U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 SCREENING-LEVEL HAZARD CHARACTERIZATION Isodecyl Diphenyl Phosphate (CASRN 29761-21-5) The High Production Volume (HPV) Challenge Program1 was conceived as a voluntary initiative aimed at developing and making publicly available screening-level health and environmental effects information on chemicals manufactured in or imported into the United States in quantities greater than one million pounds per year. In the Challenge Program, producers and importers of HPV chemicals voluntarily sponsored chemicals; sponsorship entailed the identification and initial assessment of the adequacy of existing toxicity data/information, conducting new testing if adequate data did not exist, and making both new and existing data and information available to the public. Each complete data submission contains data on 18 internationally agreed to "SIDS" (Screening Information Data Setl 2) endpoints that are screening-level indicators of potential hazards (toxicity) for humans or the environment. The Environmental Protection Agency's Office of Pollution Prevention and Toxics (OPPT) is evaluating the data submitted in the HPV Challenge Program on approximately 1400 sponsored chemicals by developing hazard characterizations (HCs). These HCs consist of an evaluation of the quality and completeness of the data set provided in the Challenge Program submissions. They are not intended to be definitive statements regarding the possibility of unreasonable risk of injury to health or the environment. The evaluation is performed according to established EPA guidance2,3 and is based primarily on hazard data provided by sponsors; however, in preparing the hazard characterization, EPA considered its own comments and public comments on the original submission as well as the sponsor's responses to comments and revisions made to the submission. In order to determine whether any new hazard information was developed since the time of the HPV submission, a search of the following databases was made from one year prior to the date of the HPV Challenge submission to the present: (ChemID to locate available data sources including Medline/PubMed, Toxline, HSDB, IRIS, NTP, AT SDR, IARC, EXTOXNET, EPA SRS, etc.), STN/CAS online databases (Registry file for locators, ChemAbs for toxicology data, RTECS, Merck, etc.), Science Direct and ECHA4. OPPT's focus on these specific sources is based on their being of high quality, highly relevant to hazard characterization, and publicly available. OPPT does not develop HCs for those HPV chemicals which have already been assessed internationally through the HPV program of the Organization for Economic Cooperation and Development (OECD) and for which Screening Initial Data Set (SIDS) Initial Assessment Reports (SIAR) and SIDS Initial Assessment Profiles (SIAP) are available. These documents are presented in an international forum that involves review and endorsement by governmental 1 U.S. EPA. High Production Volume (HPV) Challenge Program; http://www.epa.gov/chemrtk/index.htm. 2 U.S. EPA. HPV Challenge Program - Information Sources; http://www.epa.gov/chemrtk/pubs/general/guidocs.htm. 3 U.S. EPA. Risk Assessment Guidelines; http://cfpub.epa.gov/ncea/raf/rafguid.cfm. 4 European Chemicals Agency, http://echa.europa.eu. ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 authorities around the world. OPPT is an active participant in these meetings and accepts these documents as reliable screening-level hazard assessments. These hazard characterizations are technical documents intended to inform subsequent decisions and actions by OPPT. Accordingly, the documents are not written with the goal of informing the general public. However, they do provide a vehicle for public access to a concise assessment of the raw technical data on HPV chemicals and provide information previously not readily available to the public. 2 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Chemical Abstract Service Registry Number (CASRN) 29761-21-5 Chemical Abstract Index Name Phosphoric Acid, Isodecyl Diphenyl Ester Structural Formula qfJD o—P=0 ch3 SMILES: 0=P(0C1CCCCC1)(0C2CCCCC2)0CCCCCCCC(C)C Summary Isodecyl diphenyl phosphate is a clear odorless liquid with low vapor pressure and low water solubility. It is expected to possess low mobility in soil. It was found to be both readily biodegradable and inherently biodegradable in standard OECD tests and therefore is not expected to be persistent in the environment. Volatilization is considered moderate. Isodecyl diphenyl phosphate may undergo hydrolysis in the environment; however, the rate of this potential reaction is not known. The rate of atmospheric photooxidation is considered moderate. Isodecyl diphenyl phosphate is expected to have low persistence (PI) and low bioaccumulation potential (Bl). The acute oral and dermal toxicity of isodecyl diphenyl phosphate in rats and rabbits respectively, is low. The acute inhalation toxicity of isodecyl diphenyl phosphate in rats is high. In a 90-day dietary repeated-dose toxicity study in rats, isodecyl diphenyl phosphate showed changes in hematology and clinical chemistry parameters in males at >11 mg/kg- bw/day and in females at >12 mg/kg-bw/day; the NOAEL for systemic toxicity is not established. No specific reproductive toxicity study was provided, however in the 90-day dietary repeated-dose toxicity study previously mentioned, no treatment-related effects were observed on male and female reproductive organs examined during the study. In an oral prenatal developmental toxicity study, no treatment-related effects on dams or developmental malformations on offspring were observed; the NOAEL for developmental toxicity is 3000 mg/kg-day (highest dose tested). Isodecyl diphenyl phosphate was not mutagenic to bacteria or mammalian cells in vitro. Isodecyl diphenyl phosphate did not induce chromosomal aberrations in mammalian cells in vitro. Isodecyl diphenyl phosphate is irritating to rabbit skin and eye. Isodecyl diphenyl phosphate is not irritating or a dermal sensitizer to human skin. For isodecyl diphenyl phosphate, the 48-h LCso for aquatic invertebrates is 0.22 mg/L. The 21-d NOEC for reproduction is < 0.0045 mg/L for aquatic invertebrates and the LOEC for reproduction is 0.0076 mg/L. 3 ------- U.S. Environmental Protection Agency September, 2014 Hazard Characterization Document Data gaps for acute toxicity to fish and toxicity to aquatic plants were identified under the HPV Challenge Program. 4 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 The sponsor, Ferro Corporation, submitted a Test Plan and Robust Summaries to EPA for isodecyl diphenyl phosphate (CASRN 29761-21-5; CA Index name: phosphoric acid, isodecyl diphenyl ester) on January 2, 2003. EPA posted the submission on the ChemRTK HPV Challenge website on January 29, 2003 (http://www.epa.gov/chemrtk/pubs/summaries/isodecvl/cl4216tc.htm). EPA comments on the original submission were posted to the website on June 4, 2003. Public comments were also received and posted to the website. The sponsor submitted updated/revised documents on December 21, 2004, which were posted to the ChemRTK website on January 13, 2005. 1. Chemical Identity 1.1 Identification and Purity Phosphoric acid, isodecyl diphenyl ester is a clear odorless liquid with low vapor pressure and low water solubility. It is used as an intermediate in chemical processing, principally of plastics. Isodecyl diphenyl phosphate (IDP; CASRN 29761-21-5) is a general purpose plasticizer for most commercial resins including polyvinyl chloride and its copolymers, cellulose nitrate, cellulose acetate-butyrate, ethyl cellulose, polymethyl methacrylate and polystyrene. IDP is a clear, odorless liquid. Ferro Corporation sells isodecyl diphenyl phosphate under the Santicizer® S-148 trade name. The purity of IDP is 92% where indicated. 1.2 Physical-Chemical Properties The physical-chemical properties of isodecyl diphenyl phosphate are summarized in Table 1. Table 1. Physical-Chemical Properties of Isodecyl diphenyl phosphate1 Property Value CASRN 29761-21-5 Molecular Weight 390.5 Physical State Clear, odorless liquid Melting Point <-50 °C (measured pour point) Boiling Point Decomposed at 245°C and 10 mm Hg (measured) Vapor Pressure <0.1 mm Hg at 150°C (measured)2 0.5 mm Hg at 200°C (measured)2 3.3><10"7 mm Hg at 25°C (estimated)3 Dissociation Constant (pKa) Not applicable Henry's Law Constant 4.4><10"7 atm-m3/mole (estimated)4 Water Solubility 0.03 - 0.75 mg/L at 25°C (measured) Log Kow 5.44 (measured) 5 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 1 Ferro Corporation. 2004. Test Plan Revision/Updates for Isodecyl Diphenyl Phosphate. Available online at http://www.epa.gov/chemrtk/pubs/summaries/isodecvl/cl4216tc.htm as of October 4, 2012. 2 Flick EW. 1991. Industrial Solvents Handbook. 4th Edition. Park Ridge, NJ: Noyes Data Corp. p. 859. 3 N0M05. 1987. Programs to Enhance PC-Gems Estimates of Physical Properties for Organic Compounds. The Mitre Corp. The sponsor reported a value of 1.6 x 10~5 mm Hg at 25 °C. This value was obtained from a published paper [Boethling,R.S., Cooper,J.C. (1985). Environmental fate and effects of triaryl and tri-alkyl/aryl phosphate esters. RES. REV. 94:49-99], Examination of this paper indicates that this value is an estimated value using the Grain method. 4 U.S. EPA. 2012. Estimation Programs Interface Suite™ for Microsoft® Windows, v4.10. U.S. Environmental Protection Agency, Washington, DC, USA. Available online at http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm as of October 4, 2012. 2. General Information on Exposure 2.1 Production Volume and Use Pattern Isodecyl diphenyl phosphate had an aggregated production and/or import volume in the United States between 1 to 10 million pounds during calendar year 2005. Non-confidential information in the IUR indicated that the industrial processing and uses of the chemical include other plastics product manufacturing as flame retardants. Non-confidential commercial and consumer uses of this chemical include rubber and plastic products. 2.2 Environmental Exposure and Fate Isodecyl diphenyl phosphate is expected to have low mobility in soil. It was degraded 62 and 63% using an activated sludge inoculum after 28 days as measured by CO2 evolution and the modified Strum (OECD 301B) test. It was shown to be inherently biodegradable using a semi- continuous activated sludge (SCAS OECD 302A) test. A substance identified as alkyl (C=8 - 11) diphenyl phosphate achieved 0 - 1 % of its theoretical biochemical oxygen demand (BOD) using an activated sludge and the modified MITI (OECD 301C) test. Volatilization is considered moderate. Isodecyl diphenyl phosphate is susceptible to hydrolysis however, the rate is unknown. The hydrolysis half-lives for two similar structures: triphenylphosphate and O, O- diethyl-O-phenylphosphate were over 100 days suggesting that the hydrolysis half-life of isodecyl diphenyl phosphate is long. The rate of atmospheric photooxidation is considered moderate. Isodecyl diphenyl phosphate is expected to have low persistence (PI) and low bioaccumulation potential (Bl). The environmental fate properties are provided in Table 2. 6 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Table 2. Environmental Fate Properties of Isodecyl diphenyl phosphate1 Property Value CASRN 29761-21-5 Photodegradation Half-life 3.0 hours (estimated)2 Hydrolysis Half-life No data. Susceptible to hydrolysis. Biodegradation 62 - 63 % after 28 days (readily biodegradable, OECD 301B); 45-75 % after 24 hours (inherently biodegradable, OECD 302A); 0 - 1 % after 28 days (not readily biodegradable, OECD 301C)3'4 Bioaccumulation Factor 168 - 362 (measured in carp at 0.1 mg/L)3'4; 223 - 1,120 (measured in carp at 0.01 mg/L)3'4; BAF = 290.7 (estimated)2 Log Koc 5.0 (estimated)2 Fugacity (Level III Model)2 Air (%) Water (%) Soil (%) Sediment (%) 0.1 7.8 52.9 39.1 Persistence5 PI (low) Bi oaccumul ati on5 Bl (low) 1 Ferro Corporation. 2004. Test Plan Revision/Updates for Isodecyl Diphenyl Phosphate. Available online at http://www.epa.gov/chemrtk/pubs/summaries/isodecvl/cl4216tc.htm as of October 4, 2012. 2 U.S. EPA. 2012. Estimation Programs Interface Suite™ for Microsoft® Windows, v4.10. U.S. Environmental Protection Agency, Washington, DC, USA. Available online at http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm as of October 4, 2012. 3 Chemicals Inspection and Testing Institute. 1992. Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1, pp 3-129. 4Data was for a substance which had CASRN 29761-21-5 but was named Alkyl (C=8 - 11) diphenyl phosphate 5Federal Register. 1999. Category for Persistent, Bioaccumulative, and Toxic New Chemical Substances. Federal Register 64, Number 213 (November 4, 1999) pp. 60194-60204. Conclusion: Isodecyl diphenyl phosphate is a clear odorless liquid with low vapor pressure and low water solubility. It is expected to possess low mobility in soil. It was found to be both readily biodegradable and inherently biodegradable in standard OECD tests and therefore is not expected to be persistent in the environment. Volatilization is considered moderate. Isodecyl diphenyl phosphate may undergo hydrolysis in the environment; however, the rate of this potential reaction is not known. The rate of atmospheric photooxidation is considered moderate. Isodecyl diphenyl phosphate is expected to have low persistence (PI) and low bioaccumulation potential (Bl). 3. Human Health Hazard A summary of the human health toxicity data for SIDS endpoints is provided in Table 3. 7 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Acute Oral Toxicity (1) Male rats (10/dose, strain not specified) were administered a single dose of isodecyl diphenyl phosphate (purity not specified) in corn oil via oral gavage at 5, 50 or 5000 mg/kg and observed for 14 days. No additional details were provided. LDso > 5000 mg/kg (2) Sprague-Dawley rats (5/sex) were administered isodecyl diphenyl phosphate (purity not specified) via gavage at 5010 mg/kg and observed for 14 days. No mortalities were observed. This study was summarized from TSCATS submission OTS0206274; Doc ID 878211416. LD50 > 5010 mg/kg (3) Wistar rats (5/sex/group) were administered isodecyl diphenyl phosphate (92% purity) via gavage at 0, 5, 10, 20, 25 or 30 mL/kg (~0, 5400, 10,800, 21,600, 27,000 or 32,400 mg/kg) and observed for up tol4 days. One rat at 27,000 mg/kg died (sex not specified). No further details were provided. This study was summarized from TSCATS submission OTS0519255. LD50 > 27,000 mg/kg Acute Dermal Toxicity New Zealand White rabbits (5/sex) were administered undiluted isodecyl diphenyl phosphate (purity not specified) via the dermal route at 2010 mg/kg to clipped, abraded skin under occluded conditions for 24 hours and observed for up tol4 days. No mortalities were observed. This study was summarized from TSCATS submission OTS0206274; Doc ID 878211417. LD50 > 2010 mg/kg Acute Inhalation Toxicity Sprague-Dawley albino rats (6 males) were exposed whole-body to isodecyl diphenyl phosphate (purity not specified) as a vapor at 1.6 mg/L for 6 hours and observed for up tol4 days. No mortalities were observed. This study was summarized from TSCATS submission OTS0546050. LC50 > 1.6 mg/L Repeated-Dose Toxicity Sprague-Dawley rats (30 rats/sex/group) were administered isodecyl diphenyl phosphate (90.8- 91.6% purity) via the diet at measured concentrations of 0, 140, 1400 or 7000 ppm (approximately 0, 9, 100 or 510 mg/kg-bw/day in males and 0, 10, 114 or 566 mg/kg-bw/day in females5) for 90 days. Endpoints examined included mortality, clinical signs, body weights, food consumption, organ weights, gross pathology and histopathology (control and high-dose groups only; the liver was examined in all groups). Hematology, clinical chemistry, and urinalysis examinations were measured in 10/sex/group at interim and terminal sacrifice. No 5 Doses calculated using mean analytical test substance concentrations in diet and mean food consumption rates. 8 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 treatment-related effects on mortality or clinical signs were observed. A statistically significant decrease in body weight gain and food consumption was observed in both sexes at the high-dose level. At terminal sacrifice, hematological changes included: increased hematocrit in all treatment groups of both sexes; decreased mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration in both sexes in all treatment groups; increased red blood cell count in mid- and high-dose males and all groups of treated females; increased mean corpuscular volume in low- and high-dose males; reduced white blood cell count in all groups of treated females (but not in males); and decreased hemoglobin and increased platelet count in high-dose females. Effects on clinical chemistry at terminal sacrifice included: decreased creatinine in all groups of treated females and mid- and high-dose males; decreased glucose in mid- and high-dose males and females; decreased serum glutamic oxaloacetic transaminase in mid- and high-dose males; increased phosphorus in mid- and high-dose females and high-dose males; increased y-glutamyl transpeptidase in mid- and high-dose females and high-dose males; and increased cholesterol in high-dose males. Dose-related increases were observed in the levels of bilirubin (both sexes) and urobilinogen (males) in the urine. Absolute and relative liver weights were increased in mid- and high-dose males. In females absolute liver weights were increased at the high-dose and relative liver weights were increased at mid- and high-doses. The combined incidence of hepatocellular hypertrophy and/or hyperplasia increased in a dose-related manner in both sexes; the incidence was increased significantly (p < 0.01) relative to controls in high-dose animals of both sexes. High-dose females also demonstrated an increase in hepatocellular brown pigment. Electron microscopy (conducted in 2 high-dose and 2 control males) showed increased smooth endoplasmic reticulum in the hepatocytes of high-dose males compared to controls. Information provided in the robust summary was supplemented with details from a TSCATS submission (OTS0518925). LOAEL (systemic toxicity)m/f ~ 9/10 mg/kg-bw/day (based on increased red blood cell count in females, increased hematocrit in both sexes, increased mean corpuscular volume in males, decreased mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration in both sexes, decreased white blood cell counts in females and decreased creatinine in females) NOAEL = Not established Reproductive Toxicity No specific reproductive toxicity studies are available. In the 90-day dietary toxicity study in rats described previously, reproductive organs, including the ovaries, mammary gland, uterus (corpus and cervix), testes and epididymides were examined microscopically in the control and at ~ 510 and 556 mg/kg-bw/day in males and females, respectively. No treatment-related differences were observed. 9 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Developmental Toxicity In a prenatal developmental toxicity study, pregnant female Charles River COBS rats (25/group) were administered isodecyl diphenyl phosphate (purity not specified) via oral gavage at 0, 300, 1000 or 3000 mg/kg-day on days 6 through 19 of gestation. Endpoints examined included mortality, clinical signs, maternal body weights, numbers of viable and nonviable fetuses, early and late implantation sites, resorptions and corpora lutea, fetal body weights, and fetal external, soft tissue and skeletal malformations. One dam died at 300 mg/kg-day during treatment. Alopecia was observed in dams at 1000 and 3000 mg/kg-day. Dry red material was reported around the mouth, nose and forelimbs of dams in all groups. There was no difference in body weight between the treatment groups and control group. There was a slight but statistically significant increase (p value not reported) in the number of post-implantation losses in the high- dose group, but this was not considered to be biologically relevant because there were no significant differences in the mean number of viable fetuses in the high-dose group compared with the control group. There were no biologically meaningful differences or dose-related trends in uterine parameters (wet weight, number and location of viable and nonviable fetuses and numbers of early and late implantation sites, resorptions and corpora lutea) or the number of fetuses or litters with malformations or developmental variations. NOAEL (maternal and developmental toxicity) = 3000 mg/kg-day (highest dose tested) Genetic Toxicity — Gene Mutation In vitro (1) In a bacterial reverse mutation assay, Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, TA1538, and Saccharomyces cerevisiae D4 were exposed to isodecyl diphenyl phosphate (purity not specified) at five unspecified concentrations in the presence and absence of metabolic activation. Positive and negative controls were tested concurrently, but control results were not provided. Cytotoxicity was evaluated, but the results were not reported. Isodecyl diphenyl phosphate was not mutagenic in this assay. (2) In abacterial reverse mutation assay, Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537, were exposed to isodecyl diphenyl phosphate (purity not specified) in DMSO at 0, 100, 333, 1000, 3333 or 10,000 [j,g/plate in the presence and absence of metabolic activation. Positive and negative controls were tested concurrently and demonstrated appropriate responses. No cytotoxicity or precipitate was noted. This information was summarized from a National Toxicology Program study (Study ID: 083218). Isodecyl diphenyl phosphate was not mutagenic in this assay. (3) In a mammalian cell mutation assay, Fischer mouse lymphoma L5178Y cells were exposed to isodecyl diphenyl phosphate (purity not specified) in DMSO at five unspecified concentrations in the presence and absence of metabolic activation. Positive and negative controls were tested concurrently, but control results were not provided. Isodecyl diphenyl phosphate was not mutagenic in this assay. 10 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Genetic Toxicity - Chromosomal Aberrations In vitro Chinese hamster ovary (CHO) cells were exposed to isodecyl diphenyl phosphate at six concentrations between 50 - 3905 |ag/mL for 4 and 20 hours without metabolic activation and for 4 hours with metabolic activation. Cytogenetic concentrations were 15, 30.5, 61, 488, 1952 and 3905 |ig/mL at the same time intervals previously mentioned without and with metabolic activation. Precipitation was observed during initiation and termination of all cultures at 61 |ig/mL or greater. Cytotoxicity was observed at 3905 |ig/mL. A decrease in cell count was observed in cultures without activation at 4 hours (38%) and 20 hours (31%), and with metabolic activation at 4 hours (34%). The mitotic index was decreased at 3905 |ig/mL without activation at 4 hours (15%) and 20 hours (8%), and with activation at 4 hours (7%). The incidence of structural chromosome aberrations was within the normal range in all cultures. Controls produced the expected effects. Isodecyl diphenyl phosphate did not induce chromosomal aberration in this study. Additional Information Eye Irritation (1) Three rabbits (1 male, 2 female; strain not specified) were administered 0.1 mL undiluted isodecyl diphenyl phosphate (purity not specified) to the conjunctival sac and observed for 5 days. After one hour, observations included moderate discharge, mild redness, slight edema and slight corneal cloudiness. Within five days, only slight erythema was present in 2/3 animals. The maximum average irritation score, observed 24 hours after dosing, was 21.3 out of a possible 110. This study was summarized from TSCATS submission OTS0519402. Isodecyl diphenyl phosphate was mildly irritating to rabbit eyes in this study. (2) New Zealand White rabbits (6 males, 3 females) were administered 0.1 mL undiluted isodecyl diphenyl phosphate (purity not specified) to the conjunctival sac of the right eyes. The treated eyes of 3 males were washed with deionized water for one minute beginning 30 seconds after treatment. All animals were observed for 7 days following administration. The maximum average irritation scores, observed 1 hour after dosing, for non-washed and washed eyes were 5.5 and 4 (out of 110), respectively. Although the maximum score was greater in non-washed eyes, effects in washed eyes took longer to resolve. All effects were resolved within the 7-day observation period. This study was summarized from TSCATS submission OTS0206274; Doc ID 878211419. Isodecyl diphenyl phosphate was slightly irritating in non-washed rabbit eyes and mildly irritating in washed rabbit eyes in this study. (3) Three rabbits (1 male, 2 female; strain not specified) were administered 0.1 mL undiluted isodecyl diphenyl phosphate (purity not specified) to the conjunctival sac of the right eye and observed for 7 days. After one hour, moderate discharge, mild redness and slight edema were observed. All eyes appeared normal after 48 hours. The maximum average irritation score 11 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 (observed 1 hour after dosing) was 10.6 out of a possible 110. This study was summarized from TSCATS submission OTS0519417. Isodecyl diphenyl phosphate was slightly irritating to rabbit eyes in this study. (4) Six New Zealand White rabbits (sex not specified) were administered 0.1 mL of undiluted isodecyl diphenyl phosphate (purity not specified) to the conjunctival sac for 24 hours and observed for up to 7 days. After 10 minutes, slight erythema and moderate copious discharge were observed. All eyes appeared normal after 72 hours. The maximum irritation score (observed 1 hour after dosing) was 8 out of a possible 110. Study information was obtained from TSCATS submission OTS0546050. Isodecyl diphenyl phosphate was slightly irritating to rabbit eyes in this study. Skin Irritation (1) Six New Zealand White rabbits (sex not specified) were exposed to 0.5 mL undiluted isodecyl diphenyl phosphate (purity not specified) via the dermal route under unspecified conditions for 24 hours and observed for up to 14 days. Exposure resulted in moderate to severe erythema and edema during the first 2 days and a defatting effect with skin sloughing off after 10 - 14 days. The primary irritation score (24, 72 hour average) was 5.1 out of 8. This study was summarized from TSCATS submission OTS0546050. Isodecyl diphenyl phosphate was moderately irritating to rabbit skin in this study. (2) New Zealand White rabbits (2 males, 1 female) were exposed via the dermal route to 0.5 mL undiluted isodecyl diphenyl phosphate (purity not specified) on clipped, intact skin for 24 hours and observed for up to 10 days. Slight erythema with very slight edema was observed at 48 hours post-application; this effect resolved within 5 days. There was a slight defatting effect with skin sloughing off after 7-10 days. The average maximum irritation score (at 48 hours) was 3 out of 8. This study was summarized from TSCATS submission OTS0519417. Isodecyl diphenyl phosphate was mildly irritating to rabbit skin in this study. (3) In the acute dermal toxicity study previously described, New Zealand White rabbits exposed to 2010 mg/kg of undiluted isodecyl diphenyl phosphate (purity not specified) on clipped, abraded skin under occluded conditions for 24 hours showed mild erythema (average score 1.4 out of 4) and very slight edema (average score 0.4 out of 4) 24 hours after treatment. This study was summarized from TSCATS submission OTS0206274; Doc ID 878211417. Isodecyl diphenyl phosphate was slightly irritating to rabbit skin in this study. (4) In a skin corrosivity study, New Zealand White rabbits (3/sex) were exposed to 0.5 mL undiluted isodecyl diphenyl phosphate (purity not specified) via the dermal route under occluded conditions for 4 hours and observed for 48 hours. There were two intact and two abraded skin sites per rabbit. In all rabbits, both intact and abraded skin sites demonstrated very slight erythema, which was resolved by 48 hours in 3/6 rabbits. All rabbits demonstrated very slight edema at abraded skin sites, which was resolved by 48 hours in 5/6 rabbits. There were no signs of tissue destruction (ulceration or necrosis) present on any test site at any of the observation 12 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 times. This study was summarized from TSCATS submission OTS0206274; Doc ID 878211420. Isodecyl diphenyl phosphate was slightly irritating to rabbit skin in this study. (5) New Zealand White rabbits (3/sex) were exposed to 0.5 mL undiluted isodecyl diphenyl phosphate (purity not specified) via the dermal route under occluded conditions for 24 hours and observed for 72 hours. There were two intact and two abraded skin sites per rabbit. Exposure produced mean irritation grades of 1.12 and 1.38 (out of 4) for intact and abraded skin, respectively. The primary irritation score was determined to be 1.25 out of 8. This study was summarized from TSCATS submission OTS0206274; Doc ID 878211418. Isodecyl diphenyl phosphate was slightly irritating to rabbit skin in this study. (6) Rabbits (2 males, 1 female; strain not specified) were exposed via the dermal route to an unspecified amount of undiluted isodecyl diphenyl phosphate (purity not specified) on intact skin under unspecified conditions and observed for 7 days. Slight to mild erythema with no edema was observed at 24 hours post-application. Skin returned to normal in all animals within 5 days. The average maximum irritation score, observed at 24 hours, was 1.3 out of 8. This study was summarized from TSCATS submission OTS0519402. Isodecyl diphenyl phosphate was slightly irritating to rabbit skin in this study. (7) Volunteers (21 males and 29 females) were administered undiluted isodecyl diphenyl phosphate (Santicizer® 148) via the dermal route under occluded conditions for 24 hours for 3 days/week for a total of 15 applications. Skin was examined for primary irritation 24 hours after each treatment. There were no skin reactions following any of the applications in any volunteers. This study was summarized from TSCATS submission OTS0519407. Isodecyl diphenyl phosphate was not irritating to human skin in this study. Sensitization In the human skin irritation study described above, a challenge exposure of isodecyl diphenyl phosphate (Santicizer® 148) was applied to the original skin exposure site 14 days after the 15th (final) application. The site was observed for immediate and delayed reactions for 48 hours following application. No skin reactions were observed in any volunteers. This study was summarized from TSCATS submission OTS0519407. Isodecyl diphenyl phosphate was not sensitizing to human skin in this study. Conclusion: The acute oral and dermal toxicity of isodecyl diphenyl phosphate in rats and rabbits respectively, is low. The acute inhalation toxicity of isodecyl diphenyl phosphate in rats is high. In a 90-day dietary repeated-dose toxicity study in rats, isodecyl diphenyl phosphate showed changes in hematology and clinical chemistry parameters in males at >11 mg/kg-bw/day and in females at >12 mg/kg-bw/day; the NOAEL for systemic toxicity is not established. No specific reproductive toxicity study was provided, however in the 90-day dietary repeated-dose toxicity study previously mentioned, no treatment-related effects were observed on male and female reproductive organs examined during the study. In an oral prenatal developmental toxicity study, no treatment-related effects on dams or developmental malformations on offspring were observed; the NOAEL for developmental toxicity is 3000 mg/kg-day (highest 13 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 dose tested). Isodecyl diphenyl phosphate was not mutagenic to bacteria or mammalian cells in vitro. Isodecyl diphenyl phosphate did not induce chromosomal aberrations in mammalian cells in vitro. Isodecyl diphenyl phosphate is irritating to rabbit skin and eye. Isodecyl diphenyl phosphate is not irritating or a dermal sensitizer to human skin. Table 3. Summary Table of the Screening Information Data Set as Submitted under the U.S. HPV Challenge Program - Human Health Data Endpoint Isodecyl diphenyl phosphate (29761-21-5) Acute Oral Toxicity LD5o (mg/kg) >5000 Acute Dermal Toxicity LD5o (mg/kg) >2010 Acute Inhalation Toxicity LCso (mg/L) > 1.6 Repeated-Dose Toxicity NOAEL/LOAEL Oral (mg/kg-bw/day) (Rat, 90-Day) NOAEL = Not Established LOAEL(m/f) = 11/12 Reproductive Toxicity NOAEL/LOAEL Oral (mg/kg-bw/day) Reproductive Toxicity No treatment-related effects were observed following evaluation of reproductive organs in a 90-day dietary repeated-dose toxicity study in rats. Developmental Toxicity NOAEL/LOAEL Oral (mg/kg-bw/day) Maternal & Developmental Toxicity NOAEL = 3000 (highest dose tested) LOAEL = Not Established Genetic Toxicity - Gene Mutation In vitro Negative Genetic Toxicity - Chromosomal Aberrations In vitro Negative Additional Information Eye Irritation Skin Irritation Skin Sensitization Irritating Irritating (rabbit) Not Irritating (human) Negative Measured data in bold 4. Hazard to the Environment A summary of aquatic toxicity data submitted for SIDS endpoints is provided in Table 4. 14 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Acute Toxicity to Fish No adequate data. Acute Toxicity to Aquatic Invertebrates Water fleas {Daphnia magna; < 24 hours old; 15/group) were exposed to CASRN 29761-21-5 (purity not specified; dissolved in dimethylformamide) at nominal concentrations of 0 (solvent control), 0.028, 0.047, 0.078, 0.13, 0.22, 0.36 or 0.60 mg/L under static conditions for 48 hours. Exposures occurred at a pH of 8.1 ± 0.2 and a temperature of 22°C. No mortalities were observed at 24 hours in any of the concentration groups. At 48 hours, percent mortality at 0.13, 0.22, 0.36 and 0.60 mg/L was 20, 60, 87 and 80%, respectively. No mortalities were observed at lower concentrations (TSCATS# OTS0546208). 48-h LCso = 0.22 mg/L Toxicity to Aquatic Plants No adequate data. Chronic Toxicity to Aquatic Invertebrates Water fleas (Daphnia magna) were exposed to CASRN 29761-21-5 (purity not specified; dissolved in dimethylformamide) at nominal concentrations of 0 (dilution water and solvent controls), 0.0094, 0.019, 0.038, 0.075 or 0.150 mg/L under flow-through conditions for 21 days. Corresponding mean measured concentrations were < 0.004, < 0.004, < 0.0045, 0.0076, 0.020 and 0.049 mg/L. Exposures occurred at a pH of 8.1 - 8.4, a temperature of 23 ± 1°C and a dissolved oxygen concentration of 7.6 - 7.8 mg/L. All daphnids exposed to 0.049 mg/L died within 48 hours of initial exposure. Survival after 7 days and cumulative offspring production was significantly (p < 0.05) reduced at 0.020 mg/L. Offspring production was significantly (p < 0.05) decreased at 0.0076 mg/L on test days 8, 9, and 11 compared to the solvent control and on test days 11-17 compared to the dilution water control (TSCATS# OTS0546208). 21-d LOEC (reproduction) = 0.0076 mg/L 21-d NOEC (reproduction) < 0.0045 mg/L Conclusion: For isodecyl diphenyl phosphate, the 48-h LCso for aquatic invertebrates is 0.22 mg/L. The 21-d NOEC for reproduction is < 0.0045 mg/L for aquatic invertebrates and the LOEC for reproduction is 0.0076 mg/L. 15 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Table 4. Summary of the Screening Information Data Set as Submitted under the U.S. HPV Challenge Program - Aquatic Toxicity Data Endpoint Isodecyl diphenyl phosphate (29761-21-5) Fish 96-h LCso (mg/L) No adequate data Aquatic Invertebrates 48-h LCso (mg/L) 0.22 Aquatic Plants 96-h ECso (mg/L) No adequate data Chronic Toxicity to Aquatic Invertebrates 21-d NOEC/LOEC (mg/L) (reproduction) NOEC < 0.0045 LOEC = 0.0076 Bold = measured data (i.e., derived from testing) 16 ------- |