Notice of Intent to List Abiraterone Acetate

The California Environmental Protection Agency’s Office of Environmental Health Hazard Assessment (OEHHA) intends to list abiraterone acetate as known to the state to cause reproductive toxicity (developmental, female and male endpoints) 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]. 

Background on listing via the formally required to be labeled or identified mechanism:  A chemical must be listed under Proposition 65[3] and its implementing regulations (Section 25902[4]) when a state or federal agency has formally required it to be labeled or identified as causing cancer or reproductive toxicity. 

OEHHA is the lead agency for Proposition 65 implementation, and evaluates whether listing under Proposition 65 is required pursuant to the definitions set out in Section 25902.  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 reproductive toxicity” means:  “For chemicals that cause reproductive toxicity, the required label or identification uses any words or phrases intended to communicate a risk of reproductive harm to men or women or both, or a risk of birth defects or other developmental harm.” 

OEHHA’s determination:  Abiraterone acetate has been identified and labeled to communicate a risk of reproductive harm (developmental, female and male endpoints) (FDA, 2015) in accordance with formal requirements by the US Food and Drug Administration (FDA).  The FDA-approved label indicates that uses of abiraterone acetate during pregnancy can cause fetal harm and that abiraterone acetate has the potential to impair reproductive function and fertility in humans.  Zytiga is the trade name of a drug that is composed of abiraterone acetate.

Language from the FDA-approved product label (Reference ID 3686945; FDA, 2015) which meets the requirements of Section 25902 is quoted below:

Abiraterone acetate

Reproductive Toxicity (Developmental, Female and Male Endpoints)

Under HIGHLIGHTS OF PRESCRIBING INFORMATION: 

CONTRAINDICATIONS.  “ZYTIGA [abiraterone acetate] is contraindicated in women who are or may become pregnant. (4.1, 8.1)”

Under CONTRAINDICATIONS:

“4.1 Pregnancy.  ZYTIGA [abiraterone acetate] can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations (8.1)].”

Under USE IN SPECIFIC POPULATIONS: 

“8.1 Pregnancy.  Pregnancy Category X [see Contraindications (4.1)].  ZYTIGA [abiraterone acetate] can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA.”

“In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.”

Under NONCLINICAL TOXICOLOGY:

“13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility.  …ZYTIGA [abiraterone acetate] has the potential to impair reproductive function and fertility in humans based on findings in animals. In repeat-dose toxicity studies in male rats (13-and 26-weeks) and monkeys (39-weeks), atrophy, aspermia/hypospermia, and hyperplasia in the reproductive system were observed at ≥50 mg/kg/day in rats and ≥250 mg/kg/day in monkeys and were consistent with the antiandrogenic pharmacological activity of abiraterone [see Nonclinical Toxicology (13.2)]. These effects were observed in rats at systemic exposures similar to humans and in monkeys at exposures approximately 0.6 times the AUC in humans.”

“In fertility studies in rats, reduced organ weights of the reproductive system, sperm counts, sperm motility, altered sperm morphology and decreased fertility were observed in males dosed for 4 weeks at ≥30 mg/kg/day. Mating of untreated females with males that received 30 mg/kg/day abiraterone acetate resulted in a reduced number of corpora lutea, implantations and live embryos and an increased incidence of pre-implantation loss. Effects on male rats were reversible after 16 weeks from the last abiraterone acetate administration. Female rats dosed for 2 weeks until day 7 of pregnancy at ≥30 mg/kg/day had an increased incidence of irregular or extended estrous cycles and pre-implantation loss (300 mg/kg/day). There were no differences in mating, fertility, and litter parameters in female rats that received abiraterone acetate. Effects on female rats were reversible after 4 weeks from the last abiraterone acetate administration. The dose of 30 mg/kg/day in rats is approximately 0.3 times the recommended dose of 1,000 mg/day based on body surface area.”

“13.2 Animal Toxicology and/or Pharmacology.  In 13-and 26-week studies in rats and 13-and 39-week studies in monkeys, a reduction in circulating testosterone levels occurred with abiraterone acetate at approximately one half the human clinical exposure based on AUC. As a result, decreases in organ weights and toxicities were observed in the male and female reproductive system, adrenal glands, liver, pituitary (rats only), and male mammary glands. The changes in the reproductive organs are consistent with the antiandrogenic pharmacological activity of abiraterone acetate.”

Under HOW SUPPLIED/STORAGE AND HANDLING:

“Storage and Handling.  Based on its mechanism of action, ZYTIGA [abiraterone acetate] may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations (8.1)].”

Under PATIENT COUNSELING INFORMATION:

“Patients should be informed that ZYTIGA [abiraterone acetate] may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA.”  

Under PATIENT INFORMATION:

“Who should not take ZYTIGA?  Do not take ZYTIGA [abiraterone acetate] if you are pregnant or may become pregnant. ZYTIGA may harm your unborn baby.”

“Women who are pregnant or who may become pregnant should not touch ZYTIGA without protection, such as gloves.”

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 this is a ministerial listing, comments should be limited to whether FDA requires that abiraterone acetate be labeled to communicate a risk of reproductive or developmental harm.  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, February 29, 2016.  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 “abiraterone acetate” in the subject line.  Comments submitted in paper form may be mailed, faxed, or delivered in person to the address below.

Mailing Address: Michelle Robinson

Proposition 65 Implementation Program
Office of Environmental Health Hazard Assessment
P.O. Box 4010, MS-12B
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. 

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

Comment Period

• Comment Period - Intent to List Abiraterone Acetate

Chemical Reference

• Abiraterone acetate

Related Notices

• Abiraterone Acetate Listed Effective April 8, 2016 as Known to the State of California to Cause Reproductive Toxicity

  Apr 8, 2016

Footnotes and References