US EPA

667234 

Book/Book Chapter 

The biochemical toxicology of di-2-ethylhexyl and related phthalates testicular atrophy and hepatocarcinogenesis 

Albro, PW 

1987 

Elsevier 

New York, NY 

Reviews in biochemical toxicology 8 

73-119 

English 

The toxicity of di-(2-ethylhexyl)phthalate (117817) (DEHP) was reviewed. DEHP is said to be ubiquitous, and a daily uptake of up to 15 milligrams/day was estimated for adults. DEHP was rapidly metabolized by all animal species. Some 20 metabolites of DEHP and seven metabolites of 2-ethylhexanol (104767) (EH) were identified in rat urine. Metabolites were formed by hydrolases, lipases, and cytochrome-P-450 dependent monooxygenase systems in liver, lung, and kidney microsomes. Metabolites with keto groups in side chains were produced by alcohol-dehydrogenases. Hydrolysis to mono-2-ethylhexylphthalate (4376209) (MEHP) and EH was quite rapid in intestines. Highly purified pancreatic lipase could not hydrolyze DEHP. Every species tested excreted DEHP metabolites in the form of glucuronide conjugates with the exception of rats. The profiles of metabolites produced from DEHP were the same as those produced from MEHP, although there were significant interspecies differences. Rats and mice generated large amounts of carboxyl side chain metabolites, while guinea-pigs were least capable of producing oxidized metabolites. Testicular atrophy resulted from administration of dibutylphthalates, di-n-pentylphthalate (131180) (DPP), dihexylphthalates, or DEHP. DPP was found to be the most potent testicular toxin. Atrophic lesions were most severe in 4 week old male rats, indicating that phthalic-acid esters (PAE) interfered with development of testicular tissue. The role of zinc in development of testicular lesions was controversial. It appeared that testicular atrophy might result from some unidentified metabolite of PAE that reached the organ of immature animals in sufficient concentration. Hepatocarcinoma developed in rats and mice fed DEHP in diet at doses up to 1.2 percent over a 2 year period. The relevancy of this finding to primates remains unclear until a long term assay is performed or the specific causal agents are identified and the mechanism of action clarified. The author concludes that under certain conditions exposure to some PAE will result in testicular atrophy and/or hepatocarcinogenesis in several rodent species. 

DCN-158105; Phthalates; Plasticizers; Toxic effects; Metabolic study; In vivo studies; In vitro studies; Laboratory animals; Testes; Carcinogenicity; Hepatotoxicity; Environmental hazards; Tissue distribution; 117-81-7; 104-76-7; 4376-20-9; 131-18-0 

Hodgson, E; Bend, JR; Philpot, RM 

9780444011695