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Effects assessment
The human population may be exposed by the oral, dermal and inhalation route.
Toxicokinetics, metabolism and distribution
Dibutylphthalate is rapidly absorbed and excreted after oral administration as was demonstrated in studies in laboratory animals. Up to more than 90% of oral doses given to rats or hamsters was excreted in urine within 24-48 hours. Fecal excretion is low (1.0-8.2%).
Also in man oral absorption of DBP takes place.
After dermal exposure of rats to DBP ca. 60% of the dose was excreted in urine within 7 days. In feces ca. 12% of the dose was found. An in vitro study revealed slower absorption of DBP by the human skin (2.40 µg/cm2/hr) than by the rat skin (93.35 µg/cm2/hr).
Data on absorption after exposure by inhalation are not available.
A substantial fraction of DBP is initially excreted in the bile and subsequently enters the enterohepatic circulation.
No significant accumulation in tissues was observed in laboratory animals after oral as well as dermal exposure; limited inhalation data revealed an indication for some accumulation in tissues. The major part of DBP is hydrolysed to mono-n-butyl phthalate (MBP) and the corresponding alcohol prior to absorption by the small intestines, but hydrolysis can also occur in liver and kidneys. The metabolites that occur in urine are MBP, MBP-glucuronide, various ω- and ω-1- oxidation products of MBP (more polar ketones, carboxylates) and a small amount of free phthalic acid. Species differences in the excretion of MBP and its glucuronide were observed; rats excreted a larger proportion unconjugated MBP in urine than hamsters.
There are no data on biotransformation after dermal exposure and exposure by inhalation. Transplacental transfer of DBP and its metabolites was demonstrated in an oral study with 14C-labelled DBP in rats. Radioactivity in embryonic tissues contained less than 0.12-0.15% of the administered dose. MBP accounted for most of the radioactivity in maternal plasma, placenta and embryo. Unchanged DBP was found in only small amounts. No accumulation of radioactivity was seen in maternal or embryonic tissues.
Acute toxicity
None of the acute toxicity studies have been performed according to current standards. Based on the available data DBP is slightly toxic if swallowed (LD50 rat is ≥6,300 mg/kg bw), slightly to moderately toxic by inhalation (LC50 rat ≥15.68 mg/L) and slightly toxic in contact with the skin (LD50 dermal rabbit >20,000 mg/kg bw).
Irritation
With respect to skin and eye-irritation, studies performed according to current standards were available. DBP appeared to be not irritating for the skin and the eye.
In a 28-day inhalation study in rats adverse local effects in the upper respiratory tract were observed but no signs of inflammation. Hence, DBP is not irritating to the respiratory system.
Concerning sensitisation one study in animals performed according to current standards and a study performed under GLP conditions were available. DBP did not reveal skin sensitising properties in these animal studies.
The available case studies in man are not appropriate for a definite conclusion with respect to the possible induction of sensitization by DBP.
Repeated dose toxicity
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 dose- level 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.
Mutagenicity
With respect to mutagenicity in vitro studies gave an indication for a genotoxic effect in one assay, but in the same experiment, this effect was not seen with other dialkylphthalates (a.o. diethylphthalate). No genotoxic effects for dibutylphthalate were observed in in vivo studies detecting chromosomal aberrations.
Based on the data available for dibutylphthalate from a variety of genotoxicity studies as described above and taking into consideration the non-genotoxic properties of other phthalate esters, dibutylphthalate can be considered as a non-genotoxic substance.
Carcinogenicity
No adequate long-term toxicity and/or carcinogenicity studies in animals or man are available. Phthalate esters are known to induce peroxisomal proliferation in the liver of mice and rats. In general the longer chain dialkylphthalates are more potent for the induction of peroxisomal proliferation than the shorter chain ones and branched chain phthalates seemed more potent than straight. Many peroxisome proliferators have been shown to induce hepatocellular tumours when administered at high dose-levels for long periods to mice and rats despite being non-genotoxic. The mechanisms of induction of carcinogenicity by peroxisome proliferators may be complex but are considered to have a threshold. A variety of independent studies have shown that there are marked species differences in the sensitivity to chemicals that cause peroxisome proliferation. Rats and mice are extremely sensitive, hamsters show a less marked response whilst guinea-pigs, primates and man are rather insensitive or non-responsive.
Toxicity for reproduction
Based on the available developmental studies in mice an oral NOAEL of 100 mg/kg bw, can be derived for teratogenicity, embryotoxicity and maternal toxicity. At the next higher dose-level of 400 mg/kg bw embryotoxic and teratogenic effects were seen in the presence of maternal toxicity.
In rats, developmental studies with exposure during gestation or during gestation and lactation, revealed preputial separation and reproductive tract malformations in male offspring at oral doses ≥250 mg/kg bw. At the lowest oral dose of 100 mg/kg bw, studied in developmental studies in rats, still delayed preputial separation in male progeny was seen. Maternal toxicity was seen at oral doses ≥500 mg/kg bw. From the developmental studies in rats a NOAEL of 50 mg/kg bw/d could be derived.
Concerning reproduction, fertility as well as developmental studies a NOAEL of 50 mg/kg bw can be established based on embryotoxicity in a one-generation reproduction study in rats with exposure of females only. However, a LOAEL of 52 mg/kg bw can be established based on embryotoxic effects in rats in the absence of maternal toxicity in a two-generation reproduction study with a continuous breeding protocol including improved sensitive endpoints (such as sperm parameters, estrous cycle characterisation and detailed testicular histopathology) and with exposure of both male and female animals. The protocol of this study was supposed to adequately identify compounds with endocrine activity.
In some special in vitro assays DBP showed weak estrogenic activity. However, the estrogenic effects were not confirmed in in vivo studies. Therefore the relevance of the estrogenic effects observed in vitro for the in vivo estrogenic activity of DBP is questionable. Moreover results of recent developmental studies are indicative of an antiandrogenic effect rather than an estrogenic effect of DBP.
No reproduction, fertility or developmental studies with dermal exposure or exposure by inhalation to DBP are available.
The epidemiological study on possibly reproductive effects in occupationally exposed women is inadequate for assessment of possible reproductive effects caused by DBP in man in the working environment.
Based on all available studies an overall oral LOAEL of 52 mg/kg bw can be established for dibutylphthalate. This figure is derived from a two-generation reproduction study in rats with a continuous breeding protocol and based on embryotoxic effects.
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