Notice of Intent to List: Megestrol Acetate

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

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 1986¹. This action is being proposed under the “Formally Required to Be Labeled or Identified” listing mechanism².

Background on listing via the formally required to be labeled or Identified mechanism: A chemical must be listed under Proposition 65³ and its implementing regulations (Section 25902⁴) 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):

• “‘[F]ormally 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;”
• “‘[L]abeled’ 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;”
• “‘[I]dentified’ 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: “For chemicals that cause cancer, 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: Megestrol acetate has been identified or labeled to communicate a risk of cancer (FDA, 2012, 2013) in accordance with formal requirements by the U.S. Food and Drug Administration (FDA). The FDA-approved labels indicate that when assessing the risk-to-benefit ratio of megestrol acetate, consideration be given to the observations of breast and pituitary cancers from studies in dogs and rats receiving much lower doses of megestrol acetate (on a mg/kg/day basis) than the recommended clinical dose.

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

Megestrol acetate
Cancer Endpoint

• FDA-approved label Reference ID 3111413 (FDA, 2012)

Under WARNINGS: “(See PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility.)” [emphasis in original]

Under PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility: “Data on carcinogenesis were obtained from studies conducted in dogs, monkeys and rats treated with megestrol acetate at doses 53.2, 26.6, and 1.3 times lower than the proposed dose (13.3 mg/kg/day) for humans. No males were used in the dog and monkey studies. In female beagles, megestrol acetate (0.01, 0.1 or 0.25 mg/kg/day) administered for up to 7 years induced both benign and malignant tumors of the breast. In female monkeys, no tumors were found following 10 years of treatment with 0.01, 0.1 or 0.5 mg/kg/day megestrol acetate. Pituitary tumors were observed in female rats treated with 3.9 or 10 mg/kg/day of megestrol acetate for 2 years. The relationship of these tumors in rats and dogs to humans is unknown but should be considered in assessing the risk-to-benefit ratio when prescribing MEGACE Oral Suspension and in surveillance of patients on therapy. (See WARNINGS.)” [emphasis in original]

• FDA-approved label Reference ID 3308551 (FDA, 2013)

Under Carcinogenesis, Mutagenesis, Impairment of Fertility: “Data on carcinogenesis were obtained from studies conducted in dogs, monkeys and rats treated with megestrol acetate at doses up to 0.01 to 0.1-fold the recommended clinical dose (13.3 mg/kg/day) based on body mass. No males were used in the dog and monkey studies. In female beagles, megestrol acetate (0.01, 0.1 or 0.25 mg/kg/day) administered for up to 7 years induced both benign and malignant tumors of the breast. In female monkeys, no tumors were found following 10 years of treatment with 0.01, 0.1 or 0.5 mg/kg/day megestrol acetate. Pituitary tumors were observed in female rats treated with 3.9 or 10 mg/kg/day of megestrol acetate for 2 years. The relationship of these tumors in rats and dogs to humans is unknown but should be considered in assessing the risk-to-benefit ratio when prescribing Megace® ES oral suspension and in surveillance of patients on therapy.”

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 megestrol acetate 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, March 10, 2014. 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 “megestrol acetate” 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
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.

If you have any questions, please contact OEHHA at P65Public.Comments@oehha.ca.gov or at (916) 445-6900.

Comment Period

• Comment Period- Notice of Intent to List: Megestrol Acetate

Chemical Reference

• Megestrol Acetate

Related Notices

• Chemicals Listed As Known to the State to Cause Cancer (Megestrol Acetate) and Reproductive Toxicity (Methyl Isobutyl Ketone)

  Mar 28, 2014

Footnotes and References

References

Food and Drug Administration (FDA, 2012). FDA approved drug label, Reference ID 3111413, approved 4-08-2012. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020264s017lbl.pdf.

Food and Drug Administration (FDA, 2013). FDA approved drug label, Reference ID 3308551, approved 5-14-2013. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021778s016lbl.pdf.

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 See Health and Safety Code section 25249.8(b).

⁴ All referenced regulatory sections are from Title 27 of the Cal. Code of Regulations.