United States Environmental Protection 1=1 m m Agency EPA/690/R-05/019F Final 8-16-2005 Provisional Peer Reviewed Toxicity Values for o-Phthalic acid (CASRN 88-99-3) 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 i.v. intravenous IRIS Integrated Risk Information System IUR inhalation unit risk 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 1 ------- MTD maximum tolerated dose MTL median threshold limit NAAQS National Ambient Air Quality Standards NOAEL no-observed-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-observed-effect level OSF oral slope factor p-IUR provisional inhalation unit risk p-OSF provisional oral slope factor p-RfC provisional inhalation reference concentration 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 ------- 8-16-05 PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR 0-PHTHALIC ACID (CASRN 88-99-3) 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 science and available information evolve, PPRTVs are initially derived with a three-year life-cycle. However, EPA Regions (or the EPA HQ Superfund Program) sometimes request that a frequently used PPRTV be reassessed. 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. 1 ------- 8-16-05 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 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 HEAST (U.S. EPA, 1997) reports that data are inadequate for quantitative risk assessment of o-phthalic acid. There is no listing for o-phthalic acid on IRIS (U.S. EPA, 2005a) or in the Drinking Water Standards and Health Advisories list (U.S. EPA, 2002). The CARA lists (U.S. EPA, 1991, 1994) report a HEEP for Phthalic Acids (U.S. EPA, 1986). ATSDR (2003) has not published a Toxicological Profile for o-phthalic acid, and no Environmental Health Criteria Document is available (WHO, 2003). ACGIH (2003), NIOSH (2003), and OSHA (2003) have not developed occupational exposure limits for o-phthalic acid. Neither IARC (2003) nor NTP (2003) have evaluated the carcinogenicity of o-phthalic acid. Literature searches were conducted from 1985 through August, 2003 for studies relevant to the derivation of provisional toxicity values for o-phthalic acid. Databases searched included: TOXLINE (supplemented with NTIS and BIOSIS updates), MEDLINE, CANCERLIT, TSCATS, RTECS, 2 ------- 8-16-05 CCRIS, DART/ETICBACK, EMIC/EMICBACK, HSDB, and GENETOX. Additional literature searches from August 2003 through October 2004 were conducted by NCEA-Cincinnati using MEDLINE, TOXLINE, Chemical and Biological Abstracts databases. REVIEW OF PERTINENT DATA Human Studies No studies of the toxicity of o-phthalic acid in humans were located in the available literature. Animal Studies Murakami et al. (1986) fed groups of 5 male Wistar rats diets containing 0, 0.5%, or 5% of o-phthalic acid for 34-36 days (estimated doses of 0, 500, or 5000 mg/kg-day assuming a growing rat consumes 10% of its body weight per day in a subchronic study). Body weight was monitored throughout the study. At termination, serum chemistry, liver mitochondrial enzyme activity, organ weights (liver, kidney, spleen, testes), and histopathology (liver, kidney, testes) were evaluated. Body weights in both treated groups were similar to controls throughout the study. Serum chemistry and liver enzyme analyses showed no effects. Organ weights in treated rats did not differ from controls, and no lesions were found by light microscopic examination. The high dose of 5000 mg/kg-day was aNOAEL in this study. Ema et al. (1997) exposed groups of 11 pregnant female Wistar rats to 0, 1.25, 2.5, or 5% of o-phthalic acid in the diet (0, 1021, 1763, or 2981 mg/kg-day, respectively, as estimated by the study authors) from gestation days 7 through 16. Rats were observed daily for signs of clinical toxicity, and body weights, food consumption, and water consumption were recorded daily. On sacrifice at gestation day 20, the numbers of live and dead fetuses and uterine weights were determined. Fetuses were sexed and evaluated for external malformations; 2/3 of the fetuses from each litter were evaluated for skeletal malformations, while the others were evaluated for internal malformations. No deaths or clinical signs of toxicity were observed in pregnant rats. Body weight gain was lowered on gestation days 7-16 (when treatment occurred) in the 2.5 and 5% groups. Following cessation of treatment, body weight gains returned to normal or increased above controls; food consumption data during these periods suggest that changes in body weight were related to decreased food consumption. No differences between control and treated animals were seen in numbers of corpora luteaper litter, implantations per litter, resorptions and dead fetuses per litter, live fetuses per litter, postimplantation loss per litter, or sex ratio of live fetuses. The weight of high-dose male fetuses, but not female fetuses, was decreased relative to controls (=4%). No fetuses with external, skeletal, or internal malformations were found in any exposure group. Isolated skeletal variations occurred, but not at incidences significantly different from 3 ------- 8-16-05 controls. The degree of vertebral ossification was slightly lower in the high-dose group than in controls. This study found evidence of mild fetotoxicity (slightly reduced vertebral ossification and body weight of male fetuses) at the high-dose of 2981 mg/kg-day. Maternal body weight during gestation was reduced in the 1763 and 2981 mg/kg-day groups, apparently due to reduced food intake. In other developmental toxicity studies, o-phthalic acid was not teratogenic or fetotoxic to the offspring of rabbit dams treated orally at 149.5 mg/kg-day (Smith et al., 1965) or mouse dams injected intraperitoneally with up to 400 mg/kg during gestation (Kohler et al., 1971). Studies of male reproductive toxicity had mixed results. No testicular effects were observed in male rats treated by gavage with a single dose of 2300 mg/kg of o-phthalic acid (Cater et al., 1977). Oishi and Hiraga (1980) reported no changes in testes weight or the levels of testosterone or dihydrotestosterone in the serum or testes of rats exposed to diets containing 2% (=2000 mg/kg-day) of o-phthalic acid for one week. Body, liver, and kidney weights were also unaffected. There was a slight, significant increase in the level of zinc in the kidneys, but the toxicological significance of this change is not clear. Jha et al. (1998) exposed groups of male Swiss mice to daily intraperitoneal injections of 0, 40, or 80 mg/kg of o-phthalic acid for 5 days, and then evaluated the animals for the presence of dominant lethal mutations over the following 28 days. Treatment resulted in a significant increase in dominant lethal mutations in meiotic as well as postmeiotic stages of spermatogenesis; the most dramatic changes were seen from days 15-21 and 22-28 post- treatment. In a parallel study reported in the same manuscript, treatment of male mice with a single dose of 300 mg/kg of o-phthalic acid resulted in a dose-related increase in the number of abnormal sperm heads, which was most pronounced at 3 weeks post-treatment. Other Studies o-Phthalic acid was negative for mutagenicity at concentrations up to 2-10 mg/plate in Salmonella typhimurium strains TA97, TA98, TA100, TA102, TA104, and TA1535, either with or without S9 mixture (Agarwal et al., 1985; Sayato et al., 1987). Results were also negative for induction of chromosomal aberrations and sister-chromatid exchange in CHO cells (Phillips et al., 1982). o-Phthalic acid produced dominant lethal mutations in male mice treated in vivo (Jha et al., 1998). 4 ------- 8-16-05 DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC ORAL RfD VALUES FOR o-PHTHALIC ACID Data on the oral toxicity of o-phthalic acid in humans are not available. Murakami et al. (1986) conducted a 5-week dietary study of o-phthalic acid in rats that failed to identify any compound-related effects at doses up to 5000 mg/kg-day. Ema et al. (1997) found onlymild fetotoxicity in rats exposed in utero to 2981 mg/kg-day. The effects may have been related to decreased maternal body weight during gestation in this group, which apparently resulted from reduced food intake. Other studies of gestational exposure found no effects produced by o- phthalic acid. Studies of effects on the male reproductive system by oral exposure were negative, although a study conducted by intraperitoneal injection reported production of abnormal sperm and dominant lethal mutations. In the absence of suitable oral studies of the subchronic or chronic toxicity of o-phthalic acid, derivation of subchronic or chronic oral p-RfD values is precluded. DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC INHALATION RfC VALUES FOR o-PHTHALIC ACID In the absence of subchronic or chronic data on the inhalation toxicity of o-phthalic acid in humans or animals, derivation of subchronic or chronic p-RfC values is precluded. DERIVATION OF A PROVISIONAL CARCINOGENICITY ASSESSMENT FOR o-PHTHALIC ACID Data on the potential carcinogenic effects of o-phthalic acid in humans or animals are not available. Mutagenicity studies in bacteria were negative, but o-phthalic acid produced dominant lethal mutations in male mice treated in vivo. Under the new Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005b), the data are inadequate for an assessment of human carcinogenic potential for o-phthalic acid. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2003. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH, Cincinnati, OH. 5 ------- 8-16-05 Agarwal, D.K., W.H. Lawrence, L.J. Nunez and J. Autian. 1985. Mutagenicity evaluation of phthallic acid esters and metabolites in Salmonella typhimurium cultures. J. Toxicol. Environ. Health. 16: 61-69. ATSDR (Agency for Toxic Substances and Disease Registry). 2003. Internet HazDat- Toxicological Profile Query. Online, http://www.atsdr.cdc.gov/toxpro2.html Cater, B.R., M.W. Cook, S.D. Gangolli and P. Grasso. 1977. Studies on dibutyl phthalate- induced testicular atrophy in the rat: Effect on zinc metabolism. Toxicol. Appl. Pharmacol. 41: 609-618. Ema, M., E. Miyawaki, A. Harazono and K. Kawashima. 1997. Developmental toxicity evaluation of phthalic acid, one of the metabolites of phthalic acid esters, in rats. Toxicol. Lett. 93: 109-115. IARC (International Agency for Research on Cancer). 2003. Search IARC Monographs. Online. http://193.51.164.il/cgi/iHound/Chem/iH Chem Frames.html Jha, A.M., A.C. Singh and M. Bharti. 1998. Germ cell mutagenicity of phthalic acid in mice. Mutat. Res. 422(3): 207-212. Kohler, F., W. Meise and H. Ockenfels. 1971. Teratogenicity of thalidomide metabolites. Experientia. 27:1149-1150. (Cited in U.S. EPA, 1986) Murakami, K., K. Nishiyama and T. Higuti. 1986. Toxicity of dibutyl phthalate and its metabolites in rats. Jpn. J. Hyg. 41(4): 775-780. NIOSH (National Institute for Occupational Safety and Health). 2003. Online NIOSH Pocket Guide to Chemical Hazards. Online, http://www.cdc.gov/niosh/npg/npgdcas.html NTP (National Toxicology Program). 2003. Management Status Report. Online. http://ntp-server.niehs.nih.gov/cgi/iH Indexes/ALL SRCH/iH ALL SRCH Frames.html Oishi, S. and K. Hiraga. 1980. Testicular atrophy induced by phthalic acid esters: Effect on testosterone and zinc concentrations. Toxicol. Appl. Pharmacol. 53: 35-41. OSHA (Occupational Safety and Health Administration). 2003. OSHA Standard 1910.1000 Table Z-l. Part Z, Toxic and Hazardous Substances. Online. http://www.osha-slc.gov/OshStd data/1910 1000 TABLE Z-l.html 6 ------- 8-16-05 Phillips, B.J., T.E.B. James and S.D. Gangolli. 1982. Genotoxicity studies of di(2- ethylhexyl)phthalate and its metabolites in CHO cells. Mutat. Res. 102(3): 297-304. Sayato, Y., K. Nakamuro and H. Ueno. 1987. Mutagenicity of products formed by ozonation of naphthoresorcinol in aqueous solutions. Mutat. Res. 189(3): 217-222. Smith, R.L., S. Fabio, H. Schumaker and R.T. Williams. 1965. Studies on the relationship between the chemical structure and embryotoxic activity of thalidomide and related compounds. In: Embryopathic Activity of Drugs, J.M. Robson, F.M. Sullivan and R.L. Smith, Ed. J. and A. Churchill, London. (Cited in U.S. EPA, 1986) U.S. EPA. 1986. Health and Environmental Effects Profile for Phthalic Acids (o-, m-, p-). Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. April, 1991. U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. December, 1994. 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. EPA/540/R-97/036. NTIS PB97-921199. U.S. EPA. 2002. 2002 Edition of the Drinking Water Standards and Health Advisories. Office of Water, Washington, DC. Summer 2002. EPA 822-R-02-038. Online. http://www.epa.gov/waterscience/drinking/standards/dwstandards.pdf U.S. EPA. 2005a. Integrated Risk Information System (IRIS). Office of Research and Development. National Center for Environmental Assessment, Washington, DC. Online. http ://www. epa. go v/iris/ U.S. EPA. 2005b. Guidelines for Carcinogen Risk Assessment. Office of Research and Development, National Center for Environmental Assessment, Washington, DC. EPA/63 0/P-03/001F. WHO (World Health Organization). 2003. Online catalogs for the Environmental Health Criteria Series. Online, http://www.who.int/dsa/cat97/zehcl.htm 7 ------- |