/kg bw, hematological and clinical chemical changes, increased liver and kidney weights and histopathological changes in the liver were

seen. However no testicular changes were seen in this study up to and including the highest dose-level of 752 mg/kg bw while in special studies in rats on these effects even the lowest doselevel of 250 mg/kg bw showed an effect (changes in testicular enzymes associated with degeneration of spermatogenic cells). No neurotoxicity was seen in this study.

In addition a NOAEL of 19.9 mg/kg bw in rats with respect to peroxisomal proliferation was found in a special study focused on this effect. However, humans have a low sensitivity for this phenomenon.

Studies with repeated dermal exposure were not appropriate for establishing a NOAEL or LOAEL.

For repeated inhalation exposure a NOAEC of 509 mg DBP/m3 (the highest concentration tested) for systemic effects including neurotoxic effects can be established based on a 28-day inhalation study in rats performed according to current standards. In this 28-day inhalation study in rats the

lowest exposure concentration of 1.18 mg/m3 is a LOAEC for local effects (histopathological changes in upper respiratory tract).

The epidemiological studies on neurological symptoms in occupationally exposed subjects showed several limitations including lack of an appropriate control group, small size of the exposed population, lack of adequate documentation of protocol and results and mixed exposure to other compounds than DBP. Therefore these studies are inadequate for the assessment of neurotoxic effects caused by DBP in man in the working environment. (1)

Most studies examining subchronic and chronic toxicity of DBP are performed in rodents and involve dosing via the oral route. There are no reliable studies that involve repeated dermal exposure to DBP. In an inhalation study (Gamer et al. 2000*) performed according to OECD Guidelines 412 and 407 (for clinical and neurofunctional examinations and pathology) with Wistar rats, no systemic effects (including neurotoxicity) were seen at up to and including the highest dose of 509 mg/m3. Dose-dependent changes were localised in the nasal cavity and were considered to be adaptive. The systemic NOAEC was established as 509 mg/m3. The LOAEC for local adaptive effects in upper respiratory tract was 1.18 mg/m3.

The major adverse effects of DBP in the repeated oral dosing studies are related to liver and testicular toxicity. Increased kidney weight is also reported in some studies for both sexes or only in females, but not consistently through all studies and generally without any related histopathological changes.

The lowest NOAEL of 19.9 mg/kg bw/d was identified in a subchronic, two-week dietary study in rats, based on the activation of enzymes associated with peroxisome proliferation (LAH-11 and LAH-12 (11- and 12- lauric acid hydroxylase, respectively) at 60.6 mg/kg bw/d. In this study PCoA activity was also increased at higher doses (Jansen et al. 1993*).

The mechanisms by which DBP and other peroxisome proliferators induce chronic hepatotoxicity in rodents are not considered relevant to humans(2)

(1)

European Union Risk Assessment Report dibutyl phthalate, Volume 29, pp. 15 -16 (2003)

Editors: B. G. Hansen, S.J. Munn, R. A/Ianou, F. Berthault, J. de Bruin, M. Luotamo, C. Musset, S. Pakalin, G. Pellegrini, S. Scheen S. Vegro.

Office for Official Publications of the European Communities, ISBN 92—894—1276—3

(2)

Priority Existing Chemical Assessment Report No. 36, Dibutyl phthalate, November 2013, ISBN 978-0-9874434-4-1, p.82

Australian Government, Department of Health

NATIONAL INDUSTRIAL CHEMICALS NOTIFICATION AND ASSESSMENT SCHEME

GPO Box 58, Sydney NSW 2001 AUSTRALIA www.nicnas.gov.au

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

Justification for classification or non-classification