Title: Addition of National Toxicology Program Carcinogens; Community Right-to-Know Toxic Chemical Release Reporting
ACTION: Proposed rule.
Docket ID No. EPA–HQ–TRI–2010–0006
SUMMARY: EPA is proposing to add sixteen chemicals to the list of toxic chemicals subject to reporting under section 313 of the Emergency Planning and Community Right-to-Know Act (EPCRA) of 1986 and section 6607 of the Pollution Prevention Act of 1990 (PPA). These sixteen chemicals have been classified by the National Toxicology Program (NTP) in their Report on Carcinogens (RoC) as ‘‘reasonably anticipated to be a human carcinogen.’’ EPA believes that these sixteen chemicals meet the EPCRA section 313(d)(2)(B) criteria because they can reasonably be anticipated to cause cancer in humans. As in past chemical reviews, EPA adopted a production volume screen for the development of this proposed rule to screen out those chemicals for which no reports are expected to be submitted. Based on a review of the available production and use information, these sixteen chemicals are expected to be manufactured, processed, or otherwise used in quantities that would exceed the EPCRA section 313 reporting thresholds.
DATES: Comments must be received on or before June 7, 2010. [See Federal Register for details on submitting comments.]
The 16 chemicals are:
(Chemical Name and CAS#)
Vinyl Fluoride 75-02-5
Vinyl Fluoride (CAS No. 75–02–5)
(Refs. NTP Profile/Background document (Refs. 33 and 34)).
The National Toxicology Program has classified vinyl fluoride as ‘‘reasonably anticipated to be a human carcinogen.’’ The classification is based on sufficient evidence of carcinogenicity in experimental animals. The NTP substance profile for vinyl fluoride (Ref. 33) included the following summary information of the evidence of carcinogenicity:
Vinyl fluoride is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity in experimental animals. Both male and female rats exposed to vinyl fluoride by inhalation showed increased incidences of hepatic hemangiosarcoma, hepatocellular adenoma or carcinoma, and Zymbal gland carcinoma. Both male and female mice exposed to vinyl fluoride by inhalation showed increased incidences of hepatic hemangiosarcoma, bronchiolar-alveolar adenoma or adenocarcinoma, hepatocellular adenoma, and harderian gland adenoma. Female mice also showed an increased incidence of mammary gland adenocarcinoma (Bogdanffy et al. 1995, IARC 1995).
The tumor responses of laboratory animals to vinyl fluoride are similar to their responses to vinyl chloride, a known human carcinogen (IARC 1987), and to vinyl bromide, a probable human carcinogen (IARC 1986). A unique feature of vinyl chloride carcinogenicity is that vinyl chloride induces rare hepatic hemangiosarcomas in experimental animals and is causally associated with excess risk of liver hemangiosarcoma in epidemiological studies of exposed workers. The fact that vinyl fluoride, vinyl chloride, and vinyl bromide all induce rare hemangiosarcomas of the liver in experimental animals and induce the formation of similar DNA adducts suggests a possible common mechanism of carcinogenicity for all three of these chemicals.
No adequate human studies of the relationship between exposure to vinyl fluoride and human cancer were found.
Additional Information Relevant to Carcinogenicity
Vinyl fluoride is mutagenic in Salmonella typhimurium with the addition of a rat liver homogenate metabolic activation system. In addition, vinyl fluoride induces gene mutations and chromosomal aberrations in Chinese hamster ovary cells (with metabolic activation), sex-linked recessive lethal mutations in Drosophila melanogaster, and micronuclei in bone marrow cells of female mice (IARC 1995).
Vinyl fluoride likely is metabolized in a manner similar to vinyl chloride: Oxidation via cytochrome P450 to fluoroethylene oxide, followed by rearrangement to 2-fluoroacetaldehyde, which is oxidized to fluoroacetic acid.
Human, rat, and mouse liver microsomes metabolize vinyl fluoride at similar rates (Cantoreggi and Keller 1997). Vinyl fluoride metabolites form covalent DNA adducts. Inhalation exposure of rats and mice to vinyl fluoride produced a dose-related increase in the formation of the promutagenic adduct N2,3-ethenoguanine in their liver DNA (Swenberg et al. 1995).
No available data suggest that mechanisms by which vinyl fluoride induces tumors in experimental animals would not also operate in humans.’’
EPA has reviewed the NTP cancer assessment for vinyl fluoride and agrees that vinyl fluoride can reasonably be anticipated to cause cancer in humans. EPA believes that the evidence is sufficient for listing vinyl fluoride on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available carcinogenicity
Tetrafluoroethylene (CAS No. 116–14–3)
(Refs. NTP Profile/Background document (Refs. 29 and 30)).
The National Toxicology Program has classified tetrafluoroethylene as ‘‘reasonably anticipated to be a human carcinogen.’’ The classification is based on sufficient evidence of carcinogenicity in experimental animals. The NTP substance profile for tetrafluoroethylene (Ref. 29) included the following summary information of the evidence of carcinogenicity:’
Tetrafluoroethylene (TFE) is reasonably anticipated to be a human carcinogen based on sufficient evidence of malignant tumor formation at multiple sites in multiple species of experimental animals (NTP 1997). When administered by inhalation to F344 rats, TFE induced renal tubule neoplasms, hepatocellular neoplasms, liver hemangiosarcoma, and mononuclear cell leukemia. When administered by inhalation to B6C3F1 mice, TFE induced liver hemangiomas and hemangiosarcomas, hepatocellular neoplasms, and histiocytic sarcomas.
No adequate human studies of the relationship between exposure to TFE and human cancer have been reported (IARC 1999).
Additional Information Relevant to Carcinogenicity
In prokaryotic systems, TFE was negative for the induction of gene mutations in Salmonella typhimurium with and without S activation. In mammalian systems in vitro, TFE was also negative for the induction of gene mutations in Chinese hamster ovary cells (HSDB 2001). No increases in the frequency of micronucleated erythrocytes were observed in peripheral blood samples obtained from TFE-exposed mice (NTP 1997).
The frequency of H-ras codon 61 mutations observed in TFE-induced hepatocellular neoplasms (15%) was significantly less than the corresponding frequency (56 to 59%) in spontaneous liver neoplasms of B6C3F1 mice, suggesting that TFE induces liver neoplasms via a ras-independent pathway (NTP 1997).
The kidney-specific toxicity and carcinogenicity of TFE is most likely related to the selective uptake and subsequent processing of TFEglutathione conjugates by renal b-lyase (Miller and Surh 1994, Anders et al. 1988). In rats, a TFE cysteine conjugate is bioactivated in the kidney to a difluorothionacetyl fluoride, the putative reactive metabolite for TFEinduced nephrotoxicity (NTP 1997).’
No data were available that would suggest that the mechanisms thought to account for tumor induction by TFE in experimental animals would not also operate in humans.’’
EPA has reviewed the NTP cancer assessment for tetrafluoroethylene and agrees that tetrafluoroethylene can reasonably be anticipated to cause cancer in humans. EPA believes that the evidence is sufficient for listing tetrafluoroethylene on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available carcinogenicity data for this chemical.