|—nm United States 1 1 fltjk Environmental Protection LbI m mAgency EPA/690/R-07/029F Final 9-25-2007 Provisional Peer Reviewed Toxicity Values for Phosphorus pentoxide (CASRN 1314-56-3) Superfund Health Risk Technical Support Center National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268 ------- Acronyms and Abbreviations bw body weight cc cubic centimeters CD Caesarean Delivered CERCLA Comprehensive Environmental Response, Compensation and Liability Act of 1980 CNS central nervous system cu.m cubic meter DWEL Drinking Water Equivalent Level FEL frank-effect level FIFRA Federal Insecticide, Fungicide, and Rodenticide Act g grams GI gastrointestinal HEC human equivalent concentration Hgb hemoglobin i.m. intramuscular i.p. intraperitoneal IRIS Integrated Risk Information System IUR inhalation unit risk i.v. intravenous kg kilogram L liter LEL lowest-effect level LOAEL lowest-observed-adverse-effect level LOAEL(ADJ) LOAEL adjusted to continuous exposure duration LOAEL(HEC) LOAEL adjusted for dosimetric differences across species to a human m meter MCL maximum contaminant level MCLG maximum contaminant level goal MF modifying factor mg milligram mg/kg milligrams per kilogram mg/L milligrams per liter MRL minimal risk level MTD maximum tolerated dose MTL median threshold limit NAAQS National Ambient Air Quality Standards NOAEL no-ob served-adverse-effect level NOAEL(ADJ) NOAEL adjusted to continuous exposure duration NOAEL(HEC) 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 p-OSF provisional oral slope factor p-RfC provisional inhalation reference concentration 1 ------- p-RfD provisional oral reference dose PBPK physiologically based pharmacokinetic ppb parts per billion ppm parts per million PPRTV Provisional Peer Reviewed Toxicity Value RBC red blood cell(s) RCRA Resource Conservation and Recovery Act RDDR Regional deposited dose ratio (for the indicated lung region) REL relative exposure level RfC inhalation reference concentration RfD oral reference dose RGDR Regional gas dose ratio (for the indicated lung region) s.c. subcutaneous SCE sister chromatid exchange SDWA Safe Drinking Water Act sq.cm. square centimeters TSCA Toxic Substances Control Act UF uncertainty factor Hg microgram |j,mol micromoles voc volatile organic compound 11 ------- 9-25-2007 PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR PHOSPHORUS PENTOXIDE (CASRN 1314-56-3) Background On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human health toxicity values for Superfund risk assessments, establishing the following three tiers as the new hierarchy: 1. EPA's Integrated Risk Information System (IRIS). 2. Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund Program. 3. Other (peer-reviewed) toxicity values, including: ~ Minimal Risk Levels produced by the Agency for Toxic Substances and Disease Registry (ATSDR), ~ California Environmental Protection Agency (CalEPA) values, and ~ EPA Health Effects Assessment Summary Table (HEAST) values. A PPRTV is defined as a toxicity value derived for use in the Superfund Program when such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are developed according to a Standard Operating Procedure (SOP) and are derived after a review of the relevant scientific literature using the same methods, sources of data, and Agency guidance for value derivation generally used by the EPA IRIS Program. All provisional toxicity values receive internal review by two EPA scientists and external peer review by three independently selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multi-program consensus review provided for IRIS values. This is because IRIS values are generally intended to be used in all EPA programs, while PPRTVs are developed specifically for the Superfund Program. Because new information becomes available and scientific methods improve over time, PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS value for a specific chemical becomes available for Agency review, the analogous PPRTV for that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude that a PPRTV cannot be derived based on inadequate data. Disclaimers Users of this document should first check to see if any IRIS values exist for the chemical of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional Superfund and RCRA program offices are advised to carefully review the information provided in this document to ensure that the PPRTVs used are appropriate for the types of exposures and 1 ------- 9-25-2007 circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically updated; therefore, users should ensure that the values contained in the PPRTV are current at the time of use. It is important to remember that a provisional value alone tells very little about the adverse effects of a chemical or the quality of evidence on which the value is based. Therefore, users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may choose of their own initiative to use these PPRTVs are advised that Superfund resources will not generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund Program. Questions Regarding PPRTVs Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on chemicals not covered, or whether chemicals have pending IRIS toxicity values) may 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), or OSRTI. INTRODUCTION The U.S. Environmental Protection Agency's (EPA) Integrated Risk Information System (IRIS; U.S. EPA, 2007) does not list a chronic RfD, chronic RfC or cancer assessment for phosphorus pentoxide. Subchronic or chronic RfDs, RfCs or cancer assessments for phosphorus pentoxide are not listed in the Health Effects Assessment Summary Tables (HEAST; U.S. EPA, 1997) or the Drinking Water Standards and Health Advisories list (U.S. EPA, 2006). The Chemical Assessments and Related Activities (CARA) list (U.S. EPA, 1991, 1994) does not include phosphorus pentoxide. No standards for occupational exposure to phosphorus pentoxide have been established by the American Conference of Governmental Industrial Hygienists (ACGIH, 2007), the National Institute for Occupational Safety and Health (NIOSH, 2007) or the Occupational Safety and Health Administration (OSHA, 2007). The Agency for Toxic Substances and Disease Registry (ATSDR, 2007), the International Agency for Research on Cancer (IARC, 2007), and the World Health Organization (WHO, 2007) have not published toxicological reviews on phosphorus pentoxide. A toxicity review on inorganic phosphorus compounds that included phosphorus pentoxide, was consulted for relevant information (U.S. EPA, 1989). Literature searches for studies relevant to the derivation of provisional toxicity values for phosphorus pentoxide (CASRN 1314-56-3) were conducted in MEDLINE, TOXLINE special, and DART/ETIC (1960's - July 2007); BIOSIS (August 2000 - July 2007); TSCATS/TSCATS 2, CCRIS, GENETOX, HSDB, and RTECS (not date limited); and Current Contents (February 2007 - July 2007). 2 ------- 9-25-2007 Due to its high affinity for water, phosphorus pentoxide is used as drying agent. It is also used in the manufacture of other chemicals and surfactants as a catalyst in air blowing of asphalt and in other applications (U.S. EPA, 1989). Phosphorus pentoxide dissolves in water with great liberation of heat, forming metaphosphoric acid (HPO3) and then phosphoric acid (H3PO4). The empirical formula for phosphorus pentoxide is P4O10. This document has passed the STSC quality review and peer review evaluation indicating that the quality is consistent with the SOPs and standards of the STSC and is suitable for use by registered users of the PPRTV system. REVIEW OF PERTINENT LITERATURE Human Studies The only information available regarding human exposure to phosphorus pentoxide is that from an occupational study conducted by Dutton et al. (1993). The investigators studied lung function in workers exposed to phosphorus pentoxide, phosphoric acid, fluorides and coal tar pitch volatiles while refining phosphorus rock to obtain elemental phosphorus. Maximum air levels measured in the study were 2.23 mg/m3 phosphorus pentoxide, 4.21 mg/m3 fluorides and 1.04 mg/m3 coal tar pitch volatiles; levels of phosphoric acid were not provided. No additional information regarding exposure levels was reported and sampling and analytical methods were not discussed. All 131 employees of the refinery underwent annual pulmonary function testing (4-8 annual determinations). Estimated years of exposure in work area where respiratory irritant levels exceeded "recommended levels" were used as the exposure index. The years of exposure ranged from less than 5 to more than 20, with substantial numbers of workers at the higher durations. The recommended levels were 1 mg/m3 for phosphorus pentoxide, 2.5 mg/m3 for fluorides and 0.2 mg/m3 for coal tar pitch volatiles. Regression analyses of individual mean values for percent predicted pulmonary function against years of exposure revealed no statistically significant reductions in forced vital capacity (FVC), forced expiratory volume in 1 second (FEVi) and forced exploratory flow rate from 25% to 75% of FVC (FEF25-75) for nonsmokers or former smokers. In smokers, although statistically significant reductions occurred in all three parameters, these disappeared when adjustment for the effect of smoking was made. No conclusions regarding phosphorus pentoxide can be drawn from this study. Animal Studies No information was located regarding the effects of phosphorus pentoxide in animals following oral exposure. The only data regarding inhalation exposure to phosphorus pentoxide are acute toxicity data provided by Ballantyne (1981) in an abstract. The investigator exposed adult male rats, rabbits, mice and guinea pigs for 1 hour to phosphorus pentoxide smoke (36- 2130 mg/m3), generated by burning red phosphorus in an air stream, followed by a 14-day observation period. The respective 1-hour LC50 values were 1217, 1689, 271 and 61 mg/m3. Most deaths occurred during or within 24 hours of exposure. In all species, the respiratory tract was the target of toxicity. Ballantyne (1981) stated that concentrations (in mg/m3) of phosphorus 3 ------- 9-25-2007 pentoxide not associated with respiratory tract pathology in 14-day survivors were 450 in rats and rabbits, 111 in mice and <36 in guinea pigs. FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC ORAL p-RfD VALUES FOR PHOSPHORUS PENTOXIDE There are no oral data for phosphorus pentoxide. White phosphorus smoke, which is used as a screening smoke by the military, contains phosphorus pentoxide as a major constituent. There is an RfD for white phosphorus on IRIS (U.S. EPA, 1993). Therefore, white phosphorus was considered as a potential surrogate for derivation of the RfD. The RfD for white phosphorus on IRIS is based on critical effects of parturition mortality and forelimb hair loss in a one- generation reproduction study in rats (Condray, 1985). Little is known regarding the pharmacokinetics and mechanism of action of orally administered white phosphorus, but the available data suggest that some of the effects may be due to white phosphorus itself, and that white phosphorus may be transformed not only to phosphoric acid, but also to phosphine in the body (ATSDR, 1997). Phosphorus pentoxide would not be expected to undergo transformation to phosphine in the body. In addition, some of the characteristic effects of white phosphorus exposure by the inhalation, oral and dermal routes have not been seen in the studies of white phosphorus smoke, the mixture that contains phosphorus pentoxide. These effects include the critical effects on which the RfD is based (parturition mortality and forelimb hair loss), fatty degeneration of the liver, phossy jaw in humans and a particular pattern of bone effects in developing humans and animals (ATSDR, 1997; U.S. EPA, 1989, 1993). Accordingly, derivation of an RfD for phosphorus pentoxide by analogy to white phosphorus is not recommended. DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC INHALATION p-RfC VALUES FOR PHOSPHORUS PENTOXIDE The inhalation data available for phosphorus pentoxide are limited to an occupational study of workers exposed to phosphorus pentoxide, phosphoric acid, fluorides and coal tar pitch volatiles (Dutton et al., 1993). Pulmonary function tests conducted on the workers several times a year did not reveal any significant alterations. There is also information on acute lethal concentrations in four animal species presented in abstract form (Ballantyne, 1981). This information is inadequate for RfC derivation. Because the major environmental transformation of phosphorus pentoxide is by hydrolysis to phosphoric acid, and an RfC for phosphoric acid is available on IRIS, we explored the possibility of using phosphoric acid as a surrogate chemical for derivation of the RfC. Phosphorus pentoxide is an extremely hygroscopic substance that is used as a drying agent. Phosphorus pentoxide reacts readily with water to form phosphoric acid. The reaction with water is exothermic releasing 70,000 calories (Bayer, 1954). Phosphorus pentoxide will even extract the elements of water from many other substances themselves considered good dehydrating agents (i.e., it converts pure HNO3 into N2O5 and H2SO4 into SO3) (Cotton et al., 1999). The Dutton occupational study suggests that the pentoxide was measured in the 4 ------- 9-25-2007 workplace air. Therefore, we cannot conclude that the inhalation exposure was only the hydrolysis product, phosphoric acid. In addition, we have no conclusive evidence of complete and immediate hydrolysis. Due to the highly exothermic nature of the hydrolysis process, at least part of the toxicity can be a result of this process occurring in the lung. Therefore, we have no basis for using phosphoric acid as a surrogate for phosphorous pentoxide. Lacking other relevant studies, development of inhalation toxicity values is precluded. PROVISIONAL CARCINOGENICITY ASSESSMENT FOR PHOSPHORUS PENTOXIDE Weight-of-Evidence Descriptor There are no data with which to assess the potential carcinogenicity of phosphorus pentoxide. Under the 2005 Guidelines for Carcinogen Assessment (U.S. EPA, 2005), there is inadequate information to assess the carcinogenic potential of phosphorus pentoxide. Quantitative Estimates of Carcinogenic Risk Derivation of quantitative estimates of cancer risk for phosphorus pentoxide is precluded by the lack of suitable data. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2007. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH. Aranyi, C., M.C. Henry, S.C. Vana et al. 1988a. Effects of multiple intermittent inhalation exposures to red phosphorus/butyl rubber obscurant smokes in Sprague-Dawley rats. Inhalation Toxicology, Premier Issue, p. 65-78 ATSDR (Agency for Toxic Substances and Disease Registry). 1997. Toxicological Profile for White Phosphorus. Online, http://www.atsdr.cdc.gov/toxprofiles/tpl03.html ATSDR (Agency for Toxic Substances and Disease Registry). 2007. Toxicological Profile Information Sheet. Online, http://www.atsdr.cdc. gov/toxpro2 .html Ballantyne, B. 1981. Acute inhalation toxicity of phosphorus pentoxide smoke. Toxicologist. 1:140. Bayer, H.G.A. 1954. Lesions of human bronchial tract caused by incendiary bombs containing phosphorus. Am. Med. Assoc. Arch. Oto. 59:319-321. Condray, J.R. 1985. Elemental yellow phosphorus one-generation reproduction study in rats. IR-82-215; IRDNo. 401-189. Monsanto Company, St. Louis, MO. 5 ------- 9-25-2007 Cotton, F.A., G. Wilkinson, C.A. Murillo et al. (Eds.). 1999. Advanced Inorganic Chemistry. Chapter 10: The group 15 elements: P, As, Sb, Bi. p. 380-443. Dutton, C.B., M.J. Pigeon, P.M. Renzi, P.J. Feustel, R.E. Dutton and G.D. Renzi. 1993. Lung function in workers refining phosphorus rock to obtain elementary phosphorus. J. Occup. Med. 3 5(10): 1028-33. IARC (International Agency for Research on Cancer). 2007. Search IARC Monographs. Online, http://monographs.iarc.fr/ NIOSH (National Institute for Occupational Safety and Health). 2007. NIOSH Pocket Guide to Chemical Hazards. Online. http://www.cdc.gOv/niosh/npg/npgd0000.html#F OSHA (Occupational Safety and Health Administration). 2007. OSHA Standard 1910.1000 TableZ-1. Part Z, Toxic and Hazardous Substances. Online. http://www.osha-slc.gov/OshStd data/1910 1000 TABLE Z-l.html U.S. EPA. 1989. Summary Review of Health Effects Associated with Elemental and Inorganic Phosphorus Compounds: Health Issue Assessment. Prepared by the Office of Health and Environmental Assessment for the Office of Air Quality Planning and Standards, Washington, DC. EPA 600/8-89/072. U.S. EPA. 1991. Chemical Assessments and Related Activities. Office of Health and Environmental Assessment, Washington, DC. April. U.S. EPA. 1993. Integrated Risk Information System (IRIS). IRIS Assessment for White Phosphorus. Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Online, http://www.epa.gov/iris/subst/0460.htm U.S. EPA. 1994. Chemical Assessments and Related Activities. Office of Health and Environmental Assessment, Washington, DC. December. U.S. EPA. 1995. Integrated Risk Information System (IRIS). Online. IRIS Assessment for Phosphoric Acid. Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Accessed 2007. http://www.epa.gov/iris/subst/0697.htm U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by the Office of Research and Development, National Center for Environmental Assessment, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. July 1997. EPA/540/R-97/036. NTIS PB 97-921199. U.S. EPA. 2005. Guidelines for Carcinogen Risk Assessment. Risk Assessment Forum, Washington, DC. EPA/630/P-03/001F. Federal Register 70(66): 17765-17817. Online. http://www.epa.gov/raf U.S. EPA. 2006. 2006 Edition of the Drinking Water Standards and Health Advisories. Office of Water, Washington, DC. EPA 822-R-06-013. Online. http://www.epa.gov/waterscience/drinking/standards/dwstandards.pdf 6 ------- 9-25-2007 U.S. EPA. 2007. Integrated Risk Information System (IRIS). Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Online. http://www.epa.gov/iris/ WHO (World Health Organization). 2007. Online Catalogs for the Environmental Criteria Series. Online, http://www.who.int/dsa/cat98/zehc.htm 7 ------- |