Nitrite in Combination with Amines or Amides 1 August 2016
OEHHA
Evidence on the Carcinogenicity of Nitrite in Combination with Amines or Amides
August 2016
Reproductive and Cancer Hazard Assessment Branch
Office of Environmental Health Hazard Assessment
California Environmental Protection Agency
OFFICE OF ENVIRONMENTAL HEALTH HAZARD
ASSESSMENT
Proposition 65
Nitrite in Combination with Amines or Amides August 2016
OEHHA
The Office of Environmental Health Hazard Assessments (OEHHA) Reproductive and
Cancer Hazard Assessment Branch was responsible for the preparation of this
document.
Primary Authors
Jennifer C.Y. Hsieh, Ph.D.
Staff Toxicologist
Contributing Author
Rose Schmitz, M.S.
Research Scientist II
Research and Writing Assistants
Justin Qung Jing Tsui, M.P.H.
Graduate Student Assistant
Kelley T. Patten, M.P.H.
Graduate Student Assistant
Technical Support
Bryan K. Eya, Ph.D.
Staff Toxicologist
Internal OEHHA Reviewers
Martha S. Sandy, M.P.H., Ph.D.
Chief, Reproductive and Cancer Hazard Assessment Branch
Allan Hirsch
Chief Deputy Director
Acting Director
Lauren Zeise, Ph.D.
Office of Environmental Health Hazard Assessment
Amy J. Dunn, M.P.H.
Research Scientist III
Lee Ann L. Hill, M.P.H.
Graduate Student Assistant
Kenneth Kloc, M.P.H., Ph.D.
Staff Toxicologist
Nitrite in Combination with Amines or Amides i August 2016
OEHHA
PREFACE
Proposition 651 requires the publication of a list of chemicals known to the state to
cause cancer or reproductive toxicity. The Office of Environmental Health Hazard
Assessment (OEHHA) of the California Environmental Protection Agency maintains this
list in its role as lead agency for implementing Proposition 652. The Carcinogen
Identification Committee (CIC) advises and assists OEHHA in compiling the list of
chemicals that cause cancer as required by Health and Safety Code section 25249.8.
The Committee serves as the states qualified experts for determining whether a
chemical has been clearly shown to cause cancer.
On February 7, 2014, OEHHA published a public notice in the California Regulatory
Notice Register announcing its intent to list nitrite in combination with amines or
amides as causing cancer under Proposition 65 via the authoritative bodies
mechanism3. After consideration of comments received on the Notice of Intent to List
and further evaluation of the scientific evidence supporting the listing, OEHHA
determined that the regulatory criteria in Section 25306(e)4 had not been met for the
spectrum of chemicals covered by the broad class nitrite in combination with amines
and amides. Pursuant to Section 25306(i)5, OEHHA announced on May 6, 20156 that
the CIC would consider at a future meeting whether nitrite in combination with amines
or amides or a subset of chemicals of this class, have been clearly shown through
scientifically valid testing according to generally accepted principles to cause cancer.
OEHHA developed this document with information on the evidence on the
carcinogenicity of nitrite in combination with amines or amides to assist the CIC in its
deliberations. The original papers discussed in the document will also be provided to
the CIC as part of the hazard identification materials. Comments on this hazard
identification document received during the public comment period also form part of the
hazard identification materials, and are provided to the CIC members prior to their
formal deliberations.
1 The Safe Drinking Water and Toxic Enforcement Act of 1986 (California Health and Safety Code 25249.5 et seq.) 2 Health and Safety Code section 25249.12, Title 27, Cal. Code of Regs., section 25102(o) 3 See the February 7, 2014 Notice of Intent to List: Nitrite in Combination with Amines or Amides, available at: http://oehha.ca.gov/proposition-65/crnr/notice-intent-list-nitrite-combination-amines-or-amides 4 Title 27, Cal. Code of Regs., section 25306(e) 5 Title 27, Cal. Code of Regs., section 25306(i) 6 See the public notice posted May 6, 2015 on the OEHHA web site and published May 8, 2015 in the California Regulatory Notice Register, available at: http://oehha.ca.gov/proposition-65/crnr/nitrite-combination-amines-or-amides-be-considered-carcinogen-identification
http://oehha.ca.gov/proposition-65/crnr/notice-intent-list-nitrite-combination-amines-or-amideshttp://oehha.ca.gov/proposition-65/crnr/notice-intent-list-nitrite-combination-amines-or-amideshttp://oehha.ca.gov/proposition-65/crnr/nitrite-combination-amines-or-amides-be-considered-carcinogen-identificationhttp://oehha.ca.gov/proposition-65/crnr/nitrite-combination-amines-or-amides-be-considered-carcinogen-identification
Nitrite in Combination with Amines or Amides ii August 2016 OEHHA
On November 15, 2016, the CIC is scheduled to deliberate on the carcinogenicity of
nitrite in combination with amines or amides. The CIC may also consider whether a
subset (or multiple subsets) of chemicals of this broad class should be added to the
Proposition 65 list as carcinogens. A transcript of the meeting will be available at
www.oehha.ca.gov after the meeting.
http://www.oehha.ca.gov/
Nitrite in Combination with Amines or Amides iii August 2016 OEHHA
TABLE OF CONTENTS
1. EXECUTIVE SUMMARY ............................................................................................. 1
2. INTRODUCTION ......................................................................................................... 6
2.1 Chemical Identity ................................................................................................. 10
2.2 Occurrence and Use ............................................................................................ 16
3. DATA ON CARCINOGENICITY ................................................................................ 24
3.1 Carcinogenicity Studies in Humans ..................................................................... 24
3.1.1 IARC (2010) Review ...................................................................................... 24
3.1.2 Reviews other than IARC............................................................................... 25
3.1.3 Human studies of the carcinogenicity of nitrite published since IARC (2010) 26
3.1.4 2015 IARC Review of Processed Meat .......................................................... 83
3.2 Carcinogenicity Studies in Animals ...................................................................... 83
3.3 Mechanistic Evidence and Other Relevant Data ................................................ 113
3.3.1 IARC 2010 Review ...................................................................................... 113
3.3.2 Genotoxicity ................................................................................................. 113
4. SUMMARY .............................................................................................................. 169
4.1 Evidence from Studies in Humans ..................................................................... 169
4.1.1 Colorectal cancer ......................................................................................... 169
4.1.2 Esophageal and stomach cancer ................................................................. 170
4.1.3 Lymphoma ................................................................................................... 172
4.1.4 Other Cancers: Central Nervous System, Thyroid, Lung, Breast,
Pancreatic, Liver, Ovarian, Urinary Tract, Prostate and 'All' Cancer ............ 173
4.2 Evidence from Studies in Experimental Animals ................................................ 175
4.3 Evidence from Genotoxicity Studies .................................................................. 178
5. REFERENCES ........................................................................................................ 184
APPENDIX A Parameters for Literature Searches on the Carcinogenicity of
Nitrite in Combination with Amines or Amides ...................................... 196
ATTACHMENT 1 IARC 2010 ...................................................................................... 198
ATTACHMENT 2 Bouvard et al., 2015 ........................................................................ 198
Nitrite in Combination with Amines or Amides iv August 2016 OEHHA
LIST OF TABLES
Table 1. Common Uses of Amines Tested in Combination with Nitrite for Genotoxicity
or Carcinogenicity ......................................................................................... 19
Table 2. Common Uses of Amides Tested in Combination with Nitrite for Genotoxicity or
Carcinogenicity .............................................................................................. 22
Table 3. Colorectal Cancer Studies of Nitrite Exposure ............................................. 34
Table 4. Esophageal and Stomach CancerStudies of Nitrite Exposure ..................... 48
Table 5. LymphomaStudies of Nitrite Exposure ......................................................... 57
Table 6. Studies of Nitrite
