Notice of Intent to Change the Basis for Listing as Known to the State of California to Cause Reproductive Toxicity: Dichloroacetic Acid

The California Environmental Protection Agency’s Office of Environmental Health Hazard Assessment (OEHHA) intends to change the basis for the listing of dichloroacetic acid as known to the state to cause reproductive toxicity under the Safe Drinking Water and Toxic Enforcement Act of 1986¹.

Dichloroacetic acid was originally added to the Proposition 65 list as causing reproductive toxicity on August 7, 2009, pursuant to Labor Code Section 6382(d), which is incorporated by reference in Health and Safety Code Section 25249.8(a). Dichloroacetic acid was listed based on its identification as causing male reproductive toxicity in the American Conference of Governmental Industrial Hygienists (ACGIH) Threshold Limit Values (TLVs). The TLVs were previously incorporated by reference into the federal Occupational Health and Safety Administration (OSHA) Hazard Communication Standards (Title 29, Code of Federal Regulations, section 1900.1200²).

OEHHA is initiating this action based on changes to certain federal regulations that affect the basis for the original listing. In March 2012, OSHA extensively amended the regulations contained in Title 29, C.F.R., section 1910.1200. Section 1910.1200 (d)(3)(ii), which specifically referred to the ACGIH TLV list, was deleted in the 2012 version of the regulation. OEHHA has determined that these changes have eliminated the ACGIH TLVs as a definitive source for identifying chemicals that are known to cause reproductive toxicity.

However, OEHHA has determined that dichloroacetic acid meets the criteria for listing via the “authoritative bodies” listing mechanism³ and is providing this notice of its intent to change the basis for listing the chemical based on identification of male reproductive and developmental endpoints. Dichloroacetic acid will not be removed from the Proposition 65 list during this process.

Background on listing via the authoritative bodies mechanism: A chemical must be listed under Proposition 65 and its implementing regulations (Section 25306) when two conditions are met:

• An authoritative body formally identifies the chemical as causing reproductive toxicity (Section 25306(d)(1)).
• The evidence considered by the authoritative body meets the sufficiency criteria contained in the regulations (Section 25306(g)).

However, the chemical is not listed if scientifically valid data that were not considered by the authoritative body clearly establish that the sufficiency of evidence criteria were not met (Section 25306(h)).

The U.S. Environmental Protection Agency (U.S. EPA) is one of several institutions designated as authoritative for the identification of chemicals as causing reproductive toxicity (Section 25306(l)).

OEHHA is the lead agency for implementation of Proposition 65⁴. After an authoritative body has made a determination that a chemical causes cancer or reproductive toxicity, OEHHA evaluates whether listing under Proposition 65 is required using the criteria contained in the regulations.

OEHHA’s determination: Dichloroacetic acid (DCA) meets the criteria for listing as known to the State to cause reproductive toxicity under Proposition 65, based on findings by U.S. EPA (2003a,b), as outlined below.

Formal identification and sufficiency of evidence: OEHHA is relying on U.S. EPA’s conclusion that DCA causes developmental and male reproductive effects. U.S. EPA published a Toxicological Review of Dichloroacetic Acid that provides a comprehensive review and summary of the available toxicological data on DCA (U.S. EPA, 2003a). In this Toxicological Review, under “Major Conclusions in the Characterization of Hazard and Dose Response”, U.S. EPA concludes that DCA causes male reproductive and developmental toxicity:

“Reproductive/Developmental Toxicity.
In males, DCA causes decreases in testicular weight and viable sperm production. Testicular effects were observed in rats and dogs. Dogs are apparently the most sensitive species, displaying testicular toxicity at a dose substantially lower than for other test species. In female rats, DCA exposure during gestation can lead to impaired fetal maturation and result in soft tissue anomalies (primarily of cardiac origin) in the offspring.” (pages 96-97, U.S. EPA, 2003a)

This conclusion meets the formal identification requirement criteria of Section 25306(d)(1)⁵.

EPA (2003a) also highlights the consistency of the numerous animal studies in demonstrating the reproductive and developmental toxicity of DCA:

• “There is an extensive and consistent data base demonstrating the reproductive toxicity of DCA in males and females (Katz et al., 1981; Yount et al., 1982; Bhat et al., 1991; Cicmanec et al., 1991; Toth et al., 1992; De Angelo et al., 1996; Linder et al., 1997; Smith et al., 1992; Epstein et al., 1992).” (page 61, U.S. EPA, 2003a)
• “In female rats, DCA exposure during gestation resulted in the impairment of fetal maturation and soft tissue anomalies (primarily of cardiac origin) indicating that the developing fetus is susceptible to DCA-induced toxicity (Smith et al., 1992).” (page 73, U.S. EPA, 2003a)

The Toxicological Review (U.S. EPA, 2003a) supported U.S. EPA’s online Integrated Risk Information System (IRIS) entry for DCA, which includes an oral reference dose (RfD) of 0.004 mg/kg-day (U.S. EPA, 2003b). The RfD was based on “lesions observed in the testes, cerebrum, cerebellum, and liver” in dogs (U.S. EPA, 2003b). U.S. EPA (2003b) summarizes the relevant results of the study that provided the lowest observed adverse effect level (LOAEL) on which the RfD was based, as well as other relevant studies, as follows:

• “Microscopic testicular lesions, which included syncytial giant cell formation and degeneration of testicular germinal epithelium, were also noted in treated males at all doses. Lesion severity increased with dose. The testicular changes were apparent in 4/5 males at the low dose and in all animals in the mid- and high-dose groups; these lesions were also considered to be primary. A LOAEL of 12.5 mg/kg-day can be identified based on visual organ effects (neurological changes, hepatic vacuolization, and testicular effects) and increases in liver weight.”

“Although DCA-induced testicular toxicity has not been investigated in the human, it has been reported in rodent models. Bhat et al. (1991) reported significantly (p<0.01) decreased testes weight and signs of tissue atrophy with no mature spermatozoa and few spermatocytes in seminiferous tubules of male Sprague-Dawley rats exposed to 1,100 mg/kg-day DCA (in drinking water) for 90 days. Katz et al. (1981) administered doses of 0, 125, 500, or 2000 mg/kg-day DCA via gavage to adult rats (10-15/sex/dose) daily for 3 months. All males at 2,000 mg/kg-day and 40% of males at 500 mg/kg-day exhibited testicular germinal epithelial degeneration. Further, all males at 2,000 mg/kg-day had aspermatogenic testes with syncytial giant cells in the germinal epithelium and epididymis ducts that were devoid of spermatozoa. Twenty percent of the 500 mg/kg-day males also had syncytial giant cells. No other effects were noted at 500 or 125 mg/kg-day; no reproductive tissue effects were noted in females at any dose. Some evidence of regeneration of germinal epithelium with spermatogenesis was noted in some high-dose males maintained for 5 weeks on a normal control diet postexposure. Based on these results, a NOAEL of 125 mg/kg-day was identified (U.S. EPA, 2003b). The Toxicological Review (U.S. EPA, 2003a) and IRIS entry (U.S. EPA, 2003b) meet the formal identification criterion in Section 26306(d)(2)(C)⁶.

OEHHA has reviewed the studies or study descriptions cited by U.S. EPA (2003a,b) in support of its conclusions regarding the male reproductive and developmental toxicity of DCA, relative to the criteria in Section 25306(g). The criteria for listing DCA as known to cause reproductive toxicity (male reproductive and developmental endpoints) by the authoritative bodies mechanism have been met. Therefore, OEHHA has determined that DCA must stay on the Proposition 65 list.

Request for comments: OEHHA is requesting comments as to whether this chemical meets the criteria set forth in the Proposition65 regulations for listings via the authoritative bodies listing mechanism (Section 25306) and should, therefore, remain on the list of chemicals known to the State to cause reproductive toxicity, with the additional endpoint of developmental toxicity.

In order to be considered, comments must be received by OEHHA by 5:00 p.m. on MONDAY, October 21, 2013. We encourage you to submit comments in electronic form, rather than in paper form. Comments transmitted by e-mail should be addressed to P65Public.comments@oehha.ca.gov. Please include “Dichloroacetic acid” in the subject line. Comments submitted in paper form may be mailed, faxed, or delivered in person to the address below:

Mailing Address:
Office of Environmental Health Hazard Assessment
P.O. Box 4010, MS-19B
Sacramento, California 95812-4010
Fax: (916) 323-2265
Street Address: 1001 I Street
Sacramento, California 95814

Comment Period

• Comment Period - Notice of Intent to Change the Basis for Listing as Known to the State of California to Cause Reproductive Toxicity: Dichloroacetic Acid

Link to Public Comments

Chemical Reference

• Dichloroacetic Acid
• Nitrous Oxide

Related Notices

• Chemicals Listed Effective August 7, 2009 as Known to the State of California to Cause Cancer or Reproductive Toxicity

  Aug 7, 2009
• Notice of Change in the Basis for Listing as Known to the State of California to Cause Reproductive Toxicity: Nitrous Oxide and Dichloroacetic Acid

  Nov 8, 2013

Footnotes and References

U.S. Environmental Protection Agency (EPA), 2003a. Toxicological Review of Dichloroacetic Acid (CAS No. 79-43-6) In Support of Summary Information on the Integrated Risk Information System (IRIS). August 2003. EPA 635/R-03/007. U.S. EPA, Washington, D.C.
U.S. Environmental Protection Agency (EPA), 2003b. Integrated Risk Information System (IRIS): Dichloroacetic Acid.

¹ Commonly known as Proposition65, the Safe Drinking Water and Toxic Enforcement Act of 1986 is codified in Health and Safety Code section 25249.5 et seq.

² The Code of Federal Regulations will hereafter be cited as C.F.R.

³ See Health and Safety Code section25249.8(b) and Title 27, California Code of Regulations, section 25306. All further references are to sections of Title 27 of the California Code of Regulations, unless indicated otherwise.

⁴ Health and Safety Code section 25249.12 and Title 27, Cal. Code of Regs., section 25102(o).

⁵ “the chemical…is the subject of a report which is published by the authoritative body and which concludes that the chemical causes...reproductive toxicity”

⁶ “[the document is] Published by the authoritative body in a publication such as, but not limited to, the federal register…”