U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 SCREENING-LEVEL HAZARD CHARACTERIZATION SPONSORED CHEMICAL N,N,N',N'-Tetramethylethylenediamine (CASRN 110-18-9) 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 Set ) 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. 2 3 The evaluation is performed according to established EPA guidance ' 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 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 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 December, 2012 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, 2012 Chemical Abstract Service Registry Number (CASRN) Sponsored Chemical 110-18-9 Chemical Abstract Index Name Sponsored Chemical N,N,N',N'-Tetramethylethylenediamine Structural Formula CH, 1 3 H3c-rf^ sch3 ch3 SMILES: N(CCN(C)C)(C)C Summary 1,2-Ethanediamine, Nl,Nl,N2,N2-tetramethyl- is a liquid with high vapor pressure and high water solubility. It is expected to have high mobility in soil. Volatilization of 1,2- ethanediamine, Nl,Nl,N2,N2-tetramethyl- is low since this substance is expected to exist primarily as a cation in the environment, and cations do not volatilize. The rate of hydrolysis is expected to be negligible. The rate of atmospheric photooxidation is rapid. 1,2-Ethanediamine, Nl,Nl,N2,N2-tetramethyl- is expected to have moderate persistence (P2) and low bioaccumulation potential (Bl). The acute oral and inhalation toxicities of N,N,N',N'-tetramethylethylenediamine to rats, and the acute dermal toxicity to rabbits are moderate. N,N,N',N'-tetram ethyl ethyl enediamine was not mutagenic to bacterial cells in vitro. This substance is irritating to rabbit skin and eyes. No adequate data are available for the repeated-dose, reproductive, developmental toxicity and chromosomal aberrations endpoints. Data gaps for repeated-dose, reproductive, developmental and chromosomal aberrations endpoints were identified under the HPV Challenge Program. For N,N,N',N'-tetram ethyl ethyl enediamine, no data were submitted to evaluate acute toxicity to fish, aquatic invertebrates or aquatic plants. The acute toxicity to fish and invertebrates and toxicity to aquatic plants endpoints were identified as data gaps under the HPV Challenge Program. 3 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 The sponsor, Crompton Corporation, submitted a Test Plan and Robust Summaries to EPA for N,N,N',N'-tetramethylethylenediamine (CASRN 110-18-9 on August 27, 2003. EPA posted the submission on the ChemRTK HPV Challenge website on October 3, 2003 (http://www.epa.gov/oppt/chemrtk/pubs/summaries/nnnntetr/cl4715tc.htm). EPA comments on the original submission were posted to the website on February 5, 2004. Public comments were also received and posted to the website. 1. Chemical Identity 1.1 Identification and Purity Purity, where indicated in the 2003 Robust Summary, is high (98.9-99.5%). 1.2 Physical-Chemical Properties The physical-chemical properties of CASRN are summarized in Table 1. This chemical is a liquid with high water solubility and high vapor pressure at room temperature. The structure of the compound is provided in the Appendix. Table 1. Physical-Chemical Properties of 1,2-Ethanediamine, Nl,Nl,N2,N2-tetramethyl-1 Property Value CASRN 110-18-9 Molecular Weight 116.21 Physical State Liquid Melting Point -55°C (measured) Boiling Point 121°C (measured) Vapor Pressure 15.1 mm Hg at 25 °C (estimated)2 Dissociation Constant (pKa) 9.10 (measured)3 Elenry's Law Constant 5.6 x 10"8 atm-m3/mole (estimated)4 Water Solubility 877,700 mg/L at 25°C (estimated)4 Log Kow 0.3 (measured) 'Crompton Corporation. 2003. Test Plan and Robust Summary for N,N,N',N'-Tetramethylethylenediamine. Submitted by the Crompton Corporation. Available online at http://www.epa.gov/chemrtk/pubs/summaries/nnnntetr/cl4715tc.htm as of February 23, 2012. 2N0M05. 1987. Programs to Enhance PC-Gems Estimates of Physical Properties for Organic Compounds. The Mitre Corp. 3SRC. 2012. The Physical Properties Database (PHYSPROP). Syracuse, NY: Syracuse Research Corporation. Available online at http://www.svrres.com/esc/phvsprop.htm as of February 23, 2012. 4U.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 February 23,2012. 4 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 2. General Information on Exposure 2.1 Production Volume and Exposure This product is used as a biochemical reagent and epoxy resin crosslinking agent. N,N,N',N'- Tetramethylethylenediamine neutralizes acids in exothermic reactions to form salts plus water. 2.2 Environmental Exposure and Fate The environmental fate characteristics of 1,2-ethanediamine, Nl,Nl,N2,N2-tetramethyl-are provided in Table 2. 1,2-Ethanediamine, Nl,Nl,N2,N2-tetramethyl- is expected to have high mobility in soil. 1,2-Ethanediamine, Nl,Nl,N2,N2-tetramethyl- was not significantly degraded after 160 hours using a continuous stirred tank bioreactor (CSTB) to simulate a wastewater treatment plant (WWTP). Following a 20 day lag period, 1,2-ethanediamine, N1,N1,N2,N2- tetramethyl- was rapidly removed over the next 8 days, degrading 98% using the Zahn-Wellens (OECD 302B) test. Volatilization of 1,2-ethanediamine, Nl,Nl,N2,N2-tetramethyl- is low since this substance is expected to exist primarily as a cation in the environment, and cations do not volatilize. The rate of hydrolysis is expected to be negligible. The rate of atmospheric photooxidation is rapid. 1,2-Ethanediamine, N1 ,N1 ,N2,N2-tetramethyl- is expected to have moderate persistence (P2) and low bioaccumulation potential (Bl). Table 2. Environmental Fate Characteristics of 1,2-Ethanediamine, N1,N1,N2,N2- tetramethyl-1 Property Value CASRN 110-18-9 Table 2. Environmental Fate Characteristics of 1,2-Ethanediamine, N1,N1,N2,N2- tetramethyl-1 Property Value CASRN 110-18-9 Photodegradation Half-life 0.8 hours (estimated) Hydrolysis Half-life Stable Biodegradation Not degraded after 160 hours3; 98% after 28 days (inherently biodegradable)4 Bioaccumulation Factor BAF = 0.9 (estimated)2 Log Koc 1.2 (estimated)2 Fugacity (Level III Model)2 Air (%) Water (%) Soil (%) Sediment (%) 0.1 38.0 61.8 0.1 Persistence5 P2 (moderate) Bioaccumulation5 Bl (low) 5 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 'C romp ton Corporation. 2003. Test Plan and Robust Summary for N,N,N',N'- Tetramethylethylenediamine. Submitted by the Crompton Corporation. Available online at http://www.epa.gov/chemrtk/pubs/summaries/nnnntetr/c 14715tc.htm as of February 23, 2012. 2U.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 February 23, 2012. "3 Creaser CS; Lamarca DG; Dos Santos LMF; et al. 2003. On-line biodegradation monitoring of nitrogen-containing compounds by membrane inlet mass spectrometry. J Chem Technol Biotechnol 78(11): 1193-1200. 4Sykora V; Pitter P; Bittnerova I; et al. 2001. Biodegradability of Ethlenediamine-Based Complexing Agents. Water Res 35(8):2010-2016. 5Federal Register. 1999. Category for Persistent, Bioaccumulative, and Toxic New Chemical Substances. Federal Register 64, Number 213 (November 4, 1999) pp. 60194-60204. Conclusion: 1,2-Ethanediamine, Nl,Nl,N2,N2-tetramethyl- is a liquid with high vapor pressure and high water solubility. It is expected to have high mobility in soil. Volatilization of 1,2- ethanediamine, Nl,Nl,N2,N2-tetramethyl- is low since this substance is expected to exist primarily as a cation in the environment, and cations do not volatilize. The rate of hydrolysis is expected to be negligible. The rate of atmospheric photooxidation is rapid. 1,2-Ethanediamine, Nl,Nl,N2,N2-tetramethyl- is expected to have moderate persistence (P2) and low bioaccumulation potential (Bl). 3. Human Health Hazard A summary of health effects data submitted for SIDS endpoints is provided in Table 3. Acute Oral Toxicity (1) Sprague-Dawley rats (5 females and 3 males/dose) were exposed to a single dose of N,N,N',N'-tetramethylethylenediamine (Purity 98.9%) via gavage administration at 125, 250, 500, and 1000 mg/kg (females), or 0, 125, 500, 1000 and 2000 mg/kg (males) and observed for 14 days. Mortality was observed at doses > 250 mg/kg; all females treated at 1000 mg/kg and all males treated at 2000 mg/kg died on the day of exposure. LD50 females = 406 mg/kg LD50 males = 891 mg/kg (2) Female Sprague-Dawley rats (5/dose) were administered a single dose of N,N,N',N'- tetramethylethylenediamine (98.9% purity) via gavage administration at 125, 250 or 500 mg/kg and observed for 14 days. An additional group of three male rats were gavaged at 250 mg/kg- day. Mortality was observed in female rats treated at doses > 250 mg/kg; all females treated at 500 mg/kg died on the day of dosing. LD50 = 268 mg/kg 6 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 Acute Inhalation Toxicity Male and female CD(R) BR rats (5/sex/dose) were exposed to a single vapor concentration of N,N,N',N'-tetramethylethylenediamine (99.5% purity) at 1180 ppm (~ 5.6 mg/L) for 4 hours and observed for 14 days. No mortality occurred during the 14-day observation period. LC50 > 5.6 mg/L Acute Dermal Toxicity Female New Zealand White rabbits (5/dose) were exposed to a single dose of undiluted N,N,N',N'-tetramethylethylenediamine (98.9% purity) via the dermal route at 500, 1000 or 2000 mg/kg for 24 hours under occlusive conditions and observed for 14 days; three males were similarly exposed at 1000 mg/kg. All females treated at 2000 mg/kg- and one male treated at 1000 mg/kg died within 24 hours of exposure. LD50 (females) = 1230 mg/kg Repeated-Dose Toxicity Fischer 344 rats (10/sex/concentration) were exposed to vapors of N,N,N',N'- tetramethylethylenediamine (99% purity) at 0, 50, 250 or 750 ppm (~ 0.24, 1.2 or 3.6 mg/L) for 6 hours/day, 5 days/week for 9 days. All animals treated at the highest concentration died within the three days of exposure. Decreased body weight was observed at > 0.24 mg/L (males) and at 1.2 mg/L (both sexes). Hyperactivity, respiratory distress, corneal opacity, edema, keratitis and/or corneal necrosis was observed at all levels of treatment, with increased incidence and severity seen at higher concentrations. Treated rats showed decreases in absolute (and increased relative) brain (0.24 and 1.2 mg/L), liver (1.2 mg/L), kidney (1.2 mg/L), lung (1.2 mg/L) and testes weights (0.24 and 1.2 mg/L). Histopathology findings revealed treatment-related (ulcerative) lesions in the nasal mucosa and/or upper respiratory tract, squamous metaplasia of the larynx, and thymic atrophy at concentrations >1.2 mg/L. Corneal edema, lung discoloration, keratitis and squamous metaplasia of the nasal mucosa were observed at the lowest concentration (0.24 mg/L). Decedents from the highest exposure group (3.6 mg/L) showed ulcerative lesions in the cornea and nasal mucosa; epithelial cell necrosis of the larynx and congestion of the lungs and liver. Nasal lesions consisted primarily of degenerating respiratory and olfactory epithelia, with mucosal ulceration at > 1.2 mg/L. Organ weight and hematological determinations were not made for the highest treatment group (due to mortality); however, at necropsy, the histolopathogical examination of these animals showed lung discoloration, lung congestion and extensive degeneration/necrosis of the dermal epithelium surrounding the nares, with damage extending throughout the olfactory epithelium of the hard palate and into the respiratory epithelium of the upper trachea. Reproductive Toxicity No adequate data. 7 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 Developmental Toxicity No adequate data. Genetic Toxicity — Gene Mutation In vitro (1) Salmonella typhimurium (strains TA1535, TA1537, TA1538, TA98 and TA100) were exposed to aqueous N,N,N',N'-tetram ethyl ethyl enediamine (98.9% purity) at 100, 300, 1000, 3000 or 10,000 |ig/plate both in the presence and absence of metabolic activation. Cytotoxicity was observed at the highest concentration tested (10,000 |ig/plate). Positive controls (2- aminoanthracene, 4-nitro-o-phenylenediamine, sodium azide and 9-aminoacridine) and solvent (water) controls were tested concurrently and responded appropriately. The assay with strain TA100 was repeated due to bacterial contamination. No mutagenic activity was observed in any of the strains tested. N,N,N',N'-Tetramethylethylenediamine was not mutagenic in this assay. (2) Salmonella typhimurium (strains TA1535, TA1537, TA98 and TA100) were exposed to aqueous N,N,N',N' -tetram ethyl ethyl enediamine (99% purity) at 0, 100, 333, 1000, 3333 or 10,000 |ig/plate both in the presence and absence of metabolic activation. Cytotoxicity was not reported. Positive controls (2-aminoanthracene, 4-nitro-o-phenylenediamine, sodium azide and 9-aminoacridine) and solvent (water) controls were tested concurrently and responded appropriately. No mutagenic activity was observed in any of the strains tested. N,N,N',N'-Tetramethylethylenediamine was not mutagenic in this assay. Genetic Toxicity — Chromosomal Aberrations No adequate data. Additional Information Skin Irritation A 0.5 mL aliquot of undiluted N,N,N',N' -tetram ethyl ethyl enediamine (98.9% purity) was applied to the skin of rabbits for four hours (two males), two hours (one male and one female) or three minutes (three males and three females) under occlusive conditions. Animals were subsequently observed for 14 days. Moderate erythema, edema, necrosis, ecchymoses, scabs and alopecia were observed in the 4-hour treatment group. Moderate erythema, edema, necrosis, ulceration, ecchymosis, scabs and alopecia were observed in the 2-hour exposure group. Moderate erythema, minor edema, necrosis, ulceration, ecchymosis, fissuring, desquamation, scabs and alopecia were observed in the 3-minute exposure group. None of the observed treatment effects (necrosis, scabs, desquamation, and alopecia) resolved during the 14-day observation period. N,N,N',N'-Tetramethylethylenediamine was irritating to rabbit skin in this study. 8 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 Eye Irritation A 0.1 mL aliquot of undiluted N,N,N',N' -tetram ethyl ethyl enediamine (98.9% purity) was instilled into the right eye of rabbits (2/sex/dose); the untreated eye of each rabbit served as the control. Moderate to severe corneal injury, iritis, severe conjunctival irritation and hemorrhage of the nictitating membranes, were observed in treated rabbits. In addition, one rabbit developed a pus-like ocular discharge and corneal vascularization at seven days post-exposure. Another showed signs of corneal vascularization at 17 days post-exposure. Necrosis of the nictitating membrane and conjunctivae was observed in one rabbit. Adverse effects generally resolved within 17 days in three of four rabbits; however, one rabbit exhibited persistent corneal opacity and corneal vascularization at 21 days post-exposure. N,N,N',N'-Tetramethylethylenediamine was irritating to rabbit eyes in this study. Conclusion: The acute oral and inhalation toxicities of N,N,N',N'-tetramethyl ethyl enediamine to rats, and the acute dermal toxicity to rabbits are moderate. N,N,N',N' -tetram ethyl ethyl enediamine was not mutagenic to bacterial cells in vitro. This substance is irritating to rabbit skin and eyes. No adequate data are available for the repeated-dose, reproductive, developmental toxicity and chromosomal aberrations endpoints. 9 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 Table 3. Summary of the Screening Information Data Set as Submitted under the U.S. HPV Challenge Program - Human Health Data Endpoints SPONSORED CHEMICAL N,N,N',N'-Tctramcthylcthylcncdiaminc (CASRN l i 0-18-9) Acute Oral Toxicity LDS0 (mg/kg) 268 Acute InhalationToxicity LCS0 (mg/L) 5.6 Acute Dermal Toxicity LDS0 (mg/kg) 1230 Repeated-Dose Toxicity NOAEL/LOAEL Inhalation (mg/L/day) No adequate data Reproductive Toxicity (mg/kg-day) No adequate data Developmental Toxicity Oral (mg/kg-day) Maternal Toxicity Developmental Toxicity No adequate data Genetic Toxicity - Gene Mutations in vitro Negative Genetic Toxicity - Chromosomal Aberrations in vitro No adequate data Additional Information Skin Irritation Eye Irritation Irritating Irritating vleasured data in bold 10 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 4. Hazards to the Environment Acute Toxicity to Fish No Data Acute Toxicity to Aquatic Invertebrates No Data Toxicity to Aquatic Plants No Data Conclusion: For N,N,N' ,N' -tetram ethyl ethyl enediamine, no data were submitted to evaluate acute toxicity to fish, aquatic invertebrates and aquatic plants. Summary of the Screening Information Data Set under the U.S. HPV Challenge Program - Aquatic Toxicity Data Endpoints SPONSORED CHEMICAL N,N,N' ,N' -tetramethy lethylenediamine (110-18-9) Fish 96-h LCS0 (mg/L) No Data Aquatic Invertebrates 48-h ECS0 (mg/L) No Data Aquatic Plants 96-h ECS0 (mg/L) No Data 11 ------- |