Draft Hazard Identification Documents for 2-Aminofluorene and 4-Amino-2-Nitrophenol

Sep 25, 1998

The California Environmental Protection Agency's Office of Environmental Health Hazard Assessment (OEHHA) is the lead agency for the implementation of the Safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65).

The Carcinogen Identification Committee of OEHHA's Science Advisory Board advises and assists OEHHA in compiling the list of chemicals known to the State to cause cancer which is mandated by Health and Safety Code Section 25249.8. The Committee serves as the State's qualified experts for rendering an opinion as to whether a chemical has been clearly shown, through scientifically valid testing according to generally accepted principles, to cause cancer.

On June 12, 1998, OEHHA requested information in relation to the preparation of draft hazard identification documents on six chemicals to be considered by the Carcinogen Identification Committee. Two chemicals for which documents have been drafted are 2-aminofluorene and 4-amino-2-nitrophenol. (Hazard identification documents on the other four chemicals are in preparation by OEHHA.) The 60-day data call-in ended on August 11, 1998. No information or data were received.

The two draft hazard identification documents currently available are entitled: "Evidence on the Carcinogenicity of 2-Aminofluorene", and "Evidence on the Carcinogenicity of 4-Amino-2-nitrophenol". Copies of the draft documents are available from the Proposition 65 Implementation Office and may be requested by calling (916) 445-6900. The documents are also available through the Internet in the download section below. This notice marks the beginning of a 60-day public comment period. Comments should be

the Proposition 65 Office
Office of Environmental Health Hazard Assessment
Post Office Box 4010
Sacramento, CA 95812-4010
FAX (916) 327-1097

In order to be considered, comments must be received at OEHHA by 5:00 p.m. on Tuesday, November 24, 1998.

OEHHA will organize and index the comments received and forward the information to the Carcinogen Identification Committee members at least two weeks prior to the meeting at which the candidate chemical will be considered. The next meeting of the Carcinogen Identification Committee is tentatively scheduled for December 10, 1998. The date will be confirmed and the location will be announced in a future public notice.

The preface and executive summary are presented below. Download the entire draft hazard identification document in the download section below.

Evidence on the Carcinogenicity of 4-Amino-2-Nitrophenol
Reproductive and Cancer Hazard Assessment Section
Office of Environmental Health Hazard Assessment
California Environmental Protection Agency

September, 1998

The Safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65, California Health and Safety Code 25249.5 et seq.) requires that the Governor cause to be published a list of those chemicals "known to the state" to cause cancer or reproductive toxicity. The Act specifies that "a chemical is known to the state to cause cancer or reproductive toxicity...if in the opinion of the state’s qualified experts the chemical has been clearly shown through scientifically valid testing according to generally accepted principles to cause cancer or reproductive toxicity." The lead agency for implementing Proposition 65 is the Office of Environmental Health Hazard Assessment of the California Environmental Protection Agency. The "state’s qualified experts" regarding findings of carcinogenicity are identified as the members of the Carcinogen Identification Committee of the OEHHA Science Advisory

4-Amino-2-nitrophenol was assigned a final priority of ‘high’ carcinogenicity concern and placed on the Final Candidate list of chemicals for Committee review on June 12, 1998. A public request for information relevant to the assessment of the evidence on the carcinogenicity of this chemical was announced in the California Regulatory Notice Register on June 12, 1998.

This draft document Evidence on the Carcinogenicity of 4-Amino-2-nitrophenol was developed to provide the Committee with relevant information for use in its deliberations. It reviews the available scientific evidence on the carcinogenic potential of 4-amino-2-nitrophenol. A public meeting of the Committee to discuss this evidence is scheduled for December 1998. The exact meeting date will be published in the California Regulatory Notice Register. Written public comment on the document should be submitted to OEHHA by November 24, 1998, in order to be considered by the Committee in advance of the meeting. During the December meeting, the public will have an opportunity to present verbal comments to the Committee.

4-Amino-2-nitrophenol (C6H6N2O3) has been used as an oxidation base in formulations of hair dyes. Technical grade 4-amino-2-nitrophenol induced tumors of the urinary bladder in male rats, and there is some evidence for a similar effect among female rats. Tumors of the urinary bladder are extremely rare among untreated rats. Preparations of 4-amino-2-nitrophenol have also demonstrated genotoxic potential in a number of short-term tests in bacterial and mammalian cells, in vitro and in vivo. There is some evidence that a purified preparation of 4-amino-2-nitrophenol loses its genotoxic potential, although this has only been investigated in a single study. In support of the concern for the carcinogenicity of 4-amino-2-nitrophenol itself, the purity of the test substance administered in the studies showing the development of bladder tumors was of relatively high purity, i.e., 99.6 ± 0.3%. Furthermore, aromatic amines with structural homology to 4-amino-2-nitrophenol have shown evidence of carcinogenicity, some with the urinary bladder as the site of tumor development.

There is evidence for the carcinogenicity of 4-amino-2-nitrophenol, with development of transitional cell carcinomas of the urinary bladder, a rare tumor, observed in male mice. The weight of evidence is supported by observations of a small number of the same rare tumor type in female mice, by mutagenicity in several short-term tests, and by chemical structural analogies with known carcinogens, including several bladder carcinogens.

The preface and executive summary are presented below. Download the draft hazard identification document in the download section below.

Evidence on the Carcinogenicity of 2-Aminofluorene
DRAFT
Reproductive and Cancer Hazard Assessment Section
Office of Environmental Health Hazard Assessment
California Environmental Protection Agency

September 1998

Preface
The Safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65, California Health and Safety Code 25249.5 et seq.) requires that the Governor cause to be published a list of those chemicals "known to the state" to cause cancer or reproductive toxicity. The Act specifies that "a chemical is known to the state to cause cancer or reproductive toxicity...if in the opinion of the state’s qualified experts the chemical has been clearly shown through scientifically valid testing according to generally accepted principles to cause cancer or reproductive toxicity." The lead agency for implementing Proposition 65 is the Office of Environmental Health Hazard Assessment of the California Environmental Protection Agency. The "state’s qualified experts" regarding findings of carcinogenicity are identified as the members of the Carcinogen Identification Committee of the OEHHA Science Advisory Board (22 CCR 12301).

2-Aminofluorene was assigned a final priority of ‘high’ carcinogenicity concern and placed on the Final Candidate list of chemicals for Committee review on June 12, 1998. A public request for information relevant to the assessment of the evidence on the carcinogenicity of this chemical was announced in the California Regulatory Notice Register on June 12, 1998.

This draft document Evidence on the Carcinogenicity of 2-Aminofluorene was developed to provide the Committee with relevant information for use in its deliberations, and reviews the available scientific evidence on the carcinogenic potential of 2-aminofluorene. A public meeting of the Committee to discuss this evidence is scheduled for December 1998. The exact meeting date will be published in the California Regulatory Notice Register. Written public comment on the document should be submitted to OEHHA by November 24, 1998, in order to be considered by the Committee in advance of the meeting. During the December meeting, the public will have an opportunity to present verbal comments to the Committee.

Executive Summary
2-Aminofluorene (2-AF) (CAS number 153-78-6) is a synthetic arylamine. It is used as a laboratory research chemical; there is no significant industrial use of the compound. 2-AF can be converted by biological systems to a well-known animal carcinogen, 2-acetylaminofluorene (2-AAF) through acetylation. Metabolic activation is generally required to convert 2-AF to electrophiles that can react with DNA and form adducts. Most of the reactive species formed by 2-AF are also produced during the metabolism of 2-AAF. 2-AF was shown in a number of studies to induce liver tumors in male rats, mammary gland tumors in female rats, and liver tumors in mice of both sexes. It also induced rare tumors of the ear duct and small intestine in several strains of rats and mice. The cancer bioassays were all published prior to 1967, and some suffer from methodological inadequacies, which mainly diminish the power of the studies to detect carcinogenicity. It is noteworthy that 2-AF nonetheless showed a consistent and severe effect in these studies. 2-AF is mutagenic and causes genetic mutations, DNA damage, chromosomal aberrations, and sister-chromatid exchanges in vivo and in vitro.

Based on the information reviewed in the preparation of this document, there is evidence for the carcinogenicity of 2-aminofluorene at multiple sites, including rare tumor sites, in multiple studies, in both sexes of two species. Extensive observations of genetic toxicity, as well as conversion to and close chemical structural analogies with a known carcinogen contribute to the weight of evidence.