£% niA United States Environmental Protection mmAgency EPA/690/R-12/014F Final 8-15-2012 Provisional Peer-Reviewed Toxicity Values for N, N- D i n i tro sopentam ethy l en etetram in e (CASRN 101-25-7) Superfund Health Risk Technical Support Center National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268 ------- AUTHORS, CONTRIBUTORS, AND REVIEWERS CHEMICAL MANAGER Carrie R. Fleming, PhD National Center for Environmental Assessment, Cincinnati, OH CONTRIBUTOR Jason C. Lambert, PhD, DABT National Center for Environmental Assessment, Cincinnati, OH DRAFT DOCUMENT PREPARED BY National Center for Environmental Assessment, Cincinnati, OH This document was externally peer reviewed under contract to Eastern Research Group, Inc. 110 Hartwell Avenue Lexington, MA 02421-3136 Questions regarding the contents of this document may be directed to the U.S. EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300). i N, iV-Dinitrosopentam ethyl enetetramine ------- TABLE OF CONTENTS COMMONLY USED ABBREVIATIONS iii BACKGROUND 1 DISCLAIMERS 1 QUESTIONS REGARDING PPRTVs 1 INTRODUCTION 2 REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER) 4 DERIVATION 01 PROVISIONAL VALUES 6 CANCER WOE DESCRIPTOR 6 MODE-OF-ACTION DISCUSSION 6 REFERENCES 6 li A', A'-Dinitrosopentainethylenetetramine ------- COMMONLY USED ABBREVIATIONS BMC benchmark concentration BMCL benchmark concentration lower bound 95% confidence interval BMD benchmark dose BMDL benchmark dose lower bound 95% confidence interval HEC human equivalent concentration HED human equivalent dose IUR inhalation unit risk LOAEL lowest-observed-adverse-effect level LOAELadj LOAEL adjusted to continuous exposure duration LOAELhec LOAEL adjusted for dosimetric differences across species to a human NOAEL no-ob served-adverse-effect level NOAELadj NOAEL adjusted to continuous exposure duration NOAELhec NOAEL adjusted for dosimetric differences across species to a human NOEL no-ob served-effect level OSF oral slope factor p-IUR provisional inhalation unit risk POD point of departure p-OSF provisional oral slope factor p-RfC provisional reference concentration (inhalation) p-RfD provisional reference dose (oral) RfC reference concentration (inhalation) RfD reference dose (oral) UF uncertainty factor UFa animal-to-human uncertainty factor UFC composite uncertainty factor UFd incomplete-to-complete database uncertainty factor UFh interhuman uncertainty factor UFl LOAEL-to-NOAEL uncertainty factor UFS subchronic-to-chronic uncertainty factor WOE weight of evidence 111 A', A'-Dinitrosopentamethylenetetramine ------- FINAL 8-15-2012 PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR AyV-DINITROSOPENTAMETHYLENETETRAMINE (CASRN 101-25-7) BACKGROUND A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant scientific literature using established Agency guidance on human health toxicity value derivations. All PPRTV assessments receive internal review by a standing panel of National Center for Environment Assessment (NCEA) scientists and an independent external peer review by three scientific experts. The purpose of this document is to provide support for the hazard and dose-response assessment pertaining to chronic and subchronic exposures to substances of concern, to present the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to characterize the overall confidence in these conclusions and toxicity values. It is not intended to be a comprehensive treatise on the chemical or toxicological nature of this substance. The PPRTV review process provides needed toxicity values in a quick turnaround timeframe while maintaining scientific quality. PPRTV assessments are updated approximately on a 5-year cycle for new data or methodologies that might impact the toxicity values or characterization of potential for adverse human health effects and are revised as appropriate. It is important to utilize the PPRTV database (http://hhpprtv.ornl.gov) to obtain the current information available. When a final Integrated Risk Information System (IRIS) assessment is made publicly available on the Internet (www.epa. gov/iris). the respective PPRTVs are removed from the database. DISCLAIMERS The PPRTV document provides toxicity values and information about the adverse effects of the chemical and the evidence on which the value is based, including the strengths and limitations of the data. All users are advised to review the information provided in this document to ensure that the PPRTV used is appropriate for the types of exposures and circumstances at the site in question and the risk management decision that would be supported by the risk assessment. Other U.S. Environmental Protection Agency (EPA) programs or external parties who may choose to use PPRTVs are advised that Superfund resources will not generally be used to respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program. QUESTIONS REGARDING PPRTVs Questions regarding the contents and appropriate use of this PPRTV assessment should be directed to the EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300). 1 N, iV-Dinitrosopentam ethyl enetetramine ------- FINAL 8-15-2012 INTRODUCTION A', A'-Di nitrosopentam ethyl enetetrami ne (systematic name 3,7-dinitroso- l,3,5,7-tetraazabicyclo-(3,3,l)-nonane), CAS No. 101-25-7, is used as a blowing agent for production of polyvinyl chloride (PVC) plastisols, polyester and silicon resins, and unicellular rubber (both natural and synthetic, which are used in carpet underlay, thermal insulation, weather stripping, cushioning, and flotation devices) (HSDB. 2003). The chemical structure of A', A'-di nitrosopentam ethylenetetramine is given in Figure 1. A table of available physicochemical properties of A', A'-di nitrosopentam ethyl enetetrami ne is provided below (see Table 1). Figure 1. jV,jV-Dinitrosopentamethylenetetramine Structure Table 1. Physicochemical Properties of ^i'V-Dinitrosopentamethylenetetramine (CASRN 101-25-7)a Property (unit) Value Boiling point (°C) ND Melting point (°C) 203 (decomposes at 207)b Density (g/cm3) ND Vapor pressure (Pa at 25°C) ND pH (unitless) ND Solubility in water (%) 1 Relative vapor density (air =1) ND Molecular weight (g/mol) 186.2 aHSDB (2003). bIARC (1976). ND = no data. No reference dose (RfD), reference concentration (RfC), or cancer assessment for A', A'-di nitrosopentam ethyl enetetrami ne is included in the U.S. Environmental Protection Agency (U.S. EPA) Integrated Risk Information System (IRIS) (U.S. EPA, 2011b) or on the Drinking Water Standards and Health Advisories List (U.S. EPA. 2011a). No RfD or RfC values are reported in the Health Effects Assessment Summary Tables (HEAST) (U.S. EPA. 2003). The 2 N, iV-Dinitrosopentam ethyl enetetramine ------- FINAL 8-15-2012 Chemical Assessments and Related Activities (CARA) list does not include a Health and Environmental Effects Profile (HEEP) for N,iV-dinitrosopentamethylenetetramine (U.S. EPA. 1994). The toxicity of A', A'-di nitrosopentam ethyl enetetramine has not been reviewed by the Agency for Toxic Substances and Disease Registry (ATSDR. 2011) or the World Health Organization (WHO. 2011). The California Environmental Protection Agency (Cal EPA. 2008). has not derived toxicity values for exposure to A'A-dinitrosopentam ethyl enetetramine. No occupational exposure limits for N,iV-dinitrosopentamethylenetetramine have been derived or recommended by the American Conference of Governmental Industrial Hygienists (ACGIH. 2011). the National Institute for Occupational Safety and Health (NIOSH. 2007). or the Occupational Safety and Health Administration (OSHA. 2006). The HEAST (U.S. EPA. 2003) does not report a U.S. EPA (1986) cancer weight-of- evidence (WOE) classification or an oral slope factor. A', A'-di nitrosopentam ethylenetetramine is not included in the 12th Report on Carcinogens (NTP. 2011). CalEPA (2009) has not prepared a quantitative estimate of the carcinogenic potential of A'A-dinitrosopentam ethyl enetetramine. The International Agency for Research on Cancer (IARC) did review the carcinogenic potential of iV,iV-dinitrosopentamethylenetetramine in 1976 and re-evaluated the carcinogenicity again in 1987. The 1976 review found no observable carcinogenic effects when tested in rats by oral and intraperitoneal injection (IARC. 1976). and the 1987 subsequent evaluation determined that A', A'-di nitrosopentam ethyl enetetrami ne is a Class 3 Carcinogen (Not Classifiable as to its Carcinogenicity to Humans) due to the lack of data in humans and inadequate evidence in animals (IARC. 1987). Literature searches were conducted on sources published from 1900 through March 21, 2012 for studies relevant to the derivation of provisional toxicity values for iV,iV-dinitrosopentamethylenetetramine, CAS No. 101-25-7. Searches were conducted using U.S. EPA's Health and Environmental Research Online (HERO) database of scientific literature. HERO searches the following databases: AGRICOLA; American Chemical Society; BioOne; Cochrane Library; DOE: Energy Information Administration, Information Bridge, and Energy Citations Database; EBSCO: Academic Search Complete; GeoRef Preview; GPO: Government Printing Office; Informaworld; IngentaConnect; J-STAGE: Japan Science & Technology; JSTOR: Mathematics & Statistics and Life Sciences; NSCEP/NEPIS (EPA publications available through the National Service Center for Environmental Publications [NSCEP] and National Environmental Publications Internet Site [NEPIS] database); PubMed: MEDLINE and CANCERLIT databases; SAGE; Science Direct; Scirus; Scitopia; SpringerLink; TOXNET (Toxicology Data Network): ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP, GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS, ITER, LactMed, Multi-Database Search, NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI; and TSCATS; Virtual Health Library; Web of Science (searches Current Content database among others); World Health Organization; and Worldwide Science. The following databases outside of HERO were searched for risk assessment values: ACGIH, ATSDR, CalEPA, U.S. EPA IRIS, U.S. EPA HEAST, U.S. EPA HEEP, U.S. EPA OW, U.S. EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS. 3 iV,iV-Dinitrosopentamethyl enetetramine ------- FINAL 8-15-2012 REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER) The literature search revealed no usable human or animal studies (acute-, short term-, subchronic-, or chronic-duration) for development of toxicity values for N,A'-di nitrosopentam ethylenetetramine. Three studies (Hadidian et al.. 1968; Griswold et al.. 1966; Weisburger et al.. 1966) were identified that examined tumor formation in animals treated with A'A-di nitrosopentam ethyl enetetramine; however, none of these were suitable for development of toxicity values. They are summarized below and in Table 2. Wherever the word significant is used below, it refers to a change that the study authors reported to be statistically significant. In a single-dose study by Griswold et al. (1966). no tumors were observed in 20 female Sprague-Dawley rats 6 months after a single gavage dose of 90 mg iV,iV-dinitrosopentamethylenetetramine, and mortality did not differ significantly from controls. In another study by Weisburger et al. (1966). Fisher rats (15 male and 15 female) treated with unspecified doses up to 9 mg/animal-day A'A-di nitrosopentam ethyl enetetramine 5 days per week for 1 year and then observed for another 6 months had no tumors. In a third study by Hadidian et al. (1968). Fisher rats were dosed by gavage 5 days per week for 52 weeks with 0, 0.03, 0.1, 0.3, 1, 3, or 9 mg/animal-day N,/V-dinitrosopentamethylenetetramine and observed for another 6 months afterward. This study shares authors with the study by Weisburger et al. (1966) and may be a more detailed report of the same experiments. Hadidian et al. (1968) utilized 3 animals/sex/dose group for all doses except there were 15 animals/sex in the 3 mg/animal-day group. The study authors reported no significant changes in survival, body weight, or liver weight and no significant increase in tumor incidence. Due to low group sizes and/or short dosing duration, the negative results from these studies are inconclusive and do not support development of toxicity values for iV,/V-dinitrosopentamethylenetetramine. In all three of these studies, the authors performed preliminary range-finding studies aimed at identifying the maximally tolerated dose (MTD); these experiments were aimed at identifying doses at which mortality occurred, and, therefore, also do not support development of provisional reference values for /V,/V-dinitrosopentamethyl enetetramine. 4 iV,/V-Dinitrosopentamethyl enetetramine ------- FINAL 8-15-2012 Table 2. Summary of Potentially Relevant Data for j^j^Dinitrosopentamethylenetetramine (CASRN 101-25-7) Category Number of Male/Female, Strain, Species, Study Type, Study Duration Dosimetry" Critical Effects NOAELb BMDL/ BMCLb LOAELb Reference Comments Carcinogenic 0/20, Sprague-Dawley rat, gavage, once, 6 mo follow-up 90 mg No tumors observed NR NC NR (Griswold et al.. 1966) Animals were dosed once orally (presumably via gavage) and observed for tumors after 6 mo. 15/15, Fischer rat, gavage, 5 d/wk, 1 yr, 6 mo follow-up 9 mg/animal-d No tumors observed NR NC NR (Weisbureer et al.. 1966s) Animals were treated for 1 yr, then maintained for an additional 6 mo before examining for tumors. 3-15/3-15, Fischer rat, gavage, 5 d/wk, 1 yr, 6 mo follow-up 0,0.03,0.1, 0.3, 1, 3, 9 mg/animal-d No significant increase in tumors observed; one squamous cell carcinoma on the tongue of a female administered 1 mg/d NR NC NR (Hadidian et al.. 1968) Animals were treated for 52 wk, then observed for an additional 6 mo after end of treatment. There were controls (negative, untreated, or vehicle; stated to be 30/sex) for each chemical tested, but it appears that the results were combined into one table. There were only 3 animals/sex/treatment in all groups except the 3 mg/d/animal group, which had 15 animals/sex. Tor this document, these values have not been converted to adjusted daily dose (ADD in mg/kg-d), human equivalent dose (HED in mg/kg-d), or human equivalent concentration (HEC in mg/m3) units. bNR = Not relevant; NC = Not calculated. 5 A', A'-Dinitrosopentainethylenetetramine ------- FINAL 8-15-2012 DERIVATION OF PROVISIONAL VALUES Limitations in the available data preclude development of both cancer and noncancer toxicity values for A', A'-dinitrosopentamethylenetetramine. CANCER WOE DESCRIPTOR Limitations in the available data preclude development of a WOE descriptor. MODE-OF-ACTION DISCUSSION Limitations in the available data preclude a mode-of-action discussion. 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Griswold, DP, Jr; Casey, AE; Weisburger, EK; Schabel, FM, Jr. (1966). On the carcinogenicity of a single intragastric dose of hydrocarbons, nitrosamines, aromatic amines, dyes, coumarins, and miscellaneous chemicals in female Sprague-Dawley rats. Cancer Res 26: 619-625. Hadidian, Z; Fredrickson, TN; Weisburger, EK: Weisburger, JH; Glass, RM; Mantel, N. (1968). Tests for chemical carcinogens: Report on the activity of derivatives of aromatic amines, nitrosamines, quinolines, nitroalkanes, amides, epoxides, aziridines, and purine antimetabolites. J Natl Cancer Inst 41: 985-1036. HSDB (Hazardous Substances Data Bank). (2003). Dinitrosopentamethylenetetramine - CASRN: 101 25 7. Washington, DC: National Library of Medicine. IARC (International Agency for Research on Cancer). (1976). Dinitrosopentamethylenetetramine. In Cadmium, nickel, some epoxides, miscellaneous industrial chemicals and general considerations on volatile anaesthetics (Vol. 11). Lyon, France. 6 N,/V-Dinitrosopentam ethyl enetetramine ------- FINAL 8-15-2012 I ARC (International Agency for Research on Cancer). (1987). Overall evaluations of carcinogenicity: An updating of IARC monographs volumes 1 to 42 (Vol. Suppl. 7). Lyon, France. NIOSH (National Institute for Occupational Safety and Health). (2007). NIOSH pocket guide to chemical hazards. (2005-149). Cincinnati, OH. NTP (National Toxicology Program). (2011). Report on carcinogens: Twelfth edition. Washington, DC: U.S. Department of Health and Human Services. http://ntp.niehs.nih.gov/ntp/roc/twelfth/rocl2.pdf. OSHA (Occupational Safety & Health Administration). (2006). Table Z-l limits for air contaminants. Occupational Safety and Health Administration. http://www.osha.gov/pls/oshaweb/owadisp.show document?p table=STANDARDS&p id=9992. U.S. EPA (U.S. Environmental Protection Agency). (1986). Guidelines for carcinogen risk assessment. (EPA/630/R-00/004). Washington, DC: U.S. Environmental Protection Agency, Risk Assessment Forum. http://epa.gov/raf/publications/pdfs/CA%20GUIDELINES 1986.PDF. U.S. EPA (U.S. Environmental Protection Agency). (1994). Chemical assessments and related activities (CARA). (600R94904; OHEA-I-127). Washington, DC: Office of Health and Environmental Assessment, Office of Research and Development. http://nepis.epa. gov/Exe/ZvPURL.cgi?Dockev=6000 lG8L.txt. U.S. EPA (U.S. Environmental Protection Agency). (2003). Health Effects Assessment Summary Tables (HEAST), from http://epa-heast.ornl.gov/ U.S. EPA (U.S. Environmental Protection Agency). (201 la). 2011 Edition of the drinking water standards and health advisories. (EPA 820-R-11-002). Washington, DC. http://water.epa.gov/action/advisories/drinking/drinking index.cfm. U.S. EPA (U.S. Environmental Protection Agency). (201 lb). Integrated risk information system (IRIS), from http://www.epa.gov/iris/index.html Weisburger. JH; Weisburger. EK; Mantel N. (1966). New carciogenic nitrosamines in rats. Naturwissenschaften 53: 508. WHO (World Health Organization). (2011). Online catalog for the Environmental Health Criteria Series, from http://www.who.int/ipcs/publications/ehc/en/ 7 N,/V-Dinitrosopentam ethyl enetetramine ------- |