Chlorine. CAS Registry Number: Prepared by Shannon Ethridge, M.S., D.A.B.T. Toxicology Division

Transcription

1 Development Support Document Proposed, June 0 Chlorine CAS Registry Number: -0- Prepared by Shannon Ethridge, M.S., D.A.B.T. Toxicology Division Office of the Executive Director TEXAS COMMISSION ON ENVIRONMENTAL QUALITY

2 Page i TABLE OF CONTENTS TABLE OF CONTENTS... I LIST OF TABLES...II ACRONYMS AND ABBREVIATIONS... III CHAPTER SUMMARY TABLES... CHAPTER MAJOR SOURCES AND USES... CHAPTER ACUTE EVALUATION.... HEALTH-BASED ACUTE -HOUR REV AND ACUTE ESL..... Physical Chemical Properties..... Key and Supporting Human Studies Key Study (Anglen ) Supporting Human Studies..... Reproductive and Developmental Studies Mode-of-Action (MOA) Analysis and Dose Metric..... Critical Effect and Point of Departure (POD) for the Key Study..... Adjustments of the POD Default Duration Adjustment Default Dosimetric Adjustment..... Adjustments of the POD ADJ..... Health-Based Acute ReV and acute ESL..... Comparison of Acute ReV to Other Acute Regulatory Values.... HEALTH-BASED ACUTE -HOUR REV.... WELFARE-BASED ACUTE ESLS..... Odor Perception..... Vegetation Effects.... SHORT-TERM ESL AND VALUES FOR AIR MONITORING EVALUATION.... ACUTE INHALATION OBSERVED ADVERSE EFFECT LEVEL... CHAPTER CHRONIC EVALUATION.... NONCARCINOGENIC POTENTIAL..... Key and Supporting Studies Human Studies Animal Studies Key Animal Study (Klonne et al. ) Supporting Animal Study (Wolf et al. )..... Reproductive Studies MOA Analysis Dose Metric Critical Effect and POD for Key Study Adjustments of the POD Default Exposure Duration Adjustment Default Dosimetry Adjustments from Animal-to-Human Exposure..... Adjustments of the POD HEC..... Health-Based Chronic ReV and chronic ESL threshold(nc)..... Comparison of TCEQ s Chronic ReV to other Long-Term, Health Protective Comparison Levels from Other Agencies.... CARCINOGENIC POTENTIAL...

3 Page ii 0. WELFARE-BASED CHRONIC ESL.... LONG-TERM ESL AND VALUES FOR AIR MONITORING EVALUATION.... CHRONIC INHALATION OBSERVED ADVERSE EFFECT LEVEL... CHAPTER REFERENCES.... REFERENCES CITED IN THE DEVELOPMENT SUPPORT DOCUMENT... APPENDIX A... LIST OF TABLES Table. Air Monitoring Comparison Values (AMCVs) for Ambient Air a... Table. Air Permitting Effects Screening Levels (ESLs)... Table. Chemical and Physical Data... Table. Summary of Irritant Effects in Humans a... Table. Derivation of the Acute ReV and acute ESL... Table. Summary of BMD Modeling Results for Nasal Lesions in Rhesus Monkeys... Table. Derivation of the Chronic ReV and chronic ESL... Table. Long-Term, Health Protective Comparison Levels Developed by TCEQ and Other Agencies a.. Table. Summary of BMD Modeling Results for Nasal Lesions in Rhesus Monkeys...

4 Page iii Acronyms and Abbreviations Acronyms and Abbreviations AEGL Definition Acute Exposure Guideline Level AIC ACGIH AIHA AMCV ATSDR BMC BMCL0 BMDS Akaike s Information Criterion American Conference of Governmental Industrial Hygienists American Industrial Hygiene Association Air Monitoring Comparison Value Agency for Toxic Substances and Disease Registry benchmark concentration the lower % confidence limit on the benchmark concentration Benchmark Dose Software º C degrees centigrade DSD ET ESL acute ESL acute ESLgeneric acute ESLodor acute ESLveg chronic ESL linear(c) chronic ESL linear(nc) chronic ESLnonlinear(c) chronic ESLnonlinear(nc) chronic ESLveg development support document extrathoracic Effects Screening Level acute health-based Effects Screening Level for chemicals meeting minimum database requirements acute health-based Effects Screening Level for chemicals not meeting minimum database requirements acute odor-based Effects Screening Level acute vegetation-based Effects Screening Level chronic health-based Effects Screening Level for linear dose response cancer effect chronic health-based Effects Screening Level for linear dose response noncancer effects chronic health-based Effects Screening Level for nonlinear dose response cancer effects chronic health-based Effects Screening Level for nonlinear dose response noncancer effects chronic vegetation-based Effects Screening Level

5 Page iv Acronyms and Abbreviations F Definition exposure frequency, days per week FEF(-%) forced expiratory flow -% FEV FIV FVC h HEC HQ HR kg LOAEL MW forced expiratory volume at.0 second forced inspiratory volume forced vital capacity hour human equivalent concentration hazard quotient hyperresponsiveness kilogram lowest-observed-adverse-effect-level molecular weight µg microgram µg/m MMF mg mg/m min MOA mmhg MRL n N/A NOAEL NRC OEHHA micrograms per cubic meter maximal mid-expiratory flow milligrams milligrams per cubic meter minute mode of action millimeters of mercury minimal risk level number Not applicable no-observed-adverse-effect-level National Research Council California Environmental Protection Office of Environmental Health Hazard Assessment

6 Page v Acronyms and Abbreviations POD PODADJ PODHEC ppb ppm Raw REL ReV RGDR RGDRET SAR Sraw TCEQ TD TRRP UF UFH UFA UFSub UFL UFD USEPA VC WHO Definition point of departure point of departure adjusted for exposure duration point of departure adjusted for human equivalent concentration parts per billion parts per million airway resistance reference exposure level reference value regional gas dose ratio regional gas dose ratio for the extrathoracic region seasonal allergic rhinitis specific airway resistance Texas Commission on Environmental Quality Toxicology Division Texas Risk Reduction Program uncertainty factor interindividual or intraspecies human uncertainty factor animal to human uncertainty factor subchronic to chronic exposure uncertainty factor LOAEL to NOAEL uncertainty factor incomplete database uncertainty factor United States Environmental Protection Agency vital capacity world health organization

7 Page Chapter Summary Tables Table for air monitoring and Table for air permitting provide a summary of health- and welfare-based values from an acute and chronic evaluation of chlorine. Please refer to the TCEQ Guidelines to Develop Toxicity Factors (TCEQ 0a) for an explanation of air monitoring comparison values (AMCVs), reference values (ReVs) and effects screening levels (ESLs) used for review of ambient air monitoring data and air permitting. Table provides summary information on chlorine s physical/chemical data. Table. Air Monitoring Comparison Values (AMCVs) for Ambient Air a Short-Term Values Concentration Notes Acute ReV [ h] acute ESLodor acute ESLveg 0 µg/m (0 ppb) Short-Term Health 0 µg/m (0 ppb) Odor 0 µg/m (00 ppb) Short-Term Vegetation Critical Effect(s): Sensory irritation 0% detection threshold Threshold for leaf injury in alfalfa and radish plant species after -hour exposure. Long-Term Values Concentration Notes Chronic ReV chronic ESLnonthreshold(c) chronic ESLthreshold(c) 0. µg/m (0. ppb) Long-Term Health Critical Effect(s): Hyperplasia of nasal epithelium with loss of goblet cells and cilia in Rhesus monkeys Data are inadequate for an assessment of human carcinogenic potential chronic ESLveg No data found 0 a Chlorine is not monitored for by the TCEQ s ambient monitoring program. Abbreviations for Tables and : ppb, parts per billion; µg/m, micrograms per cubic meter; h, hour; ESL, Effects Screening Level; AMCV, Air Monitoring Comparison Value; HQ, hazard quotient; ReV, Reference Value; acute ESL, acute health-based ESL; acute ESL odor, acute odorbased ESL; acute ESL veg, acute vegetation-based ESL; chronic ESL nonlinear(nc), chronic health-based Effects Screening Level for nonlinear dose response noncancer effects; chronic ESL linear(c), chronic health-based ESL for linear dose-response cancer effect; chronic ESL nonlinear(nc), chronic healthbased ESL for nonlinear dose-response noncancer effects; and chronic ESL veg, chronic vegetationbased ESL

8 Page Table. Air Permitting Effects Screening Levels (ESLs) Short-Term Values Concentration Notes acute ESL [ h] (HQ = 0.) acute ESLodor acute ESLveg µg/m ( ppb) a Short-Term ESL for Air Permit Reviews 0 µg/m (0 ppb) Odor 0 µg/m (00 ppb) Short-Term Vegetation Critical Effect: Sensory irritation 0% detection threshold Threshold for leaf injury in alfalfa and radish plant species. Long-Term Values Concentration Notes chronic ESLthreshold(nc) (HQ = 0.) chronic ESLnonthreshold(c) chronic ESLthreshold(c) 0.0 µg/m (0.0 ppb) b Long-Term ESL for Air Permit Reviews Critical Effect: Hyperplasia of nasal epithelium with loss of goblet cells and cilia in Rhesus monkeys --- Data are inadequate for an assessment of human carcinogenic potential chronic ESLveg --- No data found a Based on the acute ReV of 0 ppb (0 µg/m ) multiplied by 0. (i.e., HQ = 0.) to account for cumulative and aggregate risk during the air permit review. b Based on the chronic ReV of 0. ppb (0. μg/m ) multiplied by 0. (i.e., HQ = 0.) to account for cumulative and aggregate risk during the air permit review.

9 Page Table. Chemical and Physical Data Parameter Value Reference Molecular Formula Cl ACGIH (00) Chemical Structure Cl Cl TCEQ Molecular Weight 0. ACGIH (00) Physical State at C Gas ACGIH (00) Color Greenish-yellow color at atmospheric pressure; amber liquid at -ºC ACGIH (00) Odor Pungent, suffocating odor ACGIH (00) CAS Registry Number -0- ACGIH (00) Synonyms Bertholite; hypochlorite; hypochlorous acid Budavari et al. () as cited in NRC (00) Solubility in water Soluble,,000 C TRRP (0) Log Kow 0. TRRP (0) Vapor Pressure 0 mm 0 C ACGIH (00) Relative Vapor Density (air = 0 C and. atm (liquid) ACGIH (00) Melting Point -0 C ACGIH (00) Boiling Point mm Hg ACGIH (00) Conversion Factors g/m = 0. ppb ppb =.0 g/m at C ACGIH (00)

10 Page Chapter Major Sources and Uses According to the American Chemistry Council: Chlorine and chlorine chemistry the use of chlorine in chemical processes are essential to everyday life. Chlorine is used in a vast range of chemical processes to create thousands of often indispensable products. While perhaps best known for its role in providing clean drinking water, chlorine chemistry also helps provide energy-efficient building materials, electronics, fiber optics, solar energy cells, percent of life-saving pharmaceuticals, percent of crop protection compounds, medical plastics, and much more. In most of these applications, there are no viable substitutes for chlorine....approximately 0 percent of chlorine produced in the United States is used to make polyvinyl chloride (PVC or vinyl) a versatile plastic found in such diverse products as prosthetic limbs and energy-saving windows. Another percent of chlorine produced in North America is used to produce basic organic chemicals needed for manufacturing, and solvents for metalworking, dry cleaning, and electronics. Other large uses of chlorine include producing hydrochloric acid for myriad chemical processes and titanium dioxide, a popular white pigment. As of 00, approximately facilities in Texas are dependent on chlorine or chlorine compounds (American Chemistry Council 00). Chlorine gas is not routinely monitored for in Texas. Facilities that emit chlorine gas must follow air permitting guidelines. Chapter Acute Evaluation The effects of acute chlorine inhalation exposure in humans and animals are reviewed extensively in ATSDR (00) and NRC (00). For the purpose of this development support document (DSD), only a summary of relevant information is provided. Chlorine is an eye and respiratory tract irritant and, at high doses, has direct toxic effects on the lungs. Chlorine reaches the lungs because it is only moderately soluble in water and it is not totally absorbed in the upper respiratory tract at high concentrations. Exposures at 0 ppm and 0-0 ppm were reported to cause intense coughing and serious damage (NRC 00). Chlorine exposure in the range of - ppm results in stinging or burning sensations from irritation and corrosion of mucous membranes including the eyes, skin, and the respiratory system (Baxter et al. ; Wither and Lees ). Lower concentrations of chlorine cause nasal congestion and irritation of the eyes, nose, and throat by stimulation of the trigeminal nerve.. Health-Based Acute -Hour ReV and acute ESL.. Physical Chemical Properties Chlorine is extremely reactive and enters into substitution or addition reactions with both inorganic and organic substances. Moist chlorine unites directly with most elements. Reaction with water produces hydrochloric and hypochlorous acid (Budavari et al. and Perry et al. ). Other relevant chemical and physical properties are listed in Table.

11 Page Key and Supporting Human Studies Chlorine s irritant properties have been studied with human volunteers. Respiratory tract irritation is the adverse effect which occurs at the lowest concentration and is considered the critical effect. Five well-conducted human studies were available for review and are summarized in Table (adapted from NRC 00) and described in detail below.... Key Study (Anglen ) Thirty-one human volunteers (ages 0 - years) were exposed in an inhalation chamber to 0, 0.,.0, or.0 ppm chlorine for hours (h), or to 0. or.0 ppm chlorine for h. The -h sessions were made up of two -h sessions separated by a 0- or 0-min lunch break during which the subjects were outside the chamber. For control exposures (0 ppm), the chamber was filled with an initial chlorine concentration of 0. ppm and then the chlorine supply was immediately cut off so that the concentration would drop to 0 ppm within the first min, this procedure was implemented to create a chlorine odor in the chamber so the subjects would not know it was a control exposure. Each subject filled out a questionnaire on subjective feelings of irritation upon entering the chamber and at, 0, 0, 0, 0, 0, and 0 min after entering. The same pattern was repeated during the second -h period in the case of an -h exposure. Subjects responded to a total of questions using a scale of 0 to (0 = no sensation and = unbearable). Before entering the chamber, each subject s forced vital capacity (FVC) and forced expiratory volume at.0 second (FEV) was measured using a Collins survey spirometer. Additional measurements were made at h into the -h session and at the end of the h. In the case of the -h exposure, another measurement was taken at the end of the session. In some instances, subjects returned to the laboratory the next day for an additional test. A physician examined each subject s eyes before and after exposure and recorded any signs of irritation. While in the chamber, each subject exercised for min out of each hour. Treatment of data for each sensation measured in the questionnaire included the calculation of the mean response for each combination of time and concentration. The mean response was then graphed versus time. An index of irritation was also calculated for each subject compiling scores for different sensations (excluding smell, taste, and shortness of breath). In part one, subjective irritation levels of just perceptible to distinctly perceptible were reported at 0. ppm. Clear differences were observed between exposed subjects compared to controls for the irritant sensation of itching or burning of the throat after h of exposure to ppm chlorine. The differences between subjects exposed to ppm for h and controls were highly significant, even with responses greater than or equal to (nuisance). The level of response was rated nuisance or greater at ppm. Exposure to 0.,, or ppm didn t result in in pulmonary function changes. In part, exposure to ppm for h resulted in significant decrease in FVC and FEV and increased subjective irritation. Consistent with assessments of the Anglen () study conducted by the California Environmental Protection Office of Environmental

12 Page Health Hazard Assessment (OEHHA ), NRC (00) and ATSDR (00), the TCEQ considered 0. ppm to be a NOAEL and ppm a LOAEL for sensory irritation but no pulmonary function changes after hour of exposure. The NOAEL of 0. ppm identified in this study was used as the POD to derive the acute ReV.... Supporting Human Studies As a follow-up to the Anglen () study, Rotman et al. () investigated the effects of chlorine inhalation exposure on healthy human volunteers (ages - years). All were nonsmokers, and with the exception of one subject, had no history of respiratory disease and were normal on their physical examination within week of exposure. Each subject served as his own control. On the day of the exposure, a subject would complete a series of pulmonary function tests before entering an environmental chamber. The subject then entered the exposure chamber and was exposed to either 0 (control), 0., or.0 ppm chlorine gas. Actual measured concentrations were 0, 0. ± 0. (mean ± standard deviation), and 0. ± 0.. The subject would remain in the chamber for h, after which he came out and repeated all pulmonary function tests, and then reentered the chamber. After an additional h of exposure, he came out of the chamber and again repeated all the pulmonary function tests. The total test duration was h. While in the chamber, each subject exercised for min of each hour on an inclined treadmill or by a step test. Two hours after leaving the exposure chamber, the subject repeated the pulmonary function tests again, and again after h from when the subject first entered the chamber. The function tests were then repeated daily until any persisting changes had returned to normal. The subject with a history of allergic rhinitis and indication of obstructive airway disease was the only one to experience severe distress during the exposure to ppm. He was unable to complete the full h of exposure due to shortness of breath and wheezing. The atopic individual experienced several changes in pulmonary function parameters after exposure to chlorine at 0. ppm. The other (healthy) subjects reported itchy eyes, runny nose, and mild burning in throat after exposure to ppm, but not 0. ppm or sham. For healthy subjects, pulmonary function test results (raw results) showed a decrease in FVC and FEV at ppm, but results were not as clear at 0. ppm. Airway function changes were dose and duration dependent, being more marked after h than h, and after ppm than 0. ppm. The LOAEL for healthy human subjects was ppm for a -h exposure for subjective symptoms of irritation (i.e., itchy eyes, runny nose, and mild burning in throat) as well as transient altered pulmonary function. This study identified a NOAEL of 0. ppm for healthy subjects; the atopic individual experienced slight irritation and transient slight changes in pulmonary function at 0. ppm.

13 Page D Alessandro et al. () investigated the effects of preexisting airway hyperresponsiveness on chlorine gas exposure. Study subjects included healthy volunteers aged to 0 years with and without baseline hyperreactivity defined by hyperresponsiveness (HR) to inhaled methacholine. Subjects were classified as having airway hyperreactivity if a nebulized dose of methacholine less than milligrams per milliliter (mg/ml) induced a 0% or greater fall from baseline FEV. Twelve subjects participated in the study, seven were HR to methacholine and five were not. Five of the seven HR subjects had clinical histories of asthma, but only one was being treated regularly with inhaled or systemic corticosteroids. Chlorine was not appreciable by smell by any of the subjects at any of the exposure concentrations. Subjects were exposed to 0. or ppm chlorine gas for 0 min. Subjects served as their own controls. Temperature and humidity were kept constant at 0ºC and 0%, respectively, throughout the study. Subjects were seated at rest during exposure. Subjects were coached to breathe at a rate of 0 Liters per minute (L/min) through a mouthbreathing facial mask. Chlorine gas was diluted with humidified medical grade air to the desired concentration of either 0. or ppm and mixed in a gas mixing chamber with % carbon dioxide to maintain isocapnea during hyperventilation. The chlorine concentration was monitored continuously throughout the exposure and maintained ±0.0 ppm of the target concentration. Subjects were tested for lung volumes, diffusing capacity, airway resistance (Raw), and airway responsiveness to inhaled methacholine before and after exposure. Immediately after exposure to ppm chlorine gas for 0 min, there was a statistically significant fall in FEV and forced expiratory flow -% (FEF-) and a significant increase in specific airway resistance (Sraw) in both HR subjects and subjects without HR. There were no significant group changes in airflow, lung volumes, diffusing capacity, resistance, or methacholine responsiveness h after exposure. Two HR subjects experienced unspecified respiratory symptoms following exposure to ppm. When comparing HR subjects to subjects without HR, there was as statistically significant greater response to chlorine inhalation in the HR subjects as compared to the subjects without HR, measured by relative fall in FEV or absolute increase in Sraw. In contrast, subjects exposed to 0. ppm chlorine gas, among five HR subjects, there was no statistically significant response to airflow or resistance after 0. ppm chlorine either immediately following exposure or at h. None of the subjects detected a chlorine odor at either exposure concentration. One limitation of the study is that subjects were not exposed to air alone (no chlorine) to determine if the experimental procedures had any effect on the measured parameters. This study identified a LOAEL of ppm and a NOAEL of 0. ppm in asthmatics (a sensitive subpopulation) for airway responsiveness. This study was not selected as a key study because while the LOAEL was the same, the NOAEL was lower than the NOAEL identified in the key study.

14 Page 0 0 Shusterman et al. () investigated the effects of chlorine gas exposure on a total of human subjects. Each subject served as his or her own control and breathed in either 0. ppm chlorine gas or clean air during -min exposure periods week apart using a nasal mask. Nasal airway resistance was documented by active posterior rhinomanometry perfomed before, immediately after, and min after the exposure sessions. Equal numbers of subjects with seasonal allergic rhinitis (SAR) and nonrhinitic subjects were tested. The aim of the experiment was to test the hypothesis that subjects with SAR would exhibit a more marked physiologic response (congestion) to a given nasal irritant provocation than nonrhinitic subjects. Subjects with SAR experienced congestion to a significantly greater degree than did nonrhinitic subjects when chlorine and air conditions were compared immediately after, as well as min after, provocation exposure. On a pooled basis (all subjects), statistically significant chlorine-related increases were apparent for mean ratings of nasal irritation and nasal congestion, although irritation was described as none to slight. No significant exposure-related changes were observed for rhinorrhea, postnasal drip, or headache, either on a pooled or stratified basis. None of the subjects experienced clinically significant effects on pulmonary peak flow, coughing, wheezing, or chest tightness. Statistical significance must be interpreted in light of the severity of the response. Since subjective reports of irritation were only none to slight, the significant increase in nasal congestion was not considered an adverse effect; therefore, this study identified a freestanding NOAEL of 0. ppm. 0 Joosting and Verberck () exposed eight human subjects (ages - in an exposure chamber for h to 0.,,, and ppm. Subjective reactions were noted every min. Vital capacity (VC), FEV, and forced inspiratory volume (FIV) measurements before and after exposure showed no significant differences. At 0. and ppm, all the group means were below the level of just perceptible, and the individual means figured below distinctly perceptible. At ppm, the group means for smell, eye, nose, and throat irritation increased above the level of minimum perceptibility. At ppm, irritation of the throat and coughing increased in intensity. All three subjects exposed to ppm experienced the exposure as a limit due mainly to irritation of the throat. The LOAEL identified in this study was ppm for -h exposure duration for eye, nose, and throat irritation. Individuals perceived the odor at 0. ppm after min of exposure, although the odor perception intensity decreased over time.

15 Page Table. Summary of Irritant Effects in Humans a Concentration (ppm) Exposure Time Effect 0. (NOAEL) h No pulmonary function changes in subjects with airway hyperreactivity/asthma 0. (NOAEL) min Statistically significant increase in nasal congestion, nasal irritation described as none to slight in rhinitic subjects exposed via nasal mask. No effects on nasal congestion in nonrhinitic subjects. No effects on pulmonary peak flow, rhinorrhea, postnasal drip, or headache in either type of subject 0. (NOAEL) b min - h Perception of odor, no discomfort, irritation effects reported as just perceptible to distinctly perceptible, no changes in pulmonary function measurements for healthy individuals; some slight, transient, pulmonary function changes for atopic individual.0 (LOAEL) h Statistically significant differences for respiratory tract irritation in subjects compared to controls; no significant changes in pulmonary function..0 (LOAEL) h Statistically significant but modest changes in pulmonary function measurements (FEV and R aw ) for normal and asthmatic subjects Study D Alessandro et al. () Shustermann et al. () Anglen (); Rotman et al. () Anglen () D Alessandro et al. ().0 (NOAEL) h No noticeable effects Joosting and Verberk ().0 (LOAEL) h Transient changes in pulmonary function measurements (R aw ).0 c h Irritation (itchy eyes, runny nose, mild burning in throat); transient changes in pulmonary function measurements; atopic subject could not complete full -h exposure because of wheezing and shortness of breath.0 h Itching or burning of throat, urge to cough at nuisance level.0 h Very slight irritation of eyes, nose, and throat in healthy subjects; no changes in pulmonary function.0 h 0% response of subjects to sensations characterized as nuisance; itching or burning of nose or throat, urge to cough, runny nose, general discomfort; transient changes in pulmonary function Rotman et al. () Anglen and Rotman et al. () Anglen () Joosting and Verbeck () Anglen ()

16 Page Concentration (ppm) Exposure Time Effect.0 h Not immediately irritating, objectionable after several hours; increased mucous; transient changes in pulmonary function.0 h Nuisance level of throat irritation, perceptible to nuisance level of nose irritation and cough Study Anglen () Joosting and Verberk () a Table is a reproduction of Table - in NRC (00). Studies cited in this table included Anglen () and Joosting and Verbeck () which were performed in healthy adults. Studies conducted by Shusterman et al. () and Rotman et al. () were cited and included atopic individuals. D Alessandro et al. () was also cited and was performed in both healthy subjects and asthmatic subjects. b Point of Departure used to derive the acute ReV. c h studies were composed of two segments with a 0-min or -hour break after hours... Reproductive and Developmental Studies Chlorine produces point-of-entry (POE) effects in the respiratory tract after inhalation exposure and significant systemic absorption does not occur at environmentally relevant concentrations (NRC 00). One study in humans evaluated the outcome of pregnancies among female workers at a chlorine plant from -, but did not provide any evidence of reproductive toxicity (Skjanskaya et al. as cited in ATSDR 00). No other human inhalation studies were found in the available literature. WHO () reported that early studies in rabbits exposed to chlorine concentrations 0. to. ppm during pregnancy gave birth to healthy offspring. Kutzman et al. () exposed male and female rats intermittently to up to ppm chlorine by inhalation for days (d). At the end of the d, male rats were mated with unexposed females, and 0 exposed females were mated with unexposed males. All female rats were sacrificed on gestation day for the evaluation of reproductive endpoints. The results showed no significant effects of chlorine exposure on fertility, number of corpora lutea, viable embryos, early or late deaths, or pre-implantation losses. In the males exposed for d, there were no histological alterations in the testes, and sperm morphology was unremarkable. The NOAEL identified in Kutzman et al. () is ppm for a d exposure for lack of adverse effects on fertility of male and female rats and sperm morphology. Therefore, protecting against POE effects would also protect against any possible reproductive or developmental effects. Systemic absorption and distribution of chlorine can occur following ingestion and the developmental/reproductive effects of chlorine ingestion have been studied (AIHA, USEPA ). Ingestion exposure studies demonstrated no or insufficient evidence of reproductive or developmental toxicity (NRC 00).

17 Page Mode-of-Action (MOA) Analysis and Dose Metric Chlorine is categorized as a Category gas that rapidly and irreversibly reacts with the surface liquid and tissue of the respiratory tract (NRC 00). At concentrations. ppm for up to years of exposure, chlorine is effectively scrubbed in the anterior nasal passages (NRC 00). At concentrations >. ppm, chlorine is not effectively scrubbed in the upper respiratory tract and is capable of exerting its effects in the lower respiratory tract. Based on available data, chlorine appears to have a threshold MOA. The MOA for minor eye or sensory irritation after exposure to chlorine may involve interaction with local nerve endings or trigeminal stimulation. Arts et al. (00) state the free nerve endings of the trigeminal system innervate the walls of the nasal passages and eyes and respond with nasal pungency or watery/prickly eyes to a large variety of volatile chemicals. As the concentration of chlorine increases, it first causes a perception of odor intensity, then minor eye irritation followed by irritation to the respiratory tract. Chemical stimulation of the vagal or glossopharyngeal nerves may be involved as well as trigeminal stimulation for sensory irritation. Sensory and respiratory irritation are threshold effects which may occur in tissues at sites where chlorine is deposited and absorbed (i.e., points of contact). There is no evidence nor would we expect chlorine to cause reproductive or developmental effects because chlorine exerts POE effects and there is insignificant distribution remote to the respiratory tract. In the key study, data on exposure concentration of the parent chemical are available and will be used as the dose metric... Critical Effect and Point of Departure (POD) for the Key Study In the key study by Anglen (), exposure concentrations of ppm and above after h caused nuisance levels of irritation. Pulmonary function changes were seen in subjects exposed to ppm chlorine for h. Since 0. ppm chlorine did not cause discomfort in exposed subjects, 0. ppm is considered a NOAEL. According to TCEQ (0a), the relevant POD is 0. ppm for a - h exposure and is considered a NOAEL... Adjustments of the POD... Default Duration Adjustment The Anglen () study identified a NOAEL of 0. ppm for a -h exposure duration. A duration adjustment was not necessary to convert the POD to a -h concentration PODADJ (TCEQ 0a).... Default Dosimetric Adjustment The Anglen () study was conducted in humans; therefore, a dosimetric adjustment was not necessary to determine the human equivalent POD (PODHEC). The resulting PODHEC is 0. ppm

18 Page.. Adjustments of the PODADJ The MOA by which chlorine may produce toxicity is assumed to have a threshold MOA, as discussed in Section... Therefore, the PODADJ was divided by relevant uncertainty factors (UFs). The UFs for extrapolation from animals to humans (UFA) and adjusting from a LOAELto-NOAEL (UFL) were not applicable. The following UFs were applied to the PODHEC of 0. ppm: 0 for intrahuman variability (UFH) and for database uncertainty (UFD) for a total UF = 0: a UFH of 0 was used for intrahuman variability to protect sensitive subpopulations (i.e., people with pre-existing conditions, the elderly). Although the POD used to derive the acute ReV is considered a NOAEL, there is some evidence that sensitive humans begin to experience mild effects of chlorine inhalation exposure at 0. ppm; therefore, a full UFH of 0 was used. Note that this is times more conservative than using the NOAEL of 0. ppm identified in a sensitive subpopulation (i.e., asthmatics in D Alessandro et al. ) without the need of a UFH greater than, and is times more conservative than using a potential minimal LOAEL of 0. ppm for sensitive subpopulations (e.g., increased nasal congestion in subjects with SAR in Shusterman et al., an atopic individual experienced slight irritation and transient slight changes in pulmonary function at 0. ppm in Rotman et al. ) with a UFL of but without the need of a UFH greater than. a UFD of was used to account for database uncertainty. The overall acute database is considered medium to high because there are a number of well conducted studies available that evaluate the acute effects of chlorine inhalation in humans and animals. The studies selected as key and supporting studies were all well-conducted, high quality studies. There is no evidence that chlorine directly causes reproductive or developmental effects nor would we expect chlorine to cause reproductive or developmental effects because chlorine exerts POE effects and there is insignificant distribution remote to the respiratory tract. acute ReV = PODHEC/(UFH x UFD) = 0. ppm /(0 x ) = 0.0 ppm = 0 ppb (rounded to two significant figures).. Health-Based Acute ReV and acute ESL The acute ReV of 0 ppb was rounded to two significant figures at the end of all calculations resulting in a value of 0 ppb. The acute ReV of 0 ppb (0 µg/m ) was multiplied by 0. to calculate the acute ESL. At the target hazard quotient of 0., the acute ESL is ppb ( µg/m ) (Table ).

19 Page 0 Table. Derivation of the Acute ReV and acute ESL Parameter Study Anglen () Study Population Study Quality Exposure Methods PODHEC Critical Effects Exposure Duration Extrapolation to h Values and Descriptions human volunteers (ages 0 - years) Medium to High Inhalation chamber to 0, 0.,, or ppm chlorine gas for min to h 0. ppm, NOAEL Sensory irritation h N/A Total UFs 0 Interspecies UF N/A Intraspecies UF 0 LOAEL UF Incomplete Database UF Database Quality N/A Medium to High acute ReV [ h] (HQ = ) 0 ppb (0 µg/m ) acute ESL [ h] (HQ = 0.) ppb ( µg/m ).. Comparison of Acute ReV to Other Acute Regulatory Values The acute ReV is slightly lower than California Environmental Protection Office of Environmental Health Hazard Assessment (OEHHA) Reference Exposure Level (REL) of ppb (OEHHA ) which is based on Anglen () and is protective of an exposure up to h. The acute ReV is slightly lower than the ATSDR acute-duration inhalation Minimal Risk Level (MRL) of 0 ppb (ATSDR 00) based on a NOAEL of 0. ppm for sensory irritation and pulmonary effects in volunteers exposed for up to h/d (Anglen, D Alessandro et al., Rotman et al., Schins et al. 000, Shusterman et al., 00).. Health-Based Acute -Hour ReV Texas does not monitor the air for chlorine; therefore, a -h ReV is not needed and was not derived.

20 Page 0 0. Welfare-Based Acute ESLs.. Odor Perception As reported in NRC (00), according to Amoore and Hautala (), the odor threshold for chlorine is 0. ppm, and a range of ppm was reported in other studies. The odor detection threshold reported by Nagata (00) was ppb. The detection threshold reported by Dixon () was 0 ppb. There is considerable variation in detecting the odor among subjects; for many individuals, the ability to perceive the odor decreases over exposure time (NIOSH ). Chlorine has a pungent suffocating odor. Based on a weight of evidence approach and historical information, the acute ESLodor value was set at 0 ppb. Accordingly, the acute ESLodor for chlorine is 0 ppb (0 µg/m )... Vegetation Effects Numerous studies evaluating the effects of chlorine gas exposure on vegetation have been conducted following accidental chlorine gas releases or have been conducted in a controlled environment (Schreuder and Brewer 00). According to Schreuder and Brewer (00), the most common foliar injury symptoms after exposure to chlorine gas include chlorosis (bleaching of tissues), necrotic mottling (red and black dark spots on the leaf surface), and necrosis (death of cells and cell tissue). Adverse vegetation effects can occur in both deciduous and coniferous species. Toxicity thresholds are dependent on plant species, duration of exposure, and stomatal conductance (Brennan et al. and Griffiths and Smith 0). Chlorosis and necrosis have been reported after exposure to chlorine concentrations as low as 0. to ppm. Studies evaluated in the acute assessment of chlorine gas exposure are listed below: 0 Brennan et al. () investigated the effects of 0. to. ppm chlorine gas exposure on many plant species. Concentrations of 0. to. ppm for up to h produced a variety of adverse effects, resulting in the development of bleaching and necrosis. Low soil moisture levels were associated with decreased incidence of injury. The most sensitive species were radish and alfalfa, showing adverse effects after exposure to 0. ppm chlorine for h. All other species tested showed effects at higher chlorine concentrations. Zimmerman () exposed species of plants to chlorine at concentrations ranging from 0. to. ppm for durations of 0 to 0 min. Sixteen species were found to be susceptible. The plant material took on a cooked appearance and finally turned a straw/brown colour depending upon the species. Medium to considerable injury was associated with leaf fall. Benedict and Breen () studied the effects of chlorine exposure on different types of weeds. Plants were exposed to 0. and. ppm chlorine under high and low soil moisture conditions for h. Broad-leaved species developed marginal streaks which progressed to the main vein in the region between the tip and the point where the leaf bends. Mustard,

21 Page 0 chickweed, and sunflower were the most sensitive species. Low soil-moisture levels were associated with decreased sensitivity to chlorine. Thornton and Setterstrom (0) exposed plants to chlorine gas concentrations of,,,, 0, and,000 ppm for,,, 0, 0, and 0 min. Adverse effects were both concentration- and time-dependent and the response was greater in clear weather (verses cloudy). Leaf injury was the most sensitive endpoint evaluated in this study. The doseresponse curve for leaf injury was very steep at the highest chlorine concentrations tested. Sixty ppm chlorine gas caused 0 percent leaf injury after approximately min of exposure and ppm chlorine gas caused 0 percent injury of the leaf area after approximately 0 min of exposure. Based on the time-concentration curve, we estimate that ppm chlorine gas exposure for approximately h would cause 0 percent leaf injury. All concentrations tested caused an effect so a threshold could not be determined. According to TCEQ Guidelines (0a), the vegetation-based ESL should be set at the lowestobserved effect level (LOEL). Based on the studies evaluated, the LOEL identified was 0. ppm chlorine gas after -h exposure to radish and alfalfa in Brennan et al. (). Therefore, the vegetation-based ESL is 0. ppm (00 ppb, 0 µg/m ).. Short-Term ESL and Values for Air Monitoring Evaluation The acute evaluation resulted in the derivation of the following values: 0 acute ESLodor = 0 μg/m (0 ppb) acute ESLveg = 0 μg/m (00 ppb) acute ESL = µg/m ( ppb) acute ReV = 0 μg/m (0 ppb) 0 For the evaluation of ambient air monitoring data, the acute ReV is lower than the acute ESLodor (Table ), although all values may be used for the evaluation of air monitoring data. The shortterm ESL for air permit evaluations is the health-based acute ESL of 0 μg/m ( ppb) as it is lower than the odor- and vegetation-based ESLs (Table ). The acute ESL (HQ = 0.) is not used to evaluate ambient air monitoring data and will be used in air permitting applications.. Acute Inhalation Observed Adverse Effect Level The acute inhalation observed adverse effect level would be the LOAEL from the key human study of Anglen (). The LOAELHEC determined from a human study was based on sensory irritation after exposure to ppm chlorine gas for h. This LOAELHEC will be used as the acute inhalation observed adverse effect level and represents a concentration at which it is probable that similar effects could occur in some individuals exposed to this level over the same ( h) or longer durations as those used in the study. Importantly, effects are not a certainty due to potential intraspecies differences in sensitivity. The inhalation observed adverse effect level is provided for informational purposes only (TCEQ 0a). As the basis for development of

22 Page 0 inhalation observed adverse effect levels is limited to available data, future studies could possibly identify a lower POD for this purpose. The margin of exposure between the inhalation observed adverse effect level of ppm and the - h acute ReV of 0.0 ppm is a factor of 0. Chapter Chronic Evaluation. Noncarcinogenic Potential Chlorine gas has been used in industrial processes for many years and several occupational studies have been published. No chronic controlled inhalation exposure studies have been conducted in humans although several have been conducted in animals. A detailed assessment of all available chronic inhalation human and animal studies can be found in ATSDR (00). For the purpose of this DSD, only a summary of relevant information is provided... Key and Supporting Studies... Human Studies Chronic inhalation exposure to concentrations of approximately ppm chlorine gas can cause respiratory complaints, corrosion of teeth, inflammation of the mucous membranes of the nose, and increased susceptibility to tuberculosis (Heyroth, in Patty ). Although several occupational studies were available, none of them were suitable for the derivation of a chronic ReV. 0 0 Kennedy et al. () compared pulp mill workers ( were exposed to chlorine or chlorine dioxide gassings ) to a control group of rail yard workers in similar working conditions but not exposed to chlorine. The pulp mill workers had been employed for an average of years. The rail yard workers had been employed for an average of. years. Chlorine gas and chlorine dioxide levels were measured together over a -week period during mainly during a -h shift. Time weighted averages (TWAs) were <0. ppm, with the highest of < ppm. A significantly higher prevalence of wheezing was observed in pulpmill workers who had reported more than one episode of chlorine gassing as compared to controls. Workers had more airflow obstruction, correlating to significantly lower average values for maximal mid-expiratory flow (MMF) and for the FEV to FVC ratio. Results from this study suggest that chronic respiratory health impairment is associated with exposure to chlorine and/or chlorine dioxide. Authors hypothesized that an inflammatory response occurred in small airways after the first high exposure to chlorine and/or chlorine dioxide, and this reaction did not resolve in workers who were continuously or repeatedly exposed to the irritant. Study results also suggest that chronic airflow obstruction caused by repeated minor exposures led to chronic respiratory disability in some of the workers. One major limitation of this study was that subjects were exposed to other compounds along with chlorine, so the adverse

23 Page effects experienced by workers could not be attributed solely to chlorine. Other confounding variables like smoking were not accounted for. Due to the potential confounding variables, Kennedy et al. () was not used to derive the chronic ReV. Shi et al. (0) evaluated workers from a diaphragm cell chlorine chemical plant. Average age of workers was. years (range from to years). Workers were split into two groups. Group A was compiled of 0 workers who had been employed/exposed for 0- years while Group B was compiled of workers employed/exposed for less than 0 years. Both groups of workers were exposed to a range of.0 to.0 mg/m (0. -. ppm) chlorine. The control group was compiled of workers not exposed to chlorine, with an average age of. years (range from - years). All participants were subjected to a clinical examination, ear nose and throat (ENT) examination, chest x- rays, pulmonary function tests, and were evaluated for respiratory symptoms and smoking habits. Groups A and B showed - times higher incidence of upper airway complaints (e.g., sore throat, hoarseness, dryness in the throat and respiratory symptoms, such as shortness of breath, chest tightness, chest tightness and pain, wheezing, cough, and phlegm) than the control group. Current smokers in Groups A and B experienced the highest incidence of pulmonary symptoms and Group A workers had a higher prevalence of rhino-pharyngeal signs than the control workers. Abnormalities in chest x-rays were seen in.% of Group A workers and in.% of Group B workers, compared to.% of controls. Groups A and B showed significantly impaired pulmonary function in tests of V0/H and FEF- compared to controls. Group A showed reduced FEV results compared to controls. Exposed workers experienced a number of symptoms at a higher prevalence than controls. In addition, the prevalence of a number of effects was higher in workers with a long duration of exposure (>0 years) than in workers with a shorter duration of exposure (<0 years). Adverse effects were noted in workers exposed for less than 0 years, and more severe effects were observed in workers exposed for more than 0 years. Although this study was a well conducted study and examined a number of endpoints, the exposure concentration estimates had a high degree of uncertainty; therefore, this study was not used to develop the chronic ReV. Enarson et al. () compared pulp-mill workers exposed to chlorine (unspecified duration) to a comparable group of 0 rail yard workers living in the same community, but not exposed to chlorine. Pulp-mill workers were exposed to an average of 0.0 ppm (machine room) or 0. ppm (bleach plant) chlorine. Approximately twenty-three percent of machine room workers experienced cough as did.% of bleach plant workers, compared to.% of controls. Chest tightness occurred in.% of the machine room workers and.% of the bleach plant workers, compared to.% of controls. Only data from Caucasian subjects were reported. Patil et al. (0) studied the health effects of chlorine inhalation exposure in 00 workers from plants producing chlorine in North America. The control group consisted of workers who weren t routinely exposed to chlorine. The average duration of exposure was. years. Tobacco and alcohol use were monitored and each worker received a physical exam which included evaluation of medical and occupational histories. The chlorine

24 Page concentration was monitored every two months for a period of one year in certain areas, but no other details were given. Exposure data were available for workers and showed a time-weighted average (TWA) - hour mean of 0. ± 0. ppm (range, ppm). Most workers were exposed to less than ppm, % were exposed to 0. ppm, and 0% were exposed to 0. ppm. Ninety-eight of the exposed workers were found to have abnormal teeth and gums, but not dose-response relationship could be determined. No dose response relationship could be determined from other endpoints evaluated including symptoms of sputum production, cough, dyspnea, history of frequent colds, palpitation, chest pain, VC, maximum breathing capacity, forced expiratory volume. No significant difference was found between the exposed group and controls for other endpoints (i.e., EKG abnormalities). No neurological defects, prolonged anoxia, gastrointestinal trouble, or abnormal incidence of dermatitis were noted. Exposed workers showed elevated white blood cell levels and decreased hematocrit values compared to controls. Limitations of the study (i.e., unclear analytical methodology, no clear definition of the case-control group, and lack of details regarding the method of analysis of study group) prevent its use in development of the chronic ReV. Chester et al. () evaluated workers occupationally exposed to < ppm chlorine for an unspecified duration. Fifty-five of the workers were exposed to accidental high concentrations of chlorine, which were severe enough to require oxygen therapy. Ventilation was affected by chlorine inhalation with a decrease in the maximal MMF. Fifty-six of the subjects showed abnormal posteranterior chest films, of which had parenchyma and/or hilar calcifications consistent with old granulomatous disease and of which had multiple, bilateral and diffuse calcifications. MMF is thought to be the first ventilation function affected in obstructive airway disease. Ferris et al. () evaluated the effects of chlorine exposure in pulp mill workers. A total of workers and controls were evaluated in the study and no significant difference was found in respiratory symptoms or in tests for FVC or FEV between exposed and control groups. The study did not provide details on the duration of exposure, or accurate measurements of actual exposure concentrations. The same cohort was evaluated 0 years later and did not reveal an increase in mortality or increase in specific cause of death among exposed workers Animal Studies Two high quality chronic animal inhalation studies have been conducted: Klonne et al. () and Wolf et al. () and are discussed below.... Key Animal Study (Klonne et al. ) Klonne et al. () conducted a one-year inhalation toxicity study of chlorine gas in Rhesus monkeys. Male and female monkeys (/sex/exposure level) were exposed to 0, 0., 0., or. ppm chlorine h/d, d/week for year. Pulmonary diffusing capacity of CO and distribution of ventilation, body weights, urinalysis, EKG, hematology, and clinical chemistry were evaluated monthly in the study. At termination, the heart, lungs, trachea, liver, gonads, kidneys, spleen, and