Notice of Addition of Documents and Information to Rulemaking File, OAL FILE Z-01-1019-06, Amendment to 12805, MADL for DEHP by Intravenous Injection

Notice of Addition of Documents and Information to Rulemaking File, OAL FILE Z-01-1019-06 Amendment to Title 22, California Code of Regulations Section 12805, Specific Regulatory Levels: Chemicals Causing Reproductive Toxicity (Proposition 65 Maximum Allowable Dose Level (MADL) for Reproductive Toxicity for Di(2-ethylhexyl) phthalate (DEHP) by Intravenous Injection)

Pursuant to the requirements of Government Code sections 11346.8(d), 11346.9(a)(1), and 11347.1, the Office of Environmental Health Hazard Assessment (OEHHA) is providing notice that documents and other information which the agency has relied upon in proposing the amendment to Title 22, California Code of Regulations, Section 12805, have been added to the rulemaking file and are available for public inspection and comment.

The documents and information added to the rulemaking file are listed below. These documents are available for inspection at the OEHHA’s office located at 1001 “I” Street, 19th Floor, Sacramento, CA from August 17, 2005 through September 1, 2005, between the hours of 8:00 a.m. and 5:00 p.m. If you have any comments regarding the documents and other information, OEHHA will accept written comments between August 17, 2005 and September 1, 2005. All written comments must be submitted to OEHHA by mail, fax, courier or hand-delivered, no later than 5:00 p.m. on September 1, 2005, and addressed to:

Office of Environmental Health Hazard Assessment
Street Address: 1001 I Street, 19th Floor
Sacramento, CA 95814
Mailing Address: P.O. Box 4010
Sacramento, CA 95812

Fax No.: (916) 323-8803
Telephone: (916) 445-6900

Comments may also be transmitted via email addressed to: It is requested but not required that written statements or arguments be submitted in triplicate. All written comments received by September 1, 2005, which pertain to the above-listed documents and other information will be reviewed and responded to by OEHHA’s staff as part of the compilation of the rulemaking file. Inquiries concerning the action described in this notice may be directed in writing at the address given above, or by telephone at (916) 445-6900.


Documents and information added to the rulemaking file No. Z-01-1019-06:

Awal MA, Kurohmaru M, Ishii M, Andriana BB, Kanai Y, Hayashi Y (2004 ). Mono-(2-ethylhexyl) phthalate (MEHP) induces spermatogenic cell apoptosis in guinea pig testes at prepubertal stage in vitro. Int J Toxicol 23, 349-55.

Bhattacharya N, Dufour JM, Vo MN, Okita J, Okita R, Kim KH (2005). Differential effects of phthalates on the testis and the liver. Biol Reprod 72, 745-54.

Bility MT, Thompson JT, McKee RH, David RM, Butala JH, Vanden Heuvel JP, Peters JM (2004). Activation of mouse and human peroxisome proliferator-activated receptors (PPARs) by phthalate monoesters. Toxicol Sci 82, 170-82.

Boekelheide K (2004). Cracking the nut. Toxicol Sci 81, 1-2.

Borch J, Ladefoged O, Hass U, Vinggaard AM (2004). Steroidogenesis in fetal male rats is reduced by DEHP and DINP, but endocrine effects of DEHP are not modulated by DEHA in fetal, prepubertal and adult male rats. Reprod Toxicol 18, 53-61.

Borch J, Dalgaard M, Ladefoged O (2005). Early testicular effects in rats perinatally exposed to DEHP in combination with DEHA-apoptosis assessment and immunohistochemical studies. Reprod Toxicol 19, 517-25.

Cammack JN, White RD, Gordon D, Gass J, Hecker L, Conine D, Bruen US, Friedman M, Echols C, Yeh TY, Wilson DM (2003 ). Evaluation of reproductive development following intravenous and oral exposure to DEHP in male neonatal rats. Int J Toxicol 22, 159-74.

Center for The Evaluation of Risks to Human Reproduction (CERHR, 2000). NTP-CERHR Expert Panel Report on Di (2-ethylhexyl) Phthalate. National Toxicology Program, U.S. Department of Helath and Human Services, Research Triangle Park, NC, October.

Creasy DM (2001). Pathogenesis of male reproductive toxicity. Toxicol Pathol 29, 64-76.

Creasy DM (2003). Evaluation of testicular toxicology: a synopsis and discussion of the recommendations proposed by the Society of Toxicologic Pathology. Birth Defects Res Part B Dev Reprod Toxicol 68, 408-15.

Duty SM, Calafat AM, Silva MJ, Ryan L, Hauser R (2005). Phthalate exposure and reproductive hormones in adult men. Hum Reprod 20, 604-10.

Gromoll J, Eiholzer U, Nieschlag E, Simoni M (2000). Male hypogonadism caused by homozygous deletion of exon 10 of the luteinizing hormone (LH) receptor: differential action of human chorionic gonadotropin and LH. J Clin Endocrinol Metab 85, 2281-6.

Hauser R, Williams P, Altshul L, Calafat AM (2005). Evidence of interaction between polychlorinated biphenyls and phthalates in relation to human sperm motility. Environ Health Perspect 113, 425-30.

Ito Y, Yokota H, Wang R, Yamanoshita O, Ichihara G , Wang H, Kurata Y, Takagi K, Nakajima T (2005). Species differences in the metabolism of di(2-ethylhexyl) phthalate (DEHP) in several organs of mice, rats, and marmosets. Arch Toxicol 79, 147-54.

Jarfelt K, Dalgaard M, Hass U, Borch J, Jacobsen H , Ladefoged O (2005). Antiandrogenic effects in male rats perinatally exposed to a mixture of di(2-ethylhexyl) phthalate and di(2-ethylhexyl) adipate. Reprod Toxicol 19, 505-15.

Jonsson BA, Richthoff J, Rylander L, Giwercman A, Hagmar L (2005). Urinary phthalate metabolites and biomarkers of reproductive function in young men. Epidemiology 16, 487-93.

Kijima K, Toyosawa K, Yasuba M, Matsuoka N, Adachi T, Komiyama M, Mori C (2004). Gene expression analysis of the rat testis after treatment with di(2-ethylhexyl) phthalate using cDNA microarray and real-time RT-PCR. Toxicol Appl Pharmacol 200, 103-10.

Kim HS, Ishizuka M, Kazusaka A, Fujita S (2004). Alterations of activities of cytosolic phospholipase a(2) and arachidonic Acid-metabolizing enzymes in di-(2-ethylhexyl)phthalate-induced testicular atrophy. J Vet Med Sci 66, 1119-24.

Koch HM, Bolt HM, Preuss R, Angerer J (2005). New metabolites of di(2-ethylhexyl)phthalate (DEHP) in human urine and serum after single oral doses of deuterium-labelled DEHP. Arch Toxicol (Available online on February. 8, 2005).

Kurata Y, Kidachi F, Yokoyama M, Toyota N, Tsuchitani M, Katoh M (1998). Subchronic toxicity of Di(2-ethylhexyl)phthalate in common marmosets: lack of hepatic peroxisome proliferation, testicular atrophy, or pancreatic acinar cell hyperplasia. Toxicol Sci 42, 49-56.

Kurata, Y., Makinodan, F., Shimamura, N., Okada, M., and Katoh, M. (2005). Metabolism of di(2-ethylhexyl) phthalate (DEHP) in juvenile and fetal marmoset and rat. Toxicologist 84 (S-1), 256.

Lewandowski M, Fernandes J, Chen TS (1980). Assessment of the teratogenic potential of plasma-soluble extracts of diethylhexyl phthalate plasticized polyvinyl chloride plastics in rats. Toxicol Appl Pharmacol 54, 141-7.

Lee J, Park J, Jang B, Knudsen TB (2004). Altered expression of genes related to zinc homeostasis in early mouse embryos exposed to di-2-ethylhexyl phthalate. Toxicol Lett 152, 1-10.

Li LH, Jester WF Jr, Laslett AL, Orth JM (2000). A single dose of Di-(2-ethylhexyl) phthalate in neonatal rats alters gonocytes, reduces sertoli cell proliferation, and decreases cyclin D2 expression. Toxicol Appl Pharmacol 166, 222-9.

Liu K, Lehmann KP, Sar M, Young SS, Gaido KW (2005). Gene expression profiling following in utero exposure to phthalate esters reveals new gene targets in the etiology of testicular dysgenesis. Biol Reprod 73, 180-92.

Mitsubishi Chemical Safety Institute Ltd. (MCSI, 2003). Final report: sixty-five-week repeated oral dose toxicity study of Di(2-ethylhexyl) phthalate (DEHP) in juvenile common marmosets (Study No. B000496). Submitted to the Office of Environmental Health Hazard Assessment by the American Chemistry Council, June 02, 2003.

Muller T, Simoni M, Pekel E, Luetjens CM, Chandolia R, Amato F, Norman RJ, Gromoll J (2004). Chorionic gonadotrophin beta subunit mRNA but not luteinising hormone beta subunit mRNA is expressed in the pituitary of the common marmoset (Callithrix jacchus). J Mol Endocrinol 32, 115-28.

National Institute for Occupational Safety and Health (NIOSH, 1990). NIOH and NIOSH basis for an Occupational Health Standard: Di (2-ethylhexyl) phthalate (DEHP). U.S. Department of Health and Human Services. Public Health Service. Centers for Disease Control. NIOSH.

Office of Environmental Health Hazard Assessment (OEHHA, 1997). Public Health Goal for Di(2-Ethylhexyl)Phthalate (DEHP) in Drinking Water. OEHHA, California Environmental Protection Agency, Sacramento, California. Available on-line at

Petersen SV, Lyman DJ, Roll DB, Swinyard EA (1975). Toxicology of plastic devices having contact with blood. NTIS Report (PB-250 102).

Rhodes C, Orton TC, Pratt IS, Batten PL, Bratt H, Jackson SJ, Elcombe CR (1986). Comparative pharmacokinetics and subacute toxicity of di(2-ethylhexyl) phthalate (DEHP) in rats and marmosets: extrapolation of effects in rodents to man. Environ Health Perspect 65, 299-307.

Sjoberg P, Bondesson U, Gray TJ, Ploen L (1986). Effects of di-(2-ethylhexyl) phthalate and five of its metabolites on rat testis in vivo and in in vitro. Acta Pharmacol Toxicol (Copenh) 58, 225-33.

Sjoberg P, Bondesson U, Kjellen L, Lindquist NG, Montin G, Ploen L (1985a). Kinetics of di-(2-ethylhexyl) phthalate in immature and mature rats and effect on testis. Acta Pharmacol Toxicol (Copenh) 56, 30-7.

Sjoberg P, Lindquist NG, Montin G, Ploen L (1985b). Effects of repeated intravenous infusions of the plasticizer di-(2-ethylhexyl) phthalate in young male rats. Arch Toxicol 58, 78-83.

Swan SH, Main KM, Liu F, Stewart SL, Kruse RL, Calafat AM, Mao CS, Redmon JB, Ternand CL, Sullivan S, Teague JL, Drobnis EZ, Carter BS, Kelly D, Simmons TM, Wang C, Lumbreras L, Villanueva S, Diaz-Romero M, Lomeli MB, Otero-Salazar E, Hobel C, Brock B, Kwong C, Muehlen A, Sparks A, Wolk A, Whitham J, Hatterman-Zogg M, Maifield M , and The Study for Future Families Research Group (2005). Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect (Available at online May 27, 2005).

Takeuchi S, Iida M, Kobayashi S, Jin K, Matsuda T, Kojima H (2005). Differential effects of phthalate esters on transcriptional activities via human estrogen receptors alpha and beta, and androgen receptor. Toxicology 210, 223-33.

Tanaka T (2005). Reproductive and neurobehavioural effects of bis(2-ethylhexyl) phthalate (DEHP) in a cross-mating toxicity study of mice. Food Chem Toxicol 43, 581-9.

Toda C, Okamoto Y, Ueda K, Hashizume K, Itoh K, Kojima N (2004). Unequivocal estrogen receptor-binding affinity of phthalate esters featured with ring hydroxylation and proper alkyl chain size. Arch Biochem Biophys 431, 16-21.

U.S. Environmental Protection Agency (U.S. EPA, 1996). Guidelines for reproductive toxicity risk assessment. EPA/630/R-96/009 FRL-5630-6.

U.S. Food and Drug Administration (U.S. FDA, 2001). Safety Assessment of Di (2-ethylhexyl)phthalate (DEHP) Released from PVC Medical Devices. Centers for Devices and Radiological Health. U.S. Food and Drug Administration. Rockville, MD.

Voss C, Zerban H, Bannasch P, Berger MR (2005). Lifelong exposure to di-(2-ethylhexyl)-phthalate induces tumors in liver and testes of Sprague-Dawley rats. Toxicology 206, 359-71.

Zhang FP, Kero J, Huhtaniemi I (1998). The unique exon 10 of the human luteinizing hormone receptor is necessary for expression of the receptor protein at the plasma membrane in the human luteinizing hormone receptor, but deleterious when inserted into the human follicle-stimulating hormone receptor. Mol Cell Endocrinol 142, 165-74.

Zuhlke U, Weinbauer G (2003). The common marmoset (Callithrix jacchus) as a model in toxicology. Toxicol Pathol 31 Suppl, 123-127.