U.S. Environmental Protection Agency September, 2014 Hazard Characterization Document SCREENING-LEVEL HAZARD CHARACTERIZATION Chlorinated Pyridines Category SPONSORED CHEMICALS 2,3,4,5,6-Pentachloropyridine 3,6-Dichloro-2-trichloromethylpyridine 2-Chloro-5-trichloromethylpyridine 3,4,5,6-Tetrachlo-2-pyridine carbonitrile Chloropyridine derivatives Methyl chloropyridine derivatives CASRN 2176-62-7 CASRN 1817-13-6 CASRN 69045-78-9 CASRN 17824-83-8 CASRN 68412-40-8 CASRN 70024-85-0 SUPPORTING CHEMICAL 2,3,5,6-Tetrachloropyridine CASRN 2402-79-1 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 Set2) endpoints that are screening-level indicators of potential hazards (toxicity) for humans or the 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 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. environment. ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 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, ATSDR, 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 may not develop HCs for those HPV chemicals which have recently been assessed and published 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 authorities around the world. OPPT is an active participant in these meetings and accepts these documents as reliable screening-level hazard assessments. HCs may be created if new data suggest a need to update the case work where the OECD document will be used as key support documentation. 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. 4European Chemicals Agency, http://echa.europa.eu 2 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Chemical Abstract Service Registry Number (CASRN) 2176-62-7 2402-79-1 1817-13-6 69045-78-9 17824-83-8 68412-40-8 70024-85-0 Chemical Abstract Index Name Pyridine, pentachloro- Pyridine, 2,3,5,6-tetrachloro- Pyridine, 3,6-dichloro-2-(trichloromethyl)- Pyridine, 2-chloro-5-(trichloromethyl)- 2-Pyridinecarbonitrile, 3,4,5,6-tetrachloro- Pyridine, chloro derivs. Pyridine, methyl-, chloro derivs. Structural Formulae See Appendix Summary The chlorinated pyridines category consists of seven chemicals. Chlorinated pyridines are solids at room temperature, and have high boiling points. These substances tend to possess low to moderate vapor pressure and are moderately soluble in water. Volatilization is slight to moderate based on estimated Henry's Law constants. The sponsor did not provide hydrolysis data for these chemicals, except for the supporting chemical tetrachloropyridine, which is hydrolytically stable at pHs 4, 7 or 9. Except for the supporting chemical tetrachloropyridine, all sponsored chemicals have a negligible rate of atmospheric oxidation. These chemicals have moderate mobility in soil. These chemicals are not readily biodegradable based on estimated biodegradation data for the sponsored chemicals and measured data for the supporting chemical tetrachloropyridine. These chemicals are expected to possess low bioconcentration potential (Bl) and moderate persistence (P2) under environmental conditions. Human Health Hazard Subcategory I: Pentachloropyridine The acute oral toxicity of 2,3,4,5,6-pentachloropyridine in rats is moderate. The acute inhalation toxicity of 2,3,5,6-tetrachloropyridine (supporting chemical) is low in rats. In the 90-day repeated-dose dietary toxicity study of 2,3,4,5,6,-pentachloropyridine the LOAEL for male rats is 30 mg/kg-bw/day based on increased liver and kidney weights and hyaline droplet degeneration of renal tubules. The NOAEL for males is 10 mg/kg-bw/day. No systemic toxicity was seen in females; the NOAEL for females is 30 mg/kg-bw/day, the highest dose tested. A 91-day dietary repeated-dose toxicity study of 2,3,5,6-tetrachloropyridine (supporting chemical) showed degenerative changes in the kidney of male rats at 10 mg/kg-bw/day. The NOAEL for males is 3- mg/kg-bw/day. In females, the NOAEL is 100 mg/kg-bw/day (highest dose tested). In a combined repeated-dose/reproductive/developmental toxicity study of 2,3,5,6-tetrachloropyridine (supporting chemical) in rats via gavage, the LOAEL in males is 25 mg/kg-day based on hyaline protein nephropathy with a NOAEL of 5 mg/kg-day. In females, the LOAEL of 150 mg/kg-day is based on effects on liver and kidney; the NOAEL is 25 mg/kg-day. No reproductive toxicity 3 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 study is available for 2,3,4,5,6,-pentachloropyridine. A combined repeated-dose reproductive/developmental toxicity study in rats via gavage with a supporting chemical 2,3,5,6- tetrachloropyridine showed no treatment-related effects on reproductive organs. The NOAEL for reproductive toxicity is 150 mg/kg-day, the highest dose tested. In a prenatal developmental toxicity study of 2,3,4,5,6,-pentachloropyridine in rats via gavage, maternal toxicity was seen at 50 mg/kg-day (increased liver and kidney weights) with a NOAEL of 10 mg/kg-day. The LOAEL for developmental toxicity is 200 mg/kg-day based on decreased fetal weights; the NOAEL is 50 mg/kg-day. 2,3,4,5,6,-Pentachloropyridine and 2,3,5,6,-tetrachloropyridine (supporting chemical) did not induce gene mutations in bacteria and did not induce chromosomal aberrations in rat lymphocytes in vitro or in mouse bone marrow cells in vivo. The subcategory members are irritating to rabbit skin, but not to rabbit eyes. 2,3,5,6-Tetrachloropyridine (supporting chemical) is not a dermal sensitizer in guinea pigs. No data gaps were identified for subcategory I under the HPV Challenge program. Subcategory II: Chlorinated Trichloromethylpyridines The acute oral toxicity for members of the chlorinated trichloromethylpyridine subcategory in rats is low. The acute toxicity in rats via inhalation is inconclusive (LCso > 0.108 mg/L) because the concentration tested was not high enough to establish the potential hazard. In a 3-week dermal toxicity study of 2-chloro, 5 trichloromethylpyridine in rats, the LOAEL was 500 mg/kg-day based on mortality and effects on clinical chemistry parameters, organ weight changes and histopathology of liver (vacuolation and necrosis of centrilobular hepatocytes), kidney (vacuolation of renal tubular epithelium) and testes (atrophy of the seminiferous tubular epithelium). The NOAEL is 100 mg/kg-day. There are no data for reproductive or developmental toxicity. 2-Chloro-5-trichloromethylpyridine induced gene mutations in bacteria and mouse lymphoma cells in vitro and induced chromosomal aberrations in a human lymphocyte assay in vitro. Subcategory members are irritating to rabbit skin and eyes, while 2-chloro- 5-trichloromethylpyridine is a dermal sensitizer in guinea pigs. Data gaps for the reproductive and developmental toxicity endpoints were identified for subcategory II under the HPV Challenge Program. Additional Sponsored Chemicals 3,4,5,6,-Tetrachloro-2-pyridine carbonitrile (CASRN17824-83-8) Acute toxicity of 3,4,5,6,-Tetrachloro-2-pyridine carbonitrile to rats is low. 3,4,5,6,-Tetrachloro- 2-pyridine carbonitrile was corrosive to rabbit skin and irritating to rabbit eyes. No data are available for repeated-dose, reproductive, developmental toxicity and gene mutation and chromosomal aberrations endpoints. Data gaps for acute, repeated-dose, reproductive, developmental toxicity and gene mutation and chromosomal aberrations endpoints were identified under the HPV Challenge Program. Chloropyridine derivatives (CASRN 68412-400-8) No data are available for acute, repeated-dose, reproductive, developmental toxicity and gene mutation and chromosomal aberrations endpoints. 4 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Data gaps for acute, repeated-dose, reproductive, developmental toxicity and gene mutation and chromosomal aberrations endpoints were identified under the HPV Challenge Program. Methyl chloropyridine derivatives (CASRN 70024-85-0) No data are available for acute, repeated-dose, reproductive, developmental toxicity and gene mutation and chromosomal aberrations endpoints. Data gaps for acute, repeated-dose, reproductive, developmental toxicity and gene mutation and chromosomal aberrations endpoints were identified under the HPV Challenge Program. Hazard to the Environment Subcategory I: Tetra- and Pentachloropyridines For subcategory I, the 96-h LC50 for fish is 0.47 mg/L. Based on the supporting chemical, 2,3,5,6-tetrachloropyridine, the 48-h EC50 for aquatic invertebrates is 2.05 mg/L. The 72-h EC50 for algae is 1.66 mg/L for biomass, and, based on the supporting chemical, 2,3,5,6- tetrachloropyridine, the 72-h EC50 for algae is 9.7 mg/L for growth rate. No data gaps were identified for the tetra- and penta-chloropyridines under the HPV Challenge Program. Subcategory II: Chlorinated Trichloromethylpyridines There are no adequate data available for the evaluation of the ecological toxicity of the chlorinated trichloromethylpyridines. The acute fish and aquatic invertebrate toxicity and aquatic plant toxicity endpoints were identified as a data gaps for the chlorinated trichloromethylpyridines under the HPV Challenge Program. Additional Sponsored Chemicals Chloropyridine derivatives There are no available data for the evaluation of ecological toxicity of the chloropyridine derivatives. The acute fish and aquatic invertebrate toxicity and aquatic plant toxicity endpoints were identified as a data gaps for the chloropyridine derivatives under the HPV Challenge Program. Methyl chloropyridine derivatives There are no available data for the evaluation of ecological toxicity of the methyl chloropyridine derivatives. The acute fish and aquatic invertebrate toxicity and aquatic plant toxicity endpoints were identified as a data gaps for the methyl chloropyridine derivatives under the HPV Challenge Program. 5 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 The sponsor, Dow Agro Sciences LLC, submitted a Test Plan and Robust Summaries to EPA for the chlorinated pyridines category on December 27, 2005. Test Plan and Robust Summaries for the individual category members were received by EPA, previously. EPA posted the individuals and category submissions on the ChemRTK HPV Challenge website on January 26, 2006 (http://www.epa.gov/hpv/pubs/summaries/chlrpycat/cl6113tc.htm). EPA comments on the submissions were posted to the website on September 27, 2006. Public comments were also received and posted to the website. Category Justification The sponsor originally submitted the category members as individual submissions. EPA then received a category document combining these chemicals into one category, in which the sponsor proposed a category of seven structurally-related chlorinated pyridines. EPA has modified this approach for the purposes of this Hazard Characterization as follows. For human health effects, the chlorinated pyridine category now consists of two subcategories, (I) Pentachlorinated Pyridines and (II) Chlorinated Trichloromethylpyridines, and three individually evaluated chlorinated pyridine substances. The chemicals in the subcategories have a pyridine nucleus bearing at least one chlorine atom. Subcategory I consists of 2,3,4,5,6-pentachloropyridine. Subcategory II contains 3,6-dichloro-2-trichloromethylpyridine and 2-chloro-5- trichloromethylpyridine. These two chemicals share a trichloromethylated pyridine nucleus and differ only by the presence of one vs. two chlorine atoms and the positions of the substituents. All three chemicals in Subcategories I and II have good leaving groups in the 2-position that can undergo displacement by biological nucleophiles such as --SH. In addition, the toxicity of subcategory II members may differ significantly from the other chlorinated pyridines owing to the presence of the potentially reactive trichloromethyl group. As to the remaining three proposed category members, 3,4,5,6-tetrachloro-2-pyridinecarbonitrile contains an additional functional group, the nitrile group, that is not shared by any of the other proposed single-chemical category members and that may confer additional toxicological properties. The chloropyridine derivatives and methyl chloropyridine derivatives are both complex mixtures that consist mainly of chemicals that are roughly similar in structure to the proposed category members; however, many of the constituents are significantly different or more complex (such as chlorinated bipyridines), and therefore their grouping with the other proposed category members (or with each other) is inappropriate. As such, the nitrile and two mixtures will be evaluated individually for health effects in this hazard characterization. The sponsor proposed reduced health effects testing on the basis that the chlorinated pyridines, except for 2,3,4,5,6-pentachloropyridine, are closed-system intermediates (CSIs). EPA's evaluation of the submitted information indicated that the chemicals do not meet the criteria to adequately support the CSI status. Therefore, EPA has determined that the chemicals do not qualify for reduced testing and data for the repeated-dose and reproductive toxicity endpoints are needed for the purposes of the HPV Challenge Program. For environmental toxicity, EPA is employing two subcategories based on chemical properties and structural similarity. Subcategory I, Tetra- and Pentachloropyridines, consists of 2,3,4,5,6- 6 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 pentachloropyridine and 3,4,5,6-tetrachloro-2-pyridinecarbonitrile. Subcategory II, Chlorinated Trichloromethylpyridines, consists of 3,6-dichloro-2-trichloromethylpyridine and 2-chloro-5- trichloromethylpyridine. As with human health, the single-chemical members can undergo nucleophilic substitution of the 2-chlorine by biological nucleophiles, possibly inducing toxicity beyond the typical narcosis/baseline toxicity (see Supporting Chemical Justification below). The two complex mixtures, chloropyridines and chlorinated bipyridines, do not clearly overlap with one another and contain various structure types, some not clearly identified, and therefore their grouping with the other proposed category members or with each other is inappropriate. These two sponsored chemicals will be evaluated individually for ecological effects in this hazard characterization. Toxicity and environmental fate endpoints will only be read across within subcategories and not between subcategories. Justification for Supporting Chemical For ecological toxicity the supporting chemical 2,3,5,6-tetrachloropyridine, is structurally similar to the sponsored chemicals 2,3,4,5,6-pentachloropyridine and 3,4,5,6-tetrachloro-2-pyridine carbo- nitrile, because it has a pyridine nucleus with more than three chlorine substituents. Furthermore, in biological systems, a 2-substituted pyridine can undergo displacement of a good leaving group in that position, such as chloride, by biological nucleophiles such as -SH (Hermens, J. 1985). Similar reactivity is associated with toxicity to aquatic organisms that is 22 to nearly 2000 times greater than narcosis type toxicity (Lipnick, R.L. 1989, Lipnick, R.L. 1991, Newsome, L.D., et al. 1984). Therefore, EPA considers the test data for supporting chemical 2,3,5,6-tetrachloropyridine adequate for reading across to the sponsored chemicals in Subcategory I for the purposes of this hazard characterization. 1. Chemical Identity 1.1 Identification and Purity The following information was taken from the 2005 Test Plan: All the sponsored members of the chlorinated pyridines category, except 2,3,4,5,6-pentachloropyridine, are chemicals or process streams used in other manufacturing processes or concerted to feedstock for chlorine production. 2,3,4,5,6-Pentachloropyridine is a production chemical. The purity of the sponsored chemicals in subcategories I and II is high (90-100%), where indicated. 1.2 Physical-Chemical Properties The physical-chemical properties for members of the chlorinated pyridines category are provided in Table 1. Chlorinated pyridines are solids at room temperature, and have high boiling points. These substances tend to possess low to moderate vapor pressure and are moderately soluble in water. Volatilization is slight to moderate based on estimated Henry's Law constants. 7 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 2. General Information on Exposure 2.1 Production Volume and Use Pattern The Chlorinated Pyridine Category chemicals had an aggregated production and/or import volume in the United States between 14 million and 90 million pounds during calendar year 2005. CASRN 1817-13-6, 17824-83-8 and 2176-62-7: Non-confidential information in the IUR indicated that the industrial processing and uses of the chemicals include pesticide and other agricultural chemical manufacturing as intermediates. No commercial and consumer uses were reported for the chemicals. CASRN 69045-78-9 was not reported in the 2006 IUR. CASRN 68412-40-8: No industrial processing and uses, and commercial and consumer uses were reported for the chemical. CASRN 70024-85-0: Non-confidential information in the IUR indicated that the industrial processing and uses of the chemical include other basic organic chemical manufacturing as intermediates. No commercial and consumer uses were reported for the chemical. 2.2 Environmental Exposure and Fate Except for the supporting chemical tetrachloropyridine, all sponsored chemicals have a negligible rate of atmospheric oxidation. These chemicals have moderate mobility in soil. These chemicals are not readily biodegradable, based on estimated biodegradation data for the sponsored chemicals and measured data for the supporting chemical tetratchloropyridine. These chemicals are expected to possess low bioconcentration potential (Bl) and moderate persistence (P2) under environmental conditions. The environmental fate properties of the chlorinated pyridines category members are summarized in • CASRN 2176-62-7: • CASRN 1817-13-6: • CASRN 17824-83-8 • CASRN 68412-40-8 • CASRN 70024-85-0 10 million to < 50 million pounds; 1 million to < 10 million pounds; 1 million to < 10 million pounds; 1 million to < 10 million pounds; 1 million to < 10 million pounds; Table 2. 8 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Table 1. Physical-Chemical Properties of Chlorinated Pyridines Category1 Subcategory I Subcategory II Additional Sponsored Chemicals Property SPONSORED CHEMICAL 2,3,4,5,6- Pcntachloro- pyridinc SUPPORTING CHEMICAL 2,3,5,6- Tctrachloro- pyridinc SPONSORED CHEMICAL 3,6-Dichloro-2- trichlomcthyl- pyridinc SPONSORED CHEMICAL 2-Chloro-5- trichloromcthyl- pyridinc SPONSORED CHEMICAL 3,4,5,6- Tetrachloro-2- pyridinc carbonitrilc SPONSORED CHEMICAL Chloropyridinc Derivatives (mixture of several ehemieals) SPONSORED CHEMICAL Chloropyridinc Derivatives (mixture of several chemicals) CASRN 2176-62-7 2402-79-1 1817-13-6 69045-78-9 17824-83-8 68412-40-8 70024-85-0 Melting Point 125-126 °C (m) 90.5 °C (m) 47-48°C (m) 52-54°C (m) 150.5-151.5 °C (m) No data No data Boiling Point 273 °C (e) 251.6 °C (m) 272°C (e) 245°C (e) 310.1 °C (e) No data No data Vapor Pressure 0.014 mmHg (0.018 hPa) at 25 °C (m) 0.02 mmHg (0.0267 hPa) at 25 °C (e) 0.0052 mmHg (0.0069 hPa) at 25 °C (e) 0.11 mmHg (0.14 hPa) at 25°C (e) 0.000033 mmHg (0.000044475 hPa) at 25 °C (e) No data No data Log Kow 3.53 at 25°C (m) 3.32 at 25 °C (m) 4 at 25 °C (e) 3.35 at25°C (e) 2.93 at 25 °C (e) No data No data Henry's Law Constant2 1.154 xlO"5 atm-m3/mole (e) 3.31xl0"5 atm-m3/mole (e) 1.341xl0"4 atm-m3/mole (e) 1.457xl0"4 atm-m3/mole (e) 1.341xl0"6 atm-m3/mole (e) No data No data Water solubility 8.5 mg/L at 25 °C (m) 29.8-30.2 mg/L at 23 °C (m) 7.5 mg/L at 25 °C (e) 99 mg/L at 25°C (e) 45 mg/L at 25 °C (e) No data No data 1 HPV Challenge Group Revised Test Plan and Robust Summary for Chlorinated Pyridines Category. Available at: http://www.epa.gov/oppt/chemrtk/pubs/summaries/chlrpycat/cl6113tc.htm as of July 29, 2011 2Estimated values were obtained from EPIWIN (v 3.20) (m) = measured data (i.e., derived from testing); (e) = estimated data ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Table 2. Environmental Fate Properties of Chlorinated Pyridines1 Subcategory I Subcategory II Additional Sponsored Chemicals Property SPONSORED CHEMICAL 2,3,4,5,6- Pcntachloro- pyridinc SUPPORTING CHEMICAL 2,3,5,6- Tctrachloro- pyridinc SPONSORED CHEMICAL 3,6-Dichloro-2- trichlomcthyl- pvridinc SPONSORED CHEMICAL 2-Ch!oro-5- trichloromcthyl- pyridinc SPONSORED CHEMICAL 3,4,5,6- Tctrachloro-2- pyridinc carbonitrilc SPONSORED CHEMICAL Chloropvridinc Derivatives (mixture of several chemicals) SPONSORED CHEMICAL Chloropvridinc Derivatives (mixture of several chemicals) CASRN 2176-62-7 2402-79-1 1817-13-6 69045-78-9 17824-83-8 68412-40-8 70024-85-0 Photodegradation 50 % after 974 days 50 % after 7 days 50% after 768 days 50 % after 224 days 50% after 3881 days No data No data Stability in water No rate constants could be calculated Hydrolytically stable at pHs of 4,7, or 9, up to 70 °C (m) No data No data No data No data No data Transport between environmental compartments Air (%) Water (%) Soil (%) 73.55 6.5 19.5 86 < 10 <2 32.9 6.7 59.1 17.9 27.1 53.8 1.5 55.6 41.9 No data No data Biodegradation2 Not Readily biodegradable No biodegradation observed (m) Not Readily Biodegradable Not Readily Biodegradable Not Readily Biodegradable No data No data Bioaccumulation No data No data BCF = 238.4 BCF= 153 BCF = 35.95 No data No data 1 All data, except estimated biodegradation data, obtained from HPV Challenge Group Revised Test Plan and Robust Summary for Chlorinated Pyridines Category. Available at: http://www.epa.gov/oppt/chemrtk/pubs/summaries/chlrpvcat/cl6113tc.htm as of July 29, 2011. 2Estimated biodegradation data obtained from BIOWIN (v 4.10) (m) = measured data (i.e., derived from testing). ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Conclusion: Chlorinated pyridines are solids at room temperature, and have high boiling points. These substances tend to possess low to moderate vapor pressure and are moderately soluble in water. Volatilization is slight to moderate based on estimated Henry's Law constants. The sponsor did not provide hydrolysis data for these chemicals, except for the supporting chemical tetrachloropyridine, which is hydrolytically stable at pHs 4, 7 or 9. Except for the supporting chemical tetrachloropyridine, all sponsored chemicals have a negligible rate of atmospheric oxidation. These chemicals have moderate mobility in soil. These chemicals are not readily biodegradable, based on estimated biodegradation data for the sponsored chemicals and measured data for the supporting chemical 2,3,5,6-tetrachloropyridine. These chemicals are expected to possess low bioconcentration potential (Bl) and moderate persistence (P2) under environmental conditions. 3. Human Health Hazard A summary of health effects data submitted for SIDS endpoints is provided in Table 3. The table also indicates where data for tested category members are read-across (RA) to untested members of the category as appropriate. Acute Oral Toxicity Subcategory I: Pentachloropyridine 2,3,4,5,6-Pentachloropyridine (CASRN2176-62-7) (1) Fischer 344 rats (3 males/dose) were administered 2,3,4,5,6-pentachloropyridine (> 99% w/w purity) in corn oil via gavage at 100, 250, 500 or 750 mg/kg and observed for 14 days following dosing. Mortalities were observed at 500 (2/3) and 750 (3/3) mg/kg. Additional details from TSCATS (OTS0536503). LDso = 435 mg/kg (2) 2,3,4,5,6-pentachloropyridine was administered to 3 female rats via the diet. The study summary is missing critical study information, including dose levels, duration of observation, rat strain, number of animals/dose and mortality at each dose. The reported LD50 value of 126 mg/kg > LD50 <1000 mg/kg is provided for general information purposes. 2,3,5,6-Tetrachloropyridine (CASRN2402-79-1, supporting chemical) (1) Rats (strain not specified, 5/sex/dose) were administered 2,3,5,6-tetrachloropyridine (purity not indicated) via an unspecified oral route at 500, 1000 or 2000 mg/kg. Details on mortalities and length of observation period were not specified. The reported LD50 values of 1182 mg/kg for males and 1414 mg/kg for females are provided for general information purposes. (2) Female rats (strain not specified, 2/dose) were administered 2,3,5,6-tetrachloropyridine (purity not indicated) via gavage at 126, 252, 500, 1000 or 2000 mg/kg in corn oil. Mortalities were observed at 1000 (1/2) and 2000 (2/2) mg/kg. No information was provided on the length of observation period. The reported LD50 value of - 1000 mg/kg is provided for general information purposes. 11 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Subcategory II: Chlorinated Trichloromethylpyridines 3,6-Dichloro-2-trichloromethylpyridine (CASRN1817-13-6) Rats (3 males/dose, strain not stated) were administered 3,6-dichloro-2-trichloromethylpyridine (purity not indicated) in corn oil via gavage at 130, 250, 500, 1000 or 2000 mg/kg and observed for 14 days following dosing. Mortality occurred at 2000 mg/kg (3/3). 1000 mg/kg < LDso < 2000 mg/kg 2-Chloro-5-trichloromethylpyridine (CASRN 69045-78-9) Sprague-Dawley rats (3 males/dose) were administered 2-chloro-5-trichloromethylpyridine (90- 100% w/w purity) in corn oil via gavage at 130, 250, 500, 1000 or 2000 mg/kg and observed for 14 days following dosing. Mortalities occurred at 1000 (2/3) and 2000 (2/3) mg/kg. 500 mg/kg < LD50 < 1000 mg/kg Additional Sponsored Chemicals 3,4,5,6,-tetrachloro-2-pyridine carbonitrile (CASRN 17824-83-8) Female rats (strain not specified, 2/dose) were administered 3,4,5,6-tetrachloro-2-pyridine carbonitrile via gavage as a 20% suspension in corn oil at 252, 500, 1000, 2000 or 3980 mg/kg and observed for two weeks. Mortality was seen at 2000 (1/2) and 3980 (2/2) mg/kg. LD50 = 1000 - 2000 mg/kg Chloropyridine derivatives (CASRN 68412-400-8) No data Methyl chloropyridine derivatives (CASRN 70024-85-0) No data Acute Inhalation Toxicity Subcategory I: Pentachloropyridine 2,3,5,6-Tetrachloropyridine (CASRN2402-79-1, supporting chemical) Sprague-Dawley rats (6 males) were exposed whole-body to 2,3,5,6-tetrachloropyridine (purity not indicated) at 6300 ppm (56 mg/L) for 7 hours and observed for 14 days. No mortality was observed. LC50 > 56 mg/L 12 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Subcategory II: Chlorinated Trichloromethylpyridines 2-Chloro-5-trichloromethylpyridine (CASRN 69045-78-9) Fischer 344 rats (6 males) were exposed whole-body to 2-chloro-5-trichloromethylpyridine (90- 100% w/w purity) as vapor at 11.4 ppm (~0.108 mg/L) for 6 hours and observed for 14 days following dosing. No mortality was observed. LCso > 0.108 mg/L Repeated-Dose Toxicity Subcategory I: Pentachloropyridine 2,3,4,5,6-Pentachloropyridine (CASRN2176-62-7) Rats (strain not specified, 10 - 15/sex/dose) were administered 2,3,4,5,6-pentachloropyridine (> 99% w/w purity) via the diet at 0, 0.3, 1, 3, 10 or 30 mg/kg-bw/day for 90 days. Animals were examined frequently for clinical signs of toxicity. Body weight and food consumption were measured weekly. Hematological parameters were examined during weeks 3 and 12 and at termination of the exposure. Serum glutamic pyruvic transaminase was measured on days 1, 3, 7, 14, 30 and 90. Blood urea nitrogen was measured on day 90. At the termination of exposure, complete necropsies were performed, including gross pathological and histopathological examinations. No mortalities or clinical signs of toxicity were observed. There were no treatment-related effects observed in females. Effects in males included increased relative liver and kidney weights and mild focal hyaline droplet degeneration of the convoluted tubules of the renal cortex4 at 30 mg/kg-bw/day. Testicular tubal atrophy of varying degrees was observed in all dose groups, including controls. In an effort to clarify testicular findings among dosed rats, additional groups were administered 2,3,4,5,6-pentachloropyridine via gavage or the diet. In the follow-up gavage study, male rats (10/dose) were administered 2,3,4,5,6-pentachloropyridine (vehicle not indicated) at 0, 62.5, 125 or 250 mg/kg-bw/day for 5 days/week for 2 weeks. In the follow-up dietary study, male rats (30/dose) were administered 2,3,4,5,6-pentachloropyridine at 0, 62.5, 125 or 250 mg/kg-bw/day for 242 days. No treatment-related testicular effects were observed in the two follow-up studies. LOAEL (males) = 30 mg/kg-bw/day (based on increased liver and kidney weights and degeneration of renal tubules) NOAEL (males) = 10 mg/kg-bw/day NOAEL (females) = 30 mg/kg-bw/day (highest dose tested) 2,3,5,6-Tetrachloropyridine (CASRN2402-79-1, supporting chemical) (1) Sherman rats (10/sex/dose) were administered 2,3,5,6-tetrachloropyridine (purity not indicated) in the diet at 0, 1, 3, 10, 30 or 100 mg/kg-bw/day for 91 days. Changes in organ weight included increased kidney weight in males at 30 and 100 mg/kg-bw/day, slightly increased liver weight in males at 100 mg/kg-bw/day and slightly increased liver and spleen weights in females at 30 and 100 mg/kg-bw/day. Macroscopic evaluation revealed pale kidneys in males at 30 and 100 mg/kg-bw/day. Histopathological evaluation identified mild, reversible 13 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 degenerative changes (hyaline droplets) in male kidneys at 10, 30 and 100 mg/kg-bw/day5. No mortalities, clinical signs of toxicity or changes in body weight, food consumption, hematology and clinical chemistry parameters were observed. LOAEL (males) = 10 mg/kg-bw/day (based on degenerative changes in the kidneys) NOAEL (males) = 3 mg/kg-bw/day NOAEL (females) = 100 mg/kg-bw/day (highest dose tested) (2) In a combined repeated-dose/reproductive/developmental toxicity screening test, Sprague- Dawley rats (15/sex/dose) were administered 2,3,5,6-tetrachloropyridine (purity not indicated) via gavage at 0 (vehicle), 5, 25 or 150 mg/kg-day for approximately 52 days. After 2 weeks of dosing, the parental rats were mated for 2 weeks to produce F1 litters. (The vehicle identity was not indicated in the robust summary.) Dosing of both sexes continued through the gestation and lactation periods. All parental animals and litters were euthanized following lactation day 4. No mortalities were observed. Increased liver and kidney weights were observed in males and females at 150 mg/kg-day. Effects in the liver at this dose were limited to centrilobular hypertrophy of hepatocytes. Renal effects at 150 mg/kg-day included pale kidney coloration in males and females, hyaline protein droplet nephropathy4 in males and slight to severe renal tubule epithelial cell degeneration/regeneration, very slight to slight distention of renal tubules and inflammation of renal papillae in females. Protein droplet nephropathy was also observed in males at 25 mg/kg-day. Alterations in a number of clinical chemistry parameters (not specified) were also observed in females given 150 mg/kg-day, but were considered secondary to renal and hepatic effects. No significant treatment-related effects were observed on clinical signs, food consumption, body weight or body weight gain. LOAEL (males) = 25 mg/kg-day (based on hyaline protein droplet nephropathy in the kidneys) NOAEL (males) = 5 mg/kg-day LOAEL (females) = 150 mg/kg-day (based on increased liver and kidney weights, hypertrophy of hepatocytes and renal histopathology) NOAEL (females) = 25 mg/kg-day Subcategory II: Chlorinated Trichloromethylpyridines 2-Chloro-5-trichloromethylpyridine (CASRN 69045-78-9) In a 3-week dermal toxicity study, rats (10/sex/dose, strain not stated) were administered 2- chloro-5-trichloromethylpyridine (crude, purity not indicated) in corn oil at 0 (corn oil), 20, 100 or 500 mg/kg-day under occluded conditions for 21 days. Due to mortality at 500 mg/kg-day, treatment at this dose was suspended for 4 days after the fifth day of exposure and upon re- initiation, dosing was reduced to once every 2 days. Parameters measured included clinical observations, body weight, food consumption, hematology, clinical chemistry, urinalysis, organ 5 The presence of nephropathy in association with the hyaline droplet accumulation in male rats suggests that the nephropathy in the males is occurring by an a 1 p ha - 2 |i - g 1 o b u 1 i n - mc d i a tc d mechanism, which appears to be unique to male rats and the response is probably not relevant to humans for purposes of risk assessment. However, the key events and data necessary to demonstrate this mode of action which is outlined in EPA's Risk Assessment Forum, Alpha-2|i-Globulin: Association with Chemically Induced Renal Toxicity and Neoplasia in the Rat, EPA/625/3-91/019F are not contained in the data set. 14 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 weights and histopathology. Clinical observations at 500 mg/kg-day included lethargy, a hunched appearance, ano-genital staining and bouts of continual shaking. At the application site, moderate skin irritation was observed at 500 mg/kg-day, characterized by acute dermatitis and a moderate to marked thickening of the epidermis. Depressed cholinesterase activity was observed in the plasma of females and in the brain tissue of males at 500 mg/kg-day. Males exhibited elevated alkaline phosphatase and glutamic pyruvic transaminase activity, higher plasma potassium ion concentrations, higher triglyceride levels and lower cholesterol at 500 mg/kg-day. Depressed total protein levels were observed in females at 500 mg/kg-bw/day. At 500 mg/kg- day, males exhibited increased weights of the brain, heart, kidneys and lungs, while both sexes had higher liver weights. The hepatic activity of aminopyrine-N-demethylase was elevated in males at 500 mg/kg-day. Histopathological effects observed at 500 mg/kg-day included vacuolation and necrosis of centrilobular hepatocytes, vacuolation of the renal tubular epithelium and atrophy of the seminiferous tubular epithelium. The overall toxic effect observed at 500 mg/kg-day was characterized by liver necrosis and a disturbance of lipid metabolism. Details are from TSCATS (OTS0545698). LOAEL = 500 mg/kg-day (based on mortality, changes in clinical chemistry, changes in organ weights and histopathological effects on the liver, kidneys and testes) NOAEL = 100 mg/kg-day Additional Sponsored Chemicals 3,4,5,6,-tetrachloro-2-pyridine carbonitrile (CASRN17824-83-8) No data Chloropyridine derivatives (CASRN 68412-400-8) No data Methyl chloropyridine derivatives (CASRN 70024-85-0) No data Reproductive Toxicity Subcategory I: Pentachloropyridine 2,3,5,6-Tetrachloropyridine (CASRN2402-79-1, supporting chemical) In the combined oral repeated-dose/reproductive/developmental toxicity screening test in Sprague-Dawley rats (via gavage) described previously, no treatment-related reproductive effects of 2,3,5,6-tetrachloropyridine were observed on fertility parameters of parental rats. Neonatal parameters evaluated included clinical/morphological alterations, body weight and survival. No adverse effects were reported for the fertility or neonatal parameters evaluated in the study. LOAEL (systemic toxicity, males) = 25 mg/kg-day (based on hyaline protein droplet nephropathy in the kidneys) NOAEL (systemic toxicity, males) = 5 mg/kg-day LOAEL (systemic toxicity, females) = 150 mg/kg-day (based on increased liver and kidney weights, hypertrophy of hepatocytes and renal histopathology) 15 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 NOAEL (systemic toxicity, females) = 25 mg/kg-day NOAEL (reproductive toxicity) = 150 mg/kg-day (highest dose tested) 2,3,4,5,6-Pentachloropyridine (CASRN2176-62-7) In the 91-day oral repeated-dose toxicity dietary study in rats described previously, no treatment- related effects were observed in the reproductive organs of rats exposed up to 30 mg/kg-bw/day (highest dose tested) Subcategory II: Chlorinated Trichloromethylpyridines No data Additional Sponsored Chemicals 3,4,5,6,-tetrachloro-2-pyridine carbonitrile (CASRN 17824-83-8) No data Chloropyridine derivatives (CASRN 68412-400-8) No data Methyl chloropyridine derivatives (CASRN 70024-85-0) No data Developmental Toxicity Subcategory I: Pentachloropyridine 2,3,4,5,6-Pentachloropyridine (CASRN2176-62-7) In a prenatal-development toxicity study, pregnant female Sprague-Dawley rats (25/dose) were administered 2,3,4,5,6-pentachloropyridine in corn oil via gavage at 0 (corn oil), 10, 50 or 200 mg/kg-day from days 6 to 20 of gestation. Mean measured concentrations were 94-101% of the targeted concentrations. Animals were examined daily for clinical signs and body weight. Food consumption was measured in 3-day intervals. On day 21 of gestation, complete necropsies were performed and kidney, liver and gravid uterus weights were taken. Reproductive parameters included numbers of corpora lutea, implantation sites, viable fetuses and resorptions. Fetal observations included sex, body weight and external, visceral, craniofacial and skeletal examinations. No treatment-related mortality was observed. Clinical signs of toxicity included perioral soiling (salivation) at 50 and 200 mg/kg-day and urine soiling at 200 mg/kg-day. Decreased body weight, body weight gain and food consumption were observed at 200 mg/kg-day. Increased absolute and relative kidney weights and increased relative liver weight were observed at 50 and 200 mg/kg-day. Increased absolute liver weight was observed at 200 mg/kg-day. Histopathological effects included increased size of the kidneys in one animal at 200 mg/kg-day and each had a pale cortex. Developmental effects were limited to decreased fetal body weight at 200 mg/kg-day, which was correlated with decreased maternal body weight. There were no treatment-related effects on pregnancy rates, resorption rates, litter size, numbers 16 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 of corpora lutea or implantations, percent pre-implantation loss, percent post-implantation loss, fetal sex ratios or gravid uterine weights at any dose level. LOAEL (maternal toxicity) = 50 mg/kg-day (based on increased liver and kidney weights) NOAEL (maternal toxicity) = 10 mg/kg-day LOAEL (developmental toxicity) = 200 mg/kg-day (based on decreased fetal body weight) NOAEL (developmental toxicity) = 50 mg/kg-day 2,3,5,6-Tetrachloropyridine (CASRN2402-79-1, supporting chemical) In the combined repeated-dose/reproductive/developmental toxicity screening test in Sprague- Dawley rats (via gavage) described previously, developmental effects measured included clinical/morphological alterations, body weight and survival of pups. No developmental effects of 2,3,5,6-tetrachloropyridine were observed at the highest dose of 150 mg/kg-day. LOAEL (maternal toxicity) = 150 mg/kg-day (based on increased liver and kidney weights, hypertrophy of hepatocytes and renal histopathology) NOAEL (maternal toxicity) = 25 mg/kg-day NOAEL (developmental toxicity) = 150 mg/kg-day (highest dose tested) Subcategory II: Chlorinated Trichloromethylpyridines No data Additional Sponsored Chemicals 3,4,5,6,-tetrachloro-2-pyridine carbonitrile (CASRN 17824-83-8) No data Chloropyridine derivatives (CASRN 68412-400-8) No data Methyl chloropyridine derivatives (CASRN 70024-85-0) No data Genetic Toxicity - Gene Mutation In vitro Subcategory I: Pentachloropyridine 2,3,4,5,6-Pentachloropyridine (CASRN2176-62-7) In a bacterial reverse point mutation assay, Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and Escherichia coli strain WP2uvrA were exposed to 2,3,4,5,6- pentachloropyridine ( > 99% w/w purity) at 0.33 - 3333 |ig/plate with metabolic activation and 3.3 - 3333 |ig/plate without metabolic activation. Positive and negative controls were used and yielded the expected results. 2,3,4,5,6-Pentachloropyridine did not induce an increase in revertants/plate over the negative control in any tester strain either in the presence or absence of 17 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 metabolic activation. In a preliminary mutagenic assay, which used concentrations up to 5000 |ig/plate, cytotoxicity was observed at 1000 |ig/plate in strains TA98, TA100 and TA1537 without activation. 2,3,4,5,6-Pentachloropyridine was not mutagenic in this assay. 2,3,5,6-Tetrachloropyridine (CASRN2402-79-1, supporting chemical) In an Ames test, Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537 were exposed to 2,3,5,6-tetrachloropyridine at 0.5 - 50 |ig/plate without metabolic activation and 1.67 - 166.7 |ig/plate with metabolic activation. Cytotoxicity was seen at 50 |ig/plate without activation and at 166.7 |ig/plate with activation. No information on the use or response of positive and negative controls was provided. 2,3,5,6-tetrachloropyridine did not induce a mutagenic response in any of the bacterial strains. 2,3,5,6-tetrachloropyridine was not mutagenic in this assay. Subcategory II: Chlorinated Trichloromethylpyridines 2-Chloro-5-trichloromethylpyridine (CASRN 69045-78-9) (1) Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98 and TA100 were exposed to 2-chloro-5-trichloromethylpyridine (purity not indicated) in DMSO up to 5000 |ig/plate with and without metabolic activation. Positive and negative controls were used and yielded the expected results. Increased mutation frequency was observed in strains TA98 and TA100 without activation at > 200 |ig/plate. Cytotoxicity was observed at > 1000 |ig/plate. Details are from TSCATS (OTS0509740, Doc. # 88-8500713). 2-Chloro-5-trichloromethylpyridine was mutagenic in this assay. (2) Mouse lymphoma cells (L5178Y) were exposed to 2-chloro-5-trichloromethylpyridine (purity not indicated) in DMSO at 8 - 512 |ig/mL with or without metabolic activation. Positive and negative controls were used and yielded the expected results. Cytotoxicity was observed at 512 |ig/mL, Increased mutation frequency was observed under trifluorothymidine selection without activation and under ouabain selection with or without activation. Details are from TSCATS (OTS0509740, Doc. # 88-8500704). 2-Chloro-5-trichloromethylpyridine was mutagenic in this assay. Additional Sponsored Chemicals 3,4,5,6,-tetrachloro-2-pyridine carbonitrile (CASRN 17824-83-8) No data Chloropyridine derivatives (CASRN 68412-400-8) No data Methyl chloropyridine derivatives (CASRN 70024-85-0) No data 18 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Genetic Toxicity - Chromosomal Aberrations In vitro Subcategory I: Pentachloropyridine 2,3,4,5,6-Pentachloropyridine (CASRN2176-62-7) In an in vitro cytogenicity assay, rat lymphocytes were exposed to 2,3,4,5,6-pentachloropyridine (> 99% w/w purity) in DMSO at 3.8, 15 or 30 |ag/mL for 4 or 24 hours without metabolic activation and 7.5, 30 or 60 |ag/mL for 4 hours with metabolic activation. The cytotoxic concentration was 60 |ig/mL without activation (regardless of exposure duration) or 120 |ig/mL with activation. Negative and positive controls were used and yielded the expected results. No increase in the frequency of cells with chromosomal abnormalities was observed. 2,3,4,5,6-Pentachloropyridine did not induce chromosomal aberrations in this assay. Subcategory II: Chlorinated Trichloromethylpyridines 2-Chloro-5-trichloromethylpyridine (CASRN 69045-78-9) In an in vitro cytogenicity assay, human lymphocytes were exposed to 2-chloro-5- trichloromethylpyridine (purity not indicated) in DMSO at 2.5 - 167 |ag/m L with or without metabolic activation. Positive and negative controls were used and yielded the expected results. Chromosomal aberrations were observed at an increased frequency at 100 - 167 |ag/m L with or without activation. Details are from TSCATS (OTS0509740, Doc. # 88-8500713). 2-Chloro-5-trichloromethylpyridine induced chromosomal aberrations in this assay. Additional Sponsored Chemicals 3,4,5,6,-tetrachloro-2-pyridine carbonitrile (CASRN 17824-83-8) No data Chloropyridine derivatives (CASRN 68412-400-8) No data Methyl chloropyridine derivatives (CASRN 70024-85-0) No data In vivo Subcategory I: Pentachloropyridine 2,3,4,5,6-Pentachloropyridine (CASRN2176-62-7) In a cytogenetic assay, CFLP male mice were administered 2,3,4,5,6-pentachloropyridine (> 99% w/w purity) via gavage 11.75 or 100 mg/kg in sunflower oil. Bone marrow preparation was carried out 24 or 48 hours after treatment. Positive (cyclophosphamide) and negative (sunflower oil) controls were used and yielded the expected results. No significant increase in 19 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 the number of cells showing alterations or in the frequency of numerical and structural chromosomal aberrations was observed. 2,3,4,5,6-Pentachloropyridine did not induce chromosomal aberrations in this assay. 2,3,5,6-Tetrachloropyridine (CASRN2402-79-1, supporting chemical) In a bone marrow micronucleus assay, CD-I mice were administered single doses of 2,3,5,6- tetrachloropyridine (purity not indicated) via gavage at 22.5, 75 or 225 mg/kg in males or 93, 310 or 930 mg/kg in females. Animals were sacrificed 24, 48 or 72 hours after treatment and polychromatic erythrocytes (PCEs) were evaluated for micronuclei. Negative and positive (cyclophosphamide) controls produced appropriate responses. There were no increases in the frequencies of micronucleated PCEs in mice treated with 2,3,5,6-tetrachloropyridine. 2,3,5,6-Tetrachloropyridine did not induce micronuclei in this assay. Subcategory II: Chlorinated Trichloromethylpyridines No data Additional Information Skin Irritation Subcategory I: Pentachloropyridine 2,3,4,5,6-Pentachloropyridine (CASRN2176-62-7) A male rabbit (strain not specified) was administered either a undiluted 2,3,4,5,6- pentachloropyridine ( > 99% w/w purity) or 10% dilution in Dowanol DPM to intact or abraded abdominal skin under semi-occlusive conditions. Ten applications were administered to the intact abdominal site over a period of 14 days, while three consecutive daily applications were made to the abraded site. Additionally, 10 applications of the 10% dilution were made to the ear under open conditions over a period of 14 days. Undiluted applications to the abdomen resulted in slight to moderate hyperemia, slight edema and slight necrosis. Diluted applications to the abdomen produced slight to moderate hyperemia and edema. Results were similar on intact and abraded skin. No irritation was observed on the treated ear. 2,3,4,5,6-Pentachloropyridine was irritating to rabbit skin in this study. 2,3,5,6-Tetrachloropyridine (CASRN2402-79-1, supporting chemical) (1) Rabbits (strain, number/dose not specified) were administered 3-10 applications of solid 2,3,5,6-tetrachloropyridine (purity not indicated, amount not specified) to intact or abraded skin (abdomen) over a 14-day period. Effects included slight hyperemia, which was resolved after a few days. 2,3,5,6-Tetrachloropyridine was irritating to rabbit skin in this study. (2) Rabbits (strain, number/dose not specified) were administered 3 to 10 applications of 20% 2,3,5,6-tetrachloropyridine (purity not indicated, amount not specified) in perchloroethylene for 20 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 24 hours to intact and abraded abdominal skin or the intact ear over a 14-day period. Effects on the ear included slight hyperemia and slight necrosis. Effects on the intact belly skin included moderate hyperemia, slight necrosis, slight edema and moderate exfoliation. Effects on the abraded belly skin included slight hyperemia, moderate edema and moderate necrosis. All effects were resolved by the end of the study period. 2,3,5,6-Tetrachloropyridine was irritating to rabbit skin in this study. Subcategory II: Chlorinated Trichloromethylpyridines 3,6-Dichloro-2-trichloromethylpyridine (CASRN1817-13-6) Rabbits (two males, strain not stated) were administered 0.5 g of 3,6-dichloro-2- trichloromethylpyridine (purity not indicated) dermally under semi-occluded conditions for 14 days (a total of 10 applications) to intact skin or 3 days to abraded skin. The tests were conducted using the dry, undiluted test substance and also moistened with water. Effects observed included redness, swelling, exfoliation and burns at the site of application. Effects were more severe on moistened skin. 3,6-Dichloro-2-trichloromethylpyridine was irritating to rabbit skin in this study. 2-Chloro-5-trichloromethylpyridine (CASRN 69045-78-9) Rabbits (two males, strain not stated) were administered 0.5 g of 2-chloro-5- trichloromethylpyridine (90-100% w/w purity) dermally under semi-occluded conditions for 14 days (a total of 10 applications) to intact skin or 3 consecutive daily applications to abraded skin. Effects observed included redness, edema, exfoliation and/or burns at the site of application. 2-Chloro-5-trichloromethylpyridine was irritating to the rabbit skin in this study. Additional Sponsored Chemicals 3,4,5,6,-Tetrachloro-2-pyridine carbonitrile (CASRN 17824-83-8) Two white rabbits (strain and sex not specified) were administered undiluted 3,4,5,6,-tetrachloro- 2-pyridine carbonitrile dermally onto intact and abraded sites on the abdomen under occluded conditions. Applications were repeated for up to 10 days. Another rabbit was treated in a similar fashion with a 10% solution of the test material in dipropylene glycol monomethyl ether. After two applications of the undiluted test substance to rabbits, dosing was discontinued since moderate burns occurred. The burn sites appeared to heal normally within the 8 days of observation period. The rabbit treated with a 10% solution of the test substance died overnight. 3,4,5,6,-Tetrachloro-2-pyridine carbonitrile was corrosive to rabbit skin in this study. Chloropyridine derivatives (CASRN 68412-400-8) No data Methyl chloropyridine derivatives (CASRN 70024-85-0) No data 21 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Eye Irritation Subcategory I: Pentachloropyridine 2,3,4,5,6-Pentachloropyridine (CASRN2176-62-7) One rabbit (strain and sex not specified) was administered 0.1 mL undiluted 2,3,4,5,6- pentachloropyridine ( > 99% w/w purity) to both eyes and observed for up to 8 days post- treatment. The right eye was washed within 30 seconds of exposure for 2 minutes in a flowing stream of water while the left eye remained unwashed. In both washed and unwashed eyes, the material caused very slight discomfort and conjunctival irritation, which resolved within 1 hour. 2,3,4,5,6-Pentachloropyridine was not irritating to rabbit eyes in this study. 2,3,5,6-Tetrachloropyridine (CASRN2402-79-1, supporting chemical) Rabbits (strain and number not correctly specified) were administered undiluted 2,3,5,6- tetrachloropyridine (purity not indicated) to the eyes. One eye was rinsed following application and the other was left unrinsed. Effects included very slight pain and prominence of conjunctival capillaries. Effects were nearly resolved within 1 hour. 2,3,5,6-Tetrachloropyridine was not irritating to rabbit eyes in this study. Subcategory II: Chlorinated Trichloromethylpyridines 3,6-Dichloro-2-trichloromethylpyridine (CASRN 1817-13-6) A New Zealand White rabbit was administered 0.1 g of 3,6-dichloro-2-trichloromethylpyridine (purity not indicated) in each eye. One eye was then rinsed for 2 minutes, while the other was left unrinsed. Effects observed included slight discomfort, moderate conjunctival redness and swelling, moderate reddening of the iris and transient corneal injury. Similar results were obtained regardless of rinsing. 3,6-Dichloro-2-trichloromethylpyridine was irritating to rabbit eyes in this study. 2-Chloro-5-trichloromethylpyridine (CASRN 69045-78-9) A New Zealand White rabbit was administered 0.1 g of 2-chloro-5-trichloromethylpyridine (90- 100% w/w purity) in each eye. The right eye was then rinsed within 30 seconds for 2 minutes, while the left eye remained unrinsed. Effects observed included severe discomfort, slight conjunctival redness, very slight reddening of the iris and very slight corneal haziness. Similar results were obtained regardless of rinsing. 2-Chloro-5-trichloromethylpyridine was irritating to the rabbit eyes in this study. Additional Sponsored Chemicals 3,4,5,6,-Tetrachloro-2-pyridine carbonitrile (CASRN 17824-83-8) One white rabbit (strain and sex not specified) was administered 0.1 mg undiluted 3,4,5,6,- tetrachloro-2-pyridine carbonitrile in both eyes. On eye was left unwashed and the other eye was rinsed under running water within 1 hour of test substance instillation. The rabbit was observed for 7 days. The test substance produced slight to moderate conjunctival redness, with no evidence of corneal or iridial effects. The irritation resolved within 7 days. 22 ------- U.S. Environmental Protection Agency September, 2014 Hazard Characterization Document 3,4,5,6,-Tetrachloro-2-pyridine carbonitrile was irritating to rabbit eyes in this study. Chloropyridine derivatives (CASRN 68412-400-8) No data Methyl chloropyridine derivatives (CASRN 70024-85-0) No data Sensitization Subcategory I: Pentachloropyridine 2,3,4,5,6-Pentachloropyridine (CASRN2176-62-7) In a split adjuvant test eight guinea pigs were administered 2,3,4,5,6-pentachloropyridine (> 99% w/w purity) in Dowanol DPM/Tween 80,9/1 during induction and challenge phases. The test material was reported to be sensitizing, but the study summary is missing critical study details, including method of exposure, doses tested and detailed results. These data are provided for general information purposes. 2,3,5,6-Tetrachloropyridine (CASRN2402-79-1, supporting chemical) Hartley guinea pigs (5/sex/dose) were administered six topical 0.5 mL applications of 2,3,5,6- tetrachloropyridine (purity not indicated) as a 5% solution in a 9:1 dipropylene glycol monomethyl ether: Tween 80 mixture during a 2-week induction phase to clipped abdominal skin. After a 2-week rest period, the guinea pigs were challenged with 0.3 mL of 2,3,5,6-tetrachloropyridine or vehicle and observed for up to 48 hours. No evidence of erythema or edema was observed. 2,3,5,6-Tetrachloropyridine was not sensitizing to guinea pig skin in this assay. Subcategory II: Chlorinated Trichloromethylpyridines 2-Chloro-5-trichloromethylpyridine (CASRN 69045-78-9) Hartley albino guinea pigs (10 males) were administered 0.1 mL of a 10% solution of 2-chloro- 5-trichloromethylpyridine (90-100% w/w purity) in dipropylene glycol monomethyl ether/Tween 80 dermally under semi-occluded conditions, receiving four applications over 7 days. After resting for 14 days, the guinea pig skin was challenged with the same test solution. A positive sensitization response was observed in 8 of 10 animals. 2-Chloro-5-trichloromethylpyridine was sensitizing to guinea pig skin in this assay. Additional Sponsored Chemicals 3,4,5,6,-Tetrachloro-2-pyridine carbonitrile (CASRN 17824-83-8) No data 23 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Chloropyridine derivatives (CASRN 68412-400-8) No data Methyl chloropyridine derivatives (CASRN 70024-85-0) No data Conclusion: Subcategory I: Pentachloropyridine The acute oral toxicity of 2,3,4,5,6-pentachloropyridine in rats is moderate. The acute inhalation toxicity of 2,3,5,6-tetrachloropyridine (supporting chemical) is low in rats. In the 90-day repeated-dose dietary toxicity study of 2,3,4,5,6,-pentachloropyridine the LOAEL for male rats is 30 mg/kg-bw/day based on increased liver and kidney weights and hyaline droplets degeneration of renal tubules. The NOAEL for males is 10 mg/kg-bw/day. No systemic toxicity was seen in females; the NOAEL for females is 30 mg/kg-bw/day, the highest dose tested. The 91-day dietary repeated-dose toxicity study of 2,3,5,6-tetrachloropyridine (supporting chemical) showed degenerative changes in the kidney of male rats at 10-mg/kg-bw/day. The NOAEL for males is 3-mg/kg-bw/day. In females, the NOAEL is 100 mg/kg-bw/day (the highest dose tested). In a combined repeated-dose/reproductive/developmental toxicity study of 2,3,5,6- tetrachloropyridine (supporting chemical) in rats via gavage, the LOAEL in males is 25 mg/kg- day based on hyaline protein nephropathy with a NOAEL of 5 mg/kg-day. In females, the LOAEL of 150 mg/kg-day is based on the effects on liver and kidney; the NOAEL is 25 mg/kg- day. No reproductive toxicity study is available for 2,3,4,5,6,-pentachloropyridine. The 90-day repeated-dose dietary study showed no treatment-related effects on reproductive organs for 2,3,4,5,6,-pentachloropyridine. A combined repeated-dose/reproductive/developmental toxicity study in rats via gavage with 2,3,5,6-tetrachloropyridine showed no treatment-related effects on reproductive organs. The NOAEL for reproductive toxicity is 150 mg/kg-day, the highest dose tested. In a prenatal developmental toxicity study of 2,3,4,5,6,-pentachloropyridine in rats via gavage, maternal toxicity was seen at 50 mg/kg-day (increased liver and kidney weights) with a NOAEL of 10 mg/kg-day. The LOAEL for developmental toxicity is 200 mg/kg-day based on decreased fetal weights. The NOAEL is 50 mg/kg-day. 2,3,4,5,6,-Pentachloropyridine and 2,3,5,6,-tetrachloropyridine (supporting chemical) did not induce gene mutation in bacteria and did not induce chromosomal aberrations in rat lymphocytes in vitro or in mouse bone marrow cells in vivo. The subcategory members are irritating to rabbit skin, but not to rabbit eyes. 2,3,5,6-Tetrachloropyridine (supporting chemical) is not a dermal sensitizer in guinea pigs. Subcategory II: Chlorinated Trichloromethylpyridines The acute oral toxicity for members of the chlorinated trichloromethylpyridine subcategory in rats is low. The acute toxicity in rats via inhalation is inconclusive (LCso > 0.108 mg/L) because the concentration tested was not high enough to establish the potential hazard In a 3-week dermal toxicity study of 2-chloro, 5 trichloromethylpyridine in rats, the LOAEL is 500 mg/kg- day based on mortality and effects on clinical chemistry parameters, organ weight changes and histopathology of liver (vacuolation and necrosis of centrilobular hepatocytes), kidney (vacuolation of renal tubular epithelium) and testes (atrophy of the seminiferous tubular epithelium). The NOAEL is 100 mg/kg-day. There are no data for reproductive or developmental toxicity. 2-Chloro-5-trichloromethylpyridine induced gene mutation in bacteria 24 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 and mouse lymphoma cells in vitro and induced chromosomal aberrations in a human lymphocyte assay in vitro. Subcategory members are irritating to rabbit skin and eyes, while 2- chloro-5-trichloromethylpyridine is a dermal sensitizer in guinea pigs. Additional Sponsored Chemicals 3,4,5,6,-Tetrachloro-2-pyridine carbonitrile (CASRN17824-83-8) No data are available for acute, repeated-dose, reproductive, developmental toxicity and gene mutation and chromosomal aberrations endpoints. 3,4,5,6,-Tetrachloro-2-pyridine carbonitrile was corrosive to rabbit skin and irritating to rabbit eyes. Chloropyridine derivatives (CASRN 68412-400-8) No data are available for acute, repeated-dose, reproductive, developmental toxicity and gene mutation and chromosomal aberrations endpoints. Methyl chloropyridine derivatives (CASRN 70024-85-0) No data are available for acute, repeated-dose, reproductive, developmental toxicity and gene mutation and chromosomal aberrations endpoints. 4. Hazard to the Environment A summary of aquatic toxicity data submitted for SIDS endpoints is provided in Tables 4a and 4b. The tables also indicate where data are read-across (RA) to untested members of the category. Acute Toxicity to Fish Subcategory I: Tetra- and Pentachloropyridines 2,3,4,5,6-Pentachloropyridine (CASRN2176-62-7) Fathead minnows (Pimephalespromelas) were exposed to 2,3,4,5,6-pentachloropyridine at nominal concentrations of 0, 0.28, 0.43, 0.66, 1.02 or 1.57 mg/L under flow-through conditions for 96 hours. Measured concentrations were not provided. Affected fish lost schooling behavior and swam near the tank surface. They were hypoactive and under-reactive to external stimuli, had increased respiration, were hemorrhagic and deformed, had rigid musculature and lost equilibrium prior to death. 96-h LCso = 0.47 mg/L 2,3,5,6-Tetrachloropyridine (CASRN2402-79-1, supporting chemical) (1) Rainbow trout (iOncorhynchus mykiss) were exposed to 2,3,5,6-tetrachloropyridine at unspecified measured concentrations under flow-through conditions for 96 hours. No other information was provided. 96-h LCso = 1.5 mg/L 25 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Table 3. Summary of Screening Information Data Set under the U.S. HPV Challenge Program - Human Health Data Subcategory I Subcategory II Additional Sponsored Chemicals Endpoints SPONSORED CHEMICAL 2,3,4,5,6- Pentachloro-pyridine 2176-62-7 SUPPORTING CHEMICAL 2,3,5,6-Tetrachlo ni- pv rid ine 2402-79-1 SPONSORED CHEMICAL 3,6-Dichloro- 2-trichloromethvl- pv rid ine 1817-13-6 SPONSORED CHEMICAL 2-Chloro- 5-trichloromethyl- pvridine 69045-78-9 SPONSORED CHEMICAL 3,4,5,6-Tetrachloro-2- p> riiline carbonitrile 17824-83-8 SPONSORED CHEMICAL Chloropyridine Derivatives 68412-40-8 SPONSORED CHEMICAL Chloropyridine Derivatives 70024-85-0 Acute Oral Toxicity LDso (mg/kg) 435 - 1000 < LDso < 2000 500 < LDso <1000 1000 < LDso < 2000 No Data No Data Acute Inhalation Toxicity LC50 (mg/L) No Data >56 (RA) >56 No Data >0.108a (RA) > 0.108" No Data No Data No Data Repeated-Dose Toxicity NOAEL/LOAEL Oral (mg/kg-bw/day) (rat; 90-d, dietary) NOAELmales = 10 LOAELmales = 30 NOAELfemales = 30 (highest dose tested) (rat; 90-d, dietary) NOAEL (males) = 3 LOAEL (males) = 10 NOAEL (females) = 100 (highest dose tested) (rat; 28-d, dietary) NOAELm„ies = 5 LOAELmaies — 25 NOAELfema]es = 25 LOAELfemales 150 - - No Data No Data No Data Repeated-Dose Toxicity NOAEL/LOAEL Dermal (mg/kg-day) - - No Data NOAEL = 100 LOAEL = 500 (RA) NOAEL = 100 LOAEL = 500 - - - Reproductive Toxicity NOAEL/LOAEL (mg/kg-day) No effects on reproductive organs in the 90-day repeated-dose toxicity study No Data NOAEL = 150 (RA) NOAEL = 150 (highest dose tested) No Data No Data No Data No Data No Data 26 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Table 3. Summary of Screening Information Data Set under the U.S. HPV Challenge Program - Human Health Data Subcategory I Subcategory II Additional Sponsored Chemicals Endpoints SPONSORED CHEMICAL 2,3,4,5,6- Pentachloro-pyridine 2176-62-7 SUPPORTING CHEMICAL 2,3,5,6-Tetrachlo ni- pv rid ine 2402-79-1 SPONSORED CHEMICAL 3,6-Dichloro- 2-trichloromethvl- pv rid ine 1817-13-6 SPONSORED CHEMICAL 2-Chloro- 5-trichloromethyl- pvridine 69045-78-9 SPONSORED CHEMICAL 3,4,5,6-Tetrachloro-2- p> riiline carbonitrile 17824-83-8 SPONSORED CHEMICAL Chloropyridine Derivatives 68412-40-8 SPONSORED CHEMICAL Chloropyridine Derivatives 70024-85-0 Developmental Toxicity NOAEL/LOAEL Oral (mg/kg-/day) Maternal Toxicity Developmental Toxicity NOAEL = 10 LOAEL = 50 NOAEL = 50 LOAEL = 200 NOAEL=25 LOAEL = 150 NOAEL = 150 (highest dose tested) No Data No Data No Data No Data No Data Genetic Toxicity - Gene Mutation In vitro Negative Negative No Data Positive (RA) Positive No data No data No Data Genetic Toxicity - Chromosomal Aberrations In vitro Negative - No Data Positive (RA) Positive No Data No Data No Data Genetic Toxicity- Chromosomal Aberrations In vivo Negative Negative - - No Data No Data No Data Additional Information Skin Irritation Eye Irritation Sensitization Irritating Not irritating Irritating Not irritating Not sensitizing Irritating Irritating Irritating Slightly irritating Sensitizing Corrosive Irritating - - Measured data in bold text; (RA) = Read Across; (-) indicates that endpoint was not addressed for this chemical; (a) = concentration tested is not high enough to establish the potential hazard. 27 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 (2) Fathead minnows (Pimephalespromelas) were exposed to 2,3,5,6-tetrachloropyridine at unspecified nominal concentrations under static conditions for 96 hours. 2,3,5,6- Tetrachloropyridine was lethal to all fish at 2 mg/L. No mortality occurred at 1 mg/L. 96-h LCso > 1 < 2 mg/L Subcategory II: Chlorinated Trichloromethylpyridines No adequate fish toxicity data are available. Additional Sponsored Chemicals Chloropyridine derivatives (CASRN 68412-40-8) No fish toxicity data are available. Methyl chloropyridine derivatives (CASRN 70024-85-0) No fish toxicity data are available. Acute Toxicity to Aquatic Invertebrates Subcategory I: Tetra and Pentachloropyridines 2,3,5,6-Tetrachloropyridine (CASRN2402-79-1; supporting chemical) Daphnia magna were exposed to 2,3,5,6-tetrachloropyridine at unspecified measured concentrations and conditions for 48 hours. No other information was provided. 48-h EC50 = 2.05 mg/L (filtered samples) 48-h EC50 = 2.14 mg/L (unfiltered samples) Subcategory II: Chlorinated Trichloromethylpyridines No adequate aquatic invertebrate toxicity data are available. Additional Sponsored Chemicals Chloropyridine derivatives (CASRN 68412-40-8) No aquatic invertebrate toxicity data are available. Methyl chloropyridine derivatives (CASRN 70024-85-0) No aquatic invertebrate toxicity data are available. Toxicity to Aquatic Plants Subcategory I: Tetra- and Pentachloropyridines 2,3,4,5,6-Pentachloropyridine (CASRN2176-62-7) Green algae (Pseudokirchneriella subcapitata) were exposed to 2,3,4,5,6-pentachloropyridine at nominal concentrations of 0, 0.125, 0.250, 0.500, 1.00, 2.00 or 4.00 mg/L under static conditions for 96 hours. Acetone was used as a carrier solvent at 0.01%. Mean measured concentrations ranged from 16.0 to 60.4% of target dose levels. EC50 values were calculated using nominal concentrations. 72-h EC50 (biomass) = 1.66 mg/L 72-h EC50 (growth) > 4 mg/L 28 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 2,3,5,6-Tetrachloropyridine (CASRN2402-79-1; supporting chemical) Algae (Pseudokirchneriella subcapitata) were exposed to 2,3,5,6-tetrachloropyridine at unspecified measured concentrations and conditions for 120 hours. No other information was provided. 72-h ECso (biomass) = 14.3 mg/L 72-h EC50 (growth rate) = 9.7 mg/L Subcategory II: Chlorinated Trichloromethylpyridines No aquatic plant toxicity data are available. Additional Sponsored Chemicals Chloropyridine derivatives (CASRN 68412-40-8) No aquatic plant toxicity data are available. Methyl chloropyridine derivatives (CASRN 70024-85-0) No aquatic plant toxicity data are available. Chronic Toxicity to Aquatic Invertebrates Subcategory I: Tetra- and Pentachloropyridine 2,3,5,6-Tetrachloropyridine (CASNo. 2402-79-1; supporting chemical) Daphnia magna were exposed to 2,3,5,6-tetrachloropyridine at measured concentrations of 0.25 - 2.67 mg/L under flow-through conditions for 21 days. Mortality was observed at > 0.61 mg/L, growth was affected at 2.67 mg/L and reproduction was affected at > 1.78 mg/L. 21-d EC50 (mortality) = 1.94 mg/L Conclusion: Subcategory I: Tetra- and Pentachloropyridines For subcategory I, the 96-h LC50 for fish is 0.47 mg/L. Based on the supporting chemical, 2,3,5,6-tetrachloropyridine, the 48-h EC50 for aquatic invertebrates is 2.05 mg/L. The 72-h EC50 for algae is 1.66 mg/L for biomass, and, based on the supporting chemical, 2,3,5,6- tetrachloropyridine, the 72-h EC50 for algae is 9.7 mg/L for growth rate. Subcategory II: Chlorinated Trichloromethylpyridines There are no adequate data available for the evaluation of the ecological toxicity of the chlorinated trichloromethylpyridines. Additional Sponsored Chemicals Chloropyridine derivatives There are no available data for the evaluation of ecological toxicity of the chloropyridine derivatives. Methyl chloropyridine derivatives (CASRN 70024-85-0) There are no available data for the evaluation of ecological toxicity of the methyl chloropyridine derivatives. 29 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Table 4a. Summary of Screening Information Data Set under the U.S. HPV Challenge Program - Aquatic Toxicity Data Subcategory I: Tetra- and Pentachloropyridines II: Chlorinated Trichloromethylpyridines Endpoints SUPPORTING CHEMICAL 2,3,5,6- Tetrachloro- pyridine (supporting chemical) (2402-79-1) SPONSORED CHEMICAL 2,3,4,5,6- Pentachloro- pyridine (2176-62-7) SPONSORED CHEMICAL 3,4,5,6- Tetrachloro-2- pyridine carbonitrile (17824-83-8) SPONSORED CHEMICAL 3,6-Dichloro- 2-trichlorometh yl-pyridine (1817-13-6) SPONSORED CHEMICAL 2-Chloro- 5-trichloromethy 1-pyridine (69045-78-9) Fish 96-h LCso (mg/L) 1.5 0.47 No Data 0.47 (RA) No Data No Adequate Data Aquatic Invertebrates 48-h ECso (mg/L) 2.05 No Adequate Data 2.05 (RA) No Data 2.05 (RA) No Data No Adequate Data Aquatic Plants 72-h ECso (mg/L) biomass growth rate 14.3 9.7 1.66 > 4 No Data 1.66 9.7 (RA) No Data No Data Bold = experimental data (i.e., derived from testing); (RA) = Read Across Table 4b. Summary of Screening Information Data Set under the U.S. HPV Challenge Program - Aquatic Toxicity Data Subcategory Additional Sponsored Chemicals Endpoints SPONSORED CHEMICAL Chloropyridine derivatives (1817-13-6) SPONSORED CHEMICAL Methyl chloropyridine derivatives (70024-85-0) Fish 96-h LCso (mg/L) No Data No Data Aquatic Invertebrates 48-h ECso (mg/L) No Data No Data Aquatic Plants 72-h ECso (mg/L) biomass growth rate No Data No Data 30 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 5. References Hermens, J. 1985. Quantitative correlation studies between the acute lethal toxicity of 15 organic halides to the guppy (Poecilia reticulate) and chemical reactivity towards 4- nitrobenzylpyridine, Toxicol. Environ. Chem. 9:219-236. Lipnick, R.L., et al. 1987. A QSAR Study of the Acute Toxicity of Some Industrial Organic Chemicals to Goldfish. Narcotic, Electrophile, and Proelectrophile, Xenobiotica, 17, pp 1011- 1025. Lipnick, R.L. 1989. SYMPOSIUM, Structure-Activity Relationships in Environmental Toxicology and Chemistry, Narcosis, Electrophile and Proelectrophile Toxicity Mechanism: Application of SAR and QSAR, Environmental Toxicology and Chemistry, 8, pp 1-12. Lipnick, R.L. 1991. Outliers: their origin and use in the classification of molecular mechanisms of toxicity, The Science of the Total Environment, 109/110, pp 131-153. Newsome, L.D., et al. 1984. Validation of Fish Toxicity QSARs for Certain Non-Reactive Non- Electrolyte Organic Compounds, K. L. E. Kaiser (ed.) QSAR in Environmental Toxicology, pp 279-299. 31 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 APPENDIX The following pages show: Table 1. Chemical Structures of the Chlorinated Pyridine Category Members. Table 2. Chemical Composition of the Process Streams in the Chlorinated Pyridine Category. Table 1. Chemical Structures of the Chlorinated Pyridine Category Members Chemical Name CASRN Structure Sponsored Chemicals 2,3,4,5,6 -Pentachloro -pyridine 2176-62-7 CL ,0! 3,6-Dichloro-2-trichloromethyl-pyridine 1817-13-6 01 2-Chloro-5-trichloromethyl-pyridine 69045-78-9 ,N ,CI "y" Yu 3,4,5,6-Tetrachloro-2-pyridine carbonitrile 17824-83-8 V •; N Chloropyridine Derivatives 68412-40-8 No structure is included for this chemical, since it is a process stream Methyl Chloropyridine Derivatives 70024-85-0 No structure is included for this chemical, since it is a process stream Supporting Chemical 2,3,5,6-Tetrachloro-pyridine 2402-79-1 32 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Table 2. Chemical Composition of the Process Streams in the Chlorinated Pyridine Category Members Chemical Name CASRN Composition* Chloropyridine Derivatives 68412-40-8 Pentachloropyridine, 3.3% 2,3,4,6-Tetrachloro-5-pyridinecarbonitrile, 0.1% Hexachlorobenzene, 16.2% Pentachloroethynylpyridine,28.1% 3,4,5,6-Tetrachloro-l,2-benzenedicarbonitrile ,0.8% 2,4,5,6-Tetrachloro-l,3-benzenedicarbonitrile,1.4% Trichloroethylenetetrachloropyridine isomers (3 isomers), 9.5% Pentachloro(trichloroethenyl)-benzene, 1.0% l,2,4-Trichloro-5-[(chloropheny)thio]benzene,0.2% Tetrachlorodihydromethylbenzo(A)carbazole isomers ( 3 isomers), 0.9% Hexachlorobipyridylene Isomers/Derivatives (3 isomers/derivatives), 0.5% Perchlorovinylcyanopyridine isomers (2 isomers), 0.7% 4-[p-bis(2-hydroxyethylamino]phenyl-l-bromoisoquinoline, 2.0% Heptachlorobipyridylene Isomers/Derivatives (2 isomers/derivatives), 1.1% Octachlorobipyridylene Isomers/Derivatives (5 isomers/derivatives), 6.7% Trichlorovinyltetrachloroethynylpyridine, 9.8% Hexachlorobipyridylene Isomers/Derivatives(9), 16.5% Nonachlorophenylpyridine, 0.2% Octachloronaphthalene, 0.7% Heptachlorobipyridylene Isomer or Derivative, 0.3% Irieol, 0.4% Methyl Chloropyridine Derivatives 70024-85-0 1,2,3,4,1 l-Pentachloro-8-(trichloromethyl) dipyrioimidazolium tetrachloroferrate and process contaminants, 46% Chlorinated pyridines, 31% Ferric chloride, 15% Chlorinated bipyridines, 6% Chlorohydrocarbons, 2% *The percentages represent data gathered at one point in time, and vary with the time of process stream sampling.. 33 ------- |