Notice of Intent to List: Hydrogen Cyanide and Cyanide Salts

The California Environmental Protection Agency’s Office of Environmental Health Hazard Assessment (OEHHA) intends to list the chemical hydrogen cyanide and cyanide salts as known to the State to cause reproductive toxicity (male reproductive toxicity endpoint) under the Safe Drinking Water and Toxic Enforcement Act of 1986.1 This action is being proposed under the authoritative bodies listing mechanism.2





Chemical Use

Hydrogen Cyanide (HCN) and Cyanide Salts (CN Salts)


Male Reproductive Toxicity

U.S. EPA (2010a and 2010b)

Used in mining, metallurgy, manufacturing, photography, electroplating, and as a rodenticide. Released from biomass burning, volcanoes, and natural processes. A component of tobacco smoke.

OEHHA requested information relevant to the possible listing of HCN and CN Salts in a notice published in the California Regulatory Notice Register on May 13, 2011 (Register 2011, Vol. No. 19Z). OEHHA received comments for this chemical.

Background on listing via the authoritative bodies mechanism: A chemical must be listed under the Proposition 65 regulations when two conditions are met:

  1. An authoritative body formally identifies the chemical as causing reproductive toxicity (Section 25306(d)3).
  2. 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 which 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 Proposition 65 implementation. After an authoritative body has made a determination about a chemical, OEHHA evaluates whether listing under Proposition 65 is required using the criteria contained in the regulations.

OEHHA’s determination: Hydrogen Cyanide and Cyanide Salts meet the criteria for listing as known to the State to cause reproductive toxicity (male reproductive toxicity endpoint) under Proposition 65, based on findings of the U.S. EPA (U.S. EPA, 2010a; 2010b).

Formal identification and sufficiency of evidence for HCN and CN Salts:

In 2010, U.S. EPA updated its online Integrated Risk Information System (IRIS) entry for hydrogen cyanide and cyanide salts (U.S. EPA, 2010a). The new oral chronic Reference Dose (RfD) of 0.0006 milligrams per kilogram bodyweight per day (mg/kg-day) was based on the male reproductive endpoint of decreased cauda epididymis weight in male F344/N rats. This effect on the male reproductive system was observed in a 13-week drinking water study (National Toxicology Program [NTP], 1993), with a BMDL1SD (lower 95% confidence limit on a benchmark dose associated with a 1 standard deviation (SD) change from the control mean) of 1.9 mg/kg-day.

In support of the IRIS entry, a comprehensive review and summary of the available toxicological data and the Agency's evaluation were published as a Toxicological Review (U.S. EPA, 2010b). The U.S. EPA documents (2010a and 2010b) satisfy the formal identification and sufficiency of evidence criteria in the Proposition 65 regulations.

U.S. EPA (2010a; 2010b, pp. 68-69) concludes that:

"In consideration of the available studies reporting low-dose effects of chronic and subchronic oral exposure to cyanide in animals, the NTP (1993) study was chosen as the principal study.... This study identified statistically significant male reproductive effects in rats and mice that increased in severity in a dose-dependent manner. The observed effects included decreased cauda and whole epididymis weights, decreased testes weight, and altered sperm parameters."

"EPA has selected decreased cauda epididymis weight as the critical effect because it was determined that this effect represents the most sensitive endpoint indicative of male reproductive toxicity. The cauda epididymis is one of the three primary subsections of the epididymis (along with the caput and corpus) and functions as the site of sperm storage and maturation."

U.S. EPA (2010b) concludes that:

"Reproductive effects, including decreased epididymis, cauda epididymis, and testis weights and decreased sperm parameters (epididymal sperm motility and testicular spermatid counts), have been observed in rats in a subchronic dietary study by NTP (1993). Decreases in the cauda epididymis and epididymis weights were also seen in mice (NTP, 1993).... Additionally, reproductive effects, specifically, alterations in testicular histology, have also been observed in a 14-week study in dogs (Kamalu, 1993)."

U.S. EPA (2010b) reviews direct evidence of cyanide-induced male reproductive toxicity in rats, mice and dogs, as well as mechanistic support for this effect. Numerous studies cited by U.S. EPA's Toxicological Review document (2010b) demonstrate the adverse effects of cyanide on the function of the thyroid gland. Additional studies provide evidence for hypothyroidism as a cause of male reproductive damage both during development and in adult animals. On this basis, U.S. EPA (2010b) notes that "...the observed reproductive effects following exposure to cyanide may be mediated through decreases in thyroid hormones mediated through the cyanide metabolite thiocyanate."

Request for comments: OEHHA is committed to public participation in its implementation of Proposition 65. OEHHA wants to ensure that its regulatory decisions are based on a thorough consideration of all relevant information. OEHHA is requesting comments as to whether these chemicals meet the criteria set forth in the Proposition 65 regulations for authoritative bodies listings.

In order to be considered, OEHHA must receive comments by 5:00 p.m. on Monday, April 22, 2013. We encourage you to submit comments via e-mail, rather than in paper form. Comments transmitted by e-mail should be addressed to with “NOIL” and “hydrogen cyanide and cyanide salts” in the subject line. Hard copy comments may be mailed, faxed, or delivered in person to the addresses below:

Mailing Address:
Office of Environmental Health Hazard Assessment
P.O. Box 4010, MS-19B
Sacramento, California 95812-4010
Fax: (916) 324-6511
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.

Link to Public Comments

Footnotes and References

Kamalu, BP (1993). Pathological changes in growing dogs fed on a balanced cassava (Manihot esculenta Crantz) diet. Br J Nutr 69(3):921–934.

NTP (National Toxicology Program). (1993). NTP technical report on toxicity studies of sodium cyanide (CAS No. 143-33-9) administered in drinking water to F344/N rats and B6C3F1 mice. NTP TR 37; NIH Publication 94-3386. Public Health Service, U.S. Department of Health and Human Services; NTP, Research Triangle Park, NC.

U.S. EPA (U.S. Environmental Protection Agency) (2010a). Hydrogen Cyanide and Cyanide Salts (CASRN Various). Integrated Risk Information System.

U.S. EPA (U.S. Environmental Protection Agency) (2010b). Toxicological Review of Hydrogen Cyanide and Cyanide Salts (CASRN Various); In Support of Summary Information on the Integrated Risk Information System (IRIS). EPA/635/R-08/016F. U.S. EPA, Washington DC, September.

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.

2See Health and Safety Code section 25249.8(b) and Title 27, Cal. Code of Regs., section 25306.

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