Notice of Intent to List: Nitrite in Combination with Amines or Amides

The California Environmental Protection Agency’s Office of Environmental Health Hazard Assessment (OEHHA) intends to list nitrite in combination with amines or amides 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 authoritative bodies listing mechanism.²

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 cancer (Section 25306(d)³).
2. The evidence considered by the authoritative body meets the sufficiency criteria contained in the regulations (Section 25306(e)).

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(f)).

The International Agency for Research on Cancer (IARC) is one of several institutions designated as authoritative for the identification of chemicals as causing cancer (Section 25306(m)).

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: Nitrite in combination with amines or amides meets the criteria for listing as known to the State to cause cancer under Proposition 65, based on findings of the IARC (2010).

Formal identification and sufficiency of evidence for nitrite in combination with amines or amides: In 2010, IARC published Volume 94 in the series IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, entitled Ingested Nitrate and Nitrite, and Cyanobacterial Peptide Toxins (IARC, 2010). This report satisfies the formal identification and sufficiency of evidence criteria in the Proposition 65 regulations for nitrite in combination with amines or amides.
IARC concluded “There is sufficient evidence in experimental animals for the carcinogenicity of nitrite in combination with amines or amides” (emphasis in original). OEHHA is relying on IARC’s discussion of data and conclusions in the report that nitrite in combination with amines or amides causes cancer in experimental animals. Evidence described in the report includes studies showing that nitrite in combination with amines or amides increased the incidences of malignant and combined malignant and benign tumors in multiple studies in rats:
“In many studies in rats, when sodium nitrite and specific secondary or tertiary amines or amides (e.g. morpholine, butylurea, disulfiram, aminopyrine, diphenhydramine, chlorpheniramine maleate, heptamethyleneimine hydrochloride, N,N-dimethyldodecylamine- N-oxide or bis(2-hydroxypropyl)-amine) were mixed in the diet or given in the drinking-water or by gastric intubation, an increased incidence of tumours, including benign and malignant oesophageal tumours, haemangiosarcomas, hepatocellular adenomas and carcinomas, lung squamous-cell carcinomas or benign and malignant nasal cavity tumours was observed. In some of these studies, at a constant level of sodium nitrite, the tumour incidence induced was directly related to the levels of amine. When the level of amine was kept constant, tumour yield was also directly related to the level of sodium nitrite. When pregnant rats were given ethylurea [an amide] and sodium nitrite in the drinking-water, neurogenic tumours developed in the offspring.

A dose-related increase in the incidence of renal-cell carcinoma was observed when rats were administered nitrite in the drinking-water in combination with varying amounts of fishmeal [a source of amines and amides] in the diet. Levels of N‑nitrosodimethylamine in the stomach contents also showed a dose-related increase.”

Thus, the IARC (2010) has found that nitrite in combination with amines or amides causes increased incidence of malignant and combined malignant and benign tumors at multiple sites in multiple studies in rats.

Request for comments: OEHHA is requesting comments as to whether nitrite in combination with amines or amides meets 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 May 8, 2014 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 with “NOIL – nitrite in combination with amines or amides” in the subject line. Comments submitted in paper form may be mailed, faxed, or delivered in person to the addresses below:

Mailing Address: Sam Delson
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. If you have any questions, please contact Sam Delson at sam.delson@oehha.ca.gov or at (916) 445‑6900.