Diethylhexyl phthalate

5. What health effects can DEHP cause in laboratory animals?

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4.1.2 Effects assessment

Toxicokinetics, metabolism and distribution

DEHP is readily absorbed and distributed in the body, but there is no evidence of accumulation. The metabolism of DEHP involves several pathways and yields a variety of metabolites. The major step in the metabolism of DEHP is hydrolysis by lipases to MEHP (mono(2-ethylhexyl)phthalate) and 2-ethylhexanol. The substance is excreted via the urine, mainly as MEHP-metabolites, but some excretion via bile also occurs in rodents. Additionally, there are animal and human data showing that DEHP is transferred to mothers’ milk. The relative extent to which different metabolites are produced and excreted is very complex and may depend upon the species, the age of the animal, sex, inter-individual differences, nutrition state, prior exposure to DEHP, the amount of DEHP administered, and the route of administration.

Acute toxicity

Acute toxicity studies indicate a low acute toxicity of DEHP. The oral LD50 is > 20,000 mg/kg bw in rats and >10,000 mg/kg bw in mice. An inhalation LC50 of about 10,600 mg/m³ for 4 hours in rats has been reported. Although there are no adequate acute dermal toxicity data, a low acute dermal toxicity is assumed.

Irritation, corrosion and sensitisation

Animal studies performed to current guidelines have shown a slight skin and eye irritation after administration of DEHP, but DEHP is not corrosive to the skin or eyes. DEHP has not been found to induce skin sensitisation in animals.

Repeated dose toxicity

Numerous studies have investigated the toxicity of DEHP following repeated oral administration to experimental animals. Critical organs for DEHP-induced toxicity in laboratory animals are the testis (see below) and the kidney. The effects on the kidneys include increased: absolute and relative kidney weights, incidence and severity of mineralization of the renal papilla, incidence of tubule cell pigments, and incidence and/or severity of chronic progressive nephropathy. The lowest NOAEL for kidney toxicity is 29 mg/kg/day in the males and 36 mg/kg/day in females, derived from a chronic 2-year study in rats. In the liver, hepatomegaly due to hepatocyte proliferation, peroxisome proliferation and hepatocellular tumours are observed in experimental animals, but the hepatic effects are not believed to be relevant for humans.

Mutagenicity

Concerning the genotoxicity of DEHP, several different short-term tests, comparable to guideline studies and performed according to GLP, are available. The results are negative in the majority of the in vitro and in vivo studies performed with DEHP and its metabolites for detection of gene mutation, DNA damage, and chromosomal effects. The positive results are obtained in the test systems for detection of cell transformation, induction of aneuploidy, and cell proliferation, end-points which are also sensitive to several non-mutagenic substances such as tumour promoters and/or peroxisome proliferators. Taking all data into account, DEHP and its major metabolites can be considered as non-mutagenic.

Carcinogenicity

In rodent studies, liver tumours, Leydig cell tumours, and leukaemia have been observed. The liver tumours are most likely caused by peroxisome proliferation, and are therefore not considered relevant for humans. As to the other two tumours types, a relevance to humans can not be ruled out, although the evidence is inconclusive for this endpoint.

Toxicity for reproduction

A conservative NOAEL value of 4.8 mg/kg/day has been set for testicular toxicity, based on a three-generation reproductive toxicity study, showing a low incidence of small male reproductive organs and minimal testis atrophy at 14 mg/kg/day and complete atrophy and aspermia at doses of 359 mg/kg/day. Developing and prepubertal rats have been found to be more sensitive to the DEHP-induced testicular toxicity than adults, and the NOAEL for testicular toxicity is therefore also used for developmental toxicity (4.8 mg/kg/day). Studies indicate that DEHP may also interfere with the male endocrine function and also influence the male sexual development. Testicular toxicity and developmental toxicity, observed in different animal species and at relatively low dose levels are considered relevant to humans. Effects on fertility has been observed at slightly higher exposure levels in mice and rats, with a NOAEL of 20 mg/kg/day observed in mice.

Source & ©: ECB,
 "Bis-(2-Ethylhexyl) Phthalate, DEHP), Summary Risk Assessment report" , 2008. p.14-15.

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