PEER REVIEW DRAFT. DO NOT CITE OR QUOTE SEPA United States Office of Chemical Safety and Environmental Protection Agency Pollution Prevention Draft Risk Evaluation for Perchloroethylene (Ethene, l,l»2,2-Tetrachloro) CASRN: 127-18-4 Systematic Review Supplemental File: Data Extraction for Human Health Hazard Studies CI CI x CI CI April 2020, Draft 1 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Contents 1 DATA EXTRACTION OF STUDIES CONSIDERED FOR DOSE-RESPONSE ASSESSMENT 3 Table 1.1. Summary of the epidemiologic database considered for dose-response assessment 3 Table 1.2 Summary of the animal toxicological database considered for dose-response assessment 6 2 DATA EXTRACTION OF STUDIES NOT CONSIDERED FOR DOSE-RESPONSE ASSESSMENT 13 Table 2.1 Summary of the AnimalToxicological Database for Tetrachloroethylene not considered for dose-response 13 Table 2.2 Summary of the AnimalToxicological Database for Tetrach loroeth ylen e not considered for dose-response 49 2 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE 1 Data extraction of studies considered for dose-response assessment The tables below present data summaries of animal and epidemiological studies considered for dose-response assessment, as described in Section 3.2.5 of the Risk Evaluation. Studies that were excluded due to an Unacceptable or Low data quality score are not included. The presented effect doses/concentrations are values reported by the study authors and do not necessarily represent the PODs used for risk estimation. Table 1.1. Summary of the epidemiologic database considered for dose-response assessment Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Neurological/ Behavior Sensory nervous system function, visual and auditory evoked potentials 22 healthy male volunteers with a mean age of 26.5 years, ranging 23 to 35 years of age, participated in a study conducted in former Federal Republic of Germany Exposure in inhalation chamber to 10 ppm and 50 ppm perchloroethylene, maintained during a period of 4d for 4h daily Statistically significant mild change in visual function (visually evoked potentials) but no change in transmission of auditory impulse (brainstem auditory evoked potentials) Altmann et al. 1990 Medium Renal Urinary TP, Alb, B2M, RBP, TRF, IgG, THG, GAGs, BB50, HF5, BBA, PGE2, TXB, PGF1 alpha, PGF2alpha, IAP, TNAP, NAG, and FNU,; serum creatinine, AGBM, B2M, LAM 50 workers in dry- cleaning shops (9 men and 41 women, 17-65 years old) and 50 blood donors (9 men and 41 women, 17-63 years old), Europe (country not specified), date not provided Blood and air Perc in dry-cleaning workers exposed for 10 years Significant increase in frequency of abnormal levels in Perc-exposed subjects for urinary albumin, Beta-2- microglobulins, retinol- binding proteins, transferrin, immunoglobulin G, Tamm-Horsfall glycoproteins, glycosaminoglycans, brush-border antigens, and for serum laminin fragments. Mutti et al. 1992 Medium 3 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Neurological/ Behavior Pattern memory (Number correct) 'Dry Cleaner Study Population' (n=65). men and women; Detroit, USA Percholroethylene. Cumulative lifetime exposure levels based on complete work histories, hobbies, and industrial hygiene evaluations of subjects in participating shops:. Categories: low (n=24, average 3.4 years at shop), moderate (n=18,average 8.1 years at shop), and high (n=23, average 20.2 years at shop). Significant decrease (6.7%) was observed in the adjusted mean performance on the pattern memory (number correct) between the low and high Perc exposure categories. Echeverria et al. 1995 Medium Neurological/ Behavior Color confusion index (CCI) 35 exposed dry-cleaners and ironers (33 females, 2 males) in Modena, Italy;; 35 unexposed controls Perchloroethylene (Perc) occupational, 8 hr time- weighted average (TWA) mean airborne concentrations: all workers (6.23 ppm), dry- cleaners (7.27 ppm), ironers (4.80 ppm) A statistically significant increase in mean color confusion index was observed for Perc exposed workers and in dry-cleaners specifically, compared to unexposed controls Non-significant differences were observed in the mean color confusion index for Perc-exposed ironers compared to unexposed controls. A statistically significant correlation was observed between perc exposure and color confusion index among exposed workers. Cavalleri et al 1994 Medium 4 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE 5 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Table 1.2 Summary of the animal toxicological database considered for dose-response assessment Target Organ/ System Study Type Species/ Strain/ Sex (Number/ group) Exposure Route Doses/ Concentrations Duration Cancer Incidence Effect Reference Data Quality Evaluation Cancer Chronic Rat, Fischer, M/ F (n= 100/ group) Inhalation, vapor, whole body 0, 339, 1356, or 4069 mg/ m3 (0, 50, 200, or 600 ppm) 6 hours/ day,5 days/ week for 104 weeks 600 ppm: 1/ 50 (F) and none in males Renal cell carcinoma fJISA, 1993) High Cancer Chronic Rat, Fischer, M/ F (n= 100/ group) Inhalation, vapor, whole body 0, 339, 1356, or 4069 mg/ m3 (0, 50, 200, or 600 ppm) 6 hours/ day,5 days/ week for 104 weeks control: 1/ 50, 50 ppm: 2/ 50, 200 ppm: 1/50, 600 ppm: 2/ 50 (M), only one control female Renal cell adenoma fJISA, 1993) High Cancer Chronic Mouse, Crj: BDF1, M/F(n = 100/group) Inhalation, vapor, whole body 0, 68, 339, or 1696 mg/ m3 (0, 10, 50, or 250 ppm 6 hours/ day5days/ week for 104 weeks 50 ppm: 1/ 50 (M) and none in exposed female mice Renal cell adenoma fJISA, 1993) High Cancer Chronic Mouse, Crj: BDF1, M/F (n = 100/group) Inhalation, vapor, whole body 0, 68, 339, or 1696 mg/ m3 0, 10, 50, or 250 ppm 6 hours/ day5days/ week for 104 weeks 50 ppm: 1/ 50 (M) and none in exposed female mice Renal cell carcinoma fJISA, 1993) High ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Study Type Species/ Strain/ Sex (Number/ group) Exposure Route Doses/ Concentrations Duration Cancer Incidence Effect Reference Data Quality Evaluation Cancer Chronic Rat, F344/ N, M/ F (n=100/ group) Inhalation, vapor, whole body 0, 1356, or 2713 mg/ m3 (0, 200 or 400 ppm) 103 weeks control: 0/49; low dose: 3/49; high dose:5/ 50 (M) and in one high-dose female rat Tubal cell hyperplasia fNTP, 1986) High Cancer Chronic Rat, F344/ N, M/ F (n=100/ group) Inhalation, vapor, whole body 0, 678, or 1356 mg/m3(0, 100 or 200 ppm) 103 weeks control: 1/49; low dose: 3/49; high dose: 4/ 50 (M) Renal tubule adenomas and adenocarcinomas fNTP, 1986) High Cancer Chronic Mouse, B6C3F1, M/F (n=98-100/ group) Inhalation, vapor, whole body mg/ m3 (0, 100 or 200 ppm) 103 weeks 1 low-dose male mouse Renal tubule adenocarcinoma fNTP, 1986) High Hepatic Chronic Rat, F344/ DuCrj, M/ F (n=100/ group) Inhalation, vapor, whole body 0, 339, 1356, or 4069 mg/ m3 (0, 50, 200 or 600 ppm) 6 hours/ day, 5 days/ week for 104 weeks (sacrificed at 110 weeks) LOAEL= 1356 mg/ m3 (M), spongiosis LOAEL = 4069 mg/ m3 (M), hyperplasia Spongiosis hepatitis and hyperplasia (J ISA, 1993) High Hepatic Chronic Mouse, Crj/ BDF1, M/F (n=100/ group) Inhalation, vapor, whole body 0, 68, 339, or 1696 mg/ m3 mg/ m3 (0, 10, 50 or 250 ppm) 6 hours/ day, 5 days/ week for 104 weeks (sacrificed at 110 weeks) LOAEL= 339 mg/ m3 (M) LOAEL = 1696 mg/ m3 (F) Focal necrosis liver degeneration (J ISA, 1993) High Renal Chronic Rat, F344/ DuCrj, M/ F (n=100/ group) Inhalation, vapor, whole body 0, 339, 1356, or 4069 mg/ m3 (0, 50, 200 or 600 ppm) 6 hours/ day, 5 days/ week for 104 weeks LOAEL= 1356 mg/ m3 (M/ F), increased relative kidney Increased relative kidney weights and karyomegaly in the proximal; atypical (J ISA, 1993) High ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Study Type Species/ Strain/ Sex (Number/ group) Exposure Route Doses/ Concentrations Duration Cancer Incidence Effect Reference Data Quality Evaluation (sacrificed at 110 weeks) weights and karyomegaly in the proximal tubules LOAEL = 4069 mg/ m3 (M/ F), atypical tubular dilation LOAEL = 4069 mg/ m3 (M), exacerbation of chronic renal disease tubular dilation; exacerbation of chronic renal disease Target Organ/ System Study Type Species/ Strain/ Sex (Number/ group) Exposure Route Doses/ Concentrations Duration Cancer Incidence Effect Reference Data Quality Evaluation Renal Chronic Mouse, Crj/ BDF1, M/F (n=100/group) Inhalation, vapor, whole body 0, 68, 166, Or 1696 mg/ m3 (0, 10, 50 or 250 ppm) 6 hours/ day, 5 days/ week for 104 weeks (sacrificed at 110 weeks) LOAEL= 1696 mg/ m3 (M/ F), relative kidney weight, karyomegaly in the proximal tubules, and atypical tubular dilation Increased relative kidney weights and karyomegaly in the proximal tubules and atypical tubular dilation but was not statistically significant (J ISA, 1993) High Hepatic Chronic Mouse, B6C3F1, M/ F Inhalation, vapor, 0, 678, 1356 mg/ m3 6 hours/ day, 5 days/ week for 103 weeks LOAEL= 678 mg/ m3 (M) Liver degeneration (NIP, 1986) High ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Study Type Species/ Strain/ Sex (Number/ group) Exposure Route Doses/ Concentrations Duration Cancer Incidence Effect Reference Data Quality Evaluation (n=98-100/ group) whole body (0, 100 or 200 PPm) LOAEL= 1356 mg/ m3 (F) and necrosis in Hepatic Subchroni c Mouse, Swiss- Cox, M (n=12- 15/ group all doses except two highest doses: 4-6/ group) Oral, gavage 0, 20, 100, 200, 500, 1000,1500 or 2000 mg/ kg/ day 5 days/ week for 6 weeks NOAEL= 20 mg/ kg-day (M) LOAEL= 100 mg/ kg-day (M) Increased liver/ body weight ratio at 100 mg/ kg- day; increased triglycerides at 100 mg/ kg-day; no change at 20 mg/ kg-day (Buben and O'Flahertv, 1985) High Renal Chronic Rat, F344/ N, M/ F (n=100/ group) Inhalation, vapor, whole body 0, 1356, or 2713 mg/ m3 (0 200, or 400ppm) 6 hours/ day, 5 days/ week for 103 weeks LOAEL= 1356 mg/ m3 (200 ppm) (M/ F) Karyomegaly and cytomegaly of the proximal tubules in all exposed rats (NIP, 1986) High Renal Chronic Mouse, B6C3F1, M/ F (n=98-100/ group) Inhalation, vapor, whole body 0, 678, or 1356 mg/ m3 (0, 100 or 200 ppm) 6 hours/ day, 5 days/ week for 103 weeks LOAEL= 678 mg/ m3 (M/ F) Karyomegaly and cytomegaly of the proximal tubules in all exposed mice; nephrosis was observed in exposed females, casts increased in all exposed males and in high-dose females (NIP, 1986) High ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Study Species/ Exposure Doses/ Duration Cancer Incidence Effect Reference Data Organ/ Type Strain/ Sex Route Concentrations Quality System (Number/ Evaluation group) Develop- Develop- Rat, Sprague Inhalation, Actual 6 hours/ day, Maternal LOAEL Maternal (Carney et High mental mental Dawley, F vapor, concentration 7 days/ week = 4069 mg/ m3 toxicity al„ 2006) (n=22/ group) whole s: 0, 448, on GDs 0-19 (from summary (slight, but body 1689,or 4069 table 4-38) statistically mg/ m3 significant, (0, 66, 249 or Fetal LOAEL = decreased 600 ppm) 1696 mg/ m3 body weight Target (from summary gain; concentration table 4-38) decreased s: 0, 509, gravid uterine 1696,or 4069 weight); fetal mg/ m3 (0, body weight 75, 250 or and placental 600 ppm) weight decrements, increased delays in thoracic vertebral ossification 10 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Study Species/ Exposure Doses/ Duration Cancer Incidence Effect Reference Data Organ/ Type Strain/ Sex Route Concentrations Quality System (Number/ Evaluation group) Reproduct Reproduct Rat, Sprague Inhalation, 0, 678, 2035, F0: 6 hours/ Increased (Tinston, High ive ive Dawley, M/ F vapor, or 6782 mg/ day, 5 days/ NOAEL = death of F1A 1994) (two- whole m3 week for 11 678 mg/ m3 for and F2A and generation body (0, 100, 300 weeks parental F2B pups; study) or 1000 ppm) premating; systematic decreased (n=48/ group) 6 hours/ day, toxicity body weight 7 days/ week (increased death for up to 21 of mothers) days during LOAEL = 678 mating period; mg/ m3 for F1A 6 hours/ day, pups 5 days/ week postmating until termination for males and 6 hours/ day, 5 days/ week for females postmating through GD 20 (28 litters/ dose) Develop- Developm Rat, Sprague Inhalation, 0, 678, or 7 hours/ day on NOAEL= 678 Decreased (Nelson et Medium mental ental Dawley vapor, 6104 mg/ m3 GDs 7-13 or mg/ m3 weight gain; al„ 1979) Effects (n = 13-21/ whole (0, 100 or 900 14-21 LOAEL= 6104 behavioral (Neurotoxi group) body ppm) (GDs 13-21 mg/ m37 changes, city) litters/ dose, more male and extensive for female late offspring pregnancy assessed) exposure; decreased brain acetylcholine ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Study Species/ Exposure Doses/ Duration Cancer Incidence Effect Reference Data Organ/ Type Strain/ Sex Route Concentrations Quality System (Number/ group) Evaluation Develop- Developm Rat, Sprague Inhalation, 0, 678, 2035, F0: 6 hours/ NOAEL = (Tinston, High mental ental Dawley (two- vapor, or 6782 mg/ day, 5 days/ 300 ppm CNS 1994) generation whole m3 week for 11 LOAEL = 1,000 depression/ study) body (0, 100, 300 weeks ppm Behavioral (n=48/ group) or 1000 ppm) premating; 6 hours/ day, 7 days/ week for up to 21 days during mating period; 6 hours/ day, 5 days/ week postmating until termination for males and 6 hours/ day, 5 days/ week for females postmating through D 20 (28 litters/ dose) effects (decreased activity, reduced response to sound) in F1 pups 12 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE 2 Data extraction of studies not considered for dose-response assessment Table 2.1 Summary of the Epidemiological Database for Perchloroethylene not considered for dose- response Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Acute Toxicity/Poisoning Clinical observations including nausea, irritation of the eyes, sinus discomfort, and blood pressure Five researchers, 1930s, sex and age not reported One to two hour inhalation chamber exposures at approximately 500, 1000, 1500, and 2000 PPm perchloroethylene Subjects reported feeling nauseous and having eye irritation after a 500 ppm exposure and faintness at higher exposure levels Carpenter 1937 Low Acute Toxicity/Poisoning Clinical observations including nausea, dizziness, eye irritation, and sleepiness Subject information not reported Controlled inhalation chamber exposure to approximately 100, 200, 280, 600, and 1000 ppm perchloroethylene for an unreported duration Mild eye irritation, sinus discomfort, and light headedness reported at lower concentrations, more severe symptoms at higher concentrations Rowe et al. 1952 Low 13 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Acute Toxicity/Poisoning Clinical observations including eye irritation, light headedness, and respiratory rate 21 year old male employee Accidental occupational exposure with estimated mean perchloroethylene concentration of 393 ppm Subject was initially unconscious, later reported eye irritation, light headedness, and faintness Stewart et al. 1961 Medium Acute Toxicity/Poisoning Clinical observations including eye irritation, headache, nausea and dizziness Sixteen healthy male technical employees ranging in age from 24 to 64 years; five subjects were selected for repeated exposure 7-hour inhalation chamber exposure to approximately 100 ppm perchloroethylene for 1-5 days Subjects reported low-grade chronic sinusitis, a mild frontal headache, and mild eye and throat irritation Stewart et al. 1970 Medium Acute Toxicity/Poisoning Headache, nausea, dizziness, chest pain, abdominal pain, irritation of eyes nose or throat 12 subjects, Wisconsin, 1975, 19- 42 years of age Perchloroethylene, controlled exposure of 0, 25, 100 ppm for 5.5 hrs No significant associations between perchloroethylene exposure and clinical observations Stewart et al. 1977 Medium 14 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Cancer Cancer diagnosis: liver, kidney, bladder, pancreas, lung, cervix, ovary, Hodgkin's disease, non- Hodgkin's lymphoma, and multiple myeloma Adults working in the Netherlands during the 1970 census, including 23,714 women and 5,619 men working as launderers and dry cleaners Occupation in dry cleaning or laundering industry served as surrogate for Perc exposure Significant increase in incidence of lung, cervical, and ovarian cancer diagnosis and Hodgkin's disease (women only), all other outcomes were non- significant Anderson et al. 1999 Medium Cancer Renal cell carcinoma diagnosis Renal cell carcinoma cases (n= 315) and population controls (n=313), Oklahoma City, occupational history through -1988 Primary occupation in dry cleaning industry served as surrogate for Perc exposure Non significant association between dry cleaning occupation and renal cell carcinoma in males (negative) and females (positive) Asal et al. 1988 Medium 15 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Cancer Leukemia incidence Adults, permanent residents of five Upper Cape towns, Massachusetts, in 1983-1986 (35 leukemia cases, 464 living + 723 deceased controls) Modeled household exposure to perchloroethylene through the public water distribution system; estimated dose ranged 0.01- 209.4 mg (for no latency) or 0.01-90.6 mg (for 5-year latency) A statistically significant increase in odds of leukemia was observed for "high" exposure group vs. non- exposed to perchloroethylene, after 0-year and 5- year latency periods (non- statistically significant increase for ever exposed vs. non- exposed) Aschengrau et al. 1993 Medium Cancer Kidney cancer, liver cancer, bladder cancer, Non-Hodgkin's lymphoma, Hodgkin's lymphoma, all cause cancer mortality, lung cancer, cervical cancer, esophageal cancer mortality 5,369 dry cleaners members of a dry cleaning union in St. Louis, men and women, follow-up 1948-1993 Dry cleaner occupation, perchloroethylene the dominant solvent Non-significant increase in Hodgkin's lymphoma mortality for the entire follow-up period, and for the two shorter follow- up periods Blair et al. 2003 Medium 16 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Cancer Cause-specific mortality: kidney cancer, Hodgkin lymphoma, Leukemias, ALS Camp Lejeune, North Carolina cohort; n=154,932 median age, start of follow-up: 20 median age, end of follow-up: 49 Camp Pendleton, California cohort n=154,969 median age, start of follow-up: 20 median age, end of follow-up: 49 exposure period: 1975-1985; mortality follow-up period: 1979-2008 Chemical name: Perchloroethylene (PCE); exposure matrix: estimated monthly average PCE concentration in Tarawa Terrace water system (1975-1985) Mean: 75.7 ug/L, Median: 84.9 ug/L, Range: 0-158.1 ug/L; estimated monthly average PCE concentration in Hadnot Point water system (1975-1985) Mean: 15.7 ug/L, Median: 15.4 ug/L, Range: 0-38.7 ug/L); Duration: On average an individual in the Camp Lejeune cohort resided at the base for 18 months. Positive, non- significant associations observed between cumulative exposure to PCE and mortality due to kidney cancer. Bove et al. 2014 High 17 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Cancer Excess risk of renal cell carcinoma (RCC) Hospital-based case control study of patients diagnosed with renal cell carcinoma (RCC) in Arnsberg, Germany between 1992 and 2000 (134 cases, 401 gender- and age- matched controls). TCE and Perc exposure probability and duration were based on self- assessment. Analyses of industries with exposure to TCE were based on an IARC database (CAREX). A job exposure matrix (JEM) was used to assess exposure to degreasing agents (also other agents). The ORs for RCC risk were increased for self- assessed overall exposure to TCE. RCC ORs were not significantly elevated based self assessed overall exposure to Perc. Bruning et al. 2003 High Cancer Diffuse large B- cell lymphoma Georgia population (2000 census) Geocoded toxic release sites data for Perc from 1988-1998 EPA's TRI Significantly decreased risk for diffuse large B-cell lymphoma with increasing mean distance (per 1 mile) to Perc TRI sites. Bulka et al. 2016 Medium 18 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Cancer Mortality from lymphatic and haematopoietic cancer 1704 dry cleaning workers in four US cities (San Francisco/Oakland, Chicago, Detroit, and New York) Employment in a shop using Perc, mean (sd) years of employment for exposed workers 6.2 (5.0) Significant elevated SMRs were observed for all cancers, esophageal cancer, and trachea, bronchus, and lung cancer. SMRs were significantly lower for liver cancer. No significant association was found for kidney cancer, lymphatic and haematopoietic cancer, and bladder cancer. Calvert et al. 2010 Medium 19 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Cancer Diagnosis of cancer in oral cavity, oropharynx, hypopharynx, oral cavity, and larynx (detailed list of codes in text) Case-control, women only, 296 cases, 775 controls, diagnosed 2001-2007, general population, 18-85 years, subset of I CARE cohort Perc, exposure qualitatively stated, modeled as cumulative exposure index (CEI) Statistically significant positive association between Perc and head/neck cancers in ever/never analysis; null association in continuous cumulative exposure assessment Carton et al. 2017 Medium Cancer Cancers of the bladder, prostate, colon, stomach, rectum, kidney, pancreas, esophagus, and liver, as well as melanoma and non-Hodgkin's lymphoma. 3730 male, Canadian patients aged 35 to 70 years diagnosed 1979-1985 in 18 largest Montreal hospitals; 533 controls from electoral lists in Quebec. A second control group consisted of the population controls together with patients with cancers at sites distal to the primary cancer being assessed.. PERC exposure determined from self- reported job history categorized by chemists and industrial hygienists based on degree of confidence, frequency, and relative levels (not quantitative) Significant increase in the OR for prostate cancer associated with Perc exposure (substantial), non- significant OR for all other cancers Christensen et al. 2013 Medium 20 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Cancer Renal cell carcinoma 718 cases (men) of renal cell carcinoma from the New Zeeland Cancer Registry and 12,758 male controls, 1978- 1986 Occupational (dry- cleaning and laundry workers exposed to perchloroethylene) Non-significant elevation in risk of kidney cancer among dry- cleaning workers Delahunt et al. 1995 Medium Cancer Renal cell carcinoma White newly diagnosed cases with age- and gender- stratified random sample white controls JEM (developed by NCI) No significant association between Perc and RCC for the total population nor when separated by sex. Dosemeci et al. 1999 Medium Cancer Breast cancer incidence 920 incident breast cancer cases, 1293 controls, Cape Cod, Massachusetts, 1983-1993, Water distribution modeled exposure to Perc-lined public water distribution pipelines Perc was not significantly associated with breast cancer, but there was a modest increase in risk in women with high perc exposure Gallagher 2011 Medium 21 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Cancer Bladder cancer 113,343 cases and 566,715 matched controls from the Nordic Occupational Cancer (NOCCA) project (through 2005) Perc exposure estimated via linkage between occupational codes and Nordic Occupational Cancer (NOCCA) project job exposure matrix (JEM) No significant trend in risk with increasing Perc exposure, significant increase in hazard ratio was only observed in the mid exposure group Hadkhale et al. 2017 Medium Cancer Neuroblastoma Children (75 cases, 14602 controls), ages <6 born in 1990-2007 in California within 5 km of exposure monitoring stations, cases from California Cancer Registry Perc (0.186 ppbV) in ambient air, pollution monitoring stations used to estimate maternal exposure during pregnancy from birth certificate address Non-significant positive association between Perc and neuroblastomas per interquartile increase in exposure at 5km radius Heck et al. 2013 Medium Cancer Astrocytic brain cancer risk Men in southern Louisiana, United States, exposed from 1978- 1980; in northern New Jersey and Philadelphia, Pennsylvania, United States, exposed from 1979- 1981 (n=620, 300 cases, 320 controls) Perchloroethylene, low exposure (1) Chi trend= -0.65. Exposure not significantly associate with astrocytic brain cancer Heineman et al. 1994 Medium 22 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Cancer Kidney cancer (total, parenchymal cancer, pelvical cancer, unspecified cancer) , lung cancer 1,644,958 economically active men in the census of year 1960 and 1,154,091 economically active women in the census of year 1970. from the Swedish family Center Database Occupation as launderers and dry cleaners (with perc mentioned as solvent used in dry cleaning) Non-significant elevations in excess risk of total kidney cancer and renal parenchymal cancer in men; Significant elevations of pelvical or renal unspecified cancers in men. Ji et al. 2005 Medium Cancer Cancer mortality Lockheed Martin aircraft manufacturing factory workers in Burbank, California (employed after January 1, 1960; followed up through December 31, 2008) Years of exposure to Perc based on job histories and industrial hygiene surveys No significant trend for any specific cancer or total cancer by increasing years of exposure. Lipworth et al. 2011 High Cancer Total cancer incidence, liver, pancreas; bladder kidney, lymphomas Men and women (n=378 cancer cases), aged 20-64, working on laundry and dry-cleaning shops in Denmark in 1970 Exposure during laundry or dry cleaning to percholroethylene Significant increase in pancreas cancer incidence in men and women combined Lynge and Thygesen 1990 Low 23 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Cancer Incident cancers of the esophagus, gastric cardia, pancreas, cervix uteri, bladder, and kidney, primary liver cancer, non- Hodgkin lymphoma Laundry and dry cleaning workers identified from the 1970 censuses in Denmark, Norway, Sweden, and Finland (1,616 case, 2,398 controls) Occupation (laundry and dry cleaning); mean perchloroethylene for dry cleaners 160 mg/m3 Non-significant increased risk of kidney cancer incidence among assistants in dry cleaning shops; Non-significant decrease in risk of kidney cancer for dry cleaners. No elevations in risk of kidney cancer were observed with length of employment. Lynge et al. 2006 Medium 24 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Cancer Kidney/renal cancer, all cancer discharges (with and without skin cancer) ICD9 189.0 and 189.1 All residents of New York City from 1993 to 2004, at least 45 years old, who were admitted as inpatients to a state regulated hospital (N=10,916 kidney/renal cancer discharges) Dry cleaning facilities using perchloroethylene in New York City (5 exposure levels based on the distribution of density of Perc dry cleaners per squared kilometer): 0-0.47; 0.47- 1.90, 1.90- 1.50; 1.50-2.70; 2.70-16.43 Significant association between the density of perchloroethylene dry cleaning establishments and the rate of hospital discharges that include a diagnosis of kidney cancer among persons 45 years of age and older living in New York City Ma et al. 2009 Medium Cancer Renal cell carcinoma diagnosis Renal cell carcinoma cases (n= 1732) and population controls (n=2309), complete occupational history collected 1989-1991, Australia, Denmark, Germany, Sweden, USA Renal cell carcinoma diagnosis Significantly increased risk for renal cell carcinoma with exposure to dry cleaning solvents Mandel et al. 1995 High 25 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Cancer Lung cancer Investigation of occupational exposure and environmental causes of respiratory cancers (ICARE) study subjects, population-based case-control study in France 2001-2007 (2274 men cases and 2780 men controls) Cumulative Exposure Index (CEI) based on self-reported job histories and probability, intensity, and frequency of exposure to Perc based on jobs Perc was not significantly associated with lung cancer in men. Mattei et al. 2014 Medium Cancer Kidney cancer (renal cell carcinoma), renal pelvic carcinoma 489 cases of kidney cancer, 147 cases of pelvic cancer and 523 controls in New South Wales Occupation in dry cleaning industry Significantly elevated risk of renal pelvic carcinoma associated with working in the dry cleaning industry compared to population controls McCredie and Stewart 1993 Medium Cancer Kidney cancer (renal cell carcinoma) 368 cases and 396 controls in Denmark, interviewed between 1989-1992 Occupational exposure in dry cleaning industry Non-significant elevations in risk of renal cell carcinoma in men and in women employed in the dry cleaning industry 10 or more years before the interview Mellemgaard et al 1994 Medium 26 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Cancer All Non-Hodgkin lymphoma and by non-Hodgkin lymphoma subtype (i.e,. small lymphocytic, follicular, diffuse, other), All newly diagnosed cases of non-Hodkin lymphomas, chronic lymphocytic leukemia (CLL) during 1991- 1993 among men and women age 20 to 74 years in 11 areas in Italy Perc exposure based on job-specific questionnaires and industrial hygiene experts for level of probability (i.e,. low, medium, high) and intensity of exposure (i.e., very low, low, medium, and high) with durations of less than 15 years and 15 or more years. Perc was not significantly associated with non-Hodgkin lymphoma either by intensity or duration of exposure. Miligi et al. 2006 High Cancer Mycosis fungoides (MF) 100 patients with Mycosis Fungoides and 2846 controls, 35-69 years of age, from Denmark, Sweden, France, Germany, Italy, and Spain, 1995-1997 Occupational exposure to Perc assessed with job exposure matrix A positive, non- significant association was observed between Mycosis Fungoides and male subjects with exposure to Perc >= median of control exposure vs. unexposed male subjects Morales- Suarez- Varela et al. 2013 High 27 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Cancer Brain cancer: glioma and meningioma cases 489 glioma cases, 197 meningioma cases, and 799 controls from three USA hospitals in Arizona, Massachusetts and Pennsylvania Occupational exposure to Perc via self-reported occupational history and industrial hygienist assigned level of exposure Perc was not significantly associated with glioma or meningioma Neta et al. 2012 High Cancer Mortality from all cancer (SMR) 1690 workers employed in facilities that used perc as their primary solvent in Oakland, Detroit, Chicago, or New York City, workers employed at least one year prior to 1960 Years of employment in a perc facility A positive trend of increasing risk of all cancer mortality was observed with an increase in both years of exposure and latency (time since first employment in a perc facility) NIOSH 1985 High Cancer Excess risk of renal cell carcinoma (RCC) Multi-center population level case- control study of 935 patients diagnosed with RCC between 1991 and 1995 and 4298 controls matched by geographical region, sex and age (-1:4 ratio of cases to controls). Exposure was categorized as medium, high or substantial based on a job exposure matrix (JEM or a job- exposure-task matrix (JETM). Odds ratios showed low to no significant increased risk of renal cell carcinoma for Perc exposure, no dose response trends. Pesch et al. 2000 Medium 28 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Cancer Cancer of the liver 15 million people participating in a decennial census in Denmark, Finland, Iceland, Norway, and Sweden. Aged 30-64 in years 1960-1990. Employment in dry cleaning and/or laundering during time period of predominant Perc use Significantly elevated SIRs were observed in women for stomach, liver, cervical, oral cavity, and lung cancers. No association was found for kidney, bladder, and non- Hodgkin's lymphoma cancer incidence in women. Pukkala et al. 2009 Medium Cancer Diagnosis of kidney cancer General population case-control study of kidney cancer (1217 cases; 1235 controls). Detroit (2002 - 2007) and Chicago (2003). Job exposure matrix was used to determine years exposed, average weekly exposure and cumulative hours exposed, to perc Increased risk of kidney cancer for high intensity exposure group; OR 3.0(1.3-7.4) for 3rd fertile (>1820 hours) vs. unexposed for cumulative hours exposed. No significant associations observed in for other levels of perc exposure. Purdue et al. 2016 High 29 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Cancer Mortality from multiple myeloma Aircraft maintenance workers (n = 14,457; 10,730 men and 3725 women) at Hill Air Force Base (Utah, USA), for at least one year from 1952-1956, and followed up through 2000 Occupational exposure to Perc (yes/no) based on job- exposure matrix; no quantitative assessment available Positive association between mortality from multiple myeloma and occupational exposure to Perc compared to no exposure (statistically significant for females, non- statistically significant for males) Radican et al. 2008 Medium Cancer Childhood cancers, neural tube defects, oral clefts, Children born to mothers with exposure to contaminated drinking water at Camp Lejeune : 51 cases and 526 controls Perchloroethylene (perc) in drinking water during 1st trimester of pregnancy; modelled exposure high (>=44 ppb), low (<44 ppb) Positive, non- significant associations observed between childhood cancers and any, high or low 1st trimester exposure to perc compared to unexposed). Ruckart et al. 2013 High 30 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Cancer Age of diagnosis of breast cancer (male only). Case-control, male Marines born before 1969, diagnosed 1995-2013, with identifiable tour dates/locations Perc, residential drinking water at Camp Lejeune , cumulative exposure >159 ppb Non-significant positive association between Perc exposure and breast cancer diagnosis and age of diagnosis Ruckart et al. 2015 High Cancer Glioma Non-farm workers from the Upper Midwest Health Study (798 cases and 1141 controls from lawa, Michigan, Minnesota, and Wisconsin 1995- 1997) Perc (perchloroethylene) use (self-reported occupational history through 1992, bibliographic database of published exposure) Perc was associated with a significant decrease in gliomas. Ruder et al. 2013 High Cancer Total lymphoma, HL, B-NHL, T- NHL, B-NHL subentities (DLBCL, FL, CLL, multiple myeloma, marginal zone lymphoma) 710 participating cases (matched to 710 controls) with malignant lymphoma among men and women aged 18 to 80 years in 6 regions in Germany Cumulative occupational exposure to Perc [ppm*years] based on intensity, the frequency, and duration of Perc exposure (0 to >78.8 ppm*years) Perc was not significantly associated with malignant lymphoma or any specific type of lymphoma; however, there was an increase (non-significant) in risk of total lymphoma in the highest exposure group (>78.8 ppm*years). Seidler et al. 2007 High 31 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Cancer Kidney, bladder, liver, NHL, overall cancer incidence Swedish national cohort of dry-cleaning and laundry workers (n = 10,389) assembled in 1984 followed up for new cases of cancer by matching with the Swedish cancer register from 1985 to 2006 Occupation as dry cleaners ans laundry workers exposed to perchloroethylene; exposure levels in the 1970s were of the order of 100-200 mg/m3 (15-30 ppm) Non-significant elevated risk of Hodgkin's lymphoma, kidney and liver cancer, significantly elevated risk of Non-Hodgkin's lymphoma and lung cancer; no elevated risk of bladder cancer Selden and Ahlborg 2011 Medium Cancer Kidney cancer incidence Greater Montreal metropolitan area. Case-control study of occupationally- exposed men aged 35 to 70 year old (4263 cases, 533 population controls; also hospital and cancer controls). Any or substantial exposure ORs were not significantly elevated for PCE exposure and kidney cancer (no quantitative data were provided). Siemiatycki 1991 Medium Cancer Bladder and other urinary cancer mortality National Institute for Occupational Safety and Health (NIOSH) Cohort, 34494 workers at NY microelectronics and business machine facility, 2009, 52- 65yrs Cumulative Perc exposure score based on department- exposure matrix Perc was not significantly associated with bladder and other urinary cancers mortality. Silver et al. 2014 Medium 32 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Cancer Testicular cancer National Institute for Occupational Safety and Health (NIOSH) Cohort, 34494 workers at NY microelectronics and business machine facility, 2009, 52- 65yrs Cumulative Perc exposure score based on department- exposure matrix Perc was not significantly associated with testicular cancer incidence. Silver et al. 2014 Medium Cancer Acute myeloid lymphoma Cases of acute myeloid leukemia (n=14,337) diagnosed between 1961 and 2005, and controls (n=71,027) matched by age, sex, and country identified from the Nordic Occupational Cancer Study cohort Cumulative Perc exposure estimated using job exposure matrix, Median (ppm- yr) 12.1 No significant increase in acute myeloid leukemia risk was observed with low, moderate, or high exposure to Perc, compared to referent group when hazard ratios were calculated using a 10-year lag (p- value = 0.39). Findings for analysis stratified by sex or age were not reported Talibov et al. 2014 High 33 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Cancer Cancer diagnosis: liver/biliary, kidney, bladder, pancreas, lung, cervix, Hodgkin's lymphoma, and non-Hodgkin's lymphoma Adults working in the Sweden during the 1960 and 1970 census, including 31,418 women and 15,515 men working as launderers, dry cleaners, or pressers Occupation as a dry cleaner, launderer, or presser served as surrogate for Perc exposure Increased incidence of Hodgkin's disease (significant), lung (significant), cervix (significant), liver/biliary passages, kidney, and bladder cancer, all other outcomes were non-significant Travier et al 2002 High Cancer Lung cancer Lung cancer cases and randomly selected population- based controls frequency matched by sex and age in Montreal Canada Perc exposure (any or substantial) was assessed by a team of industrial chemists and hygienists based on self-reported job histories Increase in OR for any exposure or substantial exposure to Perc, results were only significant for any exposure in Study I and in the pooled analysis Vizcaya et al. 2013 Medium Cancer Liver and kidney cancer, non- Hodgkin's lymphoma (NHL) and multiple myeloma (MM) All subjects aged 30- 64 years who participated in 1960 through 1990 censuses in Finland, Iceland, Norway and Sweden ; five matched control sper case Job-exposure matrix, intensity x prevalence of perchloroethylene exposure (90th percentile:: 0.05 units) A positive, non- significant association was observed between high cumulative perchloroethylene exposure (intensity x prevalence) and kidney cancer in men and women. Vlaanderen et al. 2013 High 34 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Cancer Renal pelvis cancer, bladder cancer Employed Swedish residents (1,014 and 360 renal pelvis cancers and 18,244 and 3,347 bladder cancers among men and women, respectively) Occupation type (workers in laundry, ironing , dyeing) or industry Non-significant excess risk of renal pelvis cancer among men working in laundry, ironing , dyeing industry. Wilson et al. 2008 Medium Cardiovascular Major cardiac birth defects 1,090 live births in the TCE study area and 3.6 million births in the comparison group (NY State without NYC) (1978- 2002). Maternal exposure to Perc through soil vapor intrusion (4.1- 9.5 ug/m3 indoor air sampling) associated with a 1979 spill from a semiconductor manufacturing facility in Endicott, New York Adjusted rate ratios for low birth weight (LBW), small for gestational age (SGA), term LBW, cardiac defects and conotruncal defects were significantly elevated in the Perc study area. Forand et al. 2012 Medium Cardiovascular Blood pressure and heart rate 21 year old male employee Accidental occupational exposure with estimated mean perchloroethylene concentration of 393 ppm No effects observed for Cardiovascular outcomes. Stewart et al. 1961 Medium 35 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Clinical Chemistry/Biochemical Urinalysis Five researchers, 1930s, sex and age not reported One to two hour inhalation chamber exposures at approximately 500, 1000, 1500, and 2000 PPm perchloroethylene No effects observed for Clinical Chemistry/Bioche mical outcomes. Carpenter 1937 Low Clinical Chemistry/Biochemical Clinical chemistry panel and urinalysis 21 year old male employee Accidental occupational exposure with estimated mean perchloroethylene concentration of 393 ppm Minor, transient elevations of alkaline phosphatase and SGP-T Stewart et al. 1961 Medium Clinical Chemistry/Biochemical Clinical chemistry panel and urinalysis Sixteen healthy male technical employees ranging in age from 24 to 64 years; five subjects were selected for repeated exposure 7-hour inhalation chamber exposure to approximately 100 ppm perchloroethylene for 1-5 days No effects observed for Clinical Chemistry/Bioche mical outcomes. Stewart et al. 1970 Medium Clinical Symptoms Ears, nose, throat, ophthalmological, cutaneous, respiratory, digestive signs, neurological symptoms, Epworth test>8, pre-narcotic syndrome 50 exposed workers from 22 dry-cleaning establishments in France , 95 matched unexposed controls Ambient perchloroethylene levels , blood perc levels; years of employment; median value of atmospheric perc was 7 ppm (0.22-33), the median blood level of perc was 73.6 |jg/l (118— 144). Perchloroethylene exposure was not associated with significant increase in clinical symptoms among dry-cleaning employees compared to unexposed controls. Lucas et al. 2015 Medium 36 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Growth (early life) and Development Childhood cancers, neural tube defects, oral clefts, Children born during 1968-1985 to mothers exposed to contaminated drinking water at Camp Lejeune during pregnancy: 51 cases and 651 controls Perchloroethylene (perc) in drinking water during 1st trimester of pregnancy; modelled exposure above MCL (>=5 ppb), below MCL (< 5 ppb) Positive non- significant association observed between neural tube defects and exposure to perc <= 5 ppb compared to unexposed. Negative, non- significant association observed between neural tube defects and any exposure to perc, or exposure > 5 ppb compared to unexposed. Ruckart et al. 2013 High Hematological and Immune Primary Sjogren syndrome Cases (n= 175) followed up in departments of Internal Medicine of three University Hospitals and matched controls (n=350) (2010-2013) Occupational Perc exposure based on self-reported occupational histories, expert judgement of industrial hygienists and occupational practitioners, as well as the French JEM (used more for the chlorinated solvents) Significant increase in risk for Sjogren' syndrome with occupational Perc exposure; increase OR with high final cumulative exposure, but was not significant Chaigne et al 2015 Medium 37 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Hematological and Immune Systemic Sclerosis Meta-analysis of 14 case-control studies (6 with TCE and/or PCE exposure analysis). The perc studies included 714 cases and 2479 controls. The TCE studies included 1029 cases and 2884 controls. Proportion of subjects exposed to solvents occupational^ A positive, non- significant association was observed between risk of SSc and perc exposure Zhao et al. 2016 Medium Mortality Mortality from all causes 5,369 dry cleaners members of a dry cleaning union in St. Louis, men and women, follow-up 1948-1993 Dry cleaner occupation, perchloroethylene the dominant solvent Significant elevations in all- cause cancer mortality for the entire follow-up period, and for the first and second follow-up periods; and for men and women, and for blacks and whites Blair et al. 2003 Medium 38 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Neurological/Behavior Risky behavior endpoints measured/analyz ed: smoking usage as a teen, smoking usage as an adult, alcohol usage as a teen, alcohol usage as an adult, drug usage as a teen, drug usage as an adult, multiple risky behaviors as a teen, multiple risky behaviors as an adult, selected risky behaviors as a teen among subjects without prenatal exposure to smoking, selected risky behaviors (smoking, alcohol, drug usage) as an adult among subjects without prenatal exposure to smoking 585 exposed and 562 unexposed born 1969-1983 in Cape Cod, MA and 365 older siblings EPA's water distribution system modeling software modeled cumulative prenatal and childhood Perc exposure Among subjects in the >=67th exposure percentile group, a higher risk of multiple risky behaviors as a teen (significant) or adult (not significant) was observed in comparison to unexposed subjects Medium 39 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Neurological/Behavior Drinking frequently as a teenager 1378 men and women in Cape Cod, MA, 1969-1983, Mean age 29 years Perchloroethylene, Cumulative exposure levels in drinking water prenatally and during childhood 9age 5 years). Mean 142 g, median 34g, range 11mg - 4668g. A positive, significant association was observed between initiating smoking at a young age, drinking frequently as a teenager at a young age, use of more than 1 drug as teenager, use of more than 1 major drug as an adult and cumulative Perc exposure in drinking water when comparing highest fertile with lowest fertile. A positive, non- significant association was observed between heavy smoking at a young age, drinking heavily in the past 30 days at a young age and cumulative Perc exposure in drinking water when comparing Medium 40 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation highest fertile with lowest fertile. Neurological/Behavior Cause-specific mortality: kidney cancer, Hodgkin lymphoma, Leukemias, ALS Camp Lejeune, North Carolina cohort; n=154,932 median age, start of follow-up: 20 median age, end of follow-up: 49 Camp Pendleton, California cohort n=154,969 median age, start of follow-up: 20 median age, end of follow-up: 49 exposure period: 1975-1985; mortality follow-up period: 1979-2008 Chemical name: Perchloroethylene (PCE); exposure matrix: estimated monthly average PCE concentration in Tarawa Terrace water system (1975-1985) Mean: 75.7 ug/L, Median: 84.9 ug/L, Range: 0-158.1 ug/L; estimated monthly average PCE concentration in Hadnot Point water system (1975-1985) Mean: 15.7 ug/L, Median: 15.4 ug/L, Range: 0-38.7 ug/L); Duration: On average an individual in the Camp Lejeune cohort resided at the base for 18 months. Positive, non- significant associations observed between cumulative exposure to PCE and mortality due to ALS Bove et al. 2014 High 41 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Percholroethylene. Cumulative lifetime exposure levels based on complete work histories, hobbies, and industrial hygiene evaluations of subjects in participating shops:. Categories: low (n=24, average 3.4 years at shop), moderate (n=18,average 8.1 years at shop), and high (n=23, average 20.2 years at shop). Significant decrease (6.7%) was observed in Neurological/Behavior Pattern memory (Number correct) 'Dry Cleaner Study Population' (n=65). men and women; Detroit, USA the adjusted mean performance on the pattern memory (number correct) between the low and high Perc exposure categories. Echeverria et al. 1995 Medium Neurological/Behavior Parkinson's Disease (PD) 99 male twin pairs 35-84 years of age from US National Academy of Sciences/National Research Council World War II Veteran Twins Registry, 1993- 1995 Self-reported exposure to Perc A positive, non- significant association was observed between Parkinson Disease and ever exposure to Perc Goldman et al. 2012 High 42 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Neurological/Behavior Autism spectrum disorders 3,137 children in North Carolina (1,931 total, 201 cases) and West Virginia (1,246 total, 173 cases), 2000-2004, 8 years old 1996 modeled perc in ambient air, geometric mean concentration: 227.0 (NC) and 172.2 (WV) ng/mA3 A positive, non- significant association between ambient perc (80th vs. 20th percentile) and autism spectrum disorder Kalkbrenner et al. 2010 High Neurological/Behavior Autism Spectrum Disorder Nurses' Health Study II children 3-18 years (US; 325 cases/22101 controls). Perc air concentrations at mother's location at birth Perc exposure was significantly associated with Autism Spectrum Disorder based on a significant increase in odds ratio comparing the highest to the lowest concentration quintile. Roberts et al. 2013 High Neurological/Behavior Diseases of the nervous system mortality National Institute for Occupational Safety and Health (NIOSH) Cohort, 34494 workers at NY microelectronics and business machine facility, 2009, 52- 65yrs Cumulative Perc exposure score based on department- exposure matrix Perc exposure was significantly associated with increased risk of mortality from diseases of the nervous system. Silver et al. 2014 Medium 43 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Neurological/Behavior Neurological examination including the Romberg test, Crawford manual dexterity tests, and Flannagan coordination, arithmetic, and inspection tests Sixteen healthy male technical employees ranging in age from 24 to 64 years; five subjects were selected for repeated exposure 7-hour inhalation chamber exposure to approximately 100 PPm perchloroethylene for 1-5 days Slightly impaired performance on the Romberg test, no other effects observed Stewart et al. 1970 Medium Michigan eye- hand coordination, rotary pursuit, Flanagan coordination, saccade eye velocity, dual- attention tasks, Lorr-McNair mood evaluation test, electroencephalo gram Neurological/Behavior 12 subjects, Wisconsin, 1975, 19- 42 years of age Perchloroethylene, controlled exposure of 0, 25, 100 ppm for 5.5 hrs Perchloroethylene (100 ppm) had statistically significant negative correlation with Flanagan coordination in Stewart et al. 1977 Medium some sessions, no other significant effects were found 44 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Neurological/Behavior Failure to meet test-based standards for English language arts in 3rd grade standardized tests. Children (n=201,559 ) born 1994-1998 in New York City , enrolled in 3rd grade public schools before 2008. Perchloroethylene in ambient air estimated from EPA's National Air Toxics Assessment (NATA) from 1996 (prenatal exposure). High perchloroethylene category: median 1.13 mg/m3, range 0.84 - 9.2 mg/m3. Low perchloroethylene category: median 0.63 mg/m3, range 0.28 - 0.84 mg/m3. A positive, not statistically significant association (borderline) was observed between English language arts test and highest quartile of Perc exposure compared to lowest 3 quartiles. Stingone et al. 2016 Medium Neurological/Behavior Autism spectrum disorder diagnosis with Social Communication Questionnaire score of 15+ 217 cases, 224 interview controls, 4856 birth certificate controls, children born from 2005-2009 in 6 counties of Pennsylvania Perc exposure (94- 267 ng/m3) during gestation estimated with National Air Toxics Assessment 2005 model from addresses at birth Perc showed non- significant positive association with Autism Spectrum Disorder diagnosis relative to birth certificate controls across all quartiles of exposure Talbott et al 2015 Medium 45 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Neurological/Behavior Autism diagnosis Children (n=619 cases) born to mothers living within 5 km of air pollutant monitoring stations in Los Angeles County during pregnancy, 1995-2006, monitored until age 6 Maternal ambient Perc exposure during entire pregnancy A positive, significant association was observed between autistic disorder by age 6 years and maternal ambient Perc exposure von Ehrenstein et al. 2014 High Neurological/Behavior Autism Spectrum Disorder Children born 1994 followed for 9 years, 284 cases and 657 birth month- and sex- matched control births from the San Francisco area 1996 EPA estimated annual average concentrations of Perc on the census tract level, mean (SD) exposure for cases: 0.61 (0.33 ug/m3) Non significant positive association observed for 3rd and 4th quartile of Perc exposure compared to those exposed to the median exposure level or less. Windham et al. 2006 Medium Renal Chronic renal disease (chronic and unspecified nephritis, renal failure, and other renal sclerosis) mortality National Institute for Occupational Safety and Health (NIOSH) Cohort, 34494 workers at NY microelectronics and business machine facility, 2009, 52- 65yrs Cumulative Perc exposure score based on department- exposure matrix Perc was not significantly associated with mortality from chronic renal diseases. Silver et al. 2014 Medium 46 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Reproductive Polycystic ovary syndrome, endometriosis, infertility (i.e., trouble getting pregnant), and miscarriage 828 women, Cape Cod, MA, 1969-1983, 24-38 years Early life Perc exposure with water modeling software (mean cumulative exposure 121.7 g) Perc was not significantly associated with polycystic ovary syndrome, endometriosis, trouble getting pregnant, or miscarriage. Mahalingaia h et al. 2016 High Reproductive Mean birth weight difference (g) 11,896 singleton births, Camp Lejeune, North Carolina Perchloroethylene, median (of exposed average monthly concentrations during pregnancy) 35.8 ppb Significant negative associations between exposure to perc and mean birth weight (quartiles compared to unexposed): Q2 - 28.5 g (-55.1, - 1.9); non- significant associations for Q1 4.4 g (-17.4, 26.1), Q3 3.8 g (- 28.3, 36.0), and Q4 8.2 g (-29.5, 46.0) Ruckart et al. 2014 High 47 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System Outcome/ Endpoint Study Population Exposure Results Reference Data Quality Evaluation Positive, statistically significant, association Aircraft maintenance between mortality from nonmalignant respiratory disease in males and occupational exposure to Perc compared to no exposure (negative, non- statistically significant association for females) Respiratory Mortality from nonmalignant respiratory disease workers (n = 14,457; 10,730 men and 3725 women) at Hill Air Force Base (Utah, USA), for at least one year from 1952-1956, and followed up through 2000 Occupational exposure to Perc (yes/no) based on job- exposure matrix; no quantitative assessment available Radican et al. 2008 Medium 48 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Table 2.2 Summary of the Animal Toxicological Database for Perchloroethylene not considered for dose-response Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 Body Weight Short-term (1- 30 days) Rat Sprague- Dawley - [rat] Female (8 ) Inhalation 0 , 686 , 2058 , 6860 mg/ m3 ( 0 , 100,300 , 1000 ppm) 6 hours/ day 5 days/ week for 4 weeks (20 exposure days) Not Reported Decreased body weight Boverhof et al (2013) High Body Weight Reproductive Rat Other Both (24/ sex/ group in F0 parents ) Inhalation 0 , 686 , 2058 , 6860 mg/ m3 ( 0 , 100,300 , 1000 ppm) 6 hours/ day 5 days / week in multi-generation study (including prior to mating through 2nd generation) Not Reported No body weight decrease greater than 10% from control; liver weights increased at 1000 ppm in F0 males and F1 females but no histopathology changes seen. Hajogenated Solvents .) Medium Body Weight Chronic (> 90 days) Rat Osborne- Mendel - [rat] Male ( 50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 471 , 941 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported decreased survival, decreased body weight gain, toxic nephropathy, hunched appearance National Institute of Heal- Medium Body Weight Chronic (> 90 days) Rat Osborne- Mendel - [rat] Female (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 474 , 949 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported decreased survival, decreased body weight gain, toxic nephropathy, National Institute of Heal- Medium 49 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 hunched appearance Body Weight Chronic (> 90 days) Mouse B6C3F1- [mouse] Male (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 536 , 1072 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported decreased survival, decreased body weight gain, hunched appearance, hepatocellular carcinoma, toxic nephropathy National Institute of Heal- Medium Body Weight Chronic (> 90 days) Mouse B6C3F1- [mouse] Female (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 386 , 772 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported decreased survival, decreased body weight gain, hunched appearance, hepatocellular carcinoma, toxic nephropathy National Institute of Heal- Medium Cancer Chronic (> 90 days) Rat Osborne- Mendel - [rat] Male ( 50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 471 , 941 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Hear Medium 50 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 Cancer Chronic (> 90 days) Mouse B6C3F1- [mouse] Male (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 536 , 1072 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported decreased survival, decreased body weight gain, hunched appearance, hepatocellular carcinoma, toxic nephropathy National Institute of Heal- Medium Cancer Chronic (> 90 days) Mouse B6C3F1- [mouse] Female (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 386 , 772 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported decreased survival, decreased body weight gain, hunched appearance, hepatocellular carcinoma, toxic nephropathy National MMituteof Heal; Medium Cancer Chronic (> 90 days) Rat Osborne- Mendel - [rat] Female (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 474 , 949 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium Cardiovascul ar Chronic (> 90 days) Rat Osborne- Mendel - [rat] Male ( 50 Oral 0 , 471 , 941 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences National Institute of Hear Medium 51 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 (treated), 20 (untreated and vehicle controls)) of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. Cardiovascul ar Chronic (> 90 days) Rat Osborne- Mendel - [rat] Female (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 474 , 949 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium Cardiovascul ar Chronic (> 90 days) Mouse B6C3F1- [mouse] Male (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 536 , 1072 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these National Institute of Heal- Medium 52 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 organs/ systems. Cardiovascul ar Chronic (> 90 days) Mouse B6C3F1- [mouse] Female (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 386 , 772 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium Endocrine Chronic (> 90 days) Rat Osborne- Mendel - [rat] Male ( 50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 471 , 941 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium Endocrine Chronic (> 90 days) Rat Osborne- Mendel - [rat] Female (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 474 , 949 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based National Institute of Hear Medium 53 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 on necropsy and histopathology examination for these organs/ systems. Endocrine Chronic (> 90 days) Mouse B6C3F1- [mouse] Male (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 536 , 1072 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium Endocrine Chronic (> 90 days) Mouse B6C3F1- [mouse] Female ( 50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 386 , 772 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium 54 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 Gastrointestin al Chronic (> 90 days) Rat Osborne- Mendel - [rat] Male ( 50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 471 , 941 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium Gastrointestin al Chronic (> 90 days) Rat Osborne- Mendel - [rat] Female (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 474 , 949 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium Gastrointestin al Chronic (> 90 days) Mouse B6C3F1- [mouse] Male (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 536 , 1072 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology National Institute of Hear Medium 55 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 examination for these organs/ systems. Gastrointestin al Chronic (> 90 days) Mouse B6C3F1- [mouse] Female (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 386 , 772 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium Growth (early life) and Development Reproductive Rat Other Both (24/ sex/ group in F0 parents ) Inhalation 0 , 686 , 2058 , 6860 mg/ m3 ( 0 , 100,300 , 1000 ppm) 6 hours/ day in multi-generation study (including prior to mating through 2nd generation) Not Reported Decreased F1 male and female pup weights from PNDs 5 to 29 Haloaenated Solvents .) Medium Hematologica I and Immune Short-term (1- 30 days) Rat Sprague- Dawley - [rat] Female (8 ) Inhalation 0 , 686 , 2058 , 6860 mg/ m3 ( 0 , 100,300 , 1000 ppm) 6 hours/ day 5 days/ week for 4 weeks (20 exposure days) Not Reported No effects on survival, hematology, antibody responses to sheep red blood cells, bronchoalveol ar lavage parameters, spleen, thymus, or kidney Boverhof et al (2013) High 56 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 weights, or spleen, thymus, lung, nasal, trachea, or bone marrow histopathology Hematologica I and Immune Chronic (> 90 days) Rat Osborne- Mendel - [rat] Male ( 50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 471 , 941 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium Hematologica I and Immune Chronic (> 90 days) Rat Osborne- Mendel - [rat] Female (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 474 , 949 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium 57 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 Hematologica I and Immune Chronic (> 90 days) Mouse B6C3F1- [mouse] Male (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 536 , 1072 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium Hematologica I and Immune Chronic (> 90 days) Mouse B6C3F1- [mouse] Female (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 386 , 772 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium Hepatic Short-term (1- 30 days) Rat Sprague- Dawley - [rat] Female (8 ) Inhalation 0 , 686 , 2058 , 6860 mg/ m3 ( 0 , 100,300 , 1000 ppm) 6 hours/ day 5 days/ week for 4 weeks (20 exposure days) Not Reported Increased liver weight Boverhof et al (2013) High Hepatic Reproductive Rat Other Both (24/ sex/ group in F0 parents ) Inhalation 0 , 686 , 2058 , 6860 mg/ m3 ( 0 , 100,300 , 1000 ppm) 6 hours/ day in multi-generation study (including prior to mating Not Reported No body weight decrease greater than 10% from Haloaenated Solvents Q Medium 58 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 through 2nd generation) control; liver weights increased at 1000 ppm in F0 males and F1 females but no histopathology changes seen. Hepatic Chronic (> 90 days) Rat Osborne- Mendel - [rat] Male ( 50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 471 , 941 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium Hepatic Chronic (> 90 days) Mouse B6C3F1- [mouse] Male (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 536 , 1072 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported decreased survival, decreased body weight gain, hunched appearance, hepatocellular carcinoma, toxic nephropathy National MMituteof Heal; Medium Hepatic Chronic (> 90 days) Mouse B6C3F1- [mouse] Female (50 Oral 0 , 386 , 772 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported decreased survival, decreased body weight National Institute of Heal- Medium 59 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 (treated), 20 (untreated and vehicle controls)) gain, hunched appearance, hepatocellular carcinoma, toxic nephropathy Hepatic Chronic (> 90 days) Rat Osborne- Mendel - [rat] Female (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 474 , 949 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium Mortality Acute (< 24hr) Fischer 344- [rat] Both ( 6 ) Oral 0 , 1300,2500 , 3200 , 4000 , 5000 mg/ kg- bw/ day 1 day Not Reported Not reported Dow Chemical i) Low Mortality Short-term (1- 30 days) Rat Sprague- Dawley - [rat] Female (8 ) Inhalation 0 , 686 , 2058 , 6860 mg/ m3 ( 0 , 100,300 , 1000 ppm) 6 hours/ day 5 days/ week for 4 weeks (20 exposure days) Not Reported No effects on survival, hematology, antibody responses to sheep red blood cells, bronchoalveol ar lavage parameters, spleen, thymus, or kidney Boverhof et al (2013) High 60 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 weights, or spleen, thymus, lung, nasal, trachea, or bone marrow histopathology Mortality Chronic (> 90 days) Rat Osborne- Mendel - [rat] Male ( 50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 471 , 941 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported decreased survival, decreased body weight gain, toxic nephropathy, hunched appearance National Institute of Heal- Medium Mortality Chronic (> 90 days) Rat Osborne- Mendel - [rat] Female (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 474 , 949 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported decreased survival, decreased body weight gain, toxic nephropathy, hunched appearance National Institute of Heal- Medium Mortality Chronic (> 90 days) Mouse B6C3F1- [mouse] Male (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 536 , 1072 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported decreased survival, decreased body weight gain, hunched appearance, hepatocellular carcinoma, toxic nephropathy National Institute of Hear Medium Mortality Chronic (> 90 days) Mouse B6C3F1- [mouse] Oral 0 , 386 , 772 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported decreased survival, decreased National Institute of Hear Medium 61 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 Female (50 (treated), 20 (untreated and vehicle controls)) body weight gain, hunched appearance, hepatocellular carcinoma, toxic nephropathy Neurological/ Behavior Reproductive Rat Other Both (24/ sex/ group in F0 parents ) Inhalation 0 , 686 , 2058 , 6860 mg/ m3 ( 0 , 100,300 , 1000 ppm) 6 hours/ day in multi-generation study (including prior to mating through 2nd generation) Not Reported Neurological: clinical signs (decreased activity and response to sound). Renal: Increased kidney weight; increased incidence of minimal chronic progressive glomerulonep hropathy; increased pleomorphism within the proximal tubular nuclei. Effects seen in F0 and F1 parents. Haloaenated Solvents Q Medium Neurological/ Behavior Chronic (> 90 days) Rat Osborne- Mendel - [rat] Male ( 50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 471 , 941 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported decreased survival, decreased body weight gain, toxic nephropathy, National Institute of Heal- Medium 62 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 hunched appearance Neurological/ Chronic (> 90 Rat Osborne- Oral 0 , 474 , 949 5 days/week Not decreased National Medium Behavior days) Mendel - [rat] Female (50 (treated), 20 (untreated and vehicle controls)) mg/ kg-bw/ day for 78 weeks Reported survival, decreased body weight gain, toxic nephropathy, hunched appearance Institute of Heal- Neurological/ Chronic (> 90 Mouse Oral 0 , 536 , 1072 5 days/week Not decreased National Medium Behavior days) B6C3F1- [mouse] Male (50 (treated), 20 (untreated and vehicle controls)) mg/ kg-bw/ day for 78 weeks Reported survival, decreased body weight gain, hunched appearance, hepatocellular carcinoma, toxic nephropathy Institute of Heal- Neurological/ Chronic (> 90 Mouse Oral 0 , 386 , 772 5 days/week Not decreased National Medium Behavior days) B6C3F1- [mouse] Female (50 (treated), 20 (untreated and vehicle controls)) mg/ kg-bw/ day for 78 weeks Reported survival, decreased body weight gain, hunched appearance, hepatocellular carcinoma, toxic nephropathy Institute of Hear Renal Reproductive Rat Other Both (24/ sex/ group in F0 parents ) Inhalation 0 , 686 , 2058 , 6860 mg/ m3 ( 0 , 100,300 , 1000 ppm) 6 hours/ day in multi-generation study (including prior to mating through 2nd generation) Not Reported Neurological: clinical signs (decreased activity and response to sound). Renal: Hajogenated Solvents .) Medium 63 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 Increased kidney weight; increased incidence of minimal chronic progressive glomerulonep hropathy; increased pleomorphism within the proximal tubular nuclei. Effects seen in F0 and F1 parents. Renal Chronic (> 90 days) Rat Osborne- Mendel - [rat] Male ( 50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 471 , 941 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported decreased survival, decreased body weight gain, toxic nephropathy, hunched appearance National Institute of Heal- Medium Renal Chronic (> 90 days) Rat Osborne- Mendel - [rat] Female (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 474 , 949 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported decreased survival, decreased body weight gain, toxic nephropathy, hunched appearance National Institute of Heal- Medium Renal Chronic (> 90 days) Mouse B6C3F1- [mouse] Male (50 (treated), Oral 0 , 536 , 1072 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported decreased survival, decreased body weight National Institute of Hear Medium 64 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 20 (untreated and vehicle controls)) gain, hunched appearance, hepatocellular carcinoma, toxic nephropathy Renal Chronic (> 90 days) Mouse B6C3F1- [mouse] Female (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 386 , 772 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported decreased survival, decreased body weight gain, hunched appearance, hepatocellular carcinoma, toxic nephropathy National Institute of Heal- Medium Reproductive   Reproductive Rat Other Both (24/ sex/ group in F0 parents ) Inhalation 0 , 686 , 2058 , 6860 mg/ m3 ( 0 , 100,300 , 1000 ppm) 6 hours/ day in multi-generation study (including prior to mating through 2nd generation) NOAEL = 2058 mg/ m3 At the 1000 ppm, there were reductions in percentage of pups born alive (F1, F2a, and F2b litters) and decreased pup survival PND 1-5 (F1 ,F2a, and F2c litters) and PND 5-22 (F1 and F2a). Decreased testes weights observed at 300 and 1000 ppm of F1 parents, but Haloaenated Solvents Q Medium 65 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 there was no associated histopathology , no male- dependent effects on fertility, and no change in testes weights in F0 males. Reproductive   Chronic (> 90 days) Rat Osborne- Mendel - [rat] Male ( 50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 471 , 941 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium Reproductive   Chronic (> 90 days) Rat Osborne- Mendel - [rat] Female (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 474 , 949 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium 66 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 Reproductive   Chronic (> 90 days) Mouse B6C3F1- [mouse] Male (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 536 , 1072 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium Reproductive   Chronic (> 90 days) Mouse B6C3F1- [mouse] Female (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 386 , 772 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium Respiratory Short-term (1- 30 days) Rat Sprague- Dawley - [rat] Female (8 ) Inhalation 0 , 686 , 2058 , 6860 mg/ m3 ( 0 , 100,300 , 1000 ppm) 6 hours/ day 5 days/ week for 4 weeks (20 exposure days) Not Reported No effects on survival, hematology, antibody responses to sheep red blood cells, bronchoalveol ar lavage parameters, Boverhof et al (2013) High 67 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 spleen, thymus, or kidney weights, or spleen, thymus, lung, nasal, trachea, or bone marrow histopathology Respiratory Chronic (> 90 days) Rat Osborne- Mendel - [rat] Male ( 50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 471 , 941 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium Respiratory Chronic (> 90 days) Rat Osborne- Mendel - [rat] Female (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 474 , 949 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these National Institute of Heal- Medium 68 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 organs/ systems. Respiratory Chronic (> 90 days) Mouse B6C3F1- [mouse] Male (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 536 , 1072 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium Respiratory Chronic (> 90 days) Mouse B6C3F1- [mouse] Female ( 50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 386 , 772 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium Skin and Connective Tissue Chronic (> 90 days) Rat Osborne- Mendel - [rat] Male ( 50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 471 , 941 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based National Institute of Hear Medium 69 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 on necropsy and histopathology examination for these organs/ systems. Skin and Connective Tissue Chronic (> 90 days) Rat Osborne- Mendel - [rat] Female (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 474 , 949 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium Skin and Connective Tissue Chronic (> 90 days) Mouse B6C3F1- [mouse] Male (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 536 , 1072 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium 70 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ Study Species/ Exposure Doses/ Duration4 NOAEL/ Effect6 Reference7 Data System1 Type Strain/ Sex (Number/ group)2 Route Concentrations 3 LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Quality Evaluation 8 Skin and Chronic (> 90 Mouse Oral 0 , 386 , 772 5 days/week Not No effects National Medium Connective days) B6C3F1- mg/ kg-bw/ day for 78 weeks Reported were observed Institute of Tissue [mouse] Female (50 (treated), 20 (untreated and vehicle controls)) on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. Heal- Thyroid Chronic (> 90 Rat Osborne- Oral 0 , 471 , 941 5 days/week Not No effects National Medium days) Mendel - [rat] Male ( 50 (treated), 20 (untreated and vehicle controls)) mg/ kg-bw/ day for 78 weeks Reported were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. Institute of Heal- Thyroid Chronic (> 90 Rat Osborne- Oral 0 , 474 , 949 5 days/week Not No effects National Medium days) Mendel - [rat] Female (50 (treated), 20 (untreated and vehicle controls)) mg/ kg-bw/ day for 78 weeks Reported were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology Institute of Hear 71 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 examination for these organs/ systems. Thyroid Chronic (> 90 days) Mouse B6C3F1- [mouse] Male (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 536 , 1072 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium Thyroid Chronic (> 90 days) Mouse B6C3F1- [mouse] Female (50 (treated), 20 (untreated and vehicle controls)) Oral 0 , 386 , 772 mg/ kg-bw/ day 5 days/week for 78 weeks Not Reported No effects were observed on incidences of neoplastic or non- neoplastic lesions based on necropsy and histopathology examination for these organs/ systems. National Institute of Heal- Medium "Unacceptable studies not included in table 72 ------- PEER REVIEW DRAFT. DO NOT CITE OR QUOTE Target Organ/ System1 Study Type Species/ Strain/ Sex (Number/ group)2 Exposure Route Doses/ Concentrations 3 Duration4 NOAEL/ LOAEL/ LC50 5i(mg/ m3 or mg/ kg-day) (Sex) Effect6 Reference7 Data Quality Evaluation 8 Developmental Effects (Neurotoxicity) Developmental Mouse, NMRI, M, n = 36-48/ group Oral, gavage 0, 5, or 320 mg/ kg-day PNDs 10-16, for exposure days and PND 60 was last day of study LOAEL = 5 mg/ kg-day Spontaneous activity (locomotion, rearing, and total activity (Fredriksson et aL 1993) 73 ------- |