International Agency for Research on Cancer (IARC) - Summaries & Evaluations

(Group 3)

For definition of Groups, see Preamble Evaluation.

Vol.: 77 (2000) (p. 149)

CAS No.: 103-23-1
Chem. Abstr. Name: Hexanedioic acid, bis(2-ethylhexyl) ester

5. Summary of Data Reported and Evaluation

5.1 Exposure data

Di(2-ethylhexyl) adipate is a liquid of low volatility, widely used as a plasticizer in flexible poly(vinyl chloride) products, notably food films, as well as in other plastics and in a number of other minor applications, such as lubricants and cosmetics. Occupational exposure may occur by inhalation of di(2-ethylhexyl) adipate as an aerosol during its manufacture and its use. Meat-wrapping workers may be exposed while cutting poly(vinyl chloride) film across a heated cutter. Food is the major source of exposure of the general population to di(2-ethylhexyl) adipate because of migration from poly(vinyl chloride) packaging, particularly into fatty foods such as cheese and meat.

5.2 Human carcinogenicity data

No data were available to the Working Group.

5.3 Animal carcinogenicity data

Di(2-ethylhexyl) adipate was tested for carcinogenicity by oral administration in one experiment in mice and one experiment in rats. In mice, liver adenomas and carcinomas were produced in both males and females. No treatment-related tumours were observed in rats.

5.4 Other relevant data

Di(2-ethylhexyl) adipate is rapidly and completely absorbed after oral administration, rapidly and extensively metabolized and rapidly excreted in humans and experimental animals. It is hydrolysed in the gastrointestinal tract before absorption.

No data on the toxic effects of di(2-ethylhexyl) adipate in humans were available to the Working Group.

In mice and rats, di(2-ethylhexyl) adipate induced hepatic markers of peroxisome proliferation (ultrastructural and biochemical) as well as hepatomegaly and increased replicative DNA synthesis. The species differences in carcinogenicity assays of di(2-ethylhexyl) adipate (increased hepatocellular tumours in mice, not rats) are consistent with a higher intake of di(2-ethylhexyl) adipate and a greater extent of peroxisome proliferation and associated responses in livers of mice compared with rats fed the same dietary doses.

In hepatocytes isolated from rats and mice, treatment of primary cultures with metabolites of di(2-ethylhexyl) adipate increased peroxisomal palmitoyl-coenzyme A oxidation activity. The same treatment of primary cultures of hepatocytes from guinea-pigs and marmosets failed to cause any similar increase in activity.

No data on reproductive and developmental effects in humans were available to the Working Group.

Exposure of rats to di(2-ethylhexyl) adipate during organogenesis caused an increased frequency of variations and retardations in the fetuses at doses below the maternally toxic range.

No effects on male or female fertility were found in rats given di(2-ethylhexyl) adipate in the feed. The body weight gain of the pups at the highest dose was reduced throughout the postnatal period. In mice, a single high intraperitoneal dose given to males before mating was associated with a reduced percentage of pregnancies and increased number of fetal deaths.

No data on the genetic and related effects of di(2-ethylhexyl) adipate in humans or human cells were available to the Working Group.

Di(2-ethylhexyl) adipate did not bind covalently to mouse liver DNA in vivo. One report showed evidence of oxidative damage in rat liver DNA in vivo but not in rat kidney DNA. A weak dominant lethal effect has been reported in male mice. Analyses of mouse bone marrow after treatment with di(2-ethylhexyl) adipate in vivo found no induction of micronuclei in one study and no induction of chromosomal aberrations in one study. Urine from rats treated with di(2-ethylhexyl) adipate by gavage was not mutagenic to Salmonella typhimurium.

Di(2-ethylhexyl) adipate did not induce gene mutations, sister chromatid exchanges, chromosomal aberrations or micronuclei in rodent cells in vitro. It did not induce sex-linked recessive lethal mutations in Drosophila when administered either by diet or injection. Di(2-ethylhexyl) adipate was not mutagenic to either Photobacterium phosphoreum or Salmonella typhimurium in the presence or absence of exogenous metabolic activation.

These data indicate that di(2-ethylhexyl) adipate is not genotoxic.

5.5 Evaluation

No epidemiological data relevant to the carcinogenicity of di(2-ethylhexyl) adipate were available.

There is limited evidence in experimental animals for the carcinogenicity of di(2-ethylhexyl) adipate.

Overall evaluation

Di(2-ethylhexyl) adipate is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Previous evaluations: Vol. 29 (1982); Suppl. 7 (1987) (p. 62)


Last updated: 21 August 2000

    See Also:
       Toxicological Abbreviations
       Di(2-Ethylhexyl) Adipate (IARC Summary & Evaluation, Volume 29, 1982)