Notice of Intent to List a Chemical by the "Formally Required to be Labeled or Identified" Mechanism: Clomiphene Citrate

The California Environmental Protection Agency’s Office of Environmental Health Hazard Assessment (OEHHA) intends to list the chemical identified in the table below as known to the State to cause cancer under the Safe Drinking Water and Toxic Enforcement Act of 1986.1 This action is being proposed under the “formally required to be labeled or identified” listing mechanism.2

Chemical

CAS No.

Endpoint

Reference

Clomiphene citrate

911-45-5

Cancer

FDA (2012)

Background on listing via the formally required to be labeled or identified mechanism: A chemical must be listed under the Proposition 65 regulations (Section 259023) when a state or federal agency has formally required it to be labeled or identified as causing cancer or reproductive toxicity.
According to Section 25902(b):

  • “‘Formally required’ means that a mandatory instruction, order, condition, or similar command, has been issued in accordance with established policies and procedures of an agency of the state or federal government to a person or legal entity outside of the agency. The action of such agency may be directed at one or more persons or legal entities and may include formal requirements of general application;”
  • “‘Labeled’ means that a warning message about the carcinogenicity or reproductive toxicity of a chemical is printed, stamped, written, or in any other manner placed upon the container in which the chemical is present or its outer or inner packaging including any material inserted with, attached to, or otherwise accompanying such a chemical;”
  • “‘Identified’ means that a required message about the carcinogenicity or reproductive toxicity of the chemical is to be disclosed in any manner to a person or legal entity other than the person or legal entity who is required to make such disclosure”; and
  • “As causing cancer” means that “the required label or identification uses any words or phrases intended to communicate a risk of cancer or tumors.”

OEHHA is the lead agency for Proposition 65 implementation. After a state or federal agency has required that a chemical be labeled or identified as causing cancer or reproductive toxicity, OEHHA evaluates whether listing under Proposition 65 is required pursuant to the definitions set out in Section 25902.

OEHHA’s determination: Clomiphene citrate has been identified or labeled to communicate a risk of cancer in accordance with formal requirements by the U.S. Food and Drug Administration (FDA).

Language from the FDA-approved product label which meets the requirements of Section 25902 is quoted below:

Clomiphene citrate

Cancer Endpoint (Under PRECAUTIONS and Adverse Reactions)
Under PRECAUTIONS: “Prolonged use of clomiphene citrate tablets USP may increase the risk of borderline or invasive ovarian tumor (see ADVERSE REACTIONS).”
Under ADVERSE REACTIONS: “Ovarian cancer has been infrequently reported in patients who have received fertility drugs. Infertility is a primary risk factor for ovarian cancer; however, epidemiology data suggest that prolonged use of clomiphene may increase the risk of a borderline or invasive ovarian tumor.”

Request for comments: OEHHA is requesting comments as to whether this chemical meets the criteria set forth in the Proposition 65 regulations for listings via the formally required to be labeled or identified mechanism (Section 25902). Because these are ministerial listings, comments should be limited to whether FDA requires that clomiphene citrate be labeled to communicate a risk of cancer or tumors. OEHHA cannot consider scientific arguments concerning the weight or quality of the evidence considered by FDA when it established the labeling requirement and will not respond to such comments if they are submitted. In order to be considered, OEHHA must receive comments by 5:00 p.m. on MONDAY, May 6, 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 with “NOIL-Clomiphene citrate” in the subject line. Comments submitted in paper form may be mailed, faxed, or delivered in person to the address below:

Mailing Address: Proposition 65
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

Comments received during the public comment period will be posted on the OEHHA web site after the close of the comment period.

Public Comments

Comment period closed on May 6, 2013.  No comments received.

Footnotes and References

Food and Drug Administration (FDA, 2012). FDA approved labeling for the drug clomiphene citrate. Approved by FDA in October 2012 and found at http://www.accessdata.fda.gov/

1 Commonly known as Proposition 65, the Safe Drinking Water and Toxic Enforcement Act of 1986 is codified in Health and Safety Code section 25249.5 et seq.

2 See Health and Safety Code section 25249.8(b) and Title 27, Cal. Code of Regs., section 25902.

3 All referenced sections are from Title 27 of the Cal. Code of Regulations.