U.S. Environmental Protection Agency Hazard Characterization Document December, 2009 SCREENING-LEVEL HAZARD CHARACTERIZATION SPONSORED CHEMICAL 2,2',2",2m-(l-Ethane-diyldinitrilo)tetrakisacetonitrile (CASRN 5766-67-6) SUPPORTING CHEMICAL Propylenediaminetetraacetonitrile (CASRN 110057-45-9) 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 Set1'2) 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.) and Science Direct. 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 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. ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2009 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 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 December, 2009 Chemical Abstract Service Registry Number (CASRN) Sponsored Chemcial 5766-67-6 Supporting Chemical 110057-45-9 Chemical Abstract Index Name Sponsored Chemcial 2,2,,2M,2,M-(l-Ethane-diyldinitrilo)tetrakisacetonitrile (EDTN) Supporting Chemical Propylenediaminetetraacetonitrile (PDTN) Structural Formula \ r\ a -J \ N V (EDTN) 1 N N V (PDTN) CASRN 5766-67-6 is a solid material that has high water solubility and low vapor pressure. It is expected to have moderate mobility in soil. Volatilization is considered low based on the estimated Henry's Law constant. The rate of hydrolysis is considered negligible based upon data from the supporting chemical, CASRN 110057-45-9. The rate of atmospheric photooxidation is considered moderate. It is expected to have moderate persistence (P2) and low bioaccumulation potential (Bl). Acute oral and acute dermal toxicity of the supporting chemical, CASRN 110057-45-9, to rats is low. CASRN 110057-45-9 is not irritating to rabbit skin and is not a dermal sensitizer in guinea pigs. Repeated oral exposure of rats to CASRN 110057-45-9 resulted in a slightly decreased survival in females and increased liver enzyme, increased relative liver weight (males only) and minimal hepatocellular hypertrophy in both sexes with a LOAEL of 1000 mg/kg-bw/day. In a combined reproductive/developmental toxicity screening test, maternal toxicity was seen at 500 mg/kg-bw/day; however, no reproductive or developmental effects were noted with aNOAEL of 500 mg/kg-bw/day, the highest dose tested. CASRN 110057-45-9 did not induce gene mutations in bacteria and did not induce chromosomal aberrations in mammalian cells in vitro. The acute toxicity values of CASRN 110057-45-9 (supporting chemical) for fish, aquatic invertebrates, and aquatic plants are >100 mg/L. 3 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2009 The sponsor, Akzo Nobel Functional Chemicals, Inc., submitted a Test Plan and Robust Summaries to EPA for 2,2',2",2"'-(l-ethane-diyldinitrilo)tetrakisacetonitrile (EDTN) [CASRN 5766-67-6] on December 26, 2002. EPA posted the submission on the ChemRTK HPV Challenge website on January 24, 2003 (http ://www. epa. gov/chemrtk/pub s/ summaries/acetonit/c 1417 9tc.htm). EPA comments on the original submission were posted to the website on May 28, 2003. Public comments were also received and posted to the website. The sponsor submitted updated/revised documents on July 11, 2003, which were posted to the ChemRTK website on August 21, 2003. The sponsor proposed reduced health effects testing, claiming that EDTN is a closed-system intermediate (CSI) under the HPV Challenge Program. EPA's evaluation of the original and revised/updated information indicated that the chemical does not meet the criteria to fully support the CSI status for this chemical and that the chemical does not qualify for reduced testing. Therefore data for reproductive toxicity are needed for the purposes of the HPV Challenge Program. The sponsor did not submit data for developmental toxicity and proposed in its revised test plan (dated July 11, 2003) to conduct a combined reproductive/developmental toxicity screening test on EDTN. EPA has not received these data to date. Justification for Supporting Chemical The sponsor submitted data for propylenediaminetetraacetonitrile (PDTN) (CASRN 110057-45- 9) as a supporting chemical. EDTN and PDTN have similar chemical structures with the only difference being that PDTN has one more carbon atom between the two nitrogen atoms. Both chemicals have four identical acetonitrile groups which determine the function and reactivity of EDTN and PDTN. Due to the similarity, EDTN and PDTN have similar physical/chemical properties. As expected, the structural similarity in structure, physical/chemical properties and reactivity suggests that EDTN and PDTN will be metabolized in similar pathways indicating that the toxicity profile of these structurally similar chemicals is expected to be the same. Therefore, EPA agrees with the use of PDTN to address data gaps for EDTN for the purposes of the HPV Challenge Program, and ChAMP. 1. Chemical Identity 1.1 Identification and Purity The HPV submission4 for this chemical did not include information on purity in the Test Plan (2003). However, where indicated in robust summaries the purity of the test material (CASRN 110057-45-9, Supporting Chemical) was 99.2% (July 2003). 4Akzo Nobel Functional Chemicals, Inc.,ny (2003). EDTN Robust SummariesCASRN 5766-67-6. http ://www. epa. gov/chemrtk/pub s/ summaries/acetonit/c 1417 9tc. htm ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2009 1.2 Physical-Chemical Properties The physical-chemical properties of CASRN 5766-67-6 (EDTN) and 110057-45-9 (PDTN) are summarized in Table 1. CASRN 5766-67-6 is a solid material that has high water solubility and low vapor pressure. Table 1. Physical-Chemical Properties of EDTN and PDTN1 Property EDTN PDTN CASRN 5766-67-6 110057-45-9 Molecular Weight 216.2 230.2 Physical State Solid Solid Melting Point 159°C (estimated); 128°C (measured)2 73-74°C (measured) Boiling Point 427°C (estimated) Decomposes above 231°C (measured) Vapor Pressure 7.5x10"" mm Hg at 25°C (estimated) 3.19x10""mm Hg at 25°C (estimated) 1.43xl0"3 mm Hg at 20°C (measured) Water Solubility 1 x 106 mg/L at 25°C (estimated) 1 x 106 mg/L at 25°C (estimated) 1,670 mg/L at 18°C (measured) Dissociation Constant (PKa) -2.5 (estimated)3 2.5 (estimated)3 Henry's Law Constant 7.1 x 10"22 atm-nrVmole (estimated)4 9.4xl0"22 atm-m3/mole (estimated)4 Log K0w -2.17 (estimated) -1.68 (estimated) -1.3 (measured) 1 Akzo Nobel Functional Chemicals, Inc. July 23, 2003. Revised Robust Summary and Test Plan for Acetonitrile, 2,2',2",2"'-(l,2-ethanediyldinitrilo)tetrakis-. http://www.epa.gov/chemrtk/pubs/summaries/acetonit/cl4179tc.htm. 2SRC. The Physical Properties Database (PHYSPROP). Syracuse, NY: Syracuse Research Corporation. Access October 15, 2008. http://www.svrres.com/esc/phvsprop.htm. 3SPARC. 2008. Online pKa and Property Calculator v. 4.2.1405-s4.2.1408. Accessed October 27, 2008. http://ibmlc2.chem.uga.edu/sparc/. 4U.S. EPA. 2008. Estimation Programs Interface Suite™ for Microsoft® Windows, v 3.20. U.S. Environmental Protection Agency, Washington, DC, USA. http://www.epa.gov/opptintr/exposure/pubs/episuite.htm. 2. General Information on Exposure 2.1 Production Volume and Use Pattern EDTN (CASRN 5766-67-6) had an aggregated production and/or import volume in the United States of 10 to 50 million pounds during the calendar year 2005. 5 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2009 The IUR information submitted on the industrial processing and use, and commercial and consumer use was all claimed as confidential. The HPV submission states that the chemical is primarily used as a chemical intermediate. 2.2 Environmental Exposure and Fate No quantitative information is available on releases of this chemical to the environment. The environmental fate properties are provided in Table 2. CASRN 5766-67-6 is a solid material that has high water solubility and low vapor pressure. It is expected to have moderate mobility in soil. Volatilization is considered low based on the estimated Henry's Law constant. The rate of hydrolysis is considered negligible based upon data from the supporting chemical, CASRN 110057-45-9. The rate of atmospheric photooxidation is considered moderate. It is expected to have moderate persistence (P2) and low bioaccumulation potential (Bl). Table 2. Environmental Fate Characteristics of EDTN and PDTN1 Property EDTN PDTN CASRN 5766-67-6 110057-45-9 Photodegradation Half- life 4.6 hours (estimated) 4.4 hours (estimated) Hydrolysis Half-life No data 5.3 years at pH 4 and 25°C; 3.9 years at pH 7 and 25°C; 0.3 years at pH 9 and 25°C Biodegradation No data (not readily biodegradable) (RA) 0% after 28 days (not readily biodegradable) Bioconcentration BCF = 3.2 (estimated)2 BCF = 3.2 (estimated)2 Log Koc 3.3 (estimated)2 3.6 (estimated)2 Fugacity (estimated for analogs using Level III Model) Air = <0.01% Water = 39.8% Soil = 60.2% Sediment = 0.01% Air = <0.01% Water = 49.5% Soil = 50.4% Sediment = 0.09% Persistence3 P2 (moderate) P2 (moderate) Bi oaccumul ati on3 Bl (low) Bl (low) 1 Akzo Nobel Functional Chemicals, Inc. July 23, 2003. Revised Robust Summary and Test Plan for Acetonitrile, 2,2',2",2"'-(l,2-ethanediyldinitrilo)tetrakis-. http://www.epa.gov/chemrtk/pubs/summaries/acetonit/cl4179tc.htm. 2U.S. EPA. 2008. Estimation Programs Interface Suite™ for Microsoft® Windows, v 3.20. U.S. Environmental Protection Agency, Washington, DC, USA. http://www.epa.gov/opptintr/exposure/pubs/episuite.htm. 3Federal Register. 1999. Category for Persistent, Bioaccumulative, and Toxic New Chemical Substances. Federal Register 64, Number 213 (November 4, 1999) pp. 60194-60204. 6 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2009 3. Human Health Hazard The human health hazard data are summarized in Table 3. Acute Oral Toxicity PDTN (CASRN110057-45-9, Supporting Chemical) Wistar rats (3/sex/dose) were administered PDTN in polyethylene glycol via gavage at 2000 mg/kg-bw and observed for 15 days. One of three females died on day 3. LD50 > 2000 mg/kg-bw Acute Dermal Toxicity PDTN (CASRN 110057-45-9, Supporting Chemical) Wistar rats (5/sex/dose) were administered PDTN dermally at 2000 mg/kg-bw under unspecified conditions for 24 hours and observed for 15 days. There was no mortality. LD50 > 2000 mg/kg-bw Repeated-Dose Toxicity PDTN (CASRN 110057-45-9, Supporting Chemical) Wistar rats (10/sex/dose) were administered PDTN in polyethylene glycol via gavage at 50, 200 or 1000 mg/kg-bw/day, once daily, 7 days/week, for 28 days. One female from the high-dose group died on day 23 of the study. At the high dose, changes in clinical chemistry included a significant increase in alanine aminotransferase (ALT) activity of males and females. High-dose males showed a significant increase in liver-to-body-weight ratio and minimal-to-slight centrilobular hepatocellular hypertrophy was observed in males and females in the high dose group. LOAEL = 1000 mg/kg-bw/day (based on liver effects and decreased survival) NOAEL = 200 mg/kg-bw/day Reproductive/Developmental Toxicity In a combined reproductive/developmental toxicity screening test, Wistar rats (10/sex/dose) were administered EDTN via gavage at 0, 50, 250 or 750 mg/kg-bw/day, once daily, 7 days/week during 2 weeks prior to mating, through mating (males), gestation and lactation until post-partum day 4 (females). The high dose for females was decreased to 500 mg/kg-bw/day after 13 days of treatment. Males were dosed for 35 days and females were dosed for 42 days. Parental toxicity indicated by mortality (1 female), trend toward decreased body weight and body gain (both sexes), decreased food consumption (females) and pigmented, mottled kidneys (females) at 750/500 mg/kg-bw/day. Percent pup survival was decreased at 500 mg/kg-bw/day (because one dam had only 3 of 14 pups survive). No treatment-related effects were noted in ovaries, testes or epididymides during microscopic examination. No other reproductive effects were seen. No statistically significant differences were detected among the groups in mean corpora lutea, implantation sites, liter size, and mean number of pus born or alive on postnatal day 0. Percent pre- and post-implantation losses were not statistically different across the groups. 7 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2009 LOAEL for Parental Toxicity = 750/500 mg/kg-bw/day (based on mortality and effects on body weight and food consumption) NAOEL for Maternal Toxicity = 250 mg/kg-bw/day NOAEL for Reproductive/Developmental Toxicity = 500 mg/kg-bw/day (based on no effects at the highest dose tested) Genetic Toxicity — Gene Mutation In vitro PDTN (CASRN110057-45-9, Ssupporting chemical) In a bacterial reverse mutation assay, Salmonella typhimurium strains TA1535, TA1537, TA98 and TA100 and Escherichia coli strain WP2uvrA were exposed to PDTN in dimethyl sulfoxide at concentrations of 3, 10, 33, 100, 333, 1000, 3330 or 5000 |ig/plate in the absence of metabolic activation and 100, 333, 1000, 3330 or 5000 |ig/plate in the presence of metabolic activation. No toxicity was observed at any concentration with or without metabolic activation. No data regarding the use or response of positive controls or numbers of revertants were provided. PDTN was not mutagenic in this assay. Genetic Toxicity — Chromosomal Aberrations In vitro PDTN (CASRN 110057-45-9, Supporting Chemical) Cultured peripheral human lymphocytes were exposed to PDTN in dimethyl sulfoxide at concentrations of 333, 1000 or 3330 |ig/mL in the absence of metabolic activation for 24- and 48-hour treatments and 100, 333, 1000, 3330 or 5000 |ig/mL in the presence of metabolic activation for a 3-hour treatment. No toxicity was observed at any dose level with or without metabolic activation. No data regarding the use or response of positive controls were provided. PDTN caused no structural chromosome damage. PDTN did not induce chromosomal aberrations in this assay. Additional Information Skin Irritation PDTN (CASRN 110057-45-9, Supporting Chemical) New Zealand White rabbits (3 males) were administered PDTN (0.5 g in water) dermally under semi-occluded conditions for 4 hours and assessed for up to 72 hours after exposure. There were no signs of erythema or edema at any observation period. PDTN was not irritating to rabbit skin in this assay. 8 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2009 Sensitization PDTN (CASRN110057-45-9, Supporting Chemical) In a guinea pig maximization test, Dunkin-Hartley guinea pigs (10 females) were administered 0.1% PDTN in the induction phase on day 1; 50% on day 8 and 50% during the challenge phase on day 21. No further details regarding exposure conditions were provided. There was no irritation observed at 24 and 48 hours after challenge application. PDTN was not sensitizing in this assay. Conclusion: Acute oral and acute dermal toxicity of the supporting chemical, CASRN 110057- 45-9, to rats is low. CASRN 110057-45-9 is not irritating to rabbit skin and is not a dermal sensitizer in guinea pigs. Repeated oral exposure of rats to CASRN 110057-45-9 resulted in a slightly decreased survival in females and increased liver enzyme, increased relative liver weight (males only) and minimal hepatocellular hypertrophy in both sexes with a LOAEL of 1000 mg/kg-bw/day. In a combined reproductive/developmental toxicity screening test, maternal toxicity was seen at 500 mg/kg-bw/day; however, no reproductive or developmental effects were noted with a NOAEL of 500 mg/kg-bw/day, the highest dose tested. CASRN 110057-45-9 did not induce gene mutations in bacteria and did not induce chromosomal aberrations in mammalian cells in vitro. 4. Hazard to the Environment The environmental hazard data are summarized in Table 3. Acute Toxicity to Fish PDTN (CASRN 110057-45-9, Supporting chemical) Zebrafish (Danio rerio, 10/group) were exposed to PDTN at nominal concentrations of 100 mg/L under static conditions for 96 hours. Measured concentrations were 107 - 109 mg/L. No mortality was observed during the study. 96-h LC50 > 100 mg/L Acute Toxicity to Aquatic Invertebrates PDTN (CASRN 110057-45-9, Supporting Chemical) Water fleas (Daphnia magna, 10 - 20/group) were exposed to PDTN at nominal concentrations of 1, 10 or 100 mg/L under static conditions for 48 hours. The measured concentration was 110 mg/L (for the nominal concentration of 100 mg/L). There was no mortality during the study. 48-h EC50 > 100 mg/L 9 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2009 Toxicity to Aquatic Plants PDTN (CASRN110057-45-9, Supporting Chemical) Green algae (Pseudokirchneriella subcapitata) were exposed to PDTN at nominal concentrations of 10, 18, 32, 56, 100 or 180 mg/L under static conditions for 72 hours. Measured concentrations were 10.5, 34 and 189 mg/L (for the nominal concentrations of 10, 32 and 180 mg/L, respectively). Three replicates were tested per concentration. No data regarding control growth were provided. 72-h EC50 (growth) = 129 mg/L 72-h EC50 (biomass) = 60 mg/L Conclusion: The acute toxicity values of CASRN 110057-45-9 (supporting chemical) for fish, aquatic invertebrates, and aquatic plants are >100 mg/L. 10 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2009 Table 3. Summary Table of the Screening Information Data Set as Submitted under the U.S. HPV Challenge Program Endpoints SPONSORED CHEMICAL 2,2\2",2'"-(l-Ethane- diyldinitrilo)tetrakisacetonitrile (EDTN) (5766-67-6) SUPPORTING CHEMICAL Propylenediaminetetraacetonitrile (PDTN) (110057-45-9) Summary of Human Health Data Acute Oral Toxicity LD5o (mg/kg-bw) No Data >2000 (RA) >2000 Acute Dermal Toxicity LD5o (mg/kg-bw) - >2000 Repeated-Dose Toxicity NOAEL/LOAEL Oral (mg/kg-bw/day) No Data NOAEL = 200 (28-d) LOAEL= 1000 (28-d) (RA) NOAEL = 200 (28-d) LOAEL = 1000 (28-d) Reproductive/Developmental Toxicity NOAEL/LOAEL Oral (mg/kg-bw/day) Parental Toxicity Reproductive/Developmental Toxicity NOAEL = 250 LOAEL = 500/750 NOAEL = 500/750 Genetic Toxicity - Gene Mutation In vitro No Data Negative (RA) Negative Genetic Toxicity - Chromosomal Aberrations In vitro No Data Negative (RA) Negative Additional Information Skin Irritation Skin Sensitization Not irritating Not a sensitizer Summary of Environmental Effects - Aquatic Toxicity Data Fish 96-h LCS0 (mg/L) No Data >100 (RA) > 100 11 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2009 Table 3. Summary Table of the Screening Information Data Set as Submitted under the U.S. HPV Challenge Program Endpoints SPONSORED CHEMICAL 2,2\2",2'"-(l-Ethane- diyldinitrilo)tetrakisacetonitrile (EDTN) (5766-67-6) SUPPORTING CHEMICAL Propylenediaminetetraacetonitrile (PDTN) (110057-45-9) Aquatic Invertebrates 48-h ECso (mg/L) No Data >100 (RA) > 100 Aquatic Plants 72-h ECso (mg/L) (growth) (biomass) No Data 129 60 (RA) 129 60 - indicates that endpoint was not addressed for this chemical; (RA) read across 12 ------- |