<<

PRELIMINARY DRAFT ECAO-R-065 DO NOT QUOTE OR CITE AUGUST 1990 EXTERNAL REVIEW DRAFT

HEALTH ASSESSMENT DOCUMENT FOR CHLORINE AND

This document is a preliminary draft and is intended for internal Agency use only. It has not been formally released by the U.S. Environmental Protection Agency and should not atthis stage be construed to represent Agency policy. It is being circulated for comments on its technical merit and policy implications.

ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE OFFICEOF HEALTH AND ENVIRONMENTAL ASSESSMENT U.S. ENVIRONMENTAL PROTECTION AGENCY RESEARCH TRIANGLE PARK, NC 27711

J: DISCLAIMER

This document is an external draft for review purposes only and does not constitute Agency policy. Mention oftrade names or commercial products does not constitute endorsement or recommendation for use.

n CONTENTS

Page

vi TABLES . vii FIGURES viii PREFACE ix ABSTRACT AUTHORS, CONTRIBUTORS, AND REVIEWERS x

1. SUMMARY AND CONCLUSIONS 1-J 1.1 BACKGROUND INFORMATION 1-1 1.1.1 Chlorine x'\ 1.1.2 Hydrogen Chloride J"2 1.2 PHARMACOKINETICS AND MECHANISM OF ACTION 1-3 1.2.1 Chlorine ]"* 1.2.2 Hydrogen Chloride J-* 1.3 ANIMAL TOXICITY j** 1.3.1 Chlorine J"* 1.3.2 Hydrogen Chloride 1-5 1.4 HUMAN HEALTH EFFECTS I"7 1.4.1 Chlorine }"7 1.4.2 Hydrogen Chloride l'l 1.5 RESEARCH NEEDS 1-8 2. PHYSICAL AND CHEMICAL PROPERTIES, QUANTIHCATION, AND ANALYSIS 2-1 2.1 PHYSICAL AND CHEMICAL PROPERTIES 2-1 2.1.1 Chlorine 2-1 2.1.2 Hydrogen Chloride 2-1 2.2 QUANTIFICATION AND ANALYSIS 2-2 2.2.1 Chlorine 2-2 2.2.2 Hydrogen Chloride 2-4 2.3 REFERENCES . 2-6 3. PRODUCTION, USE, ENVIRONMENTAL SOURCES, AND ENVIRONMENTAL LEVELS AND EXPOSURE . 3-1 3.1 PRODUCTION ANDUSE 3-1 3.1.1 Chlorine ^"1 3.1.2 Hydrogen Chloride 3-2 3.2 ENVIRONMENTAL SOURCES 3-3 3.2.1 Chlorine 3"3

ill CONTENTS (continued)

3.2.1.1 Manufacturing and Transport 3-3 3.2.1.2 Natural Sources and Photochemical Processes 3-3 3.2.1.3 Anthropogenic Processes 3-3 3.2.2 Hydrogen Chloride 3-4 3.2.2.1 Manufacturing and Transport 3-4 3.2.2.2 Natural Sources and Photochemical Processes 3-4 3.2.2.3 Anthropogenic Processes 3-4 3.3 ENVIRONMENTAL LEVELS AND EXPOSURE 3-5 3.3.1 Chlorine 3-5 3.3.2 Hydrogen Chloride 3-8 3.4 REFERENCES 3-9

4. ENVIRONMENTAL FATE AND ECOLOGICAL EFFECTS 4-1 4.1 ENVIRONMENTAL FATE 4-1 4.1.1 Chlorine 4-1 4.1.2 Hydrogen Chloride . 4-5 4.2 ECOLOGICAL EFFECTS 4-6 4.2.1 Chlorine 4-6 4.2.1.1 Fish 4-7 4.2.1.2 Invertebrates 4-7 4.2.1.3 Plants 4-7 4.2.2 Hydrogen Chloride (Hydrochloric Acid) 4-11 4.2.2.1 Aquatic Organisms 4-11 4.2.2.2 Terrestrial Organisms 4-12 4.3 REFERENCES 4-13

5. PHARMACOKINETICS AND MECHANISM OF ACTION 5-1 5.1 PHARMACOKINETICS AND METABOLISM 5-1 5.2 MECHANISM OF ACTION AND BIOCHEMICAL EFFECTS ... 5-1 5.2.1 Chlorine 5-1 5.2.2 Hydrogen Chloride 5-3 5.3 REFERENCES 5-4

6. TOXICOLOGY 6-1 6.1 EXPERIMENTAL ANIMALS 6-1 6.1.1 Chlorine 6-1 6.1.1.1 Acute Toxicity Inhalation 6-2 6.1.1.2 Subchronic Toxicity 6-6

iv CONTENTS (continued)

6.1.1.3 Chronic Toxicity 6"9 6.1.2 Hydrogen Chloride f\® 6.1.2.1 Acute Toxicity Inhalation 6-10 6.1.2.2 Subchronic Toxicity 6-22 6.1.2.3 Chronic Toxicity • M4 6.2 HUMANTOXICITY <>-24 6.2.1 Chlorine fj* 6.2.1.1 Acute Exposure 6-24 6.2.1.2 Chronic Exposure 6-34 6.2.1.3 Epidemiology Studies 6-35 6.2.2 Hydrogen Chloride 6-37 6.2.2.1 Acute Exposure 6-38 6.2.2.2 Epidemiology Studies 6-39 6.3 REFERENCES • 6Al

7. DEVELOPMENTAL TOXICITY AND REPRODUCTIVE EFFECTS • 7"1 7.1 EXPERIMENTAL ANIMALS 7"1 7.1.1 Chlorine 7'\ 7.1.2 Hydrogen Chloride 7"2 7.2 HUMAN STUDIES 7"3 7.3 REFERENCES 7"3 TABLES

Number Page

2-1 Chlorine Reactions Known to Occur in Aqueous 2-2

4-1 The Acute Toxicity ofChlorine to Fish and Aquatic Invertebrates . 4-9

6-1 Mortality in Dogs Exposed to Chlorine for 30 Minutes 6-4

6-2 LC50 Values for Chlorine in Rats and Mice 6-4

6-3 Inhalation L<(~7Values and Minimal Lethal Concentrations for Hydrogen Chloridein Mice and Rats 6-11

6-4 Acute Toxicity Values in Rats Exposed to Hydrogen Chloride 6-12

6-5 Threshold Levels for Chlorine Gas 6-26

VI FIGURES

Number EagS

4-1 Schematic outlineofchemical reactions in freshwater, estuarine, and marine waters 4-3

4-2 Principal chemical pathways for reaction, degradation, and environmental fate of free chlorine in the aquatic environment 4-4 6-1 LC50 values for hydrogen chloride exposed adult male Sprague-Dawley rats vs. time ofexposure 6-13

6-2 Incapacitation time as a function of hydrogen chloride concentration 6-17

6-3 Survival time as a function of hydrogen chloride concentration 6-18

Vll PREFACE

The Office ofHealth and Environmental Assessmenthas prepared this healthassessment to serveas a source document for EPA use. Specifically this document was developed for use by the Office of Air Quality Planning and Standards to support decision makingregarding possible regulation ofchlorineand hydrogenchloride as hazardous air pollutants. Ideally when evaluating the health effects associated with exposure ofa given compound and its by-products both oral and inhalation routes ofexposure are addressed; however, in the case ofchlorine and hydrogen chloride, a relationship between the inhalation ofthese gases and the ingestion of chlorinated liquids with respect to human health effects is questionable. With that in mind, this document will mainly address effects resulting from the inhalationof chlorineand hydrogen chloride gas or aerosol. The health effects resulting from the ingestion ofchlorinated liquids will be addressed in a separate document. In the development of the assessment document, the scientific literature has been to inventoried through April 1929, key studies have been evaluated, and summary/conclusions have been prepared so that the chemicals* toxicity and related characteristics are qualitatively identified. Observed effect levels and other measures of concentration-response relationships are discussed, where appropriate, so that the nature of the adverse health responses is placed in perspectivewith observed environmental levels. Any information regarding sources, emissions, ambient air concentrations, and public exposure has been included only to give the reader a preliminary indication of the potential presence of this substance in the ambient air. While the available information is presented as accurately as possible, it is acknowledged to be limited and dependent in many instances on assumption ratherthan specific data. This information is not intended, nor should it be used, to support any conclusions regarding risk to public health. If a review ofthe healthinformation indicates that the Agency should consider regulatory action for these substances, considerable effort will be undertaken to obtain appropriate information regarding sources, emissions, and ambientair concentrations. Such data will provide additional information for drawing regulatory conclusions regarding the extent and significance of public exposure to these substances.

viii ABSTRACT

Chlorine, anoncombustible gas with a pungent odor, is used in the manufacture of inorganic and organic chemicals and plastics, in the bleaching ofpulp and paper, and in the disinfection of wastewater and drinking water. Natural sources and photochemical processes do not contribute to levels of chlorine inthe ambient air. There isa potential for release of small amounts of chlorine during its manufacture or during loading and unloading in transpor tation. However, photodissociation in the lower atmosphere and troposphere israpid. Hydrogen chloride, acolorless gas with apungent odor, is used in the manufacture of inorganic and organic chemicals, -well acidizing, steel pickling, processing of food products, and mineral and metal processing. Hydrogen chloride may be found naturally in the atmosphere from the cooling ofvolcanic ash, the photolysis ofchlorine, and the reaction 0\> of(£l» with . Anthropogenic sources ofhydrogen chloride include the burning of fossil fuel, the incineration of municipal refuse, the burning of polyvinyl chloride plastics, and solid rocket fuel exhaust. Photodegradation of hydrogen chloride in the atmosphere is slow because of the low atmospheric concentrations of hydroxy radicals. It is, however, diluted and tends to absorb on aqueous aerosols and particulates. No data were found in the published literature on the levels ofhydrogen chloride in air from either natural or anthropogenic sources. Howcvois several studies have reported that as much as 2.11 and 5.3 ghydrogen chloride are emitted/kg ofmunicipal and hospital waste incinerated, respectively. Both chlorine and hydrogen chloride are acutely toxic gases. The effects of acute inhalation exposure are primarily respiratory and range from irritation to and death. Limited epidemiology studies indicate that cMorme is not carcinogenic. In available animal toxicity studies hydrogen chloride did not produce nasal tumors in rats nor did it enhance the carcinogenicity of formaldehyde in rats; however, it was found to have an adverse effect on the reproduction potential of rats exposed to high concentrations prior to mating or during gestation.

ix AUTHORS, CONTRIBUTORS, AND REVIEWERS

The Environmental Protection Agency's Office ofHealth and Environmental Assessment (OHEA) is responsible for the preparation ofthis health assessment document. The OHEA Environmental Criteriaand Assessment Office (ECAO-RTP) had the overall responsibility for coordination and direction ofthe document (Beverly M. Comfort, Project Manager). The document was prepared by Dynamac Corporation. The principal author is Dr. William McLellan. Other authors are Louis Borghi and Jessup Roland.

U.S. Environmental Protection Agency Reviewers and Contributors

David Bayliss Office of Health and Environmental Assessment Human Health Assessment Group Washington, DC

Arthur Chin Office of Health and Environmental Assessment Human Health Assessment Group Washington, DC

Beverly M. Comfort Office of Health and Environmental Assessment Environmental Criteria and Assessment Office Research Triangle Park, NC

Gregory Kew Office of Health and Environmental Assessment Exposure Assessment Group Washington, DC

Charles Ris Office of Health and Environmental Assessment Human Health Assessment Group Washington, DC Lawrence Valcovic Office of Health and Environmental Assessment Human Health Effects Assessment Group Washington, DC

p^ffTlffl1 ?fivfewers and Contributors ^--^Craig S. Barrow Jfr ppg Industries, Inc. 260 Kappa Drive Environmental Sciences Center Pittsburgh, PA 15238 412-963 5809 - -» Charles R. Crane FAA, CAM1, AAM-114 P.O. Box 25082 Oklahoma City, OK 73125 405-686 20H/68M866

Brian Hammond Research Management Division Alberta Environment 14th Floor, Standard Life Center 10405 Jasper Avenue Edmonton, Alberta, Canada T5J 3N4 ^103-427=625*-

Harold L. Kaplan Southwest Research Institute 6220 Culebra Road San Antonio, TX 78284 __512-684=5444-extr2424~""

Theodore B. Torkelson 315 Birch Street Roscommon, MI 48653 .-5T7-82**981(r

John Withers 141 Maplewell Road Woodhouse Eaves Leicestershire, United Kindgom LE12 8QY ^-44=509-890434-

XI i 1. SUMMARY AND CONCLUSIONS

2 3 1.1 BACKGROUND INFORMATION

4 1.1.1 Chlorine 5 Chlorine (CAS No. 7782-50-5) is a noncombustible gas with a pungent odor; for 6 shipping or storing the gas is compressed to a liquid which vaporizes at -34°C. The gas is 7 dense (1.468 at 0°C) and soluble in water, forming elemental chlorine andhypochlorous acid. 8 It is very reactive chemically with organic compounds. 9 Many ofthe methods used to monitor air levels of chlorine which are based on 10 titrimetry, potentiometryAand colorimetry are nonspecific and measure total chloride ion rather 11 than the diatomic gas. Ozone, sulfur dioxide, and nitrous oxides in air samples, as well as 12 chloramines and hydrochloric acid, caninterfere with several of theseanalytical methods. A 13 sensitiveand specific method for personal chlorine monitoring using a chlorine 14 electrochemical sensor and a microprocessor data-logger has been developed recently. 15 The domestic production of chlorine in 198p was approximately 22.7 billion pounds. It 16 is manufactured by the electrolytic decomposition ofbrinewhich is associated with the 17 production of caustic soda or alkali. Its major uses are in the manufacture of organic 18 chemicals and plastics, bleaching of pulp and paper, manufacture of inorganic chemicals, and 19 disinfection ofwastewater and drinking water. 20 There is a potential for release of small amounts ofchlorine during its manufacture or 21 during loading and unloading in transportation. Natural sources and photochemical processes 22 do not contribute to levels in ambientair, and because ofits reactivity, chlorinereleased into 23 the atmosphere from end-use applications is not detectable. Monitoring ofworkplace 24 atmospheres generally have shown concentrations ofless than 0.1 ppm withvery few samples 25 exceeding the ceiling and 8-hour-TWA of 1.0 ppm. 26 When liquid chlorine, stored under high pressure andat ambient temperature, is released 27 into the atmosphere, flash evaporation ofup to 20 percent occurs. This cools the liquid to 28 -34°C () and subsequent evaporation is dependent on the rate ofheat exchange. 29 Chlorine is rapidly diluted in theatmosphere and except in theimmediate vicinity of a spill, 30 dangerous levels exist for only a few hours. Monitoring of a release ofapproximately 31 70,000 kg chlorine in atrain derailment several hours after the accident found levels of(f0 to August 1990 1-1 DRAFT - DO NOT QUOTE ORCITE 1 100 jig/mJ(3.4 to 34.0 ppbjVith peak values of up to(400 ftg/m^0.14pprrftAin the plume at 2 adistance of0.5 to 1.0 km from the accident site. Photodissociation in the lower atmosphere 3 and troposphere is rapid in the daytime and further atmospheric reactions produce HC1. 4 Chlorine released to the soil surface evaporates and when released into water it may evaporate 5 to the atmosphere or form hypochlorous acid. 6 Chlorine is extremely toxic to fish with acute median lethal levels ranging from 0.037 to 7 0.65 mg/L. Aquatic invertebrates such as mollusks, crabs, and shrimp, as well as 8 phytoplankton appear to be more sensitive than fish.

9 10 1.1.2 Hydrogen Chloride 11 Hydrogen chloride (CAS No. 7647-01-0) is acolorless gas with apungent odor which 12 produces whitish fumes in moist air. It is very hygroscopic. When it dissolves in water it is 13 very corrosive to metals, and reacts with most organic materials. It is very soluble in water 14 (82.3 g/100 mL) and the aqueous solution is called hydrochloric acid. Concentrated 15 hydrochloric acid is 37.1 percent hydrogen chloride; at room temperature it vaporizes 16 producing awhitish pungent vapor. Twenty percent hydrochloric acid does not vaporize 17 appreciably from an open container. 18 Hydrogen chloride can be monitored by titrimetric or potentiometric methods, using a 19 chloride selective electrode. It can be absorbed in asolution ofNaBr - NaBr03, resulting in 20 the production of bromine, which is reacted with alkaline luminal and the resulting 21 chemiluminescence measured. Most methods ofanalyses are nonspecific; ozone, nitrous 22 oxides, and sulfur dioxide interfere, as well as any acid other than hydrochloric. 23 Hydrogen chloride is produced as aby-product of chemical syntheses of chlorinated 24 compounds. Domestic production of hydrogen chloride in 19$ was approximately 25 5.!n>mion pounds. End uses of hydrogen chloride include: me manufacture of inorganic 26 and organic chemicals, oil-well acidizing, steel pickling, processing of food products, mineral 27 and metal processing, and various rniscellaneous uses. 28 Because ofits captive use as agas and its use as an aqueous solution in most 29 applications, there are little emissions in nmufacture and transport. However, end uses can 30 result in emission ofacid into waste streams with the potential ofreaching groundwater.

Augustl990 1-2 DRAFT-DONOTQUOTEORCrra 1 Hydrogen chloride can be found naturally in theatmosphere from the cooling of 2 volcanic ash. A photochemical source is the photolysis of chlorine and the reaction of the Cl» 3 with methane in the atmosphere. 4 Anthropogenic sources of hydrogen chloride include the burning of fossil fuel, the 5 incineration of municipal refuse, and the burning of polyvinyl-chloride plastics. Hydrogen 6 chloride is also released into the lower stratosphere in solid rocket fuel exhaust. 7 Photochemical degradation of hydrogen chloride occurs, but it is a slow process because 8 of the low atmospheric concentrations of hydroxy radicals. When released into the 9 atmosphere, it is diluted and tends to adsorb on aqueous aerosols and particulates. The 10 National Aeronautics and Space Administration (NASA) has studied the fate of hydrogen 11 chloride in rocket exhaust. Levels in the exhaust cloud are as high asf40 pprnj ^> 12 No monitoring studies of hydrogen chloride in ambient air were found, however, it has 13 been reported that as much as 2.11 and 5.3 g hydrogen chloride are emitted/kg of municipal 14 and hospital waste incinerated, respectively. Hydrogen chloride is also toxic to several plant 15 species with leaf injury and a decrease in chlorophyll levels occurring between exposure 16 concentrations of^6.5 and 27.0 mg/m^i -L^J^ ^» ^

17

18 19 1.2 PHARMACOKINETICS AND MECHANISM OF ACTION

20 1.2.1 Chlorine 21 Chlorine reacts with tissues of the respiratory tract but does not appear to cause systemic 22 effects. Several theories have been proposed on the mechanism of chlorine's toxicity. In a 23 pH range of 6 to 8, chlorine can combine with water from tissue to form hypochlorous and 24 hydrochloric acids. Hypochlorous acid destroys the cell structure by forming N-chloro 25 derivatives with amino groups of proteins. It has been suggested that hypochlorous acid can 26 inhibit sulfhydryl-dependent enzymes by reacting with sulfhydryl groups. Cell damage may 27 also be caused by oxygen radicals generated by chlorine or by the oxidation potential of 28 chlorine. The initial oxidation process is clearly harmful and other secondary processes may

29 also be.

August 1990 1-3 DRAFT - DO NOT QUOTE OR CITE 1 1.2.2 Hydrogen Chloride 2 There is noinformation on the metabolism of hydrogen chloride; however, hydrogen 3 chloride is corrosive to tissue. The corrosive action of hydrogen chloride is associated with 4 its high solubility in water, forming hydronium ion. Hydronium ion is reactive with organic 5 molecules and produces cellular injury and necrosis.

6

7 8 1.3 ANIMAL TOXICITY 9 1.3.1 Chlorine 10 The LC50 values in mice for a 10-minute exposure to chlorine range between 618 and 11 676 ppm (1,742 and 1,960 mg/m3). For a30-minute exposure, an LC50 value of127 ppm 12 (368 mg/m3) was deterrnined, but similar exposure of mice to 10 ppm for 3 hours caused 13 death in 8 of 10animals. In one study with mice, only delayed deaths (5 to 10 days) were 14 observed; the time to50 percent mortality (LT50) was 11 minutes with exposure to 290 ppm 15 (841 mg/m3) and 55 minutes with exposure to 170 ppm (493 mg/m3). The LC50 value for a 16 60-minute exposure of Sprague-Dawley rats was 293 ppm (850 mg/m3). In dogs exposed to 17 chlorine for 30 minutes, the LC50 was 650 ppm (1,885 mg/m3). When data were normalized . 18 for a30 minute exposure, the LC50 values were 256, 414, and 650 pprnfor mice, rats, and 19 dogs, respectively. Rabbits and guinea pigs were somewhat less susceptible, but adequate 20 LC50 values were not found. 21 Mice and rats respond to exposure to sublethal levels of chlorine byareflex decrease in 22 respiratory rate. The RD50 in mice (level for 50 percent reduction in respiratory rate) for a 23 10 minute exposure is 9.3 ppm (27 mg/m3) chlorine. However, repeated exposure to 24 chlorine can induce tolerance to this reflex response. Repeated exposure of Fischer 344 rats 25 to levels as low as 1ppm (2.95 mg/m3) caused a4-fold higher level in the RD50 value than 26 in naive rats, and repeated preexposures tohigher levels caused a20-fold increase. 27 Exposure of rabbits to sublethal concentrations ofchlorine causes changes in lung 28 function tests. Exposure for 30 minutes to 50 ppm (145 mg/m3) caused no effects on 29 inspiratory-expiratory flow rate ratios (V^V^ but exposure to 100 and 200 ppm (295 and 30 590 mg/m3) caused increases inVjiVe which were related to pulmonary edema. Initially 31 there was a decrease in pulmonary compliance in all exposed animals. However, by 60 days

August 1990 1-4 DRAFT - DO NOT QUOTE OR CTIE 1 postexposure, animals inthe two highest exposure groups showed a significant increase in 2 compliance suggestive ofanatomical emphysema. This finding was confirmed by 3 histopathological examination. 4 In subchronic studies, exposure ofrats to chlorine at 9 ppm (27 mg/m3), 6 hours/day, 5 5 days/week for 6 weeks, caused inflammation of the upper and lower respiratory tract, with 6 necrotic lesions appearing in thenasal turbinates. In addition, hyperplasia and hypertrophy 7 occurred in theepithelia of thebronchi and alveoli. Less severe lesions were found after 8 repeated exposure to 1or3 ppm. When rats were exposed to lower cnncgntrationo of 9 chlorine (0.5, 1.5, and 5.0 ppm) for up to 62 days, there was upper respiratory tract irritation 10 in all exposed groups. Histopathological evaluation of the respiratory tract and other major 11 organs did not show any significant exposure-related effects; however, the mean trachea 12 pathology scores of therats exposed to 0.5 and 5.0 ppm chlorine were significantly greater 13 than those ofthe control group. There was also no chlorine-related effect on the reproductive 14 potential of either maleor female exposed animals. ,.. Id ,, „ , x> 15 In a 12-month chronic study with monkeys exposed to 0.1, 0.5, and 2.3 ppm, 16 6 hours/day, 5 days/week, noeffects on pulmonary physiology were found. Ocular irritation 17 was noted in both sexes at 2.3 ppm. The only exposure-related histopathologic changes was a 18 mild focal epithelial hyperplasia in the respiratory epithelium of the nose and trachea which 19 was associated with a loss of ciliaand goblet cellsin the group exposed to 2.3 ppm chlorine. 20 Similar but less severe changes werereported in the nasal passage ofboth sexes in the 21 0.5 ppm group and in females in the0.1 ppmgroup.

22 23 1.3.2 Hydrogen Chloride 24 The LC50 values for hydrogen chloride in rats were 4,701 ppm (7,051 mg/m3) for a 25 30 minute exposure and 40,989 ppm (61,483 mg/m3) for a5-minute exposure. In mice, the 26 LC50 values were 2,644 ppm (3,966 mg/m3) for a30-minute exposure and 13,745 ppm 27 (20,617 mg/m3) for a5-minute exposure. However, no mortality were reported in mice and 28 rats exposed to hydrogen chloride at levels of 410 and 2,078 ppm, respectively for 30 29 minutes. In a recent study, rats were exposed individually and continuously in a rotating cage 30 to concentrations of hydrogen chloride varying between 2,000 and 94,000 ppm and time-to- 31 incapacitation (tj) and time-to-death (td) were recorded. At 2,000 ppm (3,000 mg/m3) ^ was

August 1990 1-5 DRAFT - DO NOT QUOTE OR CITE 1 185 minutes, whereas at 94,000 ppm (141,000 mg/m3) tj was 5.5 minutes and ^ was 2 6.2 minutes. The exposure-response curves were hyperbolic. The LC50 value for a 3 30-minute exposure in female guinea pigs was 2,519 ppm (3,778 mg/m3). 4 When mice ale exposed to sublethal concentrations of hydrogen chloride for 10 minutes, 5 most histopathologic changes were found in the upper respiratory tract. There k-erosion of 6 the epithelium of the external nares at 17 ppm (25 mg/m3), and as the concentration is to«- 7 increased there & erosion of mucosa more distally and damage to underlying structures 8 including bone. Olfactory epithelia were affected at 1,973 ppm (29,595 mg/m3) and at 9 7,279 ppm (10,918 mg/m3) there was fetal destruction of the upper respiratory tract and eyes. 10 Hydrogen chloride is less irritating than chlorine, the RD50 in mice was 309 ppm 11 (460 mg/m3) compared to 9.4 ppm for chlorine. 12 In guinea pigs, sensory irritation occiujS after 6 minutes exposure to 320 ppm 13 (480 mg/m3) and after 1minute exposure to 680 ppm (1,020 mg/m3) hydrogen chloride; 14 pulmonary irritation occurred after 20 minutes exposure at 320 ppm and in less than 15 4 minutes at 1,380 ppm (2,070 mg/m3). Obstructive and restrictive lung changes that 16 persisted for 15 days were seen after 30-minute exposures to 1,040 or 1,380 ppm and there 17 was histologic tissue damage in both theairways and alveolar regions. 18 Exposure of ababoon to hydrogen chloride for 5 minutes atalevel of 190 ppm 19 (285 mg/m3) caused no irritation. Alevel of 810 ppm (1,215 mg/m3) caused irritation but no 20 postexposure symptoms, and alevel of2,780 ppm (4,170 mg/m3) caused apostexposure 21 cough./ArTexposure to 10,000 ppm (15,000 mg/m3) for 15 minutes caused an in 22 /respiratory rate and long-term effects on lung function./Levels of16,570 to 17,280 ppm 23 (24,855 to 25,920 mg/m3) caused respiratory damage and death. ^—^ 24 Littleinformation is available on repeated exposure ofanimals to hydrogen chloride. 25 Exposure of guinea pigs to0.1 ppm. 2 hours/day for 28 days, produced no effects. Repeated 26 exposure ofguinea pigs to 10.0 ppm (14.9 mg/m3) hydrogen chloride for 2hours/day, 27 5 days/week for 49 days, caused no changes in lung function parameters or histological 28 changes in the lungs; and exposure to 67.0 ppm (100 mg/m3), 6hours/day for 5days, caused 29 no histologic changes in the respiratory system. When rats were exposed to hydrogen 30 chloride concentrations of 10. 20; or 50'ppm 6 hours/day, 5 days/week for 90 days therewas 31 minimum to mild rhinitis that was concentration- and time-related. Mice exposed under the

August 1990 1-6 DRAFT-DO NOT QUOTE OR CITE 1 same exposure regime developed eosinophilic globules in theepithelial lining of the nasal 2 tissues. Rhinitis, epithelial or squamous hyperplasia, and squamous metaplasia were reported 3 in rats exposed to 10 ppm hydrogen chloride for 6 hours/day, 5 days/week for life. There 4 was also a high incidence of theselesions reported in control animals. However, an increased 5 incidence ofhyperplasia of the larynx and trachea of exposed animals over that of the controls

6 was noted.

7

8 9 1.4 HUMAN HEALTH EFFECTS

10 1.4.1 Chlorine 11 In humans, the odor threshold of chlorine is very broad and ranges from about 0.02 to 12 1.3 ppm (0.06 to 3.83 mg/m3). Irritation ofthe eyes, nose, and throat has been reported to 13 occur atlevels as low as fcppm (2.95 mg/m3). Exposure to 100 ppm (295 mg/m3) for 14 several minutes is intolerable and incapacitating, and exposure for a few minutes to levels of 15 40* to 60'ppm (118 to 177 mg/m3) causes severe but reversible effects on the respiratory 16 system. Controlled exposure of human volunteers to 1- ppm chlorine for 8 hours causes 17 transient changes in pulmonary function tests. Thereis a slightdecrease in forced vital 18 capacity (FVC), forced expiratory volume in 1 second (FEVj), peakexpiratory flow rate 19 (PEFR), and airway resistance (R^); most values returned to normal within a day. 20 Mortalities in humanshave occurredafter gassing of soldiers with chlorine, in catastrophic 21 spills from accidental releases at use facilities, and from accidental occupational exposures. 22 Several case reports of acute nonlethal exposures have been reviewed. The immediate 23 effects of exposure are burning of the eyes withlacrimation, burning of the nose and throat, 24 rhinorrhea, salivation, coughing and choking, dyspnea, and chest pain. Pulmonary edema, as 25 well as bronchitis mayfollow depending on the severity of exposure. Within 6 to 24 hoursof 26 exposure, abnormalities in pulmonary function may be seen which are caused by airway 27 obstruction. There is a reduction in FVC and FEVj. There is usually a reduction of 28 pulmonary compliance and increased airway resistance. Within a few weeks of exposure 29 there is usually an improvement in pulmonary function but in severecases patients havebeen 30 kept under surveillance for at least 6 months.

August 1990 1-7 DRAFT - DO NOT QUOTE ORCITE 1 There are limited epidemiologic data on chlorine. From cross-sectional surveys of 2 workers potentially exposed to chlorine, it does not appear that long-term exposure results in 3 any respiratory defects and diseases or any effects on the standard mortality rate. Exposure 4 fa** a"1 spare and unreliable, and the available reports are of limited usefulness. Adequate 5 human or animal studies to define mutagenic, teratogenic, or carcinogenic effects in humans 6 have notbeenconducted. Based on the EPA'sGuidelines for Carcinogen Risk Assessment 7 chlorine is classified asa Group D substance which means that the available data are 8 inadequate to assess the carcinogenic potential.

9 10 1.4.2 Hydrogen Chloride 11 There are few data in the literature on the effects of hydrogen chlorideexposureto 12 humans. Inhalation of hydrogen chloride results in irritation of the nose, throat, and larynx, 13 and exposure to high concentrations can cause edema, emphysema, and damage to lung 14 tissue. Levels of5 ppm (7.5 mg/m3) are considered to cause no damage, but levels between 15 10 ppm (15 mg/m3) and 35 ppm (52 mg/m3) can cause irritation ofthe throat, and levels of 16 50 to 100 ppm (75 to 150 mg/m3) are considered barely tolerable. 17 Two studies indicate that continued exposure of workers to hydrogen chloride may cause 18 an increase in dental erosion. However, lackof data on levels ofexposure and the small 19 numbers of workers examined limit the usefulness of these data. No data are available on 20 possible mutagenic, teratogenic, or carcinogenic effects of hydrogen chloride in humans. 21 Based on the EPA's Guidelines for Carcinogen Risk Assessment hydrogen chloride is 22 classified as a Group D substance which means that the available data are inadequate to assess 23 the carcinogenic potential.

24

25 26 1.5 RESEARCH NEEDS 27 The following data are needed:

28 29 • Conduct longitudinal studies onexposed human populations with adequately 30 documented levels ofchlorine including measurements of pulmonary function 31 parameters.

August 1990 1-8 DRAFT-DONOT QUOTE OR CITE 1 • Obtain additional information on the long-range effectsof chlorine and hydrogen 2 chlorideon the respiratory system.

3 4 • Examine the developmentofolfactorytolerance and tolerance to irritation ofchlorine

5 in humans.

6 7 • Perform adequate studies to define mutagenic and teratogenic effects ofchlorine and 8 hydrogen chloride.

August 1990 1-9 DRAFT- DONOT QUOTE OR CITE i 2. PHYSICAL AND CHEMICAL PROPERTIES, 2 QUANTIFICATION, AND ANALYSIS

3

4 5 2.1 PHYSICAL AND CHEMICAL PROPERTIES

6 2.1.1 Chlorine 7 Atambient temperatures, chlorine isagas with a pungent odor and a greenish yellow 8 color. Its molecular wdght is70.91 and the conversion factor at 25°C and 760 mmHg is 9 1ppm (v/v) =2.90 mg/m3 in air or 1mg/m3 =0.344 ppm (v/v). The freezing point is 10 -100.98°C and the boiling point is-34.6°C. Its specific gravity at 0°C is 1.468 and is 11 1.567 at -34°C. The solubility of chlorine in water is0.73 g/100 g (20°C) (HSDB, 12 Hazardous Substances Data Bank, 1987; Environment Canada, 1984). In pure water, 13 chlorine forms elemental chlorine, the chloride ion, and hypochlorous acid (HOC1). As the 14 pH increases, hypochlorous acid rapidly dissociates into the hypochlorite ion. The term "free 15 chlorine" refers collectively to the concentration of elemental chlorine, hypochlorous acid, 16 and hypochlorite ion in water. The stability ofchlorine in water is direcuy related to the 17 chlorine concentration, pH, temperature, exposure tolight, and the presence of catalysts or 18 organic material (National Research Council, 1980). Table 2-1 lists some ofthe major 19 chlorine reactions known to occur is water.

20 21 2.1.2 Hydrogen Chloride 22 Hydrogen chloride (anhydrous) is aclear colorless gas that produces whitish fumes in 23 moist air and has a pungent odor. Its molecular weight is 36.46 and the conversion factor at 24 25°C and 760 mmHg is 1ppm (v/v) = 1.49 mg/m3 in air or 1mg/m3 in air =0.670 ppm 25 (v/v). Thefreezmgrx>mtis-114.80Candmeboilmgrx>m Hydrogen chloride is 26 very hygroscopic. Its vapor pressure is 25.5 arm at 0°C and 41.6 arm at 20°C. As an 27 aqueous solution, concentrated hydrochloric acid is 37.1 percent hydrogen chloride and has a 28 specific gravity of 1.189 (15.3°C). When hydrogen chloride gas absorbs moisture, itis 29 highly reactive with most metals, evolving hydrogen gas. It also reacts with most organic 30 materials (TDB, Toxicology Data Bank, 1987; GEOMET Technologies, Inc., 1981).

August 1990 2-1 DRAFT-DO NOT QUOTE OR CITE 1 TABLE 2-1. CHLORINE REACTIONS KNOWN TO OCCUR 2 IN AQUEOUS SOLUTION 3 4 5 Reaction Type Examples 6 7 8 Water 9 Hydrolysis ci2 + h2o • hoci + h+ + cr 10 Ionization HOCI-m- H++ocr 11 NaOCl-Na+ + OCT 12 Ca(OCl)2-Ca2+ + OC1" 13 Ammonia 14 Substitution NH3 + HOCI - NH2C1 + H20 15 Oxidation 2NHC12 + H20 - N2 + HOCI + 3H+ + 3C1" 16 Inorganic oxidation Mn2+ + HOCI + 2H20 - MnO(OH)2 + 3H+ + CI* 17 Disproportionation 3ocr-2cr+ cio- 18 Decomposition 2H0C1 - 2H+ + 2C1" + 02 19 Organic reactants 20 Oxidation RCHO + HOCI - RCOOH + H+ + CT 21 Addition RC=CR' + HOCI - RC(OH)C(Cl)R' 22 Substitution 23 N-Cl bond RNH2 + HOCI - RNHC1 + H20 24 C-Cl bond RCOCH3 + 3H0C1 - RCOOH + HCCI3 + 2H20 25 26 27 Source: Jolley and Carpenter (1983). 28 29 30 31 2.2 QUANTIFICATION AND ANALYSIS

32 2.2.1 Chlorine

33 Although methods havebeen developed to analyze chlorine in air and in water, a 34 problem with mostis that they lackspecificity and measure totalchloride ion rather than 35 chlorinegas (WorldHealth Organization, 1982). 36 Methods based on a color changein the dye o-tolidine have been used as early as 37 1913 and havebeen modified several times. Johnson and Overby (1969) developed a method 38 to improve specificity and sensitivity in which the o-tolidine reagent was stabilized with 39 bis(2-ethylhexyl) sulfosuccinate. Their method allowed the reaction to take placeat pH 40 7 rather than in acid media, thus minimizing interference by chloramine, Mn+3, Fe+3, and 41 nitrateions, and retarding the rapid fading of the color produced by reaction with chlorine. A

August 1990 2-2 DRAFT - DO NOT QUOTE OR CITE 1 blue color, resulting from oxidation ofthe dye to asemiquinone, was quantitated 2 colorimetrically. This method is not now widely used because o-toUdine has been found to be 3 carcinogenic. 4 The American Public Health Association (1977) used acolorimetric method in which air 5 containing chlorine was passed into methyl orange and the decrease in color caused by dye 6 oxidation was measured spectrophotometrically. The level of detection is 0.05 to 1.0 ppm 7 usmga30-Lsanroleofairandasamp^ 8 in methyl orange. However, the range of the method can be extended by trapping the air in 9 sodium hydroxide and assaying an aliquot of the trap. Ozone, sulfur dioxide, and nitrous 10 oxides interfere. 11 Several analytical methods have been developed based on the oxidation of potassium 12 iodide to in acidic solution. Wagenknecht et al. (1981) titrated the iodine with 13 thiosulfate. Nirrnalchandar and Balasubramanian (1984) reacted the iodine, which was 14 formed with Rhc)damine, and extracted the colored complex into ; the sensitivity was 15 between 0.1 and 0.3 ppm. Apersonal monitor has been developed by Hardy et al. (1979) in 16 which the resulting bromine is reacted with fluorescein to form eosin, which is determined 17 spectrophotometrically. The sensitivity is about 0.1 ppm. 18 Rigdon et al. (1978) used an Orion® residual chlorine electrode which develops a 19 potential based on the relative amounts of iodine and iodide ion in solution. The method was 20 capable of determining water concentrations of free chlorine in the range of 3to 100 ppb. 21 Cheplen et al. (1984) developed amethod capable of determining low concentrations of 22 chlorine in air (0.1 ppm) in the presence of ammonia. Odorarnine, which is formed by 23 reaction of cMorme wito arnmonia, can mterfere wim me determimtion of free cWorine. Air 24 samples were collected into 100 mL of chlorine-free water containing 15 mg 25 2,6-dimethylphenol (DMP) and three drops of concentrated sulfuric acid; 4-bromo-2,6-DMP 26 was added as an internal standard in the gas collection impinger. The flow rate was 27 0.72 L/minute and collection was for 10 minutes. The resulting 4-Cl-2,6-DMP was extracted 28 with 15 mL , the organic phase was concentrated to about 1mL, and 1or 2 j*L was 29 injected into agas chromatograph with afused silica capillary column and aflame ionization 30 detector. Acalibration curve was required since alinear response was not obtained at low 31 chlorine levels.

Augustl990 2-3 DRAFT - DO NOT QUOTE OR CITE 1 Langhorst and flies (1986) have described a functional, commercially available 2 continuouschlorineanalyzer which uses an ion-specific electrode and a microprocessor data 3 logging system. Chlorine in airdiffuses to a platinum electrode whereit is reduced to 4 $ chloride; silver is oxidized atthereference electrode and a current is produced. The 5^1reference electrode is in an electrolyte solution and separated from the platinum electrode by a 6 W porous glass frit The sensor has arange of0.05 to 10 ppm (v/v) chlorine and aprecision of 7 "SjjY (±12percent. Recovery time is 1to 4minutes. The instrument can measure peak values as 8 well as time-weighed averagevalues (TWAs). It has the same sensitivity as the sulfamic acid 9 bubbler method. The latter method, however, is less convenient than a 3M dosimeter badge 10 but has the advantage of collecting continuous datawhereas the badge can only measure a 11 TWA value. A computer package is described for manipulating the data selected and 12 formatting the results. 13 Lane and Thomson (1981) have described a mobile mass spectrometer system (TAGA®) 14 that has been used for continuous and instantaneous measurement of chlorine levels in air. 15 Air is collected at a flow rate of 1 L/sec and molecules aire ionized by ion-molecule reactions 16 in a corona discharge. They are then introduced into a quadripole mass spectrometer. 17 Chlorine produces C\y and Clfwhich are stable in air; however, the Cl27 can be fragmented 18 to CI/" in the mass spectrometer and selectively monitored at a mass-to-charge ratio (m/z) of 19 35. Chloride ions may also be formed from chlorinated ; therefore, Cf ions are 20 occasionally monitored because they are more specific indicators of chlorine gas. The 21 detection limit isabout 0.1 pg/m3 (30 parts per trillion).

22 23 2.2.2 Hydrogen Chloride 24 Most of the methods used for monitoring hydrogen chloride have limitations. Methods 25 involving absorption in an alkali andtitration or colorimetric change ofa pH-indicator dye are 26 nonspecificwhen measuring ambientair or emission sources. It has been found that 27 considerable error can be introduced in sampling ofair for hydrogen chloride since the acid in 28 the collecting tube may interactwith glasswool or the filtering medium (Cheney and Fortune, 29 1984). Drabkeet al. (1982) developed a method for continuous monitoringofairborne 30 hydrogen chloride (gas or aerosol) using a chloride-sensitive flow electrode and a copper- 31 sensitive reference electrode. The absorption solution contained 10"3 M copper nitrate. This

August 1990 2-4 DRAFT- DO NOT QUOTE OR CITE 1 method measures total chloride ion and not specifically hydrogen chloride. Hlavayand 2 Guilbault (1978) developed apiezoelectric quartz crystal detector with acoating of 3 trimemylamine-HCl or triphenylamine. Moisture was removed from me sampled air through 4 acolumn of silica gel. Hydrogen chloride could easily be quantified in the range of 1to 5 100 ppm with aresponse time ofless than aminute. The lower detection limit was stated to 6 be at the parts-per-billion level.

August 1990 2-5 DRAFT - DO NOT QUOTE OR CITE 2.3 REFERENCES

3 American Public Health Association. (1977) Tentative methods for analysis for five dichlorine content ofthe 4 atmosphere (methyl orange mentod). In: Katz, M., ed. Methods of airsampling and analysis, 2nd ed. 5 Washington, DC: American Public Health Association; p. 381. 6 7 Cheney, J. L.; Fortune, C. R. (1984) Improvements in the inethodolggg for measuring hydrochloric acid in 8 combustion source emissions. J. Environ. Sci. Health A 19: 337-350.

10 Cheplen, J. M.; Barrow, C; White, E. L. (1984) Determination of airborne free chlorine in the presence of 11 ammonia by capillary column gas . Anal. Chem. ^ '56: 1194-1196. 12 V—-- 13 Drabke, P.; Kirsch, H.; Wolf, J. (1982) Eine Methode zurkontinuierlichen Bestimmung von HC1- 14 Konzentrationen in der Luft mit Hilfe einerchloridsensitiven Durchflusselektrode [A method of 15 continuous determination of HG concentrations in the air with the aid ofa chloride-sensitive flow 16 electrode]. Z. Gesamte Hyg. Ihre Grenzgeb. 28: 241-243. 17 18 Environment Canada. (1984) Chlorine: environmental and technical information for problem spills. Ottawa, 19 Canada: Environmental Protection Service, Technical Services Branch (EnviroTIPS manual). 20 21 GEOMET Technologies, Inc. (1981) Hydrogen chloride: report 4, occupational hazard assessment. Cincinnati, 22 OH: U. S. Department of Health and Human Services, National Institute for Occupational Safety and 23 Health; NIOSH contract no. 210-79-0001. Available from: NHS, Springfield, VA; PB83-10S296. 24 25 Hardy, J. K.; Dasgupta, P. K.; Reiszner, K. D.; West, P. W. (1979) A personal chlorine monitor utilizing 26 permeation sampling. Environ. Sci. Technol. 13: 1090-1093. 27 28 Hlavay, J.; Guilbault, G. G. (1978) Detection ofhydrogen chloride gas in ambient airwith a coated piezoelectric 29 quartz crystal. Anal. Chem. SO: 965-967. 30 31 HSDB, Hazardous Substances Data Bank [data base]. (1987) Bethesda, MD: U. S. Department of Health and 32 Human Services, National Library of Medicine. 33 34 Johnson, J. D.; Overby, R. (1969) Stabilized neutral orthotolidine, SNORT, colorimetric method for chlorine. 35 Anal. Chem. 41: 1744-1750. 36 37 Jolley, R. L.; Carpenter, J. H. (1983) A review of thechemistry and environmental fete of reactive oxidant 38 species in chlorinated water. In: Jolley, R. L.; Brungs, W. A.; Cotruvo, J. A.; Cumming, R. B.; 39 Mattice, J. S.; Jacobs, V. A., eds. Waterchlorination: environmental impact andhealth effects, volume 40 4, book 1, chemistryandwater treatment, proceedings ofthe fourth conference; October 1981; Pacific 41 Grove, CA. Ann Arbor, MI: Ann Arbor Science Publishers, Inc.; pp. 3-47. 42 43 Lane, D. A.; Thomson, B. A. (1981) Monitoring a chlorine spill from a train derailment. J. Air Pollut. Control 44 Assoc. 31: 122-127. 45 46 Langhorst, M. L.; Hies, S. P., Jr. (1986) A portable data-logging system for industrial hygiene personal chlorine 47 monitoring. Am. Ind. Hyg. Assoc. J. 47: 78-86. 48 49 National Research Council. (1980) The disinfection ofdrinkingwater. In: Drinking water and health: volume 2. 50 Washington, DC: National Academy Press; pp. 5-42. 51 52 Nirmalchandar, V.; Balasubramanian, N. (1984) Spectrpphotometric determination ofchlorine after fixing in 53 alkali. Z. Gesamte Hyg. Hire Grenzgeb. 30: 468-470.

August 1990 2-6 DRAFT- DO NOT QUOTE OR CITE 2 Rigdon, L. P.; Moody. G. J.; Frazer. J. W. (1978) Determination tfjwridual chlorine in water with computer 3 'automafionand aresidual-chlorine electrode. Anal. Chem.^^ 50: 465-468. 5 TDB. Toxicology Data Bank [data base]. (1987) Bethesda. MD: National library of Medicine. U. S. Department 6 * of Health and Human Services; TDB no. 206 (chlorine), 545 (hydrogen chloride). 78 Wagenknecht, J. H.; Jansson, R. E. W.; Stover, F. S. (1981) Analysis of mixtures of chlorine and chlorine 9 dioxide. Anal. Lett. 14: 197-204. 11 World Health Organization. (1982) Chlorine and hydrogen chloride. Geneva, Switzerland: World Health 12 Organization. (Environmental health criteria 21).

August 1990 2-7 DRAFT - DO NOT QUOTE OR CITE i 3. PRODUCTION, USE, ENVIRONMENTAL SOURCES, 2 AND ENVIRONMENTAL LEVELS 3 AND EXPOSURE

4

5 3.1 PRODUCTION AND USE

6 3.1*1 Chlorine 7 As of January 1, 1986, there were25 manufacturers in the U.S. producing chlorine at 8 51 plantsites, withan estimated total domestic production capacity of 26.1 billion pounds 9 (SRIInternational, 1986). Total domestic production capacity was reduced to 22.6 billion 10 pounds by September 1986as a resultof several plantclosings (Anonymous, 1986a). 11 Chlorine production in 198/ was 2/.^billion pounds^up 5 percent from the 1986 level of 12 -20.8 billion pounds (Reisch, 198$). In 1988, an estimated 22./ billion pounds of chlorine 13 was produced in the United States (Reisch, 1989). 14 In 1983, over 95 percent of the domestic chlorine production capacity was based on the 15 electrolytic decomposition of brines, usually in diaphragm cells. Chlorine is also produced by 16 oxidation or electrolysis of hydrogen chloride, as a by-product ofpotassium nitrate 17 production, and as a coproduct of potassium hydroxide production (Anonymous, 1984). The 18 manufacture of chlorine, therefore, is closely associated with the production of caustic soda or 19 alkali. This chlor-alkali industry provides an essential feedstock for a number of key 20 manufacturing activities in our industrial world, including plastics, pulp andpaper, rayon and 21 cellophane, soaps and detergents, and glass. 22 Chlorine is used mainly as an intermediate in the production oforganic chemicals. It is 23 used also in bleaching of pulp and paperproducts; as an intermediate in the production of 24 inorganic chemicals; in the treatment of potable, process, and wastewater streams by 25 municipalities and industry; and in the manufacture of cleaning and sanitation products 26 (e.g., liquid household bleaches, swimming pool chemicals, industrial sanitizing agents) 27 (Anonymous, 1984). Domestic consumption of chlorine in 1985 by end-use application was 28 as follows: production of ethylene dichloride, most of which was used to produce the vinyl 29 chloride monomer (21 percent); production of organic chemicals other than chloroethanes 30 (18 percent); chloroethanes (10 percent) and chloromethanes (8 percent); pulp and paper

August 1990 3-1 DRAFT - DO NOT QUOTE OR CITE 1 (17 percent); inorganic chemicals (15 percent); water treatment (5 percent); and miscellaneous 2 uses (6 percent) (Anonymous, 1986b).

3 4 3.1.2 Hydrogen Chloride svl 5 Domestic production of hydrogen chloride in 198^ totaled 4^9- billion pounds (Reisch, 6 198& In 1989. an estimated 5i«7-billion pounds of hydrogen chloride was produced in the 7 United States, an increase of i'fcG-percent over that of 1987lReisch, 1989). A Or 8 About 90 percent ofthe domestically produced hydrogen chloride is generated as a 9 coproduct in the manufacture ofother chemicals: e.g., production ofvinyl chloride monomer 10 from ethylene dichloride, manufacture of isocyanates and fluorocarbons, and chlorination of 11 organic compounds (Anonymous, 1982). Hence the supply depends largely on demand for 12 the primary products rather than on demand for hydrogen chloride. Hydrogen chloride can 13 also be synthesized directly by oxidation ofhydrogen with chlorine and the reaction of 14 mineral acid with alkali chlorides (Anonymous, 1984). 15 Most hydrogen chloride is sold as aqueous commonly known as muriatic acid. 16 Technical and food processing grades contain 28 to 35 percent hydrogen chloride; the 17 anhydrous grade is99.8 percent pure (Anonymous, 1982). 18 The largest consumption ofhydrogen chloride is by the organic chemicals industry. Use 19 in the production ofethylene dichloride and numerous other organic chemicals accounted for 20 64 percent of the estimated domestic consumption of 6.8 billion pounds ofhydrogen chloride 21 in 1981. Other end-use applications include use in the manufacture ofinorganic chemicals 22 (10 percent of1981 consumption), oil-well acidizing (10 percent), steel pickling (8 percent), 23 processing offood products (4 percent), mineral and metal processing (2 percent), and 24 miscellaneous uses (2 percent). In 1981, 55 percent ofthe hydrogen chloride consumed in 25 these applications was used captively, and the remaining 45 percent was sold in the merchant 26 market (Anonymous, 1982).

August 1990 3-2 DRAFT - DO NOT QUOTE OR CITE 1 3 2 ENVIRONMENTAL SOURCES

2 3.2.1 Chlorine 3 3.2.1.1 Manufacturing and Transport 4 There is a potential for the release of chlorinein its manufacture but the amount is not 5 significantwhen compared to other potentialsources. This may occur during process 6 sampling and in maintenance of electrolytic cells. Most releases, however, would be 7 expected from leaks in compressor seals or from faulty valves, or in the loading or unloading 8 oftank cars (Environment Canada, 1984; World Health Organization, 1982). The bulk of 9 chlorineis transported by rail. Its shipping containers are constructed of steel to Department 10 of Transportation (DOT) specifications and are equipped with safety devices and specially 11 designed valves (Simmonset al., 1974). Likewise, cylinders to be transported are approved 12 for safety by the DOT. 13 The Chlorine Institute (Washington, DC) has published several documents on chlorine 14 manufacturing, safe handling, packaging and transport, and emergency measures. In 15 addition, the Chemical Manufacturers Association CMA-CHEM-TREK operation maintains a 16 24-hour answering service for help and advice in regard to transportation emergencies.

17

18 3.2.1.2 Natural Sources and Photochemical Processes 19 Volcanic origins of gaseous chlorine in the atmosphere have been postulated. However, 20 Duce (1969) indicated that this is unlikely, and Johnston (1980) has reported that the cooling 21 ofvolcanic ash releases hydrogen chloride and not chlorine. It has been hypothesized that 22 photolysis of sea salt particles in clouds over the ocean can produce chlorine (Duce, 1969), 23 but there are no data to support this idea. Methods used in the past to monitor chlorine in 24 rain or ambient air detected total chloride ion and were not specific for the gas (Chapter 2). 25 There are photochemical reactions thatproduce C^in the stratosphere (e.g., photolysis of 26 nitrosyl chloride) but there is no evidence that these would produce chlorine gas (Prather 27 etal., 1984).

28 29 3.2.1.3 Anthropogenic Processes 30 The use of gaseouschlorine in treatment of drinking water, disinfection of swimming 31 pools, and treatment of wastewater can result in fugitive emissions. However, the use in

August 1990 3-3 DRAFT - DO NOT QUOTE OR CITE 1 swiniming pools has been largely replaced by me use of soUd material that generate active 2 chlorine or hypochlorite. In general, the use of chlorine in the treatment of drinking water is 3 more discrete than in the past. Proportionately less chlorine is used in the treatment ofwater 4 (World Health Organization, 1982), but the total tonnage used worldwide is probably 5 increasing. Potential releases also occur in pulp and paper imlls, where chlorine is used as a 6 bleaching agent. The use of chlorine as abiocide in arecirculating cooling water system of a 7 power plant can potentially result in release to the atmosphere in the cooling tower or release 8 into seawater, atypical system uses about 50 tons ofchlorine/year (Holzwarth et al., 1984).

9 10 3.2.2 Hydrogen Chloride 11 3.2.2.1 Manufacturing and Transport 12 Much ofthe hydrogen chloride produced as aby-product ofchlorination reactions is 13 used captively or recycled in aclosed system with efficient containment so the amount 14 released into the environment is not significant. However, potential releases can occur from 15 leaking valves, pumps, or compressor seals. Anhydrous hydrogen chloride is transported in 16 safety designed cylinders (World Health Organization, 1982) and vent gases from storage 17 tanks containing hydrogen chloride are normally scrubbed with alkaline aqueous solutions. 18 Concentrated aqueous hydrochloric acid (37.7 percent) has asubstantial vapor pressure and 19 can evolve hydrogen chloride vapor, but aqueous solutions containing less than 20 percent 20 hydrogen chloride can be used in open vessels without appreciable release of vapor (Georngt 21 Technologies, Inc., 1981).

22 23 3222 Natural Sources and Photochemical Processes 24 Magma from volcanoes can give rise to hydrogen chloride (Johnston, 1980). It was 25 estimated that degassing ofash from the St. Augustine volcano in Alaska emitted 82 to 175 x 26 106 kg hydrogen chloride into the stratosphere. Photochemically, chlorine can form Cy 27 which reacts with methane to form hydrogen chloride (Sebacher et al., 1980). (}

28 29 3.2.2.3 Anthropogenic Processes 30 The burning of fossil fuel (World Health Organization, 1982) and the incineration of 31 municipal waste containing polyvinyl chloride plastics (Chan, 1984) are sources ofhydrogen

August 1990 3-4 DRAFT - DO NOT QUOTE OR CITE 1 chloride in theatmosphere. Based on projected compositional change, plastics will make up 2 13 percent of refuse in the year 2000, compared to 2 percentin 1970. Although emission 3 controls suchas electrostatic precipitators and waterspraying of exhaust gases should trap 4 mosthydrogen chloride emission in an incinerator exhaust, there are still substantial 5 emissions. Rollins and Homolya (1979) monitored the mass emission rate for two 6 state-of-the-artincineratorsof municipalwaste and found 2.11 and 1.98 g hydrogen 7 chloride/kg refuse incinerated, respectively. It was estimated that ambient air levels could be 8 as high as 42.8 and 31.8 pg/m3 ata distance of800 mfrom each ofthe sources studied. 9 Allen et al. (1986) analyzed stack emissions from incineration ofhospital waste and found a 10 hydrogen chloride air emissions factor of 3.3 to 5.3 g/kg. Hospital waste, for which no 11 emissions controls are required, is expected to containabout four times more plastic material 12 than municipal waste. Hydrogen chloride generated from polyvinyl chloride is also a 13 potential toxicityproblem for fire fighters (Dyer and Esch, 1976). 14 Exhaust products emitted from a space shuttle vehicle contain hydrogen chloride. Potter 15 (1978) estimated that the amount emitted in the surface boundary area, the troposphere, and 16 the stratosphere were 24.7, 78.5, and 59.7 thousand 1%, respectively, and the amountin the 17 stabilized ground cloud was 35.2 x 103 kg. 18 Aqueous wastestreams are a source of hydrogen chloride released to surface waters. 19 Sourcesare overacidified swimming pool water and waste from treatment of metals in steel 20 production and electroplating industries (World Health Organization, 1982).

21 22 3.3 ENVIRONMENTAL LEVELS AND EXPOSURE

23 3.3.1 Chlorine 24 There is little information in the available literature regarding ambient air concentrations 25 of chlorine or hydrogen chloride. According to the World Health Organization (1982), the 26 presence of measurable quantities of chlorineor hydrogen chloridein ambientair has not been 27 demonstrated. Air monitoring studies generally provide data only on total chloride 28 concentrations and do not differentiate between chlorine, hydrogen chloride, or other sources 29 of chloride ions. The National Academy of Sciences (NAS) reported that mean ambient air 30 levels ofchloride range from 1mg/m3 (0.344 ppm) to 3.7 mg/m3 (1.27 ppm) (National 31 Research Council, 1976). However, AppliedScienceAssociates, Inc. (1978) reported

August 1990 3-5 DRAFT - DO NOT QUOTE ORCITE 1 atmospheric levels of 2.9 /xg/m3 (0.001 ppm) in coastal areas and 58.0 jig/m (0.02 ppm) in 2 ambient air samples from metropolitan areas, e.g., Cincinnati and Baltimore. 3 Lane and Thomson (1981) monitored achlorine plume that resulted from atrain 4 derailment at Mississauga, Ontario in 1979. The accident was followed by an explosion and

5 fire and it appears that about 70 of the 90 tons of cWorme mai^ tanker leaked out during 6 the most intense period of the fire. Amobile mass spectrometer system using atmospheric-

7 pressure chemical ionization was used to analyze ground-level concentrations of chlorine. 8 The monitoring began several hours after the accident and continued for six days until the 9 remaining chlorine had been pumped from the tanker and transported away. Forthefirst 10 three days under conditions of light wind (1 to 4km/hour), the maximum ground level 11 concentrations were in the range of10 to 100 jig/m3 (3.4 to 34 ppb) at adistance 0.5 to 1km 12 from the source, with brief excursions of up to 400 jig/m3 (137 ppb). During the fourth day, 13 the tanker was patched and levels decreased below the detection limit (0.1 /*g/m ). Chlorine 14 was confined to anarrow plume at ground level; it was about 1km wide 5 km from the 15 source when measurements were made on the third day* There was no vertical concentration 16 gradient when measurement^were made between ground level (0.15 m) and aheight of about 17 4.5 m(the plume concentration was 35 Mg/m3). No trapped chlorine gas was found in low- 18 lying areas. 19 Gudiksen et al. (1986) used computer models to estimate the surface air concentrations 20 ofchlorine that would result from the release of 9,500 gallons ofliquid chlorine from aspill 21 covering 30 x 30 m. The nominal evaporation rate of this size spill was 7.2 kg/second. The 22 steady-state concentration under nocturnal conditions was estimated to vary from about 23 10,000 ppm near the source to 60 ppm at adistance of 5,000 munder nighttime conditions. 24 Under daytime conditions, the corresponding values would be 3,000 ppm and 10 ppm. These 25 concentrations would persist for two to three hours, it was reported that release of 80 gallons 26 over a12-minute period would result in levels exceeding 25 ppm at adistance of 115 min the 27 daytime. Similarly, release of 150 gallons in a10-minute period would result in levels 28 exceedmg25ppmatadistanceof700mdurmgthemghttime. 29 Environment Canada (1984) constructed nomograms to predict the rate of release of 30 chlorine from an 80,000-L railroad tank car with punctures on the top or on the bottom. 31 With apuncture of 100 mm in diameter on the bottom, the rate of discharge was estimated to

August 1990 3-6 DRAFT - DO NOT QUOTE OR CITE 1 be about 200 kg/second and about50 percent of the chlorine in the tanker would be released 2 in 3 minutes. With a rupture ofthe same size on the top, the rate ofrelease was estimated to 3 be about 40 kg/second and 50 percent was expected to be released in 70 minutes. liquid 4 chlorine on the bottom of the tank caris released more rapidly than gaseous chlorinewhich is 5 at the top. 6 All ofthese estimates have been prepared to aid the protection of fire fighters and to 7 assist emergency-response planners. Although accuracy of me estimates depend on climatic 8 and meteorologic conditions, the estimates indicatethat releasesoflarge amounts ofchlorine 9 in accident scenarios result in high airborneconcentrations in the vicinity ofa spill and rapid 10 dilution of the chlorine in the atmosphere so that dangerous levels do not persist except for a

11 few hours. 12 The use of chlorine in potable, process, and wastewater treatment has led to release of 13 the compound to surface waters and detection ofchlorine in drinking water supplies. For 14 example, Moore et al. (1979) reported a mean residual chlorine level of 1.3 mg/L (range 15 0.3 to 4.0 mg/L) in the finished water of 19 Massachusetts communities served by water 16 treatment facilities using an average chlorineapplication of 15.2 mg/L (range 4.3 to 17 29.7 mg/L). The mean total residual chlorine level was 1.5 mg/L (range 0.4 to 6.0 mg/L). 18 Of 80 domestic groundwater and surface water supplies tested in the National Organics 19 Reconnaissance Survey, 41 percent had free residual chlorine concentrations ranging from 20 0 to 0.4 mg/L; 19 percent had concentrations of0.4 to 0.8 mg/L; 4 percent had 21 concentrations of0.8 to 1.2 mg/L; and 20 percent had concentrations of 1.2 to 1.6 mg/L 22 (Symons et al., 1975). Chlorine was alsodetected in the finished drinking water supplies of 23 Cincinnati (2.7 mg/L), Miami (2.3 mg/L), Ottumwa (1.4 mg/L), and Philadelphia 24 (2.0 mg/L). 25 Chlorine is used by the food processing industryas a general disinfectant and as a 26 bleaching agent for wheat flour. Chlorine-bleached cake flour was found to contain 131 to 27 189 mg chlorideper 100 g flour as compared to 43 to 54 mg chloride for unbleached flour 28 (Sollars, 1961). 29 Information on the exposureof the general publicto ambient levels ofchlorinewas not 30 found in the published literature. However, the National Institute for Occupational Safety and 31 Health (NIOSH) conducteda workplace survey, the National Occupational Exposure Survey

August 1990 3-7 DRAFT - DO NOT QUOTE OR CITE 1 (NOES), from 1980 to 1983 (National Institute for Occupational Safety and Health, 1984). 2 Preliminary data from this survey indicate that 147,116 workers, including 11,095 women, 3 were potentially exposed to chlorinein the workplace in 1980. The NOES estimates were 4 based only on observations of the actual use of chlorine. 5 The National Institute for Occupational Safety and Health (1976) reviewed the available 6 literature concerning chlorine concentrations in workplace air, and reported that workers are 7 generally exposed to less than 1ppm chlorine during manufacturing operations and trace 8 amounts to 64 ppm during use ofthe compound in bleaching operations in the pulp and paper 9 industry. The value of64 ppm was probably the maximum value found in apulp and paper 10 factory by Ferris et al. (1967). The average value was 7.4 ppm; when analysis were 11 performed four and five years later, the levels in the same plant were 0.0005 to 0.001 ppm. 12 Pendergrass (1964) monitored air levels in aplant producing chlorine for aperiod of five 13 months and reported that levels of <0.1 ppm were found in over 91 percent of2,785 samples 14 and fewer than 1.2 percent of the samples exceeded 1.0 ppm. Paul etal. (1970) report that 15 for 332 diaphragm cell workers in achlorine-producing plant, the TWA exposure mean for 16 chlorine was 0.15 ± 0.29 ppm and the range of exposure was from 0.006 to 1.42 ppm. 17 However, the value of 0.006 ppm that was reported is doubtful because it is below the 18 analytical capability of the method used. Chan-Yeung etal. (1980) found that mean exposure 19 to chlorine for workers in a paper mill was 0.05 ppm (range 0.05 to 0.1 ppm). Enarson 20 etal. (1984) analyzed 25 personal samples in the bleach area ofapaper pulp plant and found 21 a mean exposure of 0.18 ppm and a maximum exposure of 1.61 ppm chlorine.

22 23 3.3.2 Hydrogen Chloride 24 No data were found onthe actual level of hydrogen chloride in air orin surface water 25 and groundwater. Several studies have, however, reported as much as 2.11 and 5.3 g 26 hydrogen chloride emitted/kg ofmunicipal and hospital refuse incinerated, respectively (see 27 Section 3.2.2.3). 28 In 1980, 540,518 workers, including 114,796 women, were potentially exposed to 29 hydrogen chloride in the workplace (National Institute for Occupational Safety and Health, 30 1984). These NOES estimates consisted only of observations ofthe actual use of hydrogen

31 chloride.

August 1990 3-8 DRAFT - DO NOT QUOTE OR CITE 1 3.4 REFERENCES 2 Allen, R. J.; Brenniman, G. R.; Darling, C. (1986) Air pollution emissions from the incineration ofhospital 3 waste. J. Air Pollut Control Assoc. 36: 829-831. 4 5 Anonymous, (1982) Chemical economics handbook. Menlo Park, CA: SRI International Sections; 733.4000A- 6 733.4002J. 7 8 Anonymous, (1984) Chemical economics handbook. Menlo Park, CA: SRI International. Sections 733.1000A- 9 733.10061. 10 11 Anonymous, (1986a) Key chemicals - chlorine. Chem. Eng. News 64: 18. 12 13 Anonymous, (1986b) Top 50 chemicals output declined 3% last year. Chem. Eng. News 64:13. 14 15 Anonymous, (1986c) Chemical profile: chlorine. Chem. Mark. Rep. (April 28): 44, 46. 16 17 Applied Science Associates, Incorporated. (1978) Diagnosing vegetation injury caused by airpollution. Research 18 Triangle Park, NC: U. S. Environmental Protection Agency, Office of Air Quality Planning and 19 Standards; pp. 6-2 to 6-9; EPA report no. EPA-450/3-78-O05. Available from: NITS, Springfield, VA; 20 PB82-238924. 21 22 Chan, H. S. O. (1984) Measurement ofhydrochloric acid emission from burning PVC compounds. J. Fire Sci. 23 2: 106-122. 24 25 Chan-Yeung, M.; Wong, R.; Maclean, L.; Tan, F.; Dorken, E.; Schulzer, M.; Dennis, R.; Grzybowski, S. 26 (1980) Respiratory surveyofworkers in a pulpand paper mill in Powell River, British Columbia. Am. 27 Rev. Respir. Dis. 122: 249-257. 28 29 Duce, R. A. (1969) On the source of gaseous chlorine in the marine atmosphere. JGR J. Geophys. Res. 74: 30 4597-4599. 31 32 Dyer, R. F.; Esch, V. H. (1976) Polyvinyl chloride toxicity in fires: hydrogen chloride toxicity in fire fighters. 33 JAMA J. Am. Med. Assoc. 235: 393-397. 34 35 Enarson, D. A.; MacLean, L.; Dybuncio, A.; Chan-Yeung, M.; Grzybowski, S.; Johnson, A.; Block, G.; 36 Schragg, K. (1984) Respiratory health at a pulpmill in British Columbia. Arch. Environ. Health 39: 325- 37 330. 38 39 Environment Canada. (1984) Chlorine: environmental and technicalinformation for problem spills. Ottawa, 40 Canada: Environmental Protection Service, Technical Services Branch (EnviroTIPS manual). 41 42 Ferris, B. G., Jr.; Burgess, W. A.; Worcester, J. (1967) Prevalence ofchronic respiratory disease in a pulp mill 43 anda paper mill in the United States. Br. J. Ind. Med. 24: 26-37. 44 45 GEOMET Technologies, Inc. (1981) Hydrogen chloride: report4, occupational hazardassessment Cincinnati, 46 OH: U. S. Department of Health and Human Services, National Institute for Occupational Safety and 47 Health; NIOSH contract no. 210-79-0001. Available from: NTIS, Springfield, VA; PB83-105296. 48 49 Holzwarth, G.; Balmer, R. G.; Soni, L. (1984) The fate of chlorine and chloramines in cooling towers: Henry's 50 law constants for flashoff. Water Res. 18: 1421-1427. 51 52 Johnston, D. A. (1980) Volcanic contribution ofchlorine to the stratosphere: more significant to ozonethan 53 previously estimated? Science (Washington, DC) 209: 491-493.

August 1990 3-9 DRAFT - DO NOT QUOTE ORCITE 1 Moore GS•Tnmill, R. W.; Polakoff, D. W. (1979) Astatistical inodel for predictmg cUoroform levels in 2 ' chlorinated surfece water supplies. J. Am. Water Works Assoc. 71: 37-39. 45 NationalJ^ureInstitutetocMo^Cmcinnati,for Occupational SafetyOH:and Health.U. S. Department(1976) Criteriaof Health,for alecommendedEducation, andf*^0™^00*Welfare, NIOSH 6 publication no. 76-170. Available from: NTIS, Springfield, VA; PB-266367/2. 8 National Institute for Occm*tional Safety and Health. (1984) National c>ccupational exposure survey (1980-1983) 9 [database]. Cincinnati, OH: Department of Health and Human Services, National Institute for 10 Occupational Safety and Health. 12 NationalNatlonfllB^^Research Council.Effijct8 of'Eavilonmental(1976) Chlorine Pollutants;and hydrogenEPAchloride.report no.Washington,EPA/600/1-76^020.DC: CommitteeAvailableon Medicalfrom: and 14 NTIS, Springfield, VA; PB-253196/0. 16 Patil, L. R. S.; Smith, R. G.; Vorwald, A J.; Mooney, T. F., Jr. (1970) The health of diaphragm cell workers 17 ' exposed to chlorine. Am. Ind. Hyg. Assoc. J. 31: 678-686. 1918 Pendergrass, J. A (1964) An air monitoring program in achlorine plant Am. Ind. Hyg. Assoc. J. 25: 492-495. 2021 Potter, A E. (1978) Environmental effects ofthe space shuttle. J. Environ. Sci. 21: 15-21. 2223 Prather, M. J.; McElroy, M. B.; Wofey, S. C. (1984) Reductions in ozone at high concentrations of stratosphenc 24 halogens. Nature (London) 312: 227-231. 25 26 \ Reisch Mr377»881JIfcD'l0^h«iii^ 27 28 Reisch, M. S. (1989) Top 50 chemicals production reaches record high. Chem. Eng. News 67: 11-14. 2930 Rollins, R.; Homolya, J. B. (1979) Measurement of gaseous hydrogen chloride emissions from municipal refuse 31 energy recovery systems in the United States. Environ. Sci. Technol. 13: 1380-1383. 33 Sebacher, D. I.; Bendma, R. J.; Wornom, D. E. (1980) Hydrochloric acid aerosol and Pf^>9*°f* 34 chloride partitioning in acloud contaminated by solid rocket exhaust Atmos. Environ. 14: -543-547. 36 Simmons. J. A.; Erdmann, R. C; Naft, B. N. (1974) The risk of catastrophic spills of toxic chemicals. U>s 37 Angeles, CA: University of California School of Engineering and Applied Science; report no. UCLA- 38 ENG-7425. 4039 Sollars, W. F. (1961) Chloride content of cake flours and flour fractions. Cereal Chem. 38: 487-500. 4142 SRI International. (1986) Directory of chemical procedures, USA, 1986. Menlo Park, CA: SRI Inteniational;«i 43 pp. 547, 714, 715. 45 Symons. J. M.; Bellar, T. A; CarsweU, J. K.; DeMarco, J.; Kropp, K. L.; Robeck, G. G.; Seeger, D. R.; 46 Slocum, C. J.; Smith, B. L.; Stevens, AA (1975) National organics reconnaissance survey for 47 halogenated organics. J. Am. Water Works Assoc. 67: 634-647. 49 World Health Organization. (1982) Chlorine and hydrogen chloride. Geneva, Switzerland: World Health 50 Organization. (Environmental health criteria 21).

August 1990 3-W DRAFT - DO NOT QUOTE OR CTTE i 4. ENVIRONMENTAL FATE AND 2 ECOLOGICAL EFFECTS

3

4 5 4.1 ENVIRONMENTAL FATE

6 4.1.1 Chlorine 7 When liquid chlorine, which is stored under high pressure and at a temperature above its 8 boiling point, is released instantaneously intothe atmosphere, there is flash evaporation until 9 the liquid has cooled to -34°C, where the vapor pressure is 1 arm. Simmons et al. (1974) 10 presented a graph ofthe percent ofliquid chlorine flashed at temperatures between -30°F and 11 170°F. About 12.5 and 20 percent ofthe liquid flashes at 40°F (4°Q and 80°F (27°C), 12 respectively. Subsequent to this flashing, there is vaporization at a rate dependent on heat 13 absorption. They reported thatthe rate ofvaporization of liquid chlorine from a flat surface 14 in sunlight was 5 to 6 lb/ft^/hour. Since chlorine is aheavy gas (density = 1.5) it has been 15 found to move laterally and fails to disperse from low-lying areas. 16 The atmospheric chemistry of chlorine was reviewed by Sebacher et al. (1980). The 17 following reactions were presented:

18

19 (A <475 nm) 20 1. Cl2 + hv —> 2C1» 21 22 2. CI. + CH4 —> HCH3» + HC1 23 24 3. a. + OH —> O. + HC1 25 26 4. a. + HjO —> H02» +HC1 27 28 5. a. + CH20 —> HCO» +HC1 29

30 31 Photodissociation (reaction 1) is rapid in the lower atmosphereand troposphere. 32 Reaction 2 is the main reaction that produces hydrogen chloride. The photoexdtationrateof 33 chlorine wasestimated by Zafiriou (1974) to be 0.0027 quanta/molecule/second, and this

August 1990 4-1 DRAFT - DO NOT QUOTE OR CITE 1 indicates that in sunlight, molecular chlorine isnot the principal species of the gaseous 2 element and the chlorine present inambient air isnot elemental diatomic chlorine. 3 Prather etal. (1984) expressed concern that an increase of "inorganic chlorine" in the 4 stratosphere to levels comparable to that ofreactive nitrogen (NOx) could result in reduction 5 of ozone levels in the lower stratosphere (20 to 30 km). Inorganic chlorine consists of [Cl»], / 6 [C10»], [C1N03], [HOCI], and [HC1]. The major source ofthese species would be expected 7 to be CFCI3, CF2C12, CC14, and CH3CC13, and not chlorine gas. 8 If chlorine is released into water it is expected that much of it will eventually find its 9 way into the atmosphere. The Bureau ofMines (Murphy et al., 1970) carried out studies in 10 which liquid chlorine (5 or 10 gallons) was spilled on the surface ofapond and gaseous or 11 liquid chlorine was released underwater, and evaporation and atmospheric dispersion were 12 followed. When 5 gallons was released under 4 feet of water, the denser chlorine was 13 buoyed up by the vapor generated by reaction at the chlorine-water interface and essentially 14 all thechlorine was released to theatmosphere. When chlorine was spilled on the surface, 15 the rate of vaporization was accelerated, possibly by facilitation of heat transfer, and 16 essentially all was vaporized. It was concluded that only in slow leakage or after small spills 17 would a significant fraction of the chlorine be solubilized in water. 18 When chlorine is used as a antifouling agent in recirculating cooling water systems of 19 power plants, there isa potential for release of free chlorine into the atmosphere. The 20 chlorine is present in the water as hypochlorous acid (HOCI). Holzwarth etal. (1984) have 21 demonstrated that 10 to 15 percent of the HOCI isvolatilized from a cooling tower oneach 22 passage. Since the uncharged species (HOCI) is volatile whereas the ion OCT is not, the 23 "flashoff" of free chlorine is markedly dependent onthepH of thewater and would be 10 24 times faster at pH 6.0 than at pH 8.5. 25 In aqueous environments, chlorine occurs as elemental chlorine, hypochlorous acid, and 26 hypochlorite ion. However, the fate ofchlorine in natural waters is not well defined. The 27 primary chemical reactions of chlorine in salt water and fresh water are illustrated in 28 Figure 4-1 and a more detailed illustration of the reactions involving chlorine and chlorinated 29 compounds in the aquatic environment is given inFigure 4-2. Factors such as reactant 30 concentrations, pH, temperature, salinity, and exposure tolight control the extent of these 31 reactions (Jolley and Carpenter, 1983).

August 1990 4-2 DRAFT - DO NOT QUOTE OR CITE 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28 29 Figure 4-1.Schematic outline of chemical reactions in freshwater, estuarine, and marine 30 waters. 31 32 Source: Sugam and Helz (1980) 33

August 1990 4-3 DRAFT - DO NOT QUOTE ORCITE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 4039 Figure 4-2. Principal chemical pathways for reaction, degradation, and environmental 41 fate of free chlorine in the aquatic environment. PResumed pathways (not 42 yet proven) are shown by dashed arrows. Compounds formed at different 43 places in the reaction scheme are depicted with superscripts aand bto assist 44 in understands interrelationships. Halides (CI and Br) are not depicted but 45 are products of many ofthe chemical pathways. 46 47 Source: Sugam andHelz (1980) August 1990 4-4 DRAFT - DO NOT QUOTE OR CITE 1 4.1.2 Hydrogen Chloride 2 Hydrogen chloride canbe removed from the atmosphere by the reaction HC1 + 3 OH» •„ . > H20 + CU. However, the concentration ofOH» in the troposphere and 4 stratosphere is low, which leads to a relatively long residence time for hydrogen chloride 5 (Sebacher et al., 1980). Becauseofits solubility in water, it would be expected that 6 hydrogen chloride will be absorbed in aqueous aerosols and be removed from the troposphere 7 by rainfall. It is also expected thatits deposition velocity wouldbe at least as high as thatof 8 sulfur dioxide, which is on the order of 1 cm/second (Cocks and McElroy, 1984). Potter 9 (1978) and Pellettet al. (1983) reported incidences involving acid rain from hydrogen 10 chloride emitted in exhaust during solid rocket firing. The amount of hydrogen chloride 11 generated by the ammonium perchlorate propellant in launching a space shuttle is 12 approximately 35,200 kg. This could result in rain of pH < 1.0 at a distance of4 to 19 13 miles, depending on meteorologic conditions (Potter, 1978). Sebacher et al. (1980) measured 14 the partitioning of HC1 between gaseous hydrogen chloride and hydrochloric acid aerosol in a 15 tropospheric cloud contaminated by exhaust from launching ofa Titan m rocket. The 16 monitoring devices were capable of monitoring total airborne hydrogen chloride and airborne 17 gaseous hydrogen chloride. An aircraft with sampling and measuring equipment passed 18 through a ground cloud containing the rocket exhaust and measured gaseous and total HC1 at 19 several intervals (2 to 5 minutes apart) from about4 to 40 minutes postlaunch. The peak total 20 HC1 (gas plus aerosol) concentration was 15 ppm onthe first pass; its decrease to about 2.4 21 ppm by the sixth pass indicates therapidity of dilution with the surrounding atmosphere. 22 Aerosol hydrochloric acid was several times higher than gaseous hydrogen chloride during the 23 first pass. Relative humidity greater than 90 percent and temperatures below 20°C favored the 24 formation of aerosol hydrochloric acid. The measurements agreed with values predicted from

25 calculations. 26 More recent work by the National Aeronautics and Space Administration (NASA) 27 (Cofer et al., 1985) measured HC1 in aerosol/gas from space shuttle launchings. 28 Concentrations of HC1 in the exhaust cloud were as high as 40 ppm and decreased about an 29 order of magnitude in an hour. Early after the launch most hydrogen chloride was in the 30 aqueous phase. However, within 40to 60 minutes, the amount of gaseous HG exceeded that 31 in theaqueous phase. This was due to evaporation from theaerosol as well as a measured

August 1990 4-5 DRAFT - DO NOT QUOTE ORCITE 1 increase in hydrogen chloride in larger particles, which suggests extensive aerosol fallout 2 Prevailing meteorology will strongly determine the fate ofhydrogen chloride in the 3 atmosphere. 4 No information was found on the fate of hydrochloric acid spilled into the ocean or 5 ponds or entering the soil. If hydrogen chloride is spilled into the ocean, however, it would 6 be rapidly diluted and would no longer be a strong acid. Hydrochloric acid spilled on soil 7 might find its way into groundwater, but there would be extensive evaporation atthe surface, 8 and as hydrochloric acid percolated through the soil itwould be neutralized to some extent by

9 carbonates in the soil.

10

11 12 4.2 ECOLOGICAL EFFECTS

13 4.2.1 Chlorine 14 Theextensive useof chlorine as a biocide in 335 of 550 steam electric generating plants 15 that use once-through cooling systems has yielded substantial information on the toxicity of 16 chlorine to aquatic organisms (U. S. Enviretnhental Protection Agency, 1980). Many aquatic 17 organisms, particularly larval and other planktonic forms, are entrained in cooling water 18 systems and other cMorine-containing effluents, where they are exposed to various 19 combinations of stressors. 20 The toxicity ofchlorine to aquatic organisms depends mainly on three environmental 21 factors: temperature, exposuretime, and available form of chlorine or other halogen 22 compounds (Capuzzo etal., 1977). The assessment ofchlorine toxicity to freshwater and 23 marine organisms is very complex because ofthe complex chemistry ofchlorine inwater. 24 The particular halogen compound formed during seawater chlorination, for example, varies 25 with the relative levels of bromide, organic matter, ammonia, and other nitrogenous 26 compounds. 27 Chlorine added to seawater may remain in a free form (HOCI or OC17) or combine with 28 residual ammonium ions and organic matter, yielding mono-, di-, and trichloramines or 29 organochlorine compounds (Capuzzo etal., 1977). Chlorine generally decays rapidly (in 30 minutes or hours) to lower residual levels. Typically, the toxicant effect is measured as total 31 residual chlorine (TRQ or thesum of the concentrations of free and combined residuals,

August 1990 4-6 DRAFT - DO NOT QUOTE OR CITE 1 usually determined by amperometric titration analyses. A more detailed discussion of the 2 effects of chlorine on aquatic organisms is addressed in the Ambient Water Criteria Document 3 for Chlorine - 1984 (U. S. Environmental Protection Agency, 1985).

4

5 4.2.1.1 Fish 6 The acute toxicity ofchlorine to marineand freshwater fishes is summarized in 7 Table 4-1. Median lethal levels range from 0.037 to less than 0.65 mg/L TRC. There is • 8 little apparentdifference in toxicity between marine and freshwater fish. 9 Other trends in fish toxicity are apparent for some species. Toxicity sometimes 10 increases with ambient temperature as wellas duration and pattern ofexposure. Toxicity is 11 often lower during the egg stage and then increases during larval development 12 (e.g., metamorphosis in striped bass). Age-related trends, however, in chlorine tolerance are 13 not consistent for all species. Some fish show increasing toxicity, others show decreasing 14 toxicity, and still others show no trend in toxicity with age; this may be an artifact of the 15 specificages studied (Hall et al., 1982, 1981).

16

17 42.12 Invertebrates 18 Chlorine is toxic to aquatic invertebrates at acute levels comparable to or lower than 19 those for fish (see Table 4-1). Of the five invertebrate species described in Table 4-1, larvae 20 of two molluscan species (oyster and clam) were substantially more sensitivethan any of the

21 fish. 22 As with some fish, the interactionof chlorine, temperature, and exposure conditions has 23 been studied for some invertebrates. Hall et al. (1979a) exposed the blue crab and grass 24 shrimpto TRC levels of 0.00, 0.15, and 0.30 mg/L at 2, 6, or 10°C above ambient 25 temperatures for 0.08, 2.0, and 4.0 hours, respectively. Mortality in the shrimpincreased 26 with increased chlorine level, temperature, and exposure duration; the blue crab did not

27 exhibit a similar effect.

28

29 4.2.1.3 Plants 30 The only toxicity data for aquatic vascular plantswere for Myriophyllwn spicatum 31 (Eurasian water milfoil). Continuous exposure of plantsto concentrations as low as 0.05

August 1990 4-7 DRAFT - DO NOTQUOTE OR CITE Tabic V-/ shoJJbc f^M

1 mg/L TRC resulted in a 30 percent reduction in dryweight of shoots and total biomass and a 2 16percent reduction in shoot length when compared with controls. At a concentration of 3 0.1 mg/L, chlorophyll levels were reduced 25percent. Plants exposed intermittently for three 4 two-hour periods daily for 96 hours were more resistant to chlorine, showing no lethality at 5 concentrations below 1 mg/L (Watkins and Hammerschlag, 1984). 6 Phytoplankton (floating algae) may be more sensitive to chlorine than M. spicatum. 1 Watkins and Hammerschlag (1984) cited studies withphytoplankton showing 50 percent 8 inhibition of radiolabeled dioxide uptake at chlorinelevels as low as 0.01 mg/L and 9 inhibition of nitrate uptake at chlorinelevelsof 0.03 mg/L.

10

August 1990 4-8 DRAFT - DO NOTQUOTE OR CTTE 1 TABLE 4-1. THE ACUTE TOXICITY OF CHLORINE TO FISH 2 AND AQUATIC INVERTEBRATES 3 4 5 Exposure 6 Median lethal conditions, Reference 7 Organism level, mg/L TRC* hour 8 9 10 FISH - MARINE and ESTUARINE 11 Alosa aestivalis 12 (Blueback herring) Morgan and Prince (1977) 13 egg 0.33 80 Morgan and Prince (1977) 14 2 day larvae 0.25 48 15 Stoberetal. (1980) 16 Cymatogaster aggregata 0.23 TROb lat20°C 17 (Shiner perch, 1-3 mo) 0.31 1 at 13°C 18 Capuzzo et al. (1977) 19 Fundulus heterocUms <0.65 0.5 at 25°C Capuzzo et al. (1977) 20 (Killifish, juvenile) <0.25 0.5 at 30°C 21 Roberts et al. (1975) 22 Gobiosoma bosci 0.08 96 23 (Naked goby) 24 Middaugh et al. (1980) 25 Leiostomus xanthurus 0.13 CPOc 6 26 (Spot, juvenile) 0.37 1.5 27 28 Menidia beryllina 29 (Tidewater silversides) egg(2 to 24 hours old) 0.21-0.32 48 Morgan and Prince (1977) 30 Morgan and Prince (1977) 31 egg (2 to 3 hours old) 0.23-0.26 24 32 33 Menidia menidia 34 (Atlantic silversides) 48 Morgan andPrince (1977) 35 egg 0.30 Roberts et al. (1975) 36 juvenile 0.037 96 37 38 Morone americana (White perch) 39 Morgan andPrince (1977) egg 0.27 76 40 Morgan andPrince (1977) 41 larvae 0.31 24 Hall etal. (1979b) 42 25 day larvae 0.25 (46% died) 4 Halletal. (1979b) 43 0.20 (41% died) 4 Hall etal. (1979b) 44 0.28 (21% died) 1 45 Morone saxatilis (Striped bass) 46 Morgan andPrince (1977) 47 egg (> 40 hours old) 0.36 24 egg(<40 hours old) 0.20-0.22 48 Morgan and Prince (1977) 48 Morgan and Prince (1977) 49 1 to 3 day larvae 0.2 24 Hall etal. (1982) 50 22 day larvae 0.14 96 Halletal. (1982) 51 60 day juveniles 0.19 96 Hall etal. (1982) 52 388 day juveniles 0.23 96 53 (continued on the following page) 54

August 1990 4-9 DRAFT-DO NOT QUOTEOR CITE 1 TABLE 4-1 (can't). THE ACUTE TOXICIlY OF CHLORINE1 TO FISH 2 AND AQUATIC INVERTEBRATES 3 4

. 5 Exposure 6 Median lethal conditions, 7 Organism level, mg/L TRC8 hour Reference g w 9 10 FISH - MARINE and ESTUARINE (continued) i 4 11 Stoberetal. (1980) 12 Oncorhynchus Jdsusdi 0.13 TRO lat20°C Stoberetal. (1980) 13 (Coho salmon, 1 yr) 0.21 1 at 13°C 14 15 16 Pseudopleuronectes americanus 17 (Winter flounder, juvenile) 0.55 0.5 Capuzzo et al. (1977) 18 (100% died) 19 20 Stenotomus versicolor Capuzzo et al. (1977) 21 (Scup, juvenile) 0.65 0.5 22 (100% died) 23 Roberts et al. (1975) 24 Syngnathusjuscus 0.27 96 25 (Northern pipefish) 26 27 FISH - FRESHWATER 28 29 Lepomis macrochirus Wilde et al. (1983) 30 (Bluegill, young) 0.44 96 31 32 Pimephales promelas 33 (Fathead minnow) 34 juvenile 0.08 96 Wilde et al. (1983) Wilde etal. (1983) 35 adult 0.35 96 36 Mattice et al. (1981) 37 Gambusiaaffinis 1.59 0.5 Mattice et al. (1981) 38 (Mosquito fish) 0.84 1 39 40 INVERTEBRATE - MARINE 41 42 Acartia tonsa • Roberts etal. (1975) 43 (Copepod) <0.05 48 44 45 Callinectes sapidus Halletal. (1979a) 46 (Blue crab, juvenile) >0.30 -d 47 48 Crassostrea virginica Roberts etal. (1975) 49 (Oyster, larvae) <0.005 48 50 51 Mercenaria mercenaria Roberts et al. (1975) 52 (Hard clam, larvae) <0.005 48 53 (continued on the following page) 54

August 1990 4-10 DRAFT-- DO NOT QUOTE OR CITE 1 TABLE 4-1 (Con't). THE ACUTE TOXICITY OF CHLORINE TO FISH 2 AND AQUATIC INVERTEBRATES 3 4 5 Exposure 6 Median lethal conditions, 7 Organism level, mg/L TRC8 hour Reference 8 9 10 INVERTEBRATE - MARINE (continued) 11 .Palaemonetes pugio 12 61 13 7* (Grass shrimp) 14 unspecified age 0.22 96 Roberts et al. (1975) 15 unspecified age 0.38 24 Roberts et al. (1975) 16 adult 0.3 (53% died) 2at28°C Hall et al. (1979a) 17 adult 0.15 (43% died) 4at24°C Hall et al. (1979a) 18 19 \ INVERTEBRATE -FRESHWATER 20 21 *4 Daphnia magna 0.097 0.5 Mattice et al. (1981) 22 (Water flea) 0.063 1 Mattice et al. (1981) 23 24 25 Tests were done under continuous-flowor constant-addition conditionsusing measured 26 levels oftotal residual chlorine (TRC) unless otherwise stated. 27 TRO = Total residual oxidants. 28 «CPO »= Total chlorine-produced oxidants. 29 Data not available. 30 31 32 33 4.2.2 Hydrogen Chloride (Hydrochloric Acid)

34 4.2.2.1 Aquatic Organisms.

35 The toxic effects of hydrochloric acid on aquatic organisms are due to the acid's effect

36 on hydrogen ion concentration (Rose et al., 1977). Aquatic organisms in their natural

37 environments often exhibit a broad range ofpH tolerance. DeGraeve et al. (1979), for

38 example, concluded that aquatic organismsgenerallyexhibit no deleterious effects at a pH

39 range of 6 to 9. For freshwater fish, few adultsare harmed directly at pH 5 to 9, but

40 increases in acidity or alkalinity within this pH range may raise the toxicity ofvarious

41 common pollutants (European Inland Fisheries Advisory Commission, 1968). Many

42 freshwater organisms show no deleterious effects at pH 3 to 4 or 10 to 11. Acidification of

43 natural streams and lakes due to acid rain is particularly significant in waters that are poorly

44 buffered.

August 1990 4-11 DRAFT - DO NOT QUOTE OR CITE 1 In marine waters, the pH varies less (generally, the pH isabout 8) because of increased 2 buffering capacity. However, there may be substantial diurnal variation, as in freshwaters, 3 where photosynthesis is rapid (DeGraeve etal., 1979).

4 5 4.2.2.2 Terrestrial Organisms. 6 Laboratory studies have shown that 20-minute exposures ofavariety ofplants to levels 7 of hydrogen chloride between 6.5 and 27.0 mg/m3 caused visible leaf injury and decreased 8 chlorophyll levels (Endress et al., 1982; Granett and Taylor, 1981; Lennan et al., 1976), 9 Field studies on 50 plant species growing near an anhydrous aluminum chloride 10 nianufacturing plant indicated that the more sensitive species were American elm, bur oak, 11 eastern white pine, basswood, red ash, and several bean species. Foliar injury ofthe more 12 sensitive species was usually associated with concentrations ofchloride ion exceeding 0.2 13 percent of whole-leaf dry weight. Hydrogen chloride-tolerant species showed no leaf toxicity 14 in spite of foliar concentrations of chloride ion up to 5percent. Both plant injury and leaf 15 chloride concentrations declined as the distance from the source increased; no effects were 16 reported beyond 300 m (Harper and Jones, 1982).

August 1990 4-12 DRAFT - DO NOT QUOTE OR CITE 4.3 REFERENCES

3 Capuzzo, J. M.; Davidson, J. A.; Lawrence, S. A.; Libni, M. (1977) The differential effectsof fineand 4 combined chlorine on juvenile marine fish. Estuarine Coastal Mar. Sci. 5: 733-741. 5 6 Cocks, A. T.; McElroy, W. J. (1984) Theabsorption of hydrogen chloride by aqueous aerosols. Atmos. 7 Environ. 18: 1471-1483. 8 9 Cofer, W. R., HI; Bendura, R. J.; Sebacher, D. I.; Pellett, G. L.; Gregory, G. L.; Maddrea, G. L., Jr. (1985) 10 Airborne measurements ofspace shuttle exhaust constituents. AIAA J. 23: 283-287. 11 12 DeGraeve, G. M.; Blogoslawski, W. J.; Brungs, W. A.; Fava, J. A.; Finlayson, B. J.; Frost, T. P.; Krischan, 13 T. M.; Melanin, J. W.; Michaud, D. T.; Nakatani, R. E.; Seegert, G. L. (1979) Chlorine. In: Thurston, 14 R. V.; Russo, R. C; Fetterolf, C. M., Jr.; Edsall, T. A.; Barber, Y. M., Jr., eds. A reviewofthe EPA 15 rcdbook: quality criteria for water. Bethesda, MD: American Fisheries Society; pp. 67-75. 16 17 Endress, A. G.; Suarez, S. J.; Taylor, O. C. (1982) Photosynthetic and respiratory consequences of hydrogen 18 chloride gas exposures of Phaseolus vulgaris L. and Spinacea oleracea L. Environ. Pollut. Ser. A 29: 13- 19 26. 20 21 Environment Canada. (1984) Chlorine: environmental and technical information for problem spills. Ottawa, 22 Canada: Environmental Protection Service, Technical Services Branch (EnviroTIPS manual). 23 24 European Inland Fisheries Advisory Commission. (1968) Water quality criteria for European freshwater fish: 25 report on extreme pH values and inland fisheries. Rome, : Food and Agriculture Organization of the 26 United Nations; EIFAC technical paper no. 4. 27 28 Federal Register. (1980) Effluent limitations guidelines, pretreatment standards and new source performance 29 standards under Clean Water Act; steam electric power generating point source category. F. R. (October 30 14)45: 68328-68356. 31 32 Granett, A. L.; Taylor, O. C. (1981) Diumal and seasonal changes insensitivity of plants to short exposures of 33 hydrogen chloride gas. Agric. Environ. 6: 33-42. 34 35 Gudiksen, P.; Dickerson, M.; Chan, S.; Morris, L.; Ermak, D.; Brown, M.; Perry, J.; Vonada, M.; Robinson, 36 L. (1986) Emergency response planning for potential accidental liquid chlorine releases. Iivermore, CA: 37 Lawrence Iivermore National Laboratory; UCRL-53685. Available from: NTIS, Springfield, VA; DE86- 38 013168. 39 40 Hall, L. W., Jr.; Burton, D. T.; Margrey, S. L. (1979a) Chlorine, temperature, and exposure duration effects of 41 power plant effluents on juvenile blue crabs CaUinectes sapidus and grass shrimp Palaemonetes pugio, J. 42 Toxicol. Environ. Health 5:749-757. \ 43 44 Hall, L. W., Jr.; Burton, D. T.; Margrey, S. L. (1979b) The effects of chlorine, elevated temperature and 45 exposure duration of power plant effluents onlarval white perch Morone americana (Gmelin). Water 46 Resour. Bull. 15: 1365-1373. 47 48 Hall, L. W., Jr.; Burton, D. T.; Richardson, L. B. (1981) Comparison of ozone and chlorine toxicity tothe 49 developmental stages of striped bass, Morone saxatilis. Can. J. Fish. Aquat. Sci. 38: 752-757. 50 51 Hall, L. W., Jr.; Graves, W. C; Burton, D. T.; Margrey, S. L.; Hetrick, F. M.; Roberson, B. S. (1982) A 52 comparison of chlorine toxicity to three life stages of striped bass (Morone saxatilis). Bull. Environ. 53 Contain. Toxicol. 29:631-636. /\

August 1990 4-13 DRAFT - DO NOT QUOTE OR CITE 1 Harper, D. S.; Jones, R. D. (1982) The relative sensitivity of fifty plant species to chronic doses of hydrogen 2 chloride. Phytopathology 72: 261-262. 3 4 Holzwarth, G.; Balmer, R. G.; Soni, L. (1984) The rate ofchlorine and chloramines in cooling towers: Henry's 5 law constants for flashoff. Water Res. 18: 1421-1427. 7 Jolley, R. L.; Carpenter, J. H. (1983) Areview of the chemistry and environmental fate of reactive oxidant 8 ' species in chlorinated water. In: Jolley, R. L.; Brungs, W. A.; Cotruvo, J. A.; Dimming, R. B.; 9 Mattice, J. S.; Jacobs, V. A., eds. Water chlorination: environmental impact and health effects, volume 10 4, book 1, chemistry and water treatment, proceedings ofthe fourth conference; October 1981; Pacific \\ (hove, CA. Ann Arbor, MI: Ann Arbor Science Publishers, Inc.; pp. 3-47. 1312 Lane, D. A.; Thomson, B. A. (1981) Monitoring achlorine spill from atrain derailment J. Air Pollut Control 14 ' Assoc. 31: 122-127. 16 Lerman, S.; Taylor, O. C; Darley, E. F. (1976) Phytotoxicity ofhydrogen chloride gas with ashort-term 17 exposure. Atmos. Environ. 10: 873-878. 1819 Mattice, J. S.; Burch, M. B.; Tsai, S. C; Roy, W. K. (1981) Atoxicity testing system for exposing small 20 invertebrates and fish to short square-wave concentrations ofchlorine. Water Res. 15: 923-927. 2221 Middaugh, D. P.; Burnett, L. E.; Couch, J. A. (1980) Toxicological and physiological responses of the fish, 23 Leiostomus xanthurus, exposed to chlorine produced oxidants. Estuaries 3: 132-141. 2425 Morgan, R. P., II; Prince* R. D. (1977) Chlorine toxicity to eggs and larvae of five Chesapeake Bay fishes. 26 Trans. Am. Fish. Soc. 106: 380-385. 2728 Murphy, J. N.; Burgess, D. S.; Harris, M. E.; Lang, H.; Mattes, R.; Grainger, H.; Slomski, W. B.; Albaugh, 29 w. (1970) Hazards ofmarine transportation of liquid chlorine. Pittsburgh, PA: U. S. Department of the 30 Interior, Bureau ofMines; PMSRC report no. S-4158. Available from: NTIS, Springfield, VA; 3231 Pellett, G. L.; Sebacher, D. I.; Bendura, R. J.; Woroom, D. E. (1983) HC1 in rocket exhaust clouds: 33 *atmospheric dispersion, acid aerosol characteristics, and acid rain deposition. J. Air. Pollut Control 34 Assoc. 33: 304-311. 3536 Potter, A. E. (1978) Environmental effects ofthe space shuttle. J. Environ. Sci. 21: 15-21. 3738 Prather, M. J.; McElroy, M. B.; Wofsy, S. C. (1984) Reductions in ozone at high concentrations of stratosphenc 39 halogens. Nature (London) 312: 227-231. 41 Roberts, M. H., Jr.; Diaz, R. J.; Bender, M. E.; Huggett, R. J. (1975) Acute toxicity of chlorine to selected 42 estuarine species. J. Fish. Res. Board Can. 32: 2525-2528. 44 Rose C. D.; Williams, W. G.; Hollister, T. A.; Parrish, P. R. (1977) Method for detennining acute toxicity of 45 * an acid waste and limiting permissible conc^tra&OT at bounces ofan oceam^ 46 Sci. Technol. 11: 367-371. 48An Sebacher, D. I.; Bendura, R. J.; Womom, D. E. (1980) Hydrochloric acid aerosol and S^™^d^f* 49 chloride partitioning in acloud contaminated by solid rocket exhaust Atmos. Environ. 14: 543-547. 51 Simmons, J. A.; Erdmann, R. C; Naft, B. N. (1974) The risk of catastrophic spills of toxic chemicals. Lj* 52 Angeles, CA: University ofCalifornia School ofEngineering and Applied Science; report no. UCLA- 53 ENG-7425. 54 August 1990 4-14 DRAFT - DO NOT QUOTE OR CITE 1 Stober, Q. J.; Dinnel, P. A.; Hurlburt, E. F.; DiJulio, D. H. (1980) Acutetoxicity and behavioral responses of 2 coho salmon (Oncorhynchus kisutch) and shinerperch (Cymatogaster aggregata) to chlorinein heated sea- 3 water. Water Res. 14: 347-354. 4 5 Sugam, R.; Helz, G. R. (1980) Seawater chlorination: a description of chemical speciation. In: Jolley, R. L.; 6 Brungs, W. A.; Cranmmg, R. B.; Jacobs, V. A., eds. Water chlorination: environmental impact and 7 health effects, volume 3, proceedings ofthe third conference; October-November 1979; Colorado 8 Springs, CO. Ann Arbor, MI: Ann Arbor Science Publishers, Inc.; pp. 427-433. 9 10 U. S. Environmental Protection Agency. (1985) Ambient waterquality criteria for chlorine - 1984. Washington, 11 DC: Office ofWater Regulations and Standards, Criteria and Standards Division; EPA reportno. EPA. 12 440/5-84-030. Available from: NTIS, Springfield, VA; PB85-227429. 13 14 Watkins, C. H.; Hammerschlag, R. S. (1984) The toxicity ofchlorineto a common vascularaquaticplant Water 15 Res. 18: 1037-1043. 16 17 Wilde, E. W.; Soracco, R. J.; Mayack, L. A.; Shealy, R. L.; Broadwell, T. L.; Steffen, R. F. (1983) 18 Comparison ofchlorine and chlorine dioxide toxicity to fathead minnows andbluegill. Water Res. 17: 19 1327-1331. 20 21 Zafiriou, O. C. (1974) Photochemistry ofhalogens in the marine atmosphere. JGR J. Geophys. Res. 79: 2730- 22 2732.

August 1990 4-15 DRAFT - DO NOT QUOTE OR CITE 5. PHARMACOKINETICS AND MECHANISM OF ACTION

1 2 5.1 PHARMACOKINETICS AND METABOLISM 3 The respiratory pharmacokinetics of chlorine and hydrogen chloride has not been 4 thoroughly examined. There are data which suggest that these compounds or their reaction 5 products are absorbed from the respiratory tract bythe finding of liver and/or kidney effects 6 inanimals exposed to high levels of both compounds. However, these effects may have been 7 the resultofa disturbance in the acid-base metabolism or a decrease in blood oxygen levels 8 due to excessive pulmonary damage. Under normal breathing of low levels of chlorine or 9 hydrogen chloride, there is no evidence which suggest that much of either compound enters 10 the bloodstream (see chapter 6). 11 No information has been found addressing the oral pharmacokinetics of chlorineand 12 hydrogen chloride. There is a limited amount of information addressing the oral 13 pharmacokinetics of chlorine(related compounds (derived from water chlorination) which 14 demonstrates that these compounds are absorbed from the gastrointestinal tract. Once 15 absorbed, the chlorine molecule apparently reacts withorganic molecules in the bodyto 16 produce awide variety of chlorinated compounds. Chlorine is eliminated via urine and feces 17 as the chloride ion (Abel-Rahman et al., 1983;(^^^floaan^is?^^; Mink et al., 18 1983). A* Ounf *>hi%

19

20 21 5.2 MECHANISM OF ACTION AND BIOCHEMICAL EFFECTS

22 5.2.1 Chlorine 23 Several theories have been proposed on the mechanism ofchlorine's toxicity. One 24 theory suggests that at physiologic pH (pH range of6 to 8), chlorine reacts with water from 25 moist tissue, forming hypochlorous acid (HCIO) and hydrochloric acid (HC1). The 26 hypochlorous acid isvery reactive and rapidly dissipates, liberating hydrochloric acid and 27 nascent oxygen (C^ + HjO, > 2HC1 + O) (Kramer, 1967; World Health Organization, 28 1982; Colardyn et al., 1976). The major portion of the damage to tissues would then be 29 caused by the potent oxidizing action of the nascent oxygen, which isa strong protoplasmic a\\c\ + or*) August 1990 5-1 DRAFT - DO NOT QUOTE OR CITE 1 poison (Adelson and Kaufman, 1971; Colardyn et al., 1976). Superimposed on the primary 2 trauma is the secondary irritation produced by the hydrochloric acid (Adelson and Kaufman, 3 1971). 4 Another theory suggests that since chlorine is a more potent sensory irritant than 5 hypochloric acid, the observed response is due to hypochlorous acid (Barrow et al., 1977). 6 The hypochlorous acid penetrates thecell and forms N-chloro derivatives withamino groups 7 of proteins, which damages cell structure (National Research Council, 1976). 8 Hypochlorous acid hasbeen shown to inhibit enzymatic reactions in living cells. Pereira 9 et al. (1973) demonstrated that hypochlorous acid can convert several aminoacids into a 10 mixtureof corresponding nitriles and aldehydes. It has been theorized thatthe chlorine 11 irreversibly inhibits glucose metabolism at the point of thiosephosphoric acid oxidation to 12 phosphoglyceric acid (Green and Stumpf, 1946) and that the inhibition of glucose metabolism 13 was the result ofchlorine reacting with sulfhydryl groups (Knox et al., 1948). However, 14 Dodd et al. (1980) did not find an effect on lung total protein or nonprotein sulfhydryl levels 15 in rats exposed to 12 ppm (35 mg/m3) chlorine (6 hours aday for 1, 5, or 10 days) during 16 the exposure period. In a more recent study, McNulty et al. (1983) found a decrease in total 17 sulfhydryl content in the respiratory tract mucosa but notthe olfactory nasal mucosa ofrats 18 exposed to 5 or 10 ppm (14.5 or 29 mg/m3) chlorine for 6hours. Furthermore, experi- 19 mental work with viruses has indicated that compounds which have an effect on sulfhydryl 20 groups arenot alwaysvirucidal (National Research Council, 1976). Based on these results, it 21 is not likely thatthe oxidation of total sulfhydryl content in the lung is playing a major rolein 22 the respiratory tract toxicity ofchlorine, since the toxic effects of chlorine occur at concen- 23 trations below those required to alter sulfhydryl content. 24 It has also been demonstrated that hypochlorous acid can react with the nucleotidebases 25 ofdeoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Patton et al. (1972) found that 26 when one equivalentof hypochlorous acidwas added to cytosine, 4-N-chlorocytosine was 27 obtained. The addition of two equivalentsofhypochlorous acid to cytosine yielded a 28 precipitate identified asa mixture of 4-N-chlorocytosine and 4-N-5-dichlorocytosine. 29 Hypochlorous acid hasbeen reported to form labile intermediates and stable end products 30 when reacted with purine and pyrimidine bases (Hoyano et al., 1973).

31

August 1990 5-2 DRAFT- DO NOT QUOTE OR CITE 1 5.2.2 Hydrogen Chloride 2 The mechanismofhydrogen chloride'stoxicity hasbeen described in two parts: 3 molecular and elementary biochemical effects and disturbed function. In water, hydrogen 4 chloride dissociates almost completely, yielding hydronium and chlorine ions (HCx + H20 5 _•"___> H30 + CI). The hydronium ion donates aproton with catalytic properties capable of 6 cleaving organic molecules (World Health Organization, 1982). It has also suggested that the 7 hydrolysis of peptides and esters plays a significant role in the injury produced by hydronium 8 ions since they are components of the cell wall. Other reactions produced by the hydronium 9 ion include hydroxylation of carbonyl groups and polymerization and depolymerization of 10 organic molecules. Once the cell wall has been damaged, the cell may be depleted of 11 cytoplasmic components and die (National Research Council, 1976). 12 The most serious functional effect of hydrogen chloride exposure is cell death. 13 However, erythema and edema precede cellular death. Histologically, changes in 14 permeability and liquid transport across the cellular membrane are associated with injury of 15 the alveolar epithelium and endothelial cells (National Research Council, 1976).

August 1990 5-3 DRAFT - DO NOT QUOTE OR CITE 5.3 REFERENCES

3 Abdel-Rahman, M. S.; Berardi, M. R.; Bull, R. J. (1982) Effect ofchlorine and monochloramine in drinking 4 wateron the developing rat fetus. JAT J. Appl. Toxicol. 2: 156-159. 5 6 Abdel-Rahman, M. S.; Waldron, D. M.; Bull, R. J. (1983) A comparative kinetics study ofmonochloramine and 7 hypochlorous acid in rat JAT J. Appl.Toxicol. 3: 175-179. 8 9 Adelson, L.; Kaufman, J. (1971) Fatal chlorine poisoning: report oftwo cases with clinicopathologic correlation. 10 Am. J. Clin. Pathol. 56: 430-442. 11 12 Barrow, C. S.; Alarie, Y.; Warrick, J. C; Stock, M. F. (1977) Comparison ofthe sensory irritation response in 13 miceto chlorine andhydrogen chloride. Arch. Environ. Health .32: 68-76. 14 fa 15 Colardyn, F.; vanderStraeten, M.; Tasson, J.; van Egmond, J. (1976) Acutechlorine gas intoxication. Acta 16 Clin. Belg. 31: 70-77. 17 18 Dodd, D. E.; Bus, J. S.; Barrow, C. S. (1980) Lung sulfhydryl changes in rats following chlorine inhalation. 19 Toxicol. Appl. Pharmacol. 52: 199-208. 20 21 Green, D. E.; Stumpf, P. K. (1946) Hie modeof action of chlorine. J. Am. Water Works Assoc. 38: 1301- 22 1305. 23 24 Hoyano, Y.; Bacon, V.; Summons, R. E.; Pereira, W. E.; Halpeen, B.; Duffield, A. M. (1973) Chlorintaion 25 studies. IV. The reaction ofaqueous hypochlorous acid with pyrimidine and pyrine cases. Biochem. 26 Biophys. Res. Comm. 53: 1195-1199. 27 28 Knox, W. E.; Stumpf, P. K.; Green, D. E.; Auerbach, V. H. 0948)The inhibition of sulfhydryl enzymes as the 29 basis of bactericidal action of chlorine. J. Bacterial. Is 55: 451-458. 30 ^ 31 Kramer, C. G. (1967) Chlorine. JOM J. Occup. Med. 9: 193-196. 32 33 McNulty, M. J.; Chang, J. C. F.; Barrow, C. S.; Casanova-Schmitz, M.; Heck, H. d'A. (1983) Sulfhydryl 34 oxidation in rat nasal mucosal tissues after chlorine inhalation. Toxicol. Lett. 17: 241-246. 35 36 Mink, F. L.; Coleman, W. E.; Munch, J. W.; Kaylor, W. H.; Ringhand, H. P. (1983) In vivo formation of 37 halogenated reaction products following peroral sodium hypochlorite. Bull. Environ. Contain. Toxicol. 38 30:394-399. 4039 {v>9*r 41 National Research Council. (1976) Chlorine and hydrogen chloride. Washington, DC: Committee on Medical and 42 Biological Effects of Environmental Pollutants; EPA report no. EPA/600/1-76-020. Available from: 43 NTIS, Springfield, VA; PB-253196/0. 44 45 Pattern, W.; Bacon, V.; Duffield, A M.; Halpem, B.; Hoyano, Y.; Pereira, W.; Lederberg, J. (1972) 46 Chlorination studies. I. Thereaction of aqueous hypochlorous acid withcytosine. Biochem. Biophys. 47 Res. Commun. 48: 880-884. 48 49 Pereira, W. E.; Hoyano, Y.; Summons, R. E.; Bacon, V. A.; Duffield, A. M. (1973) Chlorination studies: II. 50 thereaction of aqueous hypochlorous acid withA-amino acids and dipeptides. Biochem. Biophys. Acta 51 313: 170-180. 52

August 1990 5-4 DRAFT - DO NOT QUOTE OR CITE 1 World Health Organization. (1982) Chlorine andhydrogen chloride. Geneva, Switzerland: World Health 2 Organization. (Environmental health criteria 21).

August 1990 5-5 DRAFT - DO NOT QUOTE OR CITE i 6. TOXICOLOGY

2

3 4 6.1 EXPERIMENTAL ANIMALS

5 6.1,1 Chlorine 6 Most ofthe experimental animal toxicity studies for chlorine evaluate the effect of 7 acute, subchronic, or chronic inhalation ofchlorine gas or aerosol. These studies indicate that 8 inhaled chlorine attacks the respiratory tract, producing irritation, pulmonary edema, and in 9 some cases death. Experimental animal studies utilizing chlorinein an aqueous medium 10 (usually as hypochlorous acid or sodium hypochlorite) not containing ammonia or other 11 nitrogen-containing compoundsor in food commodities, while limited, demonstrate that the 12 ingestion ofchlorine does not produce serious adverseeffects in animals. Cunningham 13 (1980) reported no signs of toxicity in male rats that drank water containing hypochlorite 14 (calculated as 0, 20, 40, or 80 mg/L chlorine) for 6 weeks or in guinea pigs that consumed 50 15 mg/L available chlorine for five weeks. A similar lack oftoxicity has also been reported in 16 mice that drankhighly chlorinated drinking water (Blabaum and Nichols, 1956). In a study 17 designed to evaluate the effect ofconsuming chlorine-treated ground beef, Kotula et al. 18 (1987) fed rats ground beef containing 0, 50, 200, or 600 ppm chlorine for 92 days; no 19 clinical or hematological abnormalities were reported. There have, however, been several 20 reports ofincreased or decreased organ weightsin experimental animals given cake diets 21 made from chlorinated flour. Fisher et al. (1983b) reported a decrease in spleen weight in 22 female rats given the cake diet containing 0, 1,250, or 2,500 ppm available chlorine for 23 104weeks. In another study, a dose-related increase in kidney weight (males) and liver 24 weight (both sexes) was seenin rats thatconsumed the chlorinated cake containing 0, 1,257, 25 or 2,506 ppm available chlorine for 28 days (Fisher et al., 1983a). Female mice experienced 26 a dose-related increasein heart and liver weights and a decrease in uterus weight after 27 consuming the chlorinated cake diet containing either 0, 1,250, or 2,500 ppm available 28 chlorine for 73 weeks. Nonexposure-related amyloidosis involving the spleen, liver, and 29 heart was also noted in these cake-fed animals (Ginocchio et al., 1983). It was suggested that 30 the increase in organ weights may representa physiological adaptation to the nature of the 31 diet (Fisher et al., 1983a). In the long-term studies, increased mortality was reported in the

August 1990 6-1 DRAFT-DO NOT QUOTE OR CITE 1 cake-fed animals compared tocontrol animals fed a stock diet (Ginocchio etal., 1983; Fisher 2 etal., 1983b). Itisthought that this increased mortality isdue to the cake diet and not to 3 chlorine per se (Fisher et al., 1983a).

4 5 6.1.1.1 Acute Toxicity Inhalation 6 Withers and Lees (198^ have reviewed the early work conducted between 1887 and 7 1918 that examined the toxicity of chlorine in animals. The studies were conducted in 8 Germany, Britain, Russia, and France, rmmarily in response to the use ofchlorine as awar 9 gas in World War I. The authors concluded that these data are not very useful because of 10 inadequate reporting and deficiencies in experimental design. 11 Underbill (1920) summarized work done by the U.S. War Department on the toxicity of 12 chlorine, phosgene, and chloropicrin ("war gases"). Dogs were gassed with chlorine in a 13 continuous flow chamber (with some variability of flow) and sufficient dose groups (7) 14 ranging in size from 9to 23 dogs; exposure was for 30 minutes. Withers and Lees (1985) 15 have reanalyzed Underbill's data, using the Litchfield and Wilcoxon method of probits and 16 converting the concentrations of chlorine to ppm at 25°C rather than at 0°C as in the original 17 work. The LC50 was determined to be 650 ppm. Table 6-1 presents asummary of the data.

18 19 TABLE6-1. MORTALITY IN DOGS EXPOSED TO CHLORINE FOR 30 MINUTES 20 s======^ 21 22 Chlorine Number Deaths 23 concentration of within Delayed Pe"*?*?e 24 ppma(mg/m3) dogs 3days deaths mortality 25 • 2627 164 (475.6) 9 0n 1 11 28 491 (1,423.9) 17 1 * » 29 600 (1,740.0) 10 2 c • 2 30 710 (2,059.0) 21 9 5 <>7 31 819_ ftOT.1) 18 9 J 61 32 928 (2,691.2) 23 20 1 . »*• 33 „«======' —• — 34 k> 35 aValues converted from 0°C to25°C byMiners and Lees (1985). 36 37 Source: Withers and Lees (1985).

August1990 6-2 DRAFT-DO NOT QUOTOORCTTE 1 Weedon et al. (1940) exposed groups of four mice oreight rats (age, sex, and strain not 2 specified) to chlorine at levels of 16, 63, 250, or 1,000 ppm (46.4, 182.7,725.0, or 3. 2,900.0 mg/m3) for 1,4,15, 60, 240, or 960 minutes or until they died. The LC50 values in 4 mice were 1,000, 250, and 63 ppm for exposure times of53, 440 and >960 minutes, 5 respectively. These valuesare somewhat inexactbecause some animals died during exposure 6 and were scored as having been exposed for the entireperiod. 7 Table 6-2 summarizes LC50 toxicity data for chlorine in rats and mice. Schlagbauer and 8 Henschler(1967) exposed groups of 10 female NMRI mice to levels ofchlorine between 9 55.3 and 178.8 ppm (160 and 516 mg/m3) for aperiod of30 minutes. Exposure to 55.3 ppm 10 caused no deaths. The LC50 was 127 ppm(106 to 152 ppm, 95 percent confidence limit). 11 All deaths occurred byday 4. A single exposure at 10 ppm (29 mg/m3) for 3 hours caused 12 death in 8 of 10miceand for 5 hours caused death in 9 of 10mice; exposure for 3 hours at 13 22 ppm (64 mg/m3) caused 100 percent mortality within 2days. The cause ofdeath was 14 bronchial spasm and lung damage. Thirty-minute exposures to levels above 120 ppm 15 (348 mg/m3) caused an increase in the water content ofthe lung (edema). In mice that died, 16 histologic findings were necrotic injury to the tracheal mucosal membrane, desquamation of 17 theepithelium of bronchi and bronchioles, and inflammation ofthe alveolar epithelium. 18 Bitron and Aharonson (1978) exposed groups of 14 male albino mice(about onemonth 19 old) in a tight-fitting cylindrical glass chamber with an airflow of 1 L/minute. The levels of 20 exposure were 170 or 290 ppm (348 or 841 mg/m3) chlorine and the time ofexposure was 21 varied from 5 to 30 minutes at the high level and 15to 160 minutes at the lowerlevel. The 22 animals were observed for 30 days after exposure. Most deaths were delayed, occurring 23 between 5 and 10 days. The LT50 (time of exposure causing 50 percent mortality) was 24 11 minutes exposure at 290 ppm and 55 minutes at 170 ppm. All mice (28) exposed at 25 290 ppm for 6 minutes survived. Delayed deaths inmice were not found in studies by other 26 investigators. 27 Withers and Lees (198£)b utilized the data on acute toxicity ofchlorine to adjust for a 28 common exposure period of 30 minutes. The lethal load function (L) best fittmg data where 29 the concentration (C) was held constant and time (T) varied was L = C1U5. Omitting data 30 that appeared anomalous and qualifying that the result would only givea rough comparison

August 1990 6-3 DRAFT - DO NOT QUOTE OR CTTE 1 TABLE 6-2. LC«i VALUES FOR CHLORINE IN RATS AND MICE 2 3 4 Concen- Exposure Observation Acute toxicity 5 tration, time, period, value, 6 Species Strain ppm (mg/m3) minutes days ppm (mg/m) Reference 7 8 Schlagbauerand 9 Mice NMRI 55-179 30 LCjq - 127 (368) 10 (159-519) Henschler (1967) 11 Veroot et al. (1977) 12 Mice CF-1 -a 60 LCgo - 137 (397) 13 Withers and Lees 14 Mice 10 3 LC5Q « 302 (876) 15 (hours) (198# 16 Lipton and Rotariu 17 Mice 310-2,357 10 10 LC50 = 628 (1,821) (1941)c 18 (899-6,835) 19 Silver and McGrath 20 Mice 252-1,139 10 10 LCgo = 618 (1,792) (1942) 21 (731-3,303) 22 Silver et al. 23 Mice 379-890 10 10 LCjq = 676 (1,960) (1942) 24 (1,099-2,581) 25 Bitron and Aharonson 26 Mice Albino 290 11* 30 LC50 = 290 (841) (1978) 27 (841) 28 Bitron and Aharonson 29 Mice Albino 170 55l 30 LC50 = 170 (493) (1978) 30 (493) 31 LCjo o 293 (850) Veraot et al. (1977) 32 Rat£ Sprague- - 60 33 Dawley 34 35 36 aData not available. 37 ^Minutes of exposure causing 50 percent mortality (LT50). 38 cAs cited in: Withere and Lees (1985). 39 40 41 between species, they obtained LC50 values for 30-minute exposures of mice, rats, and dogs

42 of 256, 414, and 650 ppm (742, 1,201, and 1,885 mg/m3), respectively.

43 There were no adequate data on mortality in cats, rabbits, and guinea pigs exposed to

44 chlorine. Rabbits appeared to be less susceptible than mice or rats, since a30-minute

45 exposure to levels of 50,100, and 200 ppm caused no mortaHty, but range-finding studies

46 indicated death within an hour of asimilar exposure to 1,000 ppm (2,900 mg/m3) and 2days

47 after exposure to 500 ppm (1,450 mg/m3) (Barrow and Smith, 1975).

August 1990 6-4 DRAFT - DO NOT QUOTE OR CITE 1 Variability in data for LC50 values may in part bedue to the method of exposure and 2 level of activity of me animals during exposure. In the study of Bitron and Aharonson 3 (1978), mice were restrained; hence their respiratory rate would have been low and they 4 would have taken up less chlorine than it exposed in a large chamber and allowed to respond 5 to the sensory irritation. 6 Cralley (1942) studied the effect of chlorine gas onciliary activity in excised tracheal 7 preparations of rabbits. Chlorine was passed over the tissue ata rate comparable to that of 8 breathing by the animal. Exposure to chlorine at 30 ppm (87 mg/m3) for 5 minutes or at 9 18 to 20 ppm (52 to 58 mg/m3) for 10 minutes caused acessation ofciliary activity.

10 11 Effects on Pulmonary Function. Barrow et al. (1977) studied the sensory irritation 12 responses to chlorine in male Swiss-Webster miceexposed at concentrations between 0.7 and 13 38.4 ppm (2.1 to 113.3 mg/m3). Concentration curves were plotted using percent decrease in 14 respiratory rate. The 10-minute RD50 value (concentration that causes a 50 percent reduction 15 in respiratory rate) was 9.3 ppm (27 mg/m3), while the no-measurable-effect level was 16 0.9 ppm (2.6 mg/m3); chlorine was 33 times more potent than hydrogen chloride gas 17 (RD50 = 309 ppm). 18 Barrow and Steinhagen (1982) investigated the development ofa tolerance to sensory 19 irritation by male Fischer 344 rats exposed to chlorine gas at 0, 1, 5, or 10 ppm 20 (0, 2.9, 14.7, or 29.5 mg/m3) for 6 hours/day, 5 days/week for 2 weeks as apretreatment. 21 Sixteen to 24 hours following the pretreatment period, rats were exposed to chlorine gas for 22 10 minutes at concentrations ranging from 1to 760 ppm (2.9 to 2,242.7 mg/m3). The 23 RD50 value in naive rats was 25.4 ppm (75.9 mg/m3), whereas chlorine pretreatments of 1, 24 5, or 10 ppm increased the RDS0 values to 90, 71, and 454 ppm (265.5, 209.5, and 25 1,339.7 mg/m3), respectively. 26 Chang and Barrow (1984) reported that exposure to 10 ppm (29.5 mg/m3) chlorine gas 27 for 1, 4, or 10 days induced tolerance in male Fischer 344 rats. After 1 day of exposure, the 28 RD50 value was 35.9 ppm (105.9 mg/m3), compared to 10.9 ppm (32.1 mg/m3) in naive 29 rats. Pretreatments of4 and 10days resulted in a 20-fold increase in the RDS0 (225 ppm, 30 663.9 mg/m3) over the naive animals.

August 1990 6-5 DRAFT - DO NOT QUOTEOR CITE 1 Barrow and Smith (1975) studied changes in pulmonary function in rabbits exposed to 2 sublethal levels of chlorine. Groups of four rabbits (strain not specified) of both sexes were 3 exposed to chlorine gas at 0, 50, 100, or 200 ppm (0, 145, 290, or 580 mg/m3) for 4 30 minutes. One rabbit from each group was tested for changes in pulmonary function 5 30 mmutes after exposure and after 3,14, and60days, respectively. Lung function was 6 evaluated using capacitance respirometry in which volume-pressure relationship (V-P) and 7 inspiratory-expiratory flow rate ratios (V^Ve) were measured. At 100 and 200 ppm, V^Vg 8 increased about 40 percent after 30 minutes ofexposure. At 200 ppm, V,;.VE increased 67 9 percent after 3days; no effects were seen at 50 ppm. The ratios returned to normal after 10 60 days for both the 100- and 200 ppm exposure groups. Pulmonary compliance decreased 11 25 to 50 percent at all exposure levels 0.5 hour to 3days after exposure. After 14and 12 60 days of recovery, compliance returned to normal in the rabbits exposed at 50 ppm but was 13 significantly increased in rabbits exposed at 100 or 200 ppm. Correlations were made 14 between functional changes and postmortem findings. The VjiVE ratio quantitatively related 15 to the degree of impairment resulting from pulmonary edema, while CV-P changes indicated 16 the degree of anatomical changes such as emphysema and loss of elastic properties. Recovery 17 time was related to the level of chlorine exposure and the extent of pulmonary damage.

18 19 6.1.1.2 Subchronic Toxicity 20 Buckley et al. (1984) exposed groups of 16 to 24 Swiss-Webster mice to chlorine at the 21 RD50 concentration of 9.34 ppm (27.5 mg/m3), 6hours/day for 5days. Tiie effects on the 22 respiratory and olfactory epithelia of the upper respiratory ti^t were similar to those 23 previously found in the same laboratory at 9.1 ppm chlorine (Jiang et al., 1983). Lesions of 24 the trachea were described as mild to moderate epimelial exfoliation, hyperplasia, and 25 squamous metaplasia. In the lungs, there was moderately severe tenninal bronchiotitis with 26 occlusion of the affected bronchioles by serocellular exudate. Barrow et al. (1979a) exposed 27 groups of 10 six- to eight-week-old Fischer 344 rats of both sexes to chlorine gas at 0,1, 3, 28 or 9ppm (0, 2.9, 8.7, or 26 mg/m3) for 6hours/day, 5days/week for 6weeks. Clinical 29 signs of toxicity were recorded daily, and body weights were recorded 3times aweek. Prior 30 to«sifk*bloodaodw^ After sacrifice, 31 blood was obtained for clinical chemistry determination, acomplete gross examination was August1990 6-6 DRAFT-DONOTQUOmORCrre 1 performed, organs were weighed, and tissues were fixed for histopathologic evaluation. At 2 1ppm, there were occasional slight signs of upper respiratory irritation, and at 3 and 9 ppm, 3 lacrimation and hyperemia ofthe conjunctiva; nasal discharge and salivation were seen 4 throughout thestudy. Gasping, lung rales, and mouth breathing were observed at9 ppm. 5 All groups ofexposed rats had iirinary staining of theperineal fur. One control male and 6 three high-dose females died during the study. There were significant (p <0.05) reductions 7 in body weight gains in both males and females exposed at 3 or 9 ppm when compared to 8 controls. In both males and females exposed at 9 ppm, there were significant (p <0.05) 9 increases in segmented neutrophils and increases in blood urea nitrogen (BUN) and serum 10 gamma-glutamyl transpeptidase. Significant increases in serum alkaline phosphatase were 11 also observed in the groups of males and females exposed at 3 and 9 ppm, and elevations 12 were noted in serum glutamic oxaloacetic transaminase in females exposed at 9 ppm. The 13 specific gravity of urine tended to increase in all exposed groups. 14 Histopathologic examination ofthe rats exposed to chlorine at 9 ppm indicated 15 inflammation of the upper and lower respiratory tract (Barrow et al., 1979a). There was 16 focal to multifocal mucopurulent inflammation ofthe nasal turbinates with increased secretory 17 material and necrotic lesions. The tracheobronchial region showed epithelial hyperplasia and 18 hypertrophy of the bronchiolar and alveolar duct epithelia, an increase of alveolar 19 macrophages, and focal areas of necrosis. In rats exposed to 1 or 3 ppm, similar but less 20 severelesions were noted. At 9 ppm, the histologic changes correlated with increased 21 absolute and relative lung weights. Kidneys ofboth males and females exposed at 9 ppm 22 showed some congestion and changes in the renal tubules; these changes correlated with the 23 increased BUN values. There were increases in hepatocellular vacuolization in the liver of 24 males and females exposed to 3 or 9 ppm when compared to controls. The histologic changes 25 in the liver correlated with increased levels of serumenzymes. There was also focal erosion 26 of the gastric mucosa, but only in the high-exposed animals. The authors believed that the 27 results of this study may have been affected by the presence of chloramines (NH2C1) 28 produced by the reaction ofchlorine with excreta. Barrowand Dodd (1979) detected 29 ammonia and chloramines in inhalation chambers ofrats exposed to chlorine, and they 30 showed that chloramines are producedby the reaction ofchlorine with excreta. Ammonia 31 concentrations in a chamber with an airflow of26 L/minute and an animal loading of

August 1990 6-7 DRAFT - DO NOT QUOTE OR CITE 1 3.1 percent reached 1.6 ppm (4.7 mg/m3) after 6hours (no chlorine exposure). The 6-hour 2 TWA for an ain^ toad of 1.4 percent exposed to chloral 3 airflow of26 L/minute was 0.13 ppm for chloramines. 4 Jiang et al. (1983) exposed groups of 9or 10 eight-week-old male Fischer 344 rats and 5 6-week-old male Swiss-Webster mice to chlorine gas at aconcentration of 9.1 ppm 6 (26.4 mg/m3), 6hours/day for 1,3, or 5days. The level of exposure was close to the 7 RD50 value (9.3 ppm) (Banow et al., 1977). After 1,3, and 5days, groups of animals were 8 sacrificed for histologic examination of the respiratory tract Five levels of the respiratory 9 tract were examined by Ught microscopy. Lesions were found in the nasal passages of 10 exposed animals, with less severe changes noted in the luisopharyiix, larynx, trachea, and 11 lungs. Nasal lesions involved bolh olfactory and respiratory epithelia. In contrast to day 1, 12 after days 3and 5of exposure the lesions became more severe and were more posteriorly 13 extended. There was epithelial degeneration, erosion, and ulceration after 1to 3days and 14 neutrophil infiltration and squamous metaplasia at 5days. The most severe lesions were 15 found in the olfactory epithelium covering the middle third of the dorsal meatus in both mice 16 and rats. There was some degeneration of the olfactory nerves in mice. Electron microscopy 17 indicated complete loss of cilia in extensive areas and cellular exfoliation of the naso- and 18 maxilloturbinates. 19 in asubchronic inhalation study conducted by the National Toxicology Program (NTP) 20 (Kutzman, 1983), male and female Fischer 344 rats were exposed to 0, 0.5,1.5, or 5.0 ppm 21 (0,1.4,4.3, or 14.7 mg/m3) chlorine, 6hours/day, 5days/week for 62 days. All animals 22 were observed daily, weighed weekly, and sacrificed after exposure was terminated. 23 Histologic sections were prepared of the respiratory tract, heart, liver, kidneys, spleen, and 24 testes. Pulmonary function tests were performed on 24 anesthetized rats from each exposure 2526 group.Animalsin the 5g ppm exposure group had nasal discharge, excessive saUvation, and 27 lacrimation. Similar but less severe symptoms were noted in the rats exposed to 1.5 ppm 28 chlorine. No outward signs of irritation were noted in the animals exposed to 0.5 ppm 29 chlorine. None of the pulmonary function parameters examined demonstrated astatistically 30 significant change in pulmonary function in exposed animals; however, AEFR?£ ameasure 31 of the degree of convexity of concavity of the effort-independent limb of the MEFV curve,

August 1990 ** DRAFT"D0 N0T QUOTE °R aTE 1 was significantly reduced (p = 0.04, ANOVA) in chlorine exposed animals indicating some 2 degree of small airwayinvolvement. Histopathological evaluation ofthe trachea of exposed 3 animals showed a loss ofepithelium and cilia. These changes were not severe and were 4 similar to those findings in the control animals but the meantrachea pathology scoresofthe 5 0.5 and 5.0 ppm chlorine exposed animals, using Kruskal-Wallis nonparametric test and 6 Dunn'sand Millers' multiplecomparisons techniques, were significantly greater than thoseof 7 the control group. Histopathological evaluation ofotherorgans showedno exposure-related 8 effects. There was alsoa significant increase in the lung collagen content in rats exposed to 9 1.5 and 5.0 ppm chlorine. The elastin content in the lungs ofchlorine exposed animals was 10 not significantly different from that ofcontrol animals. The authors also reported a mean 11 concentration of0.0395, 0.466, and0.585 ppm chloramines in the cages ofthe chloramines 12 contributed to the effects seen in the chlorine exposed animals could not be determined.

13 14 6.1.13 Chronic Toxicity 15 In a 12-month chronic study, groups of ftmr male and few female young adult rhesus 16 monkeys were exposed to chlorine at concentrations of 0.1, 0.5, or 2.5 ppm (0.29, 1.45, or 17 7.25 mg/m3) for 6 hours/day, 5days/week for 1year. The actual monitored concentrations 18 were 0.1, 0.5, and 2.3 ppm (total chlorine); the concentrations ofchloramine were 0.04, 19 0.14, and 0.13 ppm atthe low, middle, and high exposures. Animals were observed daily 20 for toxic signs and body weight and food consumption throughout the study. Pulmonary 21 physiology was evaluated three times prior to study initiation and monthly thereafter, with 22 measurement of nitrogen washout and pulmonary diffusing capacity. Electrocardiography 23 evaluations, hematology, clinical biochemistry, and urinalyses were performed onallanimals 24 prior to initiation and monthly during the study; arterial blood gases were also measured. At 25 theend of 1 year, the monkeys were sacrificed, selected organs were weighed, and all tissues 26 were examined grossly and histologically. 27 There wereno deaths, and the only toxic sign was overtocular irritation afterthe 28 6-week exposure to 2.3 ppm chlorine. Opthalmologic examination at 12 months showed that 29 irritation involved the conjunctiva but not the cornea. There were no effects on clinical 30 chemistry or hematologic or urinary parameters and pulmonary function parameters did not 31 differ significantly from the control values at any interval.

August 1990 6-9 DRAFT - DO NOT QUOTE OR CITE 1 The only exposure-related histopathologic change was a mild focal epithelial hyperplasia 2 in the respiratory epithelium of the nose and trachea which was associated with aloss of cilia 3 and goblet cells. These lesions were induced in both sexes exposed to 2.3 ppm chlorine. 4 Similar but less distinct changes were present only in the nasal passage of both sexes animals 5 in the 0.5 group in females inthe 0.1 ppm group (Ulrich, 1984). Moderate to severe 6 granulomatous rhinitis and pulmonary lesions typical ofacariasis were reported in the monkey 7 population as the result ofanematode and mite infestation. However, according to the 8 authors, the histopathological changes produced by the parasites were separate and distinct 9 from those changes caused bythe chlorine exposure (Klonne etal., 1987). 10 A two-year chronic inhalation study ofchlorine in rats is being conducted by the 11 Chemical Industry Institute ofToxicology. The in-life portion ofthe study has been 12 completed, but the histopathology has not. The final report should be available in 1990 13 (personal communication, R. Bachman, CIIT Information Office, Research Triangle Park,

14 NC).

15 16 6.1.2 Hydrogen Chloride 17 6.1.2.1 Acute Toxicity Inhalation 18 Darmer et al. (1974) reported the acute LC50 values for hydrogen chloride in male CF-1 19 mice and CFE rats (Table 6-3). Groups of 10 to 15 animals were exposed to various 20 concentrations of hydrogen chloride gas or aerosol for 5or 30 minutes. About 93 percent of 21 the particlesize of the aerosol droplets was in the range of lto2microns. No mortalities 22 occurred in mice exposed for 30 minutes to 410 ppm (615 mg/m3) and in rats exposed for the 23 same duration to 2,078 ppm (3,117 mg/m3) hydrogen chloride gas. Death patterns observed 24 were similar for both the gas and the aerosol. Most deaths occurred in 1to 2days, but some 25 deaths occurred up to 8days after exposure. Hydrogen chloride was extremely irritating to 26 the eyes, mucous membranes, and exposed areas of the skin, such as the scrotum. Corneal 27 erosion and clouding occurred in both species. Primary pathological lesions observed in the 28 respiratory tract were alveolar emphysema, atelectasis, and edema of the lungs, as well as 29 severe injury to the epithelium of the nose and trachea.

Augustl990 6-10 DRAFT-DONOTQUOTEORCITE 1 TABLE 6-3. INHALATION IX^TALUES AND MINIMAL LETHAL CONCENTRATIONS 2 FOR HYDROGEN CHLORIDE IN MICE AND RATS 3 4 5 Minimal 6 Exposure Q lethal No. of 7 Time, ™$ . concentration, deaths 8 Species niin ppm (mg/m3) ppm (mg/m3) observed 9 10 11 Gas 12 Mice 5 13,745 (20,618) 3,200 (4,800) 1/10 13 Rats 5 40,989 (61,483) 32,355 (48,532) 1/10 14 Mice 30 2,644 (3,966) 1,134 (1,701) 2/15 15 Rats 30 4,701 (7,051) 2,678 (4,017) 1/10 16 17 Aerosol 18 Mice 5 11,238 (16,857) 9,058 (13,587) 3/10 19 Rats 5 31,008 (46,512) 19,312 (28,968) 1/10 * 20 Mice (0 2,142 (3,213) 1,204 (1,806) 2/10 » 21 Rats to 5,666 (8,499) 2,910 (4,365) 1/10 22 23 24 Source: Darmer et al. (1974). 25 26

27 More recently, HartzeU et al. (1985) determined LC50 values for hydrogen chloride for 28 exposure times of5, 10, 15, 22.5, 30, and 60 minutes. Groups of 6 to 8 adult male 29 Sprague-Dawley rats were exposed to at least 5 concentrations of hydrogen chloridefor each 30 of the exposure times followed by a 14-day observation period. Table 6-4 presents the 31 LC50 values. A graph of LC50 versus time of exposure is shown in Figure 6-1. However-, 32 Jhere isa discrepancy inthe LC50 value reported by HartzeU et al.^ (15,900 ppm) and Darmer ^ 33 et al.x(40,809 ppm) fora 5-minute exposure. This emphasizes the fact that LC50 values may S 34 vary considerably. 35 Lucia et al. (1977) reported the histopathologic changes in the upper respiratory tracts of 36 maleSwiss-Webster micefollowing acuteexposure to hydrogen chloride. Mice were exposed 37 to concentrations ranging from 17 to 7,279 ppm (25 to 10,918 mg/m3) for 10 minutes; 38 24 hours after the exposure, coronal sectionsat four levels of the head were prepared and 39 transverse sections were examined histologically. At 17 ppm (25 mg/m3), small superficial 40 ulcerations occurred only in the respiratory epithelium at its junction with the squamous

August 1990 6-11 DRAFT-DONOTQUOTEORCITE 1 TABLE 6-4. ACUTE TOXICITY VALUES IN RATS EXPOSED TO 2 HYDROGEN CHLORIDE 3 === 4 5 Exposure Time 6 (minutes) 7 9 5 15,900 (11,540-21,890)^* 79,500 10 10 8,370(7,770-9,010) 83,700 11 15 6,920(5,380-8,900) 103,800 12 27.5 5,920(3,455-10,145) 133,200 13 30 3,715 (2,540-4,435) 111,450 14 60 2,810(2,250-3,510) 168,600 15 ======^ 16 1U17 Vefrhe 95 percent confidence limits are in parentheses. 18 19 Source: HartzeU et al. (1985). 20 2221 epithelium. Asthe concentration was increased, the mucosal ulceration....increased, ma 23 contiguous fashion, gradually extending up the sides and the nasal septum. At723 ppm 24 (1,084 mg/m3), more than the lower two thirds ofthe upper respiratory tract was damaged, 25 and the entire mucosa was destroyed at 1,973 ppm (2,954 mg/m3). A concentration of 26 493 ppm (739 mg/m3) completely destroyed the squamous epithelium ofthe external nares. 27 At 1,088 ppm (1,632 mg/m3), the underlying support structures were damaged; the cartilage 28 of the nasal epithelium was necrotic and the bone ofthe maxilloturbinate was eroded. At 29 concentrations of 1,973 ppm or above, portions of the squamous, respiratory, and olfactory 30 epithelium were all affected. At 7,279 ppm (10,918 mg/m3), total destruction of the mucosa 31 and support structures along with total destruction ofthe eyes was observed in all animals. 32 Barrow etal. (1979b) compared the acute inhalation toxicity of hydrogen chloride and 33 the thermal decomposition products of polyvinyl chloride (PVC). Groups of-feur male 34 Swiss-Webster mice were exposed to hydrogen chloride at concentrations ranging from 20 to 35 20,000 ppm (30 to 30,000 mg/m3) for 10 minutes. Mortality occurred at concentrations 36 between 8,276 to 20,000 ppm (12,414 to 30,000 mg/m3) hydrogen chloride compared to 37 20,690 to 27,586 ppm (31,035 to 41,379 mg/m3) PVC products. Histopathologic 38 examination revealed that both hydrogen chloride and PVC produced changes in the upper 39 respiratory tract and the eyes similar to those in the study by Lucia et al. (1977). There was August 1990 6-12 DRAFT-DONOTQUOTEORCITE Figure 6-1. LC50 values for hydrogen chloride exposed adult male Sprague-Dawley rats vs. time exposure.

Source: HartzeU et al. (1985).

August 1990 6-13 DRAFT-DONOTQUOTEORCITE 1 also passive congestion in the lungs, intestine, liver, and kidney with bothhydrogen chloride 2 and PVC, products; however, it was not clear at which exposure levelsthese changes 3 occurred. Based on the theoretical amount ofhydrogen chloride evolved from PVC it was 4 indicated by the authors that acute toxicity ofPVC was due primarily to the hydrogen 5 chlorideevolved in the thermal decomposition. 6 Studies conducted in the 1930s with guinea pigs and rabbits showed that single 7 exposures to hydrogen chloride gas at concentrations less than 200 ppm (300 mg/nr) were 8 tolerated without any aftereffects orwith slight aftereffects, while exposure at300 ppm 9 (450 mg/m3) for 6 hours caused slight ocular and respiratory irritation in both species. 10 Exposure to 1,350 ppm (2,025 mg/m3) for 90 minutes caused severe irritation, while n exposure to 3,400 ppm (5,100 mg/m3) for the same duration caused death in 2to 6days. 12 The authors stated that guinea pigs were, in general, more sensitive than cats and rabbits 13 (World Health Organization, 1982). 14 Machle et al. (1942) exposed groups of three guinea pigs and three rabbits to hydrogen 15 chloride gas concentrations of 33 to 13,667 ppm (50 to 20,500 mg/m3). Exposure to 16 3,685 ppm (5,500 mg/m3) for 5minutes caused no deaths, whereas exposure to 4,2"88 ppm 17 (6,500 mg/m3) for 30 minutes or to 670 ppm (1,000 mg/m3) for 2to 6hours resulted in 18 100 percent mortality in both species. Guinea pigs were more severely affected, with deaths 19 occurring in 22 of 57 animals 6 days after exposure because of histological changes in the 20 liver (parenchymal edema, congestion, necrosis, and hemorrhage) and lung in animals 21 exposed to high levels ofhydrogen chloride. Cirrhotic sclerosis was noted in the liver of 22 some animals in the high-exposure groups for months after exposure. There were also 23 histological changes in the kidneys and heart ofexposed animals, but it was not indicated at 24. what levels these effects were seen. Exposure tohigh concentrations induced necrosis of the 25 tracheal, bronchial, and alveolar epithelia and necrosis was accompanied by pulmonary 26 edema, atelectasis, and emphysema (Machle etal., 1942). It is difficult to determine whether 27 the effects noted in the liver, heart, and kidney are toxic effects of hydrogen chloride 28 exposure in the absence ofhematological and clinical analyses, or the result ofrespiratory 29 failure since respiratory failure or inadequacies are known to affect various organs and

30 systems.

August 1990 6-14 DRAFT-DONOTQUOTEORCITE 1 Kirsch andDrabke (1982) exposed groups ofeight3-month-old female guinea pigs 2 (320 g mean weight) to hydrogen chloride by nose-only exposure for 30 minutes at levels 3 between 1,309 and 5,708 ppm (1,963 and 8,562 mg/m3) and observed the animals for 7 days. 4 The LCS0 (based on monitored levels) was 2,519 ppm (3,778 mg/m3) (68 percent confidence 5 limit at 1,770to 3,584 ppm). No deaths occurred at anexposure level of 1,309 ppm. The 6 main causeof death at the higherexposurelevels was adverseeffects on the respiratory 7 system. 8 Kaplan et al. (1984) and Kaplan (1987) exposednine juvenile male baboons 9 (Papio cynocephalus) for 5 minutesto various levels ofhydrogen chloridebetween 190and 10 17,290 ppm (285 and 25,935 mg/m3) and evaluated their ability to escape. The animals had n been pretrained to operate a lever to open a door and exit from the chamber in response to 12 , ^audio and visual cues. There was no significant increase inescape time at any exposure level; 13 s^iit was 7.39 ft)4.26 seconds in exposed baboons and the pretest average was 14 6.54 (±?1.37 seconds. At 190 ppm hydrogen chloride, there were no reactions and no 15 postexposure symptoms. At levels of 810, 890, and 940 ppm (1,215, 1,335, and 16 1,410 mg/m3), there was immediate agitation, salivation, and frothing at the mouth but no 17 significant postexposure symptoms. At levels of2,780 and 11,400 ppm (4,170 and 18 17,100 mg/m3) there was immediate coughing and choking, copious salivation, and eye 19 irritation. At 2,780 ppm, there were no significant postexposure symptoms except a dry 20 cough; at 11,400 ppm there was coughing and frothing from the nose and mouth for 3 to 21 4 days (Kaplan et al., 1984). 22 Atlevels of 16,570 and 17,290 ppm (24,855 and 25,920 mg/m3), symptoms during 23 exposurewere more severe. There were severe postexposure dyspneaand respiratory 24 difficulties at these levels, and death occurred at 18days and76 days. There was obliteration 25 ofthe normal mucosa, tracheitis, and pneumonia in the animal thatdied at day 18, whereas 26 the animal that died at day 76 had pulmonaryedema and hemorrhage, bronchopneumonia, 27 erosionofthe epitheliaofthe trachea, and hepatocellular degeneration. These authors also 28 studied escape impairment in male Sprague-Dawley rats. Exposure to levels ofhydrogen 29 chloride between 11,800 and 76,730 ppm (17,700 and 115,095 mg/m3) did not affect the 30 escape time appreciably. Exposure to 87,660 ppm resultedin collapse ofthe animal after 31 about 4 minutes of exposure, with death approximately 1 minute later. However, there were

August 1990 6-15 DRAFT - DO NOT QUOTE OR CITE 1 severe toxic effects atall levels, and mortality occurred atlevels above 14,410 ppm 2 (21,615 mg/m3) hydrogen chloride. 3 In arecent study, Crane etal. (1985) exposed male Sprague-Dawley rats to hydrogen 4 chloride gas at target levels between 2,000 and 100,000 ppm (3,000 and 150,000 mg/m3) 5 while the animals were enclosed singly in acylindrical cage similar to an exercise wheel 6 rotating at 6rpm. When the animal could no longer walk in acoordinated fashion in the 7 cage, the time to incapacitation (q) was noted and rotation was stopped. Observation was 8 continued until respiration ceased, and the time to death (td) was recorded. Thetwoend 9 points measured, ti and td, were equated to measured hydrogen chloride concentration 10 (integrated over the duration of the exposure) by statistically derived regression equations. 11 The observed response time for mcapadtation(^ 12 (141,000 mg/m3) to 185 minutes at 2,000 ppm. When the regression equations were fitted to 13 each data set using anonlinear least squares technique, the resulting response equations were

14 as follows:

15 16 tj » 3+336/(HCl -0.3) for incapacitation, and 17 td =3 + 411/(HC1 - 0.4) for lethality

18 19 ti and ^ are in minutes; HQ concentrations are in parts per thousand. The relationship 20 between response time and hydrogen chloride concentration is shown in Figure 6-2 for the 21 incapacitation end point and in Figure 6-3 for lethality. The constants 0.3 and 3.0 in the 22 equation suggest that the threshold for an infinitely long exposure would be 300 ppm and the 23 shortest tj at infinite exposure concentration would rje 3minutes. The authors suggested that 24 the results indicate that hydrogen cUoride was not nearly as mcapadtatmg as had been 25 previously thought. 26 Cralley (1942) studied the effect of chlorine and hydrogen chloride gas on ciliary 27 activity in excised tracheal preparations of rabbits. The gases were passed over the tissue at a 28 rate comparable to that of breathing by the experimental animal. Exposure to hydrogen 29 cMOTdeal60ppm(90mg/m3)for5i 30 cessation of ciliary activity with no recovery when the tissue was exposed to air. Exposure to

Augustl990 6-16 DRAFT-DO NOT QUOITS OR CTIE Figure 6-2. Incapacitation time as a function of hydrogen chloride concentration. Regression parameters: correlation coefficient = 0.96, standard error of estimate = 11.2, 95% confidence interval for the constant, 336, is 314 to 358.

Source: Crane et al. (1985).

August 1990 6-17 DRAFT-DONOTQUOTEORCITE Figure 6-3. Survival time as a function ofhydrogen chloride concentration. Regression parameters: correlation coefficient = 0.92, standard error of estimate = 22.0, 95% confidence interval for the constant 411, is 364 to 374.

Source: Crane et al. (1985).

August 1990 6-18 DRAFT-DONOTQUOTEORCITE 1 chlorine at 30 ppm (87 mg/m3) for 5 minutes or at 18 to 20 ppm (52 to 58 mg/m3) for 2 10 minutes also caused cessation of ciliary activity.

3 4 Effects on Pulmonary Function. Barrow et al. (1977) compared the sensory irritation 5 responses in mice exposed to chlorine and hydrogen chloride gas. Male Swiss-Webster mice 6 were exposed for 10 minutes to concentrations ranging from 40 to 943 ppm (60 to 7 1,404 mg/m3) hydrogen chloride, and concentration-response curves were plotted using 8 percent decrease in respiratory rate. The 10-minute RD50 value for hydrogen chloride was 9 309 ppm (463 mg/m3), while the no-measurable-effect level was 3 ppm (4 mg/m3). Chlorine 10 with an RD50 value of9.3 ppm was shown to be 33 times morepotent than hydrogen

11 chloride. 12 Burleigh-Flayer et al. (1985) exposed groups oflour male English smooth-haired guinea 13 pigs in head-only chambers to 0, 320, or 680 ppm (0, 480, 1,020 mg/m3) dry hydrogen 14 chloride in air and groups ofeight guinea pigs to 1,040or 1,380 ppm (1,560 or 15 2,070 mg/m3) for a30-minute exposure. Sensory irritation was characterized by adecrease 16 in respiratory rate and a lengthened expiratory phase; pulmonary irritation was evaluated by a 17 change in wave pattern characterized by an initial increased respiratory rate and followed by a 18 decrease caused by a pause after eachexpiration. Sensory irritation occurred within a minute 19 at 680, 1,040, or 1,380 ppm (1,020, 1,560, and 2,070 mg/m3) and after 6 minutes at 20 320 ppm. A concentration-response relationship was noted for pulmonary irritation. At 21 1,380 ppm it occurred in less than 4 minutes but at 320 ppm it took about20 minutes to 22 produce pulmonary irritation. At 1,040 ppm, two animals died after the exposure, whereas at 23 1,380 ppm, two died during exposure andone after exposure. 24 The ventilatory response to breathing 10percent carbon dioxidein 20 percent 25 oxygen/70 percent nitrogen was measured prior to hydrogen chloride exposure andat various 26 intervals thereafter. Carbon dioxide is sometimes used to cause hyperventilation. Maximal 27 respiratory frequency during carbon dioxide challenge was lowerin the hydrogen 28 chloride-exposed animals than in controls; this effect was seen at 0.5 hours at all 29 concentrations and persisted for 15days in the groups at the two highestexposure levels 30 (1,040 or 1,380 ppm). Tidal volume was not affected. Lungs ofthe animalsin the 31 1,040-ppm group were examined histologically at 2 and 15 days postexposure. There was

August 1990 6-19 DRAFT - DO NOT QUOTE OR CITE 1 tissue damage in both the airways and alveolar regions. At2 days, there was multifocal 2 alveolitis and mild hemorrhaging in the alveolar regions, and squamous metaplasia, loss of cilia, and acute inflammation in the larger airways. At 15 days, residual hyperplastic and inflammatory changes were still apparent in the alveoli and bronchi. The effect of hydrogen chloride exposure on pulmonary function and blood gases was reported by Kaplan et al. (1986; 1988). Four groups ofthree anaesthetized male baboons were exposed to air or to 500, 5,000, or 10,000 ppm (750, 7,500, or 15,000 mg/m3) 8 hydrogen chloride for 15 minutes using head-only exposure. Pulmonary function tests were 9 taken during the week prior to exposure and 3days and 3months postexposure. During 10 exposure to hydrogen chloride there was arapid increase in respiratory frequency in all n exposed groups but the increase became statistically significant in the 2highest exposure 12 groups. There was also an exposure-related increase in minute volume in hydrogen chloride 13 exposed animals but the increase was only significant in the 10,000 ppm exposed group. 14 Blood pH (7.2) and Pa02 (59) were reduced and PaC02 (59) increased at the two higher 15 concentrations. There were no significant changes in pulmonary function values up to one 16 year following exposure. However, in one of three animals exposed to 10,000 ppm HC1, 17 there was chronic nasal obstruction, mouth breathing, hypoxemia and focal pulmonary 18 fibrosis at one year after exposure (Anzueto etal., 1987).

19 20 Intratracheal Exposures. The effects ofintratracheal instillation ofhydrochloric acid 21 have been studied in dogs and goats. Greenfield et al. (1969) gave intratracheal instillation of 22 1, 2, or 3mL/kg of 0.1 Nhydrochloric acid to mongrel dogs and sacrificed the animals at 23 various time intervals up to 48 hours. When instilled with 1mL/kg, dogs exhibited 24 hyperventilation, increases in arterial pH and P02, and adecrease in arterial PC02; no deaths 25 occurred. Instillation of 2or 3mL/kg hydrochloric add resulted marapid M marterial 26 P02 and pH,with an increase in PC02 followed by death. Increases in lung weights and 27 hematocrits were similar for all groups, and early decreases mpulmonary surfed 28 observed regardless ofdosage. At the 3mL/kg level, hemodynamic changes observed 29 included amarked increase in pulmonary vascular resistance and afall in cardiac output and 30 systemic pressure. Air pressure-volume curves confirmed the presence of altered mechanical 31 properties of the lung, principally areduction in surfactant. Electron microscopy revealed

August 1990 6-20 DRAFT-DONOTQUOTEORCITE 1 extensive damage to the alveoli and capillaries and severe degenerative changes in the type I

2 and II cells. 3 Four adult New Zealand white male rabbits that received intratracheal injections of 4 hydrochloric add (pH 1.5,2 mL/kg body wdght) and were sacrificed 4 hours later exhibited 5 a few red-brown patches of compression atelectasis in thelungs (Dodd et al., 1976). 6 Microscopic examination revealed a severe exudative necrotizing bronchitis, bronchiolitis, and 7 alveolitis. Intraalveolar hemorrhage and edema were also observed. Electron microscopic 8 examination indicated folds, projections, and focal swellings oftype I cells lining the alveoli. 9 A morphometric study showed 69 percent of the parenchyma to be normal, 26 percent 10 edematous, and 5 percent hemorrhagic; 58 percent ofthe epithelium in the airways was 11 damaged. 12 In mongrel dogs, instillation of2 mL/kg 0.1 N hydrochloric add produced pulmonary 13 edema that was caused, at least in part, by increased vascularpermeability (Grimbert et al., 14 1981). In goats, instillation of 2.5 mL/kg 0.1 N hydrochloric add reduced the total lung 15 capacity (TLC) from 39 to 21 mL/kg at 4 hours (using a transpulmonary pressure of 35 cm 16 H20). The TLC returned to nearly control value after 48 hours. The decrease in TLC was 17 attributed to pulmonary edema and airway obstructions TLC (Winn et al., 1983).

18 19 Dermal Toxicity. Vernot et al. (1977) tested the effects of hydrochloric add on the skin 20 of shaved rabbits. The test solution (0.5 mL) was applied to the back, and the areawas 21 covered with a patch and latex film, and then washed after 4 hours. A 17 percent solution 22 was corrosive, whereas a 15 percentsolution was not. In another study with rats, a 1-minute 23 contact with concentrated hydrochloric add caused minorburns, a 2-minute contact produced 24 lesions that healed in 15 to 19 days, and a 5- to 7-minute contactproduced more serious 25 burns that required26 days to heal (GEOMETTechnologies, Inc., 1981).

26 27 OcularToxicity. Darmer et al. (1974) notedcorneal clouding and erosion in the eyes of 28 rats and mice after 5- or 30-minute exposures to hydrogen chloride gasor aerosol; however, 29 it was not stated ifthose effects occurred at all the levels tested [2,000 to 30,000 ppm 30 (3,000 to 45,000 mg/m3)].

August 1990 6-21 DRAFT-DONOTQUOTEORCITE 1 Buritigh-Flayer et al. (1985) found corneal oparity in 4/6 guinea pigs exposed for 2 30 minutes to 1,040 ppm (1,560 mg/m3) and in 5/5 exposed at 1,380 ppm (2,070 mg/m3) but 3 not manimals similarly exposed at 320 or 680 ppm (480 or 1,020 mg/m3). 4 In another study, mice were exposed to hydrogen chloride vapor for 10 minutes and the 5 following ocular effects were noted: at 490 ppm (730 mg/m3) moderate to marked 6 polymorphonuclear leukocyte (PMN) iiifiltration of the palpebral and global conjunctiva; at 7 1,074 ppm (1,600 mg/m3) necrosis of the exposed cornea and marked PMN infiltration of the 8 eyelids; at 1,946 ppm (2,900 mg/m3) necrosis of the margins of the eyelids and extensive 9 damage of the globes; and at 3,188 ppm (4,750 mg/m3) rupture of the globes (GEOMET i io Technologies, Inc., 1981). 11 Guidry et al. (1957) found eye burns in New Zealand white rabbits after instillation of 12 1.0 Nhydrochloric add fori minute. The pH rapidly returned to normal by the natural 13 buffering mechanism of the eye. Hydration of the corneal tissue increased until 120 hours, 14 followed by adecrease and return to normal 168 hours after onset of injury. Glycolysis and 15 oxygen intake were markedly inhibited immediatdy after the injury. The inhibition of 16 metabolism was due to the denaturation ofglycolytic enzymes.

17 18 6.1.2.2 Subchronic Toxicity 19 Very littte information was found on the effects of hydrogen chloride gas in animals 20 Mowing repeated exposure. No mortalities occurred intnrecrabbits or dsee gumearags 21 exposed to hydrogen chloride at 67 ppm (100 mg/m3), 6hours/day for 5days nor in toe-

22 rabbits, three guinea pigs, or oik monkey exposed to 33.5 ppm (50 mg/m3), 6hours/day,

23 5days/week for 4weeks (Machle etal., 1942). No evidence of toxic damage was noted when the animals were sacrificed several monthslater. The concentrations used were 24

25 irritating to the eyes and mucous membranes. The World Health Organization (1982)

26 reported eye and nasal irritation and ^ght respiratory difficulty mrabbite

27 exposed to hydrogen chloride at 100 ppm (149 mg/m3) for 6hours/day for 5days. In a90-day inhalation study using B6C3F! mice and Sprague-Dawley and Fischer 28 344 rats, groups of 31 males and 21 females of each species/stram were exrx>sed to hydrogen 29 chloride at target levels of 0,10, 20, or 50 ppm (0,15J* 30jy, or 75^mg/m3), 30 6hours/day, 5days/week for 90 days. Several animals died during the study; however, the 31 August 1990 6-22 DRAFT - DO NOT QUOTE OR CTTE 1 deaths did not appear tobeexposure-related. There was a slight but significant decrease in 2 body wdght gain in male and female mice and in male Fischer 344 rats in the high-exposure 3 groups. There was no effect on hematology, clinical chemistry, or urinalysis. Histologic 4 examination showed minimum tn mild rhinitis in both strains ofrats. Lesions occurred in the 5 anterior portion of the nasal cavity and were concentration- and time-related. In mice 6 exposed to 50 ppm there was cheilitis and accumulation of macrophages in the perioral tissues 7 after 90 days. Mice in all exposure groups devdqped eosinophilic globules in the epithelial 8 lining of thenasal tissues (Toxigenics Incorporated, 1984). 9 Kirsch and Drabke (1982) macroscopically examined the respiratory tract ofguinea pigs io exposed to hydrogen chloride at 0.1 ppm (0.15 mg/nr), 2 hours/jlay, 5 days/week for u 28 days and found no effects from the hydrogen chloride exposure. Oddoy et al. (1982) 12 exposed 23 guinea pigs (mean wdght, 385 g) to hydrogen chloride at 10 ppm (15 mg/m3), 13 2 hours/day, 5 days a week for 7 weeks. From the fifth day of exposure, lung function 14 parameters such as tidal volume, respiratory resistance, minute volume, and compliance were 15 measured. No effects were found when mean values were compared to results with 16 15 controls. In addition, there were no effects on blood gases and no histologic changes in the 17 lungs. •& 18 Buckley et al. (1984) found that damage to the upper respiratory tract wasmore severe 19 in Swiss-Webster mice exposed to hydrogen chloride 6 hours/day for 3 days at the 20 RD50 concentration (304 ppm, TWA) than in mice similarly exposed to chlorine for 5 days at 21 the RD50 concentration (9.7 ppm, TWA). Body wdghts in mice exposed to hydrogen 22 chloride were decreased 10 to 25 percent, and all 24 exposed mice were found dead or 23 moribund by the end ofthe third exposure. There was severe exfoliation, erosion, ulceration, 24 and necrosis ofthe respiratory epithelium ofthe nasal cavity, but no squamous metaplasia. 25 Ulceration and necrosis of the olfactoryepithelium were less severe after exposure to 26 hydrogen chloride than afterexposure to chlorine, and there were no lesions in the trachea or 27 lungs. 28 Krishnan and Rao (1981) studied the effect ofhydrogen chloride on the lung surfactant, 29 a lipoprotein complex with high phospholipid content, in male albino rats. Oxygen and 30 carbon dioxide exchange occurs in the alveolar region ofthe lungs. The alveoli arecoated 31 witha pulmonary surfactant that functions to maintain alveolar stability via lowering surface

August 1990 6-23 DRAFT - DO NOT QUOTE OR CITE tension. Alterations ofthe surfactant can lead to various pulmonary disorders. Rats were exposed to a400 ppm (600 mg/m3) hydrogen chloride, 5hours/day for 1, 2, 3, or4 weeks; control animals were exposed to filtered air. The animals were sacrificed and the surfactant material in the lungs was removed by lavage. The surface tension and phosphoUpid content of the washes were detennined. Exposure to hydrogen chloride at 400 ppm for up to 2 weeks caused no effects, whereas a significant decrease in surface tension was noted after 3or 4weeks. The decrease was accompanied by adecrease in total phospholipid, phosphatidyl 8 choline, and phosphatidyl ethanolamine.

9 10 6.1.2.3 Chronic Toxicity 11 The only studies found on the effects of chronic exposure to hydrogen chloride 12 (discussed in fection 8.2.1.2) evaluate the ability of hydrogen chloride to enhance the 13 potential of formaldehyde to produce nasal tumors in rats. In these studies hydrogen chloride 14 was not found to enhance the carcmogematy potentM of formaldehyde. Additional studies 15 are needed to adequately define the effects of chronic exposure to hydrogen chloride.

16

17 is 6.2 HUMAN TOXICITY 19 6.2.1 Chlorine

20 The toxidty of chlorine to man as well as to other higher living organisms is primarily a function of its chemical form. For example, chlorine gas is toxic, affecting the respiratory 21 tract. Chlorine in an aqueous medium not containing ammonia or other nitrogen-containing 22

23 compounds is basically nontoxic; however, chlorine in an aqueous medium containing ammonia or another mtrogen-cOTtaimng compound may lead to the formation of cMoramines. 24

25 26 62.1.1 Acute Exposure 27 Controlled Human Studies. Experimental studies on chlorine in humans havebeen 28 limited to the detection of the odor, the irritation threshold, and pulmonary function.tests in 29 volunteers exposed to low levels. The World Health Organization (1982) dted a1969 30 doctoral dissertation by Beck mdicatmg that m2of 10 subjects me odor u^ 31 0.04 ppm (0.13 mg/m3) and in 10 of 10 subjects the odor threshold was 0.26 ppm Augustl990 6-24 DRAFT - DO NOT QUOTE OR CITE 1 (0.09 mg/m3). There was aloss ofodor perception after 1to 24 minutes of exposure. 2 Leonardos et al. (1969) reported an odor threshold of0.3 ppm (0.8 mg/m3). Trained odor 3 specialists capable of analyzing character and intensity of odor were used for the studies and 4 the threshold was defined as the level perceived by all four panelists. Ruppand Henschler 5 (1967) studied a group of chemistry students (18 to 20) and found the threshold for 50 percent 6 was 0.02 (lowest concentration tested) to 0.05 ppm (0.06 to 0.15 mg/m3). In adouble blind 7 study, Dixon and Dcels (1977) found that 0.08 ppm (0.23 mg/m3) was percdved by • 8 50 percent of me subjects mat least 50 percent of me trials. TheWorld Health Organization 9 (1982) tites a number ofother studies with a wider spread of ranges, but thechemical purity io and laboratory conditions ofthese studies may have caused thewide scatter in thedata. n Table 6-5 lists some ofthe threshold levels for chlorine gas. 12 The sensory irritation threshold (pain and discomfort) is probably very close to the odor 13 threshold. However, a review ofliterature values and standard toxicology sources cited 14 irritation values of 3 to 6 ppm and as high as 14 ppm (Withers and Lees, 1985J). In a study y 15 by Rotman et al. (1983), theirritation threshold was found to be 1 ppm, and 0.5 ppmwas not 16 irritating. 17 The effects ofexposure to low levels of chlorine on respiratory function in human 18 volunteers havebeen studied by Rotman et al. (1983). Eight nonsmoking male subjects, 19 19to 33 years ofage, with no history ofrespiratory disease, were exposed to 0.5 or 1.0 ppm 20 (1.5 or 3 mg/m3) chlorine for 4 or 8hours. The subjects exercised for 15 minutes every hour 21 during the exposure so thatthe heartbeat reached 100beats/minute. Pulmonary function tests 22 were performed priorto exposure and after4 hours ofexposure; the subjects were then 23 exposed for an additional 4 hours and pulmonary function tests were performed immediately 24 afterexposure, 2 and 24 hours postexposure, and daily until all valuesreturned to normal. 25 Sham exposures were also carried out. The parameters measured included forced vital 26 capadty(FVC), forced expiratory volumein 1 second (FEVj), peakexpiratory flow rate 27 (PEFR), FEV at50 percent and 25 percent (FEVS0 and FEV25) ofvitalcapadty, residual 28 volume (RV), total lung capadty (TLC), airway resistance (R^), and diffusing capadty for 29 carbon monoxide (DLC0). 30 Subjects experienced itchy eyes, runny nose, and mild burning ofthe throat at 1.0 ppm 31 butno subjective symptoms at0.5 ppm. One subject who had a history of allergic rhinitis

August 1990 6-25 DRAFT-DONOTQUOTEORCITE 1 TABLE 6-5. THRESHOLD LEVELS FOR CHLORINE GAS

3 4 Threshold Level 5 Effect mg/m3 (ppm) 6 ___

78 Odor perception u0.06 - 3.8 mg/nr3 9 (jO.02 - 1.3 ppm) 10 u Sensory irritation 0.06 - 8.7 mg/m3 12 OhcclL, r**A«J«v (P-02 " 2-3 PPm> 13 ^ 14 Intolerable 2.9- 11.6 mg/m3 15 dl.O - 4.0 ppm)PI 16 17 Chronaxie/visual adaptation 1.5 mg/m3 18 changes (p-52 ppm) 19 ___==^^=^= 20 21 Source: World Health Organization (1982). 22 23 24 experienced severe distress during exposure and shortness ofbreath and wheezing forced him 25 to exitthechamber before the full 8 hours of exposure to 1.0 ppm chlorine. Values for the 26 pulmonary function tests were compared longitudinally (to preexposure values) and also were 27 compared to sham controls to correct for any differences in the preexposure data from one 28 day to the next. When the 0.5-ppm exposure was compared with the sham controls, only 29 trivial changes were seen inpulmonary function tests. TLC was less before the 0.5 ppm 30 chlorine exposure than before the sham exposure and DLC0 was smaller 24 hours after 31 chlorine exposure than after the sham exposure. With exposure to ifbpm chlorine there was a 32 significant (p <0.05) decrease in FVC, FEVlf PEFR, FEV^, FEV25, and R^ after 8 hours 33 when compared to sham exposure using the paired t test. After only 4 hours at 1.0 ppm, 34 FEV^ PEFR, FEV50, FEV^, TLC, and R^ were decreased. The test results for the one 35 subject with allergic rhinitis were markedly depressed after 4 hours exposure at 1.0 ppm 36 (FVC, FEV, PEFR, FEV25, FEV50, RV, and TLQ, but the effects were also transient 37 When the values for the pulmonary function tests were compared lonmrodinally there were 38 decreases in FEVX, PEFR, FEF50, FEF^, ERV, TLC, FRC, and DLco and an increase in 39 Raw in subjects exposed to 0.5 ppm chlorine. Exposure to 1.0 ppm chlorine caused decreases

August 1990 6-26 DRAFT - DO NOT QUOTE OR CITE 1 in FVC, FEV^ PEFR, FEF50, and FEF25 and increases in TLC and R^. These changes 2 were more significant and longer lived. The authors concluded that exposure to even low 3 levels of chlorine can produce adverse effects on pulmonary function and that the magnitude . 4 of the change are related to the level of exposure.

5 6 Case Reports. The acute toxic effects of chlorine gas in humans were realized during 7 WorldWar I when chlorine was usedas a war gas. According to several historical reports, 8 chlorine was usedonly on a few occasions and accounted for less than 3 percentofthe 9 casualtiesfrom gassing (World Health Organization, 1982). Withers and Lees (1985a) 10 reported that in the battle of Ypresthere were 685 British casualties treated at a field station 11 after soldiers were exposed from a gas cloud attack with chlorine; 120 of the 685 examined 12 were considered severe and of these 33 died. Twenty-nine of the 33 died within 36 hours of 13 exposure and 4 during the following 3 days. Postmortem examination of 10 of the deceased 14 confirmed that the acute deaths involvedpulmonary edema. Other mortalities caused by 15 chlorine wereprobably soldiers whodiedin the field (90) and thoseadmitted to ambulances 16 (58). The immediate symptoms were choking, coughing, and gasping for air, smarting of the 17 eyes, burning of the throat, and in manyretchingand vomiting; these was followed by pain 18 behind the sternum and in the chest, weakness, and collapse. Delayed deaths were probably 19 due to bronchial infection and pneumonia. 20 Mortality has occurred from several acddental releases ofchlorine from storage tanks, 21 railroad cars, barges, pipelines, and cylinders. Simmons et al. (1974) have tabulated 22 significant acddental chlorine releases that were recorded by the Chlorine Institute between 23 1926and 1972. In five inddents (France, United States, Romania, Finland, and Germany) 24 where storage tanks failed and released 15 to 30 tons, approximately 117 deaths were 25 reported. Eight railroad car acddents were recorded between 1934 and 1967 in the United 26 States and Canada, involving releases of9 to 55 tons; several persons were "gassed" but only 27 one death was reported. Four inddences occurring between 1920 and 1954 involving 28 150-pound cylinders accounted for 7 deaths. 29 One of the earliest accounts in which the clinical course ofvictims exposed to chlorine 30 was well documented concerned an acddent in Brooklyn, NY (Chasis et al., 1947). A 31 cylinder containing approximately 100 poundsofchlorineleaked through an orifice about

August 1990 6-27 DRAFT - DO NOT QUOTE OR CITE 1 1/8 inch in diameter for 17 minutes. The dense gas found its way into ventilation grates 2 leading to the subway. No deaths occurred, but 418 persons were examined at dght hospitals 3* and 208 were admitted for observation and therapy. Of 133 persons admitted to Cumberland 4 Hospital, 33 were hospitalized fori to2 weeks and are the basis ofthe published description. 5 Few persons on the street at the time ofthe acddent were affected; when the site ofexposure 6 was recorded on the medical charts, the location of 102 of 104 persons was in the subway. 7 The immediate effects were burning of the eyes with lacrimation, burning of the nose and 8 throat, rhinorrhea and salivation, and coughing and choking. Substernal pain and frequent 9 nausea, vomiting, and headache were experienced within 2hours. Loss ofconsdousness was 10 recorded for 8of 115 persons. Most ofthe symptoms except substernal pain, cough, and 11 respiratory distress subsided within 24 hours. 12 Tracheobronchitis developed in all 33 patients within 2 to 4 days and generally subsided 13 in 5to 7 days. Cough increased in the admitted patients after about 3days and became 14 productive of thick mucus; cough disappeared in all patients after 14 days. Pulmonary 15 edema was observed in 23 and pneumonia developed in 14 patients. Chest X-ray findings 16 were not remarkable on first examination, but when they were examined serially for each 17 individual, asequence ofabnormal changes was recognized (mottling, irregular densities, and 18 differences in the degree ofaeration ofrespiratory fields). These changes were interpreted as 19 pneumonia and obstructive emphysema. Respirograms were made on dght patients 48 hours 20 after exposure. The vital capadty and 1-minute maximum breathing capadty were markedly 21 reduced but progressively returned to normal in 2 to 3days. Eleven ofthe patients were 22 observed for 16 months after discharge. There was no evidence of pulmonary disease or any 23 residual symptoms related to thechlorine exposure. 24 Approximately 100 persons were treated for various degrees ofexposure to chlorine 25 when approximately 30 tons ofliquid chlorine was released from atank car in aderailment in 26 1951 near Morganza, MS (Joyner and Durel, 1962). Seven hours after the acddent, levels of 27 400 ppm (1,160 mg/m3) were found 75 yards from the wreck and levels of10 ppm 28 (29 mg/m3) at the fringe ofthe area. Of the 75 people treated at alocal hospital, 17 were 29 hospitalized and an infant ina house near the wreck died. Ten ofme hospitalized victims 30 devdoped pulmonary edema. Most symptoms had cleared 12 days after the exposure.

August 1990 6-28 DRAFT-DONOTQUOTEORCITE 1 Weill et al. (1969) followed 12ofthese subjects 3 and7 years afterthe exposure and 2 detected no appreciable effects onVC, TLC, RV, FEV1} or DLC0. This was based on 3 observed values being within two standard deviations ofthe "predicted value." However, it 4 could not be determined ifthe standard valueswere corrected for age, sex, or weight factors. 5 The authors concluded that permanent lung damage did not result from acute exposure to 6 chlorine gas. 7 In 1961, 156 longshoremen in Baltimore, MD, exposed to chlorine when a valve 8 snapped offa cylinder that was being unloaded, were examined in local hospitals. Kowitz 9 et al. (1967) followed 11 of 17 ofthe most serious cases serially for 2 years. In addition, 10 59 subjects, who had not been hospitalized, were examined 18 to 35 months after the 11 exposure. There were no fatalities. Functional residual capadty, VC, RV, FEVlf PEFR, 12 pulmonary compliance, blood gases, and carbon monoxide diffusion capadty were measured. 13 Seven ofthe 11 who were hospitalized had severerespiratory distress. Exertional dyspnea, 14 , and cough were still noted 3 weeks after exposure; other symptoms had disappeared. 15 Pulmonary function tests 4 to 6 weeks after exposure showed decreased lung volume and 16 diffusing capadty and an increased airwayresistance. At 6, 14, and 24 months, there was 17 some repair, but there were still residual abnormalities. In the 59 who were examined later 18 (20 to 35 months), there were similar functional defidts that indicated slight, but permanent 19 lung damage. However, these findings are not exact, especially in the group studied after 20 18 months, becausethere were no continuous dataand no preexposuredata for comparison; 21 controls may not have been well matched with regard to age, sex, color, or smoking habits. 22 Adelson and Kaufman (1971) reported two fatalities that occurred when chlorine 23 acddentally leakedbecauseofa malfunction in a water filtration plant. The inddent also 24 resulted in approximately 35 nonfatal exposures. Chlorine leaked into the house while a 25 husband and wife were sleeping. They were admitted to a hospital within 15 minutes of 26 exposure, their level ofexposure unknown. They were alertbut were coughing, dyspndc, 27 and cyanotic. Moist rales developed. The husband was given oxygen and remained without 28 severe respiratory distress for about 10 hours; then he became hypertensive and tachypndc 29 (respiratory rate, 50) and had respiratory acidosis. He died 25 hours after exposure. On 30 autopsy, the lungs were congested and edematous. Thrombi were present in the pulmonary 31 blood vessels and there was capillary occlusion. After 24 hours on oxygen therapy, when her

August 1990 6-29 DRAFT-DONOTQUOTEORCITE 1 respiratory distress, cyanosis, and moist rales had improved, the wife became acutely 2 dyspndc and coughed upa frothy, bloody fluid. A tracheostomy was performed and 3 mechanical ventilatory assistance was instituted. At 57 hours shebecame cyanotic and 4 comatose and blood drawn did not clot. The wife died 75 hours after exposure. Autopsy 5 findings were similar to those for the husband. In addition, the trachea and bronchi were 6 ulcerated and their vasculature was occluded with thrombi. Hemorrhagic lesions were also 7 found in the brain and glomeruli of the kidneys. In the 35 survivors from this acddent, 8 transient minor reduction in diffusing capadty and moderate degrees ofairway obstruction 9 were observed and were reversed within a month ofexposure. 10 Chester et al. (1977) reported two siblings who had been acddentally exposed to 11 chlorine inthe same room. Both had reduced FEV! and TLC when examined, and the values 12 returned to normal ranges within a month. However, abnormalities in gas exchange persisted 13 for 55 months in one patient. 14 Beach et al. (1969) presented case reports of 7 persons who had been acddentally 15 exposed to chlorine gas for 3to 10 minutes duration in separate acddents. Symptoms of 16 cough, dyspnea, and chest pains started 10 minutes after exposure and lasted 2to 8days. In 17 one severe case, there was cyanosis, rapid and shallow breathing, pulmonary edema, and lung 18 consolidation. The symptoms and lung changes usually cleared within aweek, except in the 19 most severe case where they persisted for 10 weeks. No residual effects were found after 20 2 months, and lung function tests were normal except in the most severe case where FVC, 21 FEV, and carbon monoxide transfer rate were still depressed. 22 Ploysongsang et al. (1982) performed pulmonary function tests in few-healthyT young 23 men, ages 18 to 33 years old, acddentally exposed to chlorine gas leaking from acontainer at 24 apublic swimming pool. Thelevdof exposure was not known, but the tiB^otexposure was 25 2 to 5 minutes. The subjects were admitted to ahospital with symptoms ofeye irritation, 26 irritation ofthe upper respiratory tract, cough, tightness ofthe chest, and shortness ofbreath. 27 All showed some degree ofarterial hypoxemia. Chest roentgenograms appeared normal. 28 Pulmonary function tests were conducted 14 to 16 hours after exposureas well as 29 1month after exposure. Vital capadty (VC), ftmntionnl Trcridnnl cajaacityffitCfl, and TLC 30 were within the normal range at 14 to 16 hours after exposure, but at retesting after 1 month Forced e%9ir^j*£i\ fblume «^ \ i»eoi»€\ 4 31 these values were increased when compared to normal. (FEVXand FEV25.75 were slightiy

August 1990 6-30 DRAFT - DO NOT QUOTE OR OFE 1 lower thanthe normal range afterthe exposure (nonsignificant decrease) but were normal at 2 1 month. Carbon monoxide diffusing capadty was significandy increased (p <0.01) at 3 1 monthas compared to immediately afterexposure. The results ofthese tests suggest some 4 obstruction ofthe small airways, impaired gas transfer, mild pulmonary edema, and stiff 5 lung. No residual injurywas found in two subjects tested 3 monthsafterexposure. 6 Hasan et al. (1983) also evaluated subjects acddentally exposed to chlorine for 7 pulmonary dysfunction. Twenty-dght subjects were exposed and 18 (14 females and 4 males) 8 with respiratory signs and symptoms were admitted to a hospital for observation. Airway 9 obstruction was evident in all subjects 1 day after exposure (lowered FEVlf FEV25, and 10 FEV50). When subjects were separated into groups whose chiefcomplaint was either cough 11 or dyspnea, abnormal expiratory flow rates returned to normal in the cough group by 7 days 12 postexposure, but were still diminished in the dyspnea group at 2 weeks. Although the 13 variable rate of resolution ofthe obstructive abnormalities may have been associated with 14 smoking habits, the number of subjects was too small to draw a conclusion. 15 Charan et al. (1985) reported an industrial acddent in which a large volume of chlorine 16 gas was released, rose along the walls ofa building, and settled on the roof where 17 19 construction workers were exposed for a few seconds to a few minutes. All were admitted 18 to a hospital for 24 to 48 hours of observation; they were examined physically, had chest 19 roentgenograms and arterial blood gas measurements, and received pulmonary function tests 20 within 24 hours. Pulmonary function tests were done atintervals up to 2 years on 11 of the 21 subjects. 22 None of the subjects developed pulmonary edema. The ratio of FEVj/VC was less than 23 75 percent ofthe expected value in 10of 19 patients at 24 hours, suggesting airflow 24 obstruction. After 700 days, this finding was present in 3 of 11; however, 2 ofthe 3 affected 25 were heavy smokers. Residual volume (RV) was > 120 percent ofthe predicted value in 26 13of 19; it progressively dropped and by day 30 was less than 80 percent ofthe predicted 27 value in 4 ofthe 13 that were examined. The clinical implication ofthe decrease is not 28 apparent and it is unlikely it would cause major symptoms. The long-term effects are not 29 clearly apparent because ofthe smallnumberof patients. 30 Jones et al. (1986) carried out a 6-year longitudinal follow-up studyon 20 of 23 people 31 hospitalized, 21 of25 people not hospitalized but having respiratory injury, and 53 uninjured

August 1990 6-31 DRAFT-DONOTQUOTEORCITE 1 people exposed to chlorine that had been released during atrain derailment in Florida in 2 1978. Pulmonary function tests (FVC, FEV^ FEF^^, TLC, RV, and DLco) were 3 conducted at 3 weeks, 9 months, and annually for the 6-year period. In the absence of valid 4 estimates of exposure, severity of injury and distance from the site of chlorine release were 5 used asdeterminants oflongitudinal change in respiratory function. 6 Current smokers and former smokers and individuals who had never smoked were 7 distinguished in the study results. Hospitalized and nonhospitalized individuals with 8 respiratory tract injury were compared to exposed persons who appeared normal. 9 Preexposure pulmonary function measurements were not taken; general population values io were used comparativdy. Three weeks after the chlorine release, mean lung function indices 11 did not show aconsistent pattern ofabnormality based on severity ofinjury or distance from 12 the release; there were some differences according to smoking category. Over the first year, 13 "lower respiratory tract symptoms" (cough, wheeze, and dyspnea) declined from 90 to 14 64 percent, and even inconsistent relationships to severity of injury or distance from release 15 were reported to disappear. Two years following exposure, the mean annual pulmonary 16 function indices were reported to be decreased mexrx>sed current smokers when compared to 17 former smokers, "never smokers," and the general population; FVC and ¥EVX were 18 significandy (0.01

August 1990 6-33 DRAFT-DONOTQUOTEORCITE 1 plugging ofthe f™*11 and medium bronchi, and atelectasis are common findings during phase 2 n (6 hours to 8days). A reduction in vital capadty and pulmonary compliance and increased 3 airway resistance is also seen during this phase. Improvements in pulmonary function occur 4 during phase HI (1 to 4 weeks); however, coughing may persist throughout this period. 5 During phase IV (after 4 weeks), airway obstruction continues to improve and lung volume, 6 diffusing capadty, and arterial blood gases return to normal (Summer and Haponik, 1981). 7 The levels and timeof exposure to cause adverse effects in humans are ill defined. 8 Standard reference sources givevariable values ofexposure that cause irritation, that are 9 dangerous tohumans, or that are intolerable or lethal (Withers and Lees 1985b). Itis 10 generally considered that inhalation of 4ppm (11.6 mg/m3) chlorine causes irritation, 11 inhalation of 14 to 21 ppm (40.6 to 60.9 mg/m3) or 40 to 60 ppm (116.0 to 174.0 mg/m3) 12 for a0.1 to 1hour isdangerous, 100 ppm (290 mg/m?) is intolerable and incapacitating, and 13 1,000 ppm (2,900 mg/m3)jreven ashort inhalationfc)is lethal. However, there are many 14 factors that maydetermine thedegree of response and whether there is complete recovery or 15 residual effects^i.e., the respiratory health of the victim, predisposition to asthma, age, 16 smoking habits, degree of respiratory damage, and specific care and therapy.

17 18 6.2.1.2 Chronic Exposure 19 Faure et al. (1983) and Barret and Faure (1984) haverecorded theirexperience over a 20 span of 20 years with 186 subjects occupationally exposed tochlorine. Pulmonary edema 21 developed in about 4 percent of the cases. One hundred twenty nine of these workers 22 underwent spirometric measurements, and of these 43 had abnormal tests: an obstructive 23 pattern in 27 cases, a restrictive pattern in 13 cases, and mixed syndrome in 3 cases. Forced 24 expiratory volume in 1 second (FEV^ and VC were measured. In 21 of 79 cases studied, 25 carbon monoxide diffusing capadty wasabnormal; most ofthe subjects (11 of 13)with 26 restrictive syndrome had abnormal carbon monoxide diffusing capadty. Subjects (56) who 27 had at least Arte acute episodes ofexposure in the previous 5 years werecompared with 28 197 controls; there were no long-term effects on FEVj, VC, or FEVj/VC ratio when exposed 29 and nonexposed groups were corrected for age, bright, or smoking habits.

30

31

August 1990 6-34 DRAFT - DO NOT QUOTE OR CITE 1 6.2.1.3 Epidemiology Studies 2 Patil et al. (1970) conducted a retrospective cohort study on 600 diaphragm cell workers 3 and 382 controls from 25 plants. There may have been selection bias, since the examinations 4 took place only in cooperating plants; furthermore, laboratory data, other than chlorine levels, 5 may not have been evaluated in a standardized way. Chest X-rays were taken and evaluated 6 blind, and chlorine levels were assayed bimonthly using a standardized protocol. The study 7 population ranged in age from 19 to 69 years, with the mean age of the two groups being 8 J 031.2mOi1.0 years. The duration of exposure was approximately 11 years; some workers had 9 ^k also concurrent exposure to mercury. Time-weighted average (TWA) exposures to chlorine 10 ranged from 0.006 to 1.42 ppm (0.02 to 4.12 mg/m3) with a mean of0.15 /H0.29 ppm n (0.4^± 0.84 mg/m3). Practically all exposures were less than the ACGIH threshold limit 12 value of 1.0 ppm (2.9 mg/m3) (2 percent greater than 1.0 ppm). Exposure data were 13 obtained from only 332 of 600 workers; hence, the useful population was 332 workers. The 14 parameters examined included oropharyngeal disturbances (tooth decay), cardiorespiratory 15 system, and blood and urine studies. Pulmonary function, vital capacity, maximum breathing 16 capacity, and FEV were measured. With the exception of positive correlation between 17 exposure and increased tooth decay (p = 0.025) and between exposure and leukocytosis 18 (p = 0.05), no other parameters were affected. Pulmonary function tests revealed normal 19 values in the vast majority of workers, including controls and those exposed to chlorine. 20 A cross-sectional study of 139 workers at risk in a chlorine gas plant was conducted 21 over a 3-day period (Chester et al., 1969). The workers were polled by questionnaire-for-©« 22 smoking history and chlorine exposure. Significant exposure was operationally defined as 23 severe enough to have been treated with oxygen; 55 of the 139 workers had been so exposed 24 at least once during their employment. All others were considered to be exposed to less than 25 1 ppm chlorine gas; in continuous air sampling, 99 percent of the samples had less than 26 1 ppm chlorine. Duration of worker exposure was not presented. Postanterior lung X-ray 27 films were normal in 82 subjects and abnormal in 56 (data for one subject were lost). Only 28 one of the 56 workers with abnormal findings on X-ray had abnormal respiratory function. 29 Regardless of chlorine exposure, 75 percent of the workers denied cough or sputum 30 production. Differences in FEV0 5, among other function tests, did notcorrelate with cough 31 and sputum production or abnormal chest films. The study showed a decreased FEV and

August 1990 6-35 DRAFT - DO NOT QUOTE OR CITE 1 FVC for smokers compared to nonsmokers (in agreement with others) and adecrease in 2 maximal mid-expiratory flow (MMF) between no smoke/no chlorine and smoke/chlorine. 3 Although few effects were noted in this study, the major defidendes are small numbers of 4 workers and uncontrolled potentially confounding variables. 5 Ferris et al. (1979) reported on the follow-up ofa 1963 mortality and morbidity study 6 with pulp and paper workers who were potentially exposed to chlorine, sulfur dioxide, 7 chlorine dioxide, and/or hydn^en sulfide in Berlin, NH. This was aprospective cohort study 8 of200 subjects (271 in 1963), which indicated that the observed deaths were greater than 9 expected; i.e., 33 versus 26.1 for astandardized mortality ratio (SMR) of1.26 (not 10 significant) based on age-specific death rates of U.S. white males, excluding Hawaii and 11 Alaska. This discrepancy is due probably to an excess in the paper exposure category only; 12 the SMR of71 workers identified in 1963 as being exposed to chlorine was 99 (9 deaths 13 observed, 9.06 expected). There were no increases in specific causes ofdeath. There were 14 no differences in respiratory symptoms or prevalence ofchronic nonspecific respiratory 15 diseases in the pulp or paper mill when data were not adjusted for smoking. When data were 16 standardized for smoking and values compared for the general population of Berlin, NH, 17 there was not much difference in relative risk for devdoping chronic respiratory disease in 18 pulp workers; however, current dgarette smokers and pipe smokers (combined) had an 19 increased relative risk. The chronic nonspecific respiratory effects ofchlorine exposure could 20 not be separated from the results presented. There was no chlorine-related effect on 21 pulmonary function in 27 actively employed chlorine-exposed workers. Two defidendes of 22 this study are the use ofthe general population as controls, which may have underestimated 23 relative risk, and the self-selection ofworkers remaining at the mill in the chlorine or sulfur 24 dioxide groups because they were more tolerant. With these limitations noted, the authors 25 concluded that long-term, low-level exposure to chlorine did not increase the inddence of 26 mortality or morbidity. 27 Enarsonetal. (1984) evaluated the respiratory health ofworkers (392) at apulpmill 28 and for the purpose ofcomparison studied acohort of310 workers in arailroad maintenance 29 yard approximately 10 miles distant Potential exposures in the pulp mill were to chlorine, 30 sulfur dioxide, hydrogen sulfide, and methylmercaptan. Several sites in the pulp mill were 31 surveyed for these contaminant gases. In the bleach area the mean 8-hour TWA for chlorine

August 1990 6-36 DRAFT-DONOTQUOTEORCITE 1 was 0.18 ppm (0.52 mg/m3) and the maximum level was 1.61 ppm (4.67 mg/m3). Levels of 2 chlorine were low but detectable in the machine room and office area but not detectable in 3 otherareas. Chest tightness was the most common symptom in pulp mill workers, especially 4 for those working in the bleach plant, but the increase was not significandy different. Cough, 5 phlegm, wheeze, and dyspnea did not differ between any groups when analyzed after 6 standardization for age and smoking habits. Spirometric values were compared using a 7 multipleregression modd adjusted for age, height, and age-group interactions. The . 8 individuals most affected appeared to be younger nonsmokers who worked in the bleach area 9 whereme likely exposure would havebeen to chlorine. These workers had lower MMF, 10 FEF25.75, and FEV1/FVC ratio; theolder workers in this group had higher values when 11 compared to the rail repair yard workers. This difference may have been due to older 12 workers leaving employment. The numberofworkers in the bleacharea ofthe plantwas 13 only 15, and 4 were nonsmokers; the small numbers in this group weaken the conclusions of

14 the authors. 15 Savad (1982) reported a 1980outbreak ofenamelerosion in users ofa public swimming 16 pool that was chlorinated by gassing with chlorine. Prindle et al. (1983) reported a 17 cross-sectional study ofenamel erosion in competitive swimmers. Using a questionnaire 18 mailedto swim club members (747 respondents), they quantified exposure by number of laps 19 swum perday. Of the 452 frequent swimmers, 69 (15 percent) reported enamel erosion (or 20 symptoms), while only 9 ofthe 295 infrequent or nonswimmers reported symptoms 21 (3 percent). In addition, of the 59 members on the swim team, 23 (39 percent) reported signs 22 of tooth erosion, compared to 15 percent ofall frequent swimmers (p <0.001). 23 Confirmation ofrandomly selected cases andcontrols was conducted by an oral pathologist. 24 However, the dental erosion may havebeen an effect ofthe acidity ofthe waterrather than 25 chlorine per se.

26 27 6.2.2 Hydrogen Chloride 28 Only limited information was found in the primary literature on the inhalation toxirity of 29 hydrogen chloride gas or aerosol in humans, and this information has been largely restricted 30 to the detection ofodor and irritation thresholds. It is known, however, that hydrogen 31 chloride is a strong irritant, and because ofits high water solubility the major effectsofacute

August 1990 6-37 DRAFT - DO NOT QUOTE OR CITE 1 inhalation exposure are thought to be limited to the upper respiratory tract (National Research 2 Council, 1976).

3 4 6.2.2.1 Acute Exposure 5 Threshold levels for odor perception have been reported to be as low as 0.07 ppm 6 (0.1 mg/m3) and as high as 306 ppm (459 mg/m3). Under laboratory conditions, however, 7 the threshold levd is likdy to be about 0.2 ppm (0.3 mg/m3) (World Health Organization, 8 1982). Leonardos etal. (1969) reported an odor threshold of 10 ppm (15 mg/m). Trained 9 odor specialists capable of analyzing character and intensity of odor were used for the studies 10 and the threshold was defined as the levd percdved by all four panelists. Inhalation of 11 irritating levds of hydrogen chloride has resulted in coughing, pain, inflammation, and edema 12 ofthe nasal passages and larynx (National Research Council, 1976; World Health 13 Organization, 1982). 14 Sustained inhalation ofhigh concentrations causes edema, emphysema, and damage to 15 pulmonary blood vessels (GEOMET Technologies, Inc., 1981). Male volunteers exposed to 16 hydrogen chloride gas found concentrations of 50 to 100 ppm (75 to 150 mg/m3) barely 17 tolerable for 1hour; 35 ppm (52 mg/m3) caused throat irritation on brief exposures; 10 ppm 18 (15 mg/m3) was considered acceptable for prolonged exposure; and concentrations below 19 5ppm (7 mg/m3) produced no lasting effects (Clayton and Clayton, 1981). The World 20 Health Organization (1982) reported that inhalation of approximately 35 ppm (52 mg/m3) can 21 induce sneezing, laryngitis, chest pain, hoarseness, and afeeling ofsuffocation. 22 Ingestion of hydrochloric add results in severe corrosion of the mouth, throat, and 23 stomach followed by vomiting with loss of blood; kidney damage may also occur during acute 24 intoxication. Ingestion of acorrosive dose will cause pain in the mouth, destruction oftissue, 25 salivation, and severe gastroenteric distress (GEOMET Technologies, Inc., 1981). 26 Skin contact with concentrated hydrochloric add causes tissue irritation and necrosis. 27 GEOMET Technologies, Inc. (1981) reported that 1Nhydrochloric add (3.6 percent) 28 induced severe changes and inflammation in human epidermal cells. In one study, application 29 of1.4 Nhydrochloric add (3 percent) to human skin in patch tests produced inflammatory 30 responses but did not alter the rate ofceU imtosis, and anc^er study show 31 apphcation of 0.001 Nhydrochloric add (0.0036 percent) did not produce pain or itching.

August 1990 6-38 DRAFT-DONOTQUOTEORCITE 1 CaseReport. In one report, a 41 yearold male with a historyof mild asthma, 2 experienced a rapid and severe bronchospasm afterbeingexposed to a pool cleaning product 3 containing hydrochloric add. The patient was treated with bronchodilators and steroids. One 4 year later, while still on bronchodilators and steroids, he was still experiencing marked 5 symptoms ofasthma triggered by exposure to niUd irritants or minimal exercise. He also 6 experienced frequent episodes ofnocturnal asthma. Airway obstruction was completely 7 reversed by albuterol; however, a progressive decline ofmore than 20 percent in FEV! was 8 observed 4 hours after inhalation. No effect on carbon monoxide diffusion was noted 9 (Boulet, 1988). 10 Soni et al. (1985) reported the death ofa 44-year-old man5 days after intentional 11 ingestion of200 mL of muriatic add (27 percent hydrochloric add). On arriving at the 12 hospital, he had severe epigastric pain, was sweating profusely, and was agitated. One hour 13 later, blood tests showed hemolysis and coagulation studies showed abnormal values. A 14 .gastroscopy performed 18 hours later showed a white slough throughout the esophagus, and 15 the stomach was coated with a thick black coagulum. Laparotomy revealed gross necrosis of 16 the esophagus, along with total gastric and duodenal necrosis and large areas of necrosis 17 through the small and large bowels. Extensive areas ofburnttissue on the liver surface and 18 mesentery were found, suggesting extensive leakage ofthe add. The massive extent of 19 damage precluded surgical repair, his condition deteriorated, and he died.

20 21 6.2.2.2 Epidemiology Studies 22 Two epidemiology studies showed thatcontinued exposure ofworkers to hydrogen 23 chloride may cause an increase in dental erosion. In a cross-sectional investigation, with a 24 prospective phase, ten Bruggen Cate (1968) studied the inddenceofindustrial dental erosion 25 in a totalof555 add workers in 48 plants over a period of2 years. The workers were 26 exposed to a number ofadds including hydrochloric add. The selection ofthe control group 27 was questionable. Unskilled workers from add-free departments were used, but they were 28 younger than the skilled workers who were exposed to theadds. The inddence and severity 29 ofdental erosion in the teeth ofexposed workers increased over the periodofthe study. 30 Only the anterior teeth wereaffected; cuspids and molars, which are protected by the cheeks, 31 werenot. Grading oferosion severity was as follows: grade 1, loss ofenamel only; grade 2,

August 1990 6-39 DRAFT - DO NOT QUOTE OR CTT^ 1 loss ofenamel with involvement ofdentine; and grade 3, loss ofenamel and dentine with 2 exposure of secondary dentine. 3 Exposure measurements were qualitative and varied for manyofthe 48 plants and 4 555 workers involved. The major exposures occurred in the pickling and galvanizing 5 operations, which correspond with themore severe erosion of thelabial surfaces of the 6 incisors. However, the inddence of mild erosion increased in the control population as a 7 function of years of service; after 15 years of service theinddence in controls and 8 lower-exposed group was similar (ar^nx>ximately 35 percent ofworkers). The results ofthe 9 prospective phase ofthe study (several examinations of the same workers overa 2-year 10 period) support the conclusions of the cross-sectional phase that continued exposure n exacerbates the lesions. Interestingly, the exposed workers had no perceived or reported 12 pain. Periodontal disease appeared to be more prevalent in the exposed workers, but the 13 inddence was not statistically significant. 14 Remijnet al. (1982) examined a cohort ofapproximately 60 workers potentially exposed 15 to hydrochloric add, zinc chloride, and zincoxide ata two-shift, hot-dip galvanizing plant in 16 the Netherlands. The investigation involvedquantification ofexposure and dental erosion, 17 which was assessed in 38 workers. The remaining workershad dentures or refused 18 examination. These authors supported andexpanded uponthe conclusion often Bruggen Cate 19 (1968). Based on their results, Remijn and coworkers^concluded that inhalation of 20 hydrochloric add first affects the "incisal one-third to one-half ofthe surfaces ofthe inrisor 21 teeth," and that 90 percent ofthe workers had at least a grade 1 erosion; no cases of 22 grade 3 erosion werediagnosed. The monitoring study leads to the conclusion that the 23 picklers worked approximately 27 percent oftheir timewithconcentrations ofhydrochloric 24 add greater than the maximum allowable concentration-ceiling (MAC-Q valueof5 ppm 25 (7 mg/m3). The probability of zinc levels exceeding the MAC-C was 1percent Upon 26 examination, the picklers showed the greatest inddence and severityofdental erosion. 27 Because ofthe small numberof workers, multivariate analysis ofthe data as a function of 28 age, exposure time, and exposure levd was not possible. A control cohort was notincluded in 29 the study.

August 1990 6-40 DRAFT- DO NOT QUOTE OR CITE 6.3 REFERENCES

4 Adelson, L.; Kaufman, J. (1971) Fatal chlorine poisoning: report oftwo cases with clinicopathologic 5 correlation. Am. J. Clin. Pathol. 56: 430-442. 6 7 Anzneto, A.; Switzer, W.; Kaplan, H.; Moore, G. T.; Johanson, W. G., Jr. (1986) Pulmonary effects of 8 hydrochlorideacid inhalation in nonhuman primates. In: American Lung Association-AmericanThoracic 9 Society annualmeeting; May; Kansas City, MO. Am. Rev. Respir. Dis. 133: A3S9. 10 11 Anzneto, A; Switzer, W. G.; Kaplan, H. L.; Hinderer, R. K. (1987) Long-term effects ofhydrogen chloride 12 on pulmonary function and morphology in nonhuman primates. Toxicologist 7: 192. 13 14 Barret, L.; Faure, J. (1984) Chlorine poisoning. Lancet (8376): 561-562. 15 16 Barrow, C. S.; Dodd, D. E. (1979) Ammonia production in inhalation chambersand its relevanceto chlorine 17 inhalation studies. Toxicol. Appl. Pharmacol. 49: 89-95. 18 19 Barrow, R. E.; Smith, R. G. (1975) Chlorine-induced pulmonary function changes in rabbits. Am. Ind. Hyg. 20 Assoc. J. 36: 398-403. 21 22 Barrow, C. S.; Steinhagen, W. H. (1982) Sensory irritationtolerancedevelopment to chlorine in F-344 rats 23 following repeatedinhalation. Toxicol. Appl. Pharmacol. 65: 383-389. 24 25 Barrow, C. S.; Alarie, Y.; Warrick, J. C; Stock, M. F. (1977) Comparison ofthe sensory irritation response 26 in mice to chlorine and hydrogen chloride. Arch. Environ. Health 32: 68-76. 27 28 Barrow, C. S.; Kociba, R. J.; Rampy, L. W.; Keyes, D. G.; Albee, R. R. (1979a) An inhalation toxicity study 29 ofchlorine in Fischer 344 rats following 30 days ofexposure. Toxicol. Appl. Pharmacol. 49: 77-88. 30 31 Barrow, C. S.; Lucia, H.; Alarie, Y. C. (1979b) A comparison ofthe acute inhalation toxicity ofhydrogen 32 chloride versus the thermaldecomposition products of polyvinylchloride. J. Combust Toxicol. 6: 3-12. 33 34 Beach, F. X. M.; Jones, E. S.; Scarrow, G. D. (1969) Respiratory effects ofchlorine gas. Br. J. Ind. Med. 35 26:231-236. 36 /*? 37 f Bitron, M. D.; Aharonson, E. F. (1978) Delayed mortality of mice following inhalation of acute doses of 38 / CH20, SO2, Cl2, and Br2. Am. Ind. Hyg. Assoc. J. 39: 129-138. 39/ 40 / Blabaum, D. J.; Nichols, M. S. (1956) Effect ofhighly chlorinated drinking water on white mice. J. Am. 41 Water Works Assoc. 48: 1503-1506. 42 43/ Boulet, L.-P. (1988) Increases in airway responsiveness following acute exposure to respiratory irritants: reactive airway dysfunction syndrome or occupational asthma? Chest 94: 476-481.

Buckley, L. A.; Jiang, X. Z.; James, R. A.; Morgan, K. T.; Barrow, C. S. (1984) Respiratory tract lesions 47l induced by sensory irritants at the RD50 concentration. Toxicol. Appl. Pharmacol. 74: 417-429. 48 49 Burleigh-Flayer, H.; Wong, K. L.; Alarie, Y. (1985) Evaluation of the pulmonary effects of HC1 using C02 50 challenges in guinea pigs. Fundarn. Appl. Toxicol. 5: 978-985. 51 V feern^L.f. ;e.**e.U, fU.J y~£ir. A; M^£I.;>•*£•£ m- >*^A^ Xb^e&Kc thlorlne pol*»©AUw ^ TWJ^ **»*"* 'W*^ WbehaU aXttneC* August 1990 6-41 DRAFT-DONOTQUOTEORCITE 1 Chang, J. C. F.; Barrow, C. S. (1984) Sensory irritation tolerance and cross-tolerance in F-344 rats exposed to 2 chlorine or formaldehyde gas. Toxicol. Appl. Pharmacol. 76: 319-327. 3 4 Charan, N. B.; Lakshminarayan, S.; Myers, G. C; Smith, D. D. (1985) Effects of accidental chlorine 5 inhalation on pulmonary function. West J. Med. 143: 333-336. 6 7 Chasis, H.; Zapp, J. A; Bannon, J. H.; Whittenberger, J. L.; Helm, J.; Doheny, J. J.; MacLeod, C. M. 8 (1947) Chlorine accident in Brooklyn. Occup. Med. 4: 152-176. 10 Chester, E. H.; Gfflespie, D. G.; Krause, F. D. (1969) The prevalence of chronic obstructive pulmonary disease 11 jnchlorine gas workers. Am. Rev. Respir. Dis. 99: 365-373. 12 13 Chester, E. H.; Kaimal, P. J.; Payne, C. B., Jr.; Kohn, P. M. (1977) Pulmonary injury following exposure to 14 chlorine gas: possible beneficial effects of steroid treatment. Chest 72: 247-250. 15 16 Conner, E. H.; DuBois, A. B.; Comroe, J. H., Jr. (1962) Acute chemical injury of the airway and tangs: 17 experience with six cases. Anesthesiology 23: 538-547. 18 19 Galley, L. V. (1942) The effect ofirritant gases upon the rate ofciliary activity. J. Ind. Hyg. Toxicol. 20 24: 193-198. 21 22 Crane, C. R.; Sanders, D. C; Endecott, B. R.; Abbott, J. K. (1985) Inhalation toxicology: IV. Times to 23 incapacitation and death for rats exposed continuously to atmospheric hydrogen chloride gas. 24 Washington, DC: Federal Aviation Administration; FAA report no. FAA-AM-85-4. 25 26 Cunningham, H. M. (1980) Effect ofsodium hypochlorite on the growth ofrats and guinea pigs. Am. J. Vet. 27 Res. 41: 295-297. 28 29 Darmer, K. I., Jr.; Kinkead, E. R.; DiPasquale, L. C. (1974) Acute toxicity in rats and mice exposed to 30 hydrogen chloride gas and aerosols. Am, Ind. Hyg. Assoc. J. 35: 623-631. 31 32 Dewhurst, F. (1981) Voluntary chlorine inhalation [letter]. Br. Med. J. 282: 565-566. 33 34 Dixon, W. M.; Drew, D. (1968) Fatal chlorine poisoning. JOM J. Occup. Med. 10: 249-251. 35 36 Dixon, G. A.; Bcels, K. G. (1977) Olfactory threshold of chlorine inoxygen. Brooks AFB, TX: USAF School 37 ofAerospace Medicine; report no. SAM-TR-77-22. Available from: Defense Technical Information 38 Center, Alexandria, VA; ADA046015. 39 .. 40 Dodd, D. C; Marshall, B. E.; Soma, L. R.; Leatherman, J. (1976) Experimental acid- m 41 the rabbit: a pathologic and morphometric study. Vet Pathol. 13: 436-448. 42 43 Enarson, D. A; MacLean, L.; Dybuncio, A.; Chan-Yeung, M.; Grzybowski, S.; Johnson, A; Block, G.; 44 Schragg, K. (1984) Respiratory health at apulpnrill inBritish Columbia. Arch. Environ. Health 45 39:325-330. 4* .. 47 Faure, J.; Arsac, P.; Bouissou, X.; Barret, L. (1983) Intoxication par les vapeurs dechlore. Suites mmwdiatiw 48 et tardives [Chlorine gas exposure: early and late sequelae]. Toxicol. Eur. Res. 5: 207-210. 49 . ' . ^ 50 Ferris, B. G., Jr.; Puleo, S.; Chen, H. Y. (1979) Mortality and morbidity inapulp and apaper mill m the 51 United States: a ten-year follow-up. Br. J. Ind. Med. 36: 127-134. 52

August 1990 6-42 DRAFT-DONOTQUOTEORCITE 1 Fisher, N.; Hutchinson, J. B.; Berry, R.; Hardy, J.; Ginocchio, A. V. (1983a) Long-term toxicityand 2 carcinogenicitystudies ofcake made from chlorinated flour: 1. studies in rats. Food Chem. Toxicol. 3 21:427-434. 4 5 Fisher, N.; Berry, R.; Hardy, J. (1983b) Short-term toxicity study in rats ofchlorinated cake flour. Food 6 Chem. Toxicol. 21: 423-426. 7 8 Gapany, M.; Tirosh, M. (1984) Exposure to domestic lung irritants. Harefuah J. Israel Med. Assoc. 9 107: 147-149, 164.

11 GEOMET Technologies, Inc. (1981) Hydrogen chloride: report4, occupational hazard assessment Cincinnati, 12 OH: U. S. Department ofHealth and Human Services, National ft1***?*^ for Occupational Safety and' 13 Health; NIOSH contractno. 210-79-0001. Available from: NTIS, Springfield, VA; PB83-105296. 14 15 Ginocchio, A. V.; Fisher, N.; Hutchinson, J. B.; Berry, R.; Hardy, J. (1983) Long-term toxicity and 16 carcinogenicity studies ofcake made from chlorinated flour: 2, studies in mice. Food Chem. Toxicol. 17 21:435-439. 18 19 Greenfield, L. J.; Singleton, R. P.; McCaffree, D. R.; Coalson, J. J. (1969) Pulmonary effects ofexperimental 20 graded aspiration ofhydrochloricacid. Arm. Surg. 170: 74-86. 21 22 Grimbert, F. A.; Parker, J. C; Taylor, A. E. (1981) Increased pulmonary vascular permeability following acid 23 aspiration. J. Appl. Physiol. 51: 335-345. 24 25 Guidry, M. A.; Allen, J. H.; Kelly, J. B. (1957) Some biochemical characteristics ofhydrochloric-acid injury 26 ofthe cornea: II. Carbohydrate metabolism. Am. J. Ophthalmol. 44: 243-248. 27 28 HartzeU, G. E.; Packham, S. C; Grand, A. F.; Switzer, W. G. (1985) Modeling oftoxicological effects of fire 29 gases: in. quantification of post-exposure lethality ofrats from exposure to HC1 atmospheres. J. Fire 30 Sci. 3: 195-207. 31 32 Hasan, F. M.; Gehshan, A.; Fuleihan, F. J. D. (1983) Resolution of pulmonary dysfunction following acute 33 chlorine exposure. Arch. Environ. Health 38: 76-80. 34 35 Jiang, X. Z.; Buckley, L. A.; Morgan, K. T. (1983) Pathology of toxic responses to the RD50 concentration of 36 chlorine gas in the nasal passages ofrats and mice. Toxicol. Appl. Pharmacol. 71: 225-236. 37 38 Jones, F. L., Jr. (1972) Chlorine poisoning from mixing household cleaners. JAMA J. Am. Med. Assoc. 39 222: 1312. 40 41 Jones, R. N.; Hughes, J. M.; Glindmeyer, H.; Weill, H. (1986) Lung function after acutechlorineexposure. 42 Am. Rev. Respir. Dis. 134: 1190-1195. 43 44 Joyner, R. E.; Durel, E. G. (1962) Accidental liquid chlorine spill in a rural community. JOM J. Occup. Med. 45 4: 152-154. 46 47 Kaplan, H. L. (1987) Effects ofirritant gases on avoidance/escape performance and respiratory responseofdie 48 baboon. Toxicology 47:165-179. 49 50 Kaplan, H. L.; Grand, A. F.; Rogers, W. R.; Switzer, W. G.; HartzeU, G. E. (1984) A research study ofthe 51 assessment ofescapeimpairmentby irritantcombustion gasesin postcrash aircraft fires. Atlantic City 52 Airport, NJ: U. S. Department ofTransportation, Federal Aviation Administration; report no. 53 DOT/FAA/CT-84/16. Available from: NTIS, Springfield, VA; AD-A146484. 54

August 1990 643 DRAFT - DO NOT QUOTE OR CITE 1 Kaplan, H. L.; Anzneto, A; Switzer, W. G.; Hmderer, R. K. (1986) Respiratory effects of hydrogen chloride 2 in the baboon. Toxicologic 6: 52. 3 4 Kaplan, H. L.; Anzueto, A; Switzer, W. G.; Hmderer, R. K. (1988) Effects of hydrogen chloride on 5 respiratory response and pulmonary function of the baboon. J. Toxicol. Environ. Health 23: 473-493. 6 7 Kirsch, V. H.; Drabke, P. (1982) Zur Beurttihmg biologischer Wirkungen von Chlorwasserstoff [Assessing the 8 biological effects of hydrogen chloride]. Z. Gesamte Hyg. Hire grenzgeb. 28: 107-109. 9 10 Home, D. R.; Ulrich, C. E.; Riley, M. G.; Hamrn, T. E., Jr.; Morgan, K. T.; Barrow, C. S. (1987) One- 11 year inhalation toxicity study ofchlorine inRhesus monkeys (Macaco mulatto). Fundam. Appl. Toxicol. 12 9:557-572. 13 14 Kotula, A W.; Emswiler-Rose, B. S.; Cramer, D.V. (1987) Subacute study of rats fed ground beeftreated 15 with aqueous chlorine: hematologic and clinical pathology. J. Toxicol. Environ. Health 20: 401-409. 16 17 Kowitz, T. A.; Reba, R. C; Parker, R. T.; Spicer, W. S., Jr. (1967) Effects of chlorine gas upon respiratory 18 function. Arch. Environ. Health 14: 545-558. 19 20 Krishnan, B.; Rao, A. S. (1981) Surface activity & phospholipid content of saline extract from control & 21 hydrogen chloride exposed lungs. Indian J. Exp. Biol. 19: 637-639. 22 23 Kutzman, R. S. (1983) A study of Fischer-344 rats subchronically exposed to 0, 0.5, 1.5,or5.0 ppm chlorine. 24 Upton, NY: Brookfaaven National Laboratory, National Toxicology Program; pp. 1-3; interagency 25 agreement no. 222-Y01-ES-9-0043. 26 27 Leonardos, G.; Kendall, D.; Barnard, N. (1969) Odor threshold determinations of 53 odorant chemicals. J. Air 28 Pollut Control Assoc. 19: 91-95. 3029 Lipton, M. A.; Rotariu, G. J. (1941) In: Geiling, E. M. K.; McLean, F. C, eds. Progress report on toxicity.. of* 31 chlorine gas for mice. Washington, DC: U. S. National Defense Committee, Office of Scientific 32 Research and Development; report no. 286. [As cited in: Withers and Lees, 1985]. 33 34 Lucia, H. L.; Barrow, C. S.; Stock, M. F.; Alarie, Y. (1977) A semi-quantitative method for assessing 35 anatomic damage sustained by the upper respiratory tract of the laboratory mouse, Mus musculis. J. 36 Combust. Toxicol. 4: 472-486. 37 38 Machle, W.; Kitzmiller, K. V.; Scott, E. W.; Treon, J. F. (1942) The effect of theinhalation of hydrogen 39 chloride. J. Ind. Hyg. Toxicol. 24: 222-225. 40 ^ 41 National Research Council. (1976). Chlorine and hydrogen chloride. Washington, DC: National Academy of 42 Science. 43 44 Oddoy, A.; Drabke, P.; Feigner, U.; Kirsch, H.; Lachmarm, B.; Merker, G.; Robertson, B.; Vogel, J. (1982) 45 Der WbAiibi einer mtermitnerenden Chlorwasserstofrexposition aufdie Lungenfunktion des 46 Meerschweinchens [The effect of intermittent hydrogen chloride gas exposure onthe lung function of the 47 guinea pig]. Z. Erkr. Atmungsorgane 158: 285-290. 48 49 Paril, L. R. S.; Smith, R. G.; Vorwald, A. J.; Mooney, T. F., Jr. (1970) The health of diaphragm cell workers 50 exposed to chlorine. Am. Ind. Hyg. Assoc. J. 31: 678-686. 52 Ploysongsang, Y.; Beach, B. C; Dilisio, R. E. (1982) Pulmonary function changes after acute inhalation of 53 chlorine gas. South. Med. J. 75: 23-26. 54

August 1990 6-44 DRAFT - DO NOT QUOTE OR CITE 1 Prindle, R. A; Elzay, R. P.; Armstrong, C. W.; Funkhouser, L. S.; Miller, G. B., Jr. (1983) Erosion of 2 dental enamel among competitive swimmers • Virginia. Morb. Mortal. Wkly. Rep. 32: 361-362. 3 4 Rafferty, P. (1980) Voluntary chlorine inhalation: a new form ofself-abuse? Br. Med. J. 281: 1178-1179. 5 6 Remijn, B.; Koster, P.; Houthuijs, D.; Boleij,J.; Willems, H.; Brunekreef, B.; Biersteker, K.; 7 van Loveren, C. (1982) Zinc chloride, zinc oxide, hydrochloric acid exposureand dental erosionin a 8 zinc galvanizing plantin the Netherlands. Ann. Occup. Hyg. 25: 299-307. 9 10 Rotman, H. H.; Fliegelman, M. J.; Moore, T.; Smith, R. G.; Anglen, D. M.; Kowalski, C. J.; Weg, J. G. 11 (1983) Effects oflow concentrations ofchlorine on pulmonary function in humans. J. Appl. Physiol. 12 54: 1120-1124. 13 14 Rnpp, H.; Henschler, D. (1967) Effects oflow chlorine andbromineconcentrations on man. Int. Arch. 15 Gewerbepathol. Gewerbehyg. 23: 79-90. 16 17 Savad, E. N. (1982) Enamelerosion ... multiple cases with a common cause(?) J. Natl. Dent. Assoc. 18 53: 32, 35-37, 60. 19 20 Schlagbauer, M.; Henschler, D. (1967) Toxicitaet von Chlor und Brom bei einmaligerund wiederholter 21 Inhalation [Toxicity ofchlorineand bromineafter singleand repeated inhalation]. Int. Arch. 22 Gewerbepathol. Gewerbehyg. 23: 91-98. 23 24 Silver, S. D.; McGrath, F. P. (1942) Chlorine. Medianlethalconcentration data for mice. Edgewood Arsenal, 25 MD: War Department, ChemicalWarfare Service; reportno. E.A.T.R. 351. Available from: Defense 26 Technical Information Center, Alexandria, VA; ADB955268. [As cited in: Withers and Lees, 1985]. 27 28 Silver, S. D.; McGrath, F. P.; Ferguson, R. L. (1942) Chlorine. Median lethal concentration for mice. 29 Edgewood Arsenal, MD: War Department, Chemical Warfare Center; report no. E.A.T.R. 373. 30 Available from: Defense Technical Information Center, Alexandria, VA; ADB955266. [As cited in: 31 Withers and Lees, 1985]. 32 33 Simmons, J. A.; Erdmann, R. C; Naft, B. N. (1974) The risk ofcatastrophic spills of toxic chemicals. Los 34 Angeles, CA University ofCalifornia School of Engineering and Applied Science; reportno. UCLA- 35 ENG-7425. 36 37 Soni, N.; O'Rourke, I.; Pearson, I. (1985) Ingestion ofhydrochloric acid. Med. J. Aust. 142: 471-472. 38 39 Stokinger, H. E. (1981) The halogens and the nonmetals boron and silicon. In: Clayton, G. D.; Clayton, F. E., 40 eds. Patty's industrial hygiene and toxicology: volume 2B, toxicology. 3rd rev. ed. New York, NY: 41 John Wiley & Sons, Inc.; pp. 2959-2961. 42 43 Summer, W.; Haponik, E. (1981) Inhalation ofirritantgases. Clin. Chest Med. 2: 273-287. 44 45 ten Bruggen Cate, H. J. (1968) Dentalerosionin industry. Br. J. Ind. Med. 25: 249-266. 46 47 Toxigenics Incorporated. (1984) 90-day inhalation toxicity study of hydrogen chloride gas in BgC^Fj mice, 48 Sprague-Dawley ratsand Fischer-344 rats. Research TrianglePark, NC: Chemical Industry Institute of 49 Toxicology; CUT docket no. 20915. 50 51 Ulrich, C. E. (1984) Chlorine: chronicinhalation toxicity study on chlorine in non-human primates. Mattawan, 52 MI: International Research and Development Corporation; unpublished; CUT docket no. 480-001. 53

August 1990 6-45 DRAFT - DO NOT QUOTE OR CITE 1 Underbill, F. P. (1920) The lethal wargases: physiology and experimental treatment. New Haven, CT: Yale 2 University Press. 3 4 Vemot, E. H.; MacEwen, J. D.; Haun, C. C; Kinkead, E. R. (1977) Acute toxicity and skincorrosion data 5 for some organic and inorganic compounds and aqueous solutions. Toxicol. Appl. Pharmacol. 6 42:417-423. 7 8 Weedon, F. R.; HartzeU, A.; Setterstrom, C. (1940) Toxicity of ammonia, chlorine, hydrogen cyanide, 9 hydrogen sulphide and sulphur dioxide gases. V. animals. Contrib. Boyce Thompson Inst. 11: 365-385. 10 11 Weill, H.; George, R.; Schwarz, M.; Ziskind, M. (1969) Late evaluation of pulmonary function after acute 12 exposure to chlorine gas. Am, Rev. Respir. Dis. 99: 374-379. 13 14 Weill, H.; Jones, R. N.; Hughes, J.; Glindmeyer, H. W. (1986) Respiratory health following acute chlorine 15 exposure. Thorax 41: 249-250. 16 17 Winn, R.; Stothert, J.; Nadir, B.; Hfldebrandt, J. (1983) Lung mechanics following aspiration of 0.1 N 18 hydrochloric acid. J. Appl. Physiol. 55: 1051-1056. 19 20 Withers, R. M. J.; Lees, F. P. (1985a) The assessment of major hazards: the lethal toxicity of chlorme; part 1, 2i reviewofinformation on toxicity. J. Hazard. Mater. 12: 231-282. 22 23 Withers, R. M. J.; Lees, F. P. (1985b) The assessment of major hazards: the lethal toxicity of chlorine; part 2, 24 modeloftoxicity to man. J. Hazard. Mater. 12: 283-302. 25 26 Withers, R. M. J.; Lees, F. P. (1986) Tne assessment of major hazards: the factors affecting lethal toxicity 27 ^mflteg and the associated uncertainties. In: Hazards in the process industry: hazards 9, a three-day 28 syrnposium; Manchester, United Kingdom, Inst. Chem, Eng. Symp. Ser. (97): 185-199. 29 30 World Health Organization. (1982) Chlorine and hydrogen chloride. Geneva, Switzerland: World Health 31 Organization. (Environmental health criteria 21).

Augustl990 6-46 DRAFT-DONOTQUOTEORCITE i 7. DEVELOPMENTAL TOXICITY AND 2 REPRODUCTIVE EFFECTS

3

4 5 7.1 EXPERIMENTAL ANIMALS

6 7.1.1 Chlorine 7 A number of studies have addressed theteratological and reproductive effectsofingested 8 chlorine and the by-products of w^ter cUorination (hypocUorous addand hypcwUorite). For 9 the most part, chlorine and the by-products of water chlorination were not found to affect 10 reproduction in mice (Les, 1968; Chernoff etal., 1979; Staples etal., 1979) or rats (Carlton 11 et al., 1986; Druckrey, 1968; AMd-Rahman et al., 1982). There was, however, an increase 12 in thenumber of sperm head abnormalities in mice given sodium hypochlorite in drinking 13 water (Meier et al., 1985). A significant increase in the number of soft tissue anomalies has 14 also been reported in rats treated with 100 mg/L hypochlorous add for 2.5 months prior to 15 mating and throughout gestation, but the results of this experiment were limited by the small 16 numbers ofanimals tested and the finding ofa higher rate of soft tissue anomalies in the 17 control group compared tothe low-exposure group (10 mg/mL) (Abdel-Rahman etal., 1982). 18 Only limited information was found on the reproductive and/or teratoSlogical effects of 19 theinhalation ofchlorine gas by experimental animals. In the study by Kutzman (1983), 20 male and female Fischer 344 rats were exposed to 0, 0.5, 1.5, or 5.0 ppmchlorine gas for 21 6 hours/day, 5 days/week for 62 days. Six days after termination of exposure 8 male and 22 10 female rats from each exposure group were mated with unexposed animals. Female/^ats 23 were then sacrificed on day 19 of gestation. Analysis ofthenumber ofviable embryos, late 24 and early reabsorptions, and corpea lutea did not show a chlorine-related effect onthe 25 reproductive potential of dther male or female animals. 26 The only other study on the teratological or reproductive effects ofchlorine inhalation 27 was a study by Skljanskaja and Rappoport (1935), as reported^the World Health Organization •^ 28 (1982). In that study, eigat rabbits were exposed tochlorine gas at concentrations of 0.6to 29 1.5 ppm (1.7 to 4.4 mg/m3), 5hours/day, every other day for 1to 9 months. Only one 30 rabbit served as a control. The animals were said to have delivered healthy, well developed 31 fetuses except for macerated fetuses inthe abdomen of two exposed rabbits. The rabbits were August 1990 7-1 DRAFT-DONOTQUOTEORCITE 1 reported to have exhibited nasal irritation, sneezing, and laboured breathing. 2 Histopathological examination ofthe respiratory tract showed catarrhal inflammation ofthe 3 upper respiratory tract, metaplasia of the bronchi, suppurative bronchitis and pneumonia, 4 pleuritis, emphysema, and atelectasis. There was also granulomas in the brain and other 5 organs and necrosis ofthe liver. The authors believe that all ofthe changes noted in the 6 exposed rabbits were the direct result of the toxic action ofchlorine. However, the World. 7 Health Organization (1982) reported that lesions ofthe nature noted in the exposed rabbits are 8 typical ofseveral infectious diseases common to rabbits.

9 10 7.1.2 Hydrogen Chloride 11 Only two reports were found in the published literature on developmental toxidty and 12 reproductive effects ofinhaled hydrogen chloride. In the first ofthese studies, Pavlova 13 (1976) exposed two groups of 8to 15 female Wistar rats to 302 ppm (450 mg/m3) hydrogen 14 chloride gas for 1 hour; one group was exposed 12 days prior to mating and the other group 15 on day 9ofgestation. In both groups signs ofsevere dyspnea and cyanosis were noted, and 16 mortality occurred in one third ofthe animals. Lungs revealed congestion, edema, and 17 hemorrhage. In addition, exposure lowered blood oxygen saturation, increased absorption of 18 vital dye by lung tissue, and disturbed kidney and liver functions. Fetal mortality was 19 significantly (p <0.05) higher in rats exposed during pregnancy. When the progeny were 20 subjected to an additional exposure of 35 ppm (52 mg/m3) at the age of 2to 3months, 21 functional abnormalities in theorgans of theprogeny were similar to those found in the 22 mothers. Progeny ofdams exposed before pregnancy were affected more severely than were 23 progenies ofthose exposed during pregnancy. In both groups, the male offspring were more 24 sensitive than the females. 25 Inthe other study, female Wistar rats and mixed-strain rats were exposed to 302 ppm 26 (450 mg/m3) hydrogen chloride for 1hour prior to mating. Exposure killed 30 percent of 27 Wistar and 20 percent ofthe mixed-strain rats. Inrats surviving 6 days after exposure, a 28 decrease inblood oxygen saturation was noted, as was kidney, liver, and spleen damage. In 29 addition, treatment altered the estrous cycles. In rats mated 12 to 16 days postexposure and 30 killed on day 21 ofpregnancy, fewer live fetuses, a decrease in fetal wdght, and an increase 31 in relative lung wdghts ofthe fetus were observed (GEOMET Technologies, Inc., 1981).

August 1990 7-2 DRAFT - DO NOT QUOTE OR CITE 1 12 HUMAN STUDIES 2 No adequate studies were found in the literature on developmental toxidty or 3 reproductive effects ofdther chlorine or hydrogen chloride. However, Skljanskaja et al. 4 (1935) followed the pregnandes of 15 female workers who had been exposed for 6 hours/day 5 to levels ofchlorine between 0.9 to 1.8 ppm (2.5 and 5 mg/m3). Although 2of 15 had 6 spontaneous abortions, the authors concluded that thesewere not related to chlorineexposure. 7 The smallnumber ofpregnandes and the lack of a controlgroup precludes any conclusions 8 based on this study.

9

10 11 7.3 REFERENCES

12 13 Abdel-Rahman, M. S.; Berardi, M. R.; Bull, R. J. (1982) Effect ofchlorine and monochloramine in drinking 14 water on the developing rat fetus. JAT J. Appl. Toxicol. 2: 156-159. 15 16 Carlton, B. D.; Barlett, P.; Basaran, A.; Colling, K.; Osis, I.; Smith, M. K. (1986) Reproductive effects of 17 alternative disinfectants. EHP Environ. Health Perspect. 69: 237-241. 18 19 Chemoff, N.; Rogers, E.; Carver, B.; Kavlock, R.; Gray, E. (1979) The fetotoxic potential of municipal 20 drinking water in the mouse. Teratology 19: 165-169. 21 22 Druckrey, H. (1968) Chloriertes Trinkwasser, Toxizitaets-Pruerungen anRatten ueber sieben Generationen 23 [Chlorinated drinking water, toxicity studies in sevengenerations of rats]. Food Cosmet. Toxicol. 6: 24 147-154. 25 26 GEOMET Technologies, Inc. (1981) Hydrogen chloride: report 4, occupational hazard assessment. Cincinnati, 27 OH: U. S. Department ofHealth and Human Services, National Institute for Occupational Safety and 28 Health; NIOSH contract no. 210-79-0001. Available from: NHS, Springfield, VA; PB83-105296. 29 30 Kutzman, R. S. (1983) A study ofFischer-344 rats subchronicalty exposed to 0, 0.5, 1.5, or 5.0 ppm chlorine. 31 Upton, NY: Brookhaven National Laboratory, National Toxicology Program; pp. 1-3; interagency 32 agreement no. 222-Y01-ES-9-0043. 33 34 Les, E. P. (1968) Effect ofacidified-chlorinated water on reproduction in C3H/HeJ andC57BL/6J mice. Lab. 35 Anim. Care 18: 210-213. 36 37 Meier, J. R.; Bull, R. J.; Stober, J. A.; Cimino, M. C. (1985) Evaluation ofchemicals used for drinking water 38 disinfection tor production of chromosomal damage and sperm-head abnormalities in mice. Environ. 39 Mutagen. 7: 201-211. 40 41 Pavlova, T. E. (1976) Disturbance ofdevelopment ofthe progenyofratsexposed to hydrogenchloride. Bull. 42 Exp. Biol. Med. 82: 1078-1081.

August 1990 7-3 DRAFT-DONOTQUOTEORCITE 1 SHjanskaja, R. M.; Raprwport, T. 1^ 2 KaiimchenimtgeriiigenChlorkonzentrationenui^ 3 chlorvergifteten K™™<*<" [Experimental studies on chronic poisoning and the development the offspring 4 of cWorme-poisoned rabbits]. Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 177: 276-287. 6 Skljanskaja. R. M.; Haus, L. M.; Ssidorowa, L. M. (1935) Ueber die Einwiricung des Chlors auf den 7 weiblichen [On the effect ofchlorine on the female organism]. Arch. Hyg. Baktenol. 114: 103-114. 9 Staples, R. E.; Worfliy, W. C; Marks, T. A (1979) Influence of drinking water-tap versus punfied-on 10 embryo and fetal development in mice. Teratology 19: 237-243. 12 World Health Organization. (1982) Chlorine and hydrogen chloride. Geneva, Switzerland: World Health 13 Organization. (Environmental health criteria 21).

August 1990 7-4 DRAFT - DO NOT QUOTE OR CUE i 8. MUTAGENIC AND CARCINOGENIC EFFECTS

2

3 4 8.1 MUTAGENIC EFFECTS

5 8.1.1 Chlorine 6 Chlorine is a highlyreactive compound and consequently the determination ofthe direct 7 mutagenic potential ofchlorine is a difficult undertaking. For instance, a number ofthe 8 chlorine reaction products, chlorinated organic and inorganic compounds formed during the 9 treatment ofdrinking water and waste water, have been shown to possess mutagenic potential 10 in various test systems (Meier et al., 1983; Dolara et al., 1981; Mickey and Holden, 1971; 11 Cumming, 1978; Shin and Lederberg, 1976; Zoeteman et al., 1982; Stover et al., 1983; 12 Rannug et al., 1981; Douglas et al., 1982; Lee et al., 1981) and it hasbeen reported that dry 13 seeds treated with chlorine gas for 25 hours and then sprouted developed chlorophyll 14 mutations at twice the frequency observedin untreated plants (Ehrenberg, 1956). However, 15 there is no indication that chlorine per se is mutagenic in humans or other mammals (National 16 Research Council, 1976). In fact, analysis of metaphase cells ofbone marrow and peripheral 17 bloodlymphocytes for sister chromatid exchange in rats subchronically exposed to up to 18 5 ppm chlorine showed no significant effects. There were also no effects reported on cellular 19 proliferation ofbone marrow cells, the frequency of chromosomal aberrations in peripheral 20 blood lymphocytes, or the morphology of sperm cells in the chlorine exposed rats (see 21 ^Section 6.1.1.2) (Kutzman, 1983).

22 23 8.1.2 Hydrogen Chloride 24 No information was found in the published literature, on the mutagenic potential of 25 hydrogen chloride.

August 1990 8-1 DRAFT - DO NOT QUOTE OR CITE 1 8.2 CARCINOGENIC EFFECTS 2 8.2.1 Experimental Animals

3 8.2.1.1 Chlorine 4 No inhalation carcinogenicity studies were found in the available literature for chlorine. 5 A2-year inhalation study is currently in progress by the Chemical Industry Institute of 6 Toxicology (CIIT). However, there was no increased incidence of malignant tumors » ^ta r^orVcd c/t 7 236 BDII rats given highly cWorinated water (containing 100 mg/L free chlorine) over 8 7 generations (Druckrey, 1968). There was also no increase in malignant tumors in rats fed a 9 cake diet containing 1,250 or 2,500 ppm chlorine for 104 weeks (Fisher etal., 1983).

10 11 8.2.1.2 Hydrogen Chloride 12 No standard carcinogenicity bioassays for hydrogen chloride were found. However, 13 Albert et al. (1982) conducted astudy designed to assess the carcinogenic response of male 14 Sprague-Dawley rats following combined and separate exposures to formaldehyde and 15 hydrogen chloride. The rationale was that bis (chloromethyl) ether, acompound 16 demonstrated to be carcinogenic in mice, rats, and humans, may be formed by the gas-phase 17 reaction ofhydrogen chloride and formaldehyde. Exposure to hydrogen chloride at 18 10.2 ppm, 6hours/day, 5days/week for 382 exposures over 588 days, did not induce any 19 nasal tumors. The addition ofhydrogen chloride gas (10 ppm) to formaldehyde (14 ppm) did 20 not enhance the carcinogenic response of formaldehyde. When hydrogen chloride and 21 formaldehyde were premixed at high concentrations to maximize the formation ofbis 22 (chloromethyl) ether and then diluted 75-fold to give chamber concentrations of10 ppm 23 hydrogen chloride and 14 ppm formaldehyde, there was no clear increase in the carcinogenic 24 response. The authors concluded that under the conditions of the study, hydrogen chloride 25 was not carcinogenic, and that formaldehyde accounted for most if not all ofthe carcinogenic 26 activity ofthe mixture. 27 In similar studies, Sellakumar etal. (1985) concluded that hydrogen chloride did not 28 appreciably influence the nasal carcinogenicity of formaldehyde. Groups of100 male 29 Sprague-Dawley rats were exposed to filtered air, 14 ppm formaldehyde, or 10 ppm hydrogen 30 chloride or to formaldehyde and hydrogen chloride at the above levels, 6 hours/day, 31 5days/week for life. In rats exposed to hydrogen chloride, there were no serious irritating

August 1990 8-2 DRAFT-DONOTQUOTEORCITE 1 effects in the nasal epithelium, norwere there anypreneoplastic or neoplastic lesions. 2 Lesions found in the nasal mucosaofrats exposed to hydrogen chloride included rhinitis 3 (81/99 exposed compared to 72/99 controls), epithelial or squamous hyperplasia 4 (62/99 exposed compared to 51/99 controls), and squamous metaplasia (9/99 exposed 5 compared to 5/99 controls). There was also hyperplasia ofthe larynx (22/99 exposed 6 compared to 2/99 controls) and trachea (26/99 exposedcompared to 2/99 controls).

7 8 8.2.2 Epidemiological Studies 9 It must be kept in mind that when chlorine is used as a disinfectant in drinking water it 10 hasthe potential to form chloroform from the reaction oforganic compounds which persist 11 through the purification process. Chloroform hasbeen shown to be a carcinogenic substance 12 and reported as such by the U.S. Environmental Protection Agency (1985). The overall 13 weight ofevidenceclassification for chloroform hasbeen determined by the Environmental 14 Protection Agency to be B2, meaning there is adequate evidence to-classify chloroform as an 15 animal carcinogen but inadequate evidence in humans. 16 With respect to chlorine itself, the evidence again is not convincing in humans. The 17 following studies appear to be the only epidemiologic studies where there may have been 18 exposure to chlorine or hydrogen chloride. 19 A cohort mortality study (Reeve et al., 1983) was performed on some 1,666 white male 20 employees ofa Texas based chemicalcompany. These employees constituted a 5 percent 21 systematic sample ofan alphabetized list of the production and nonproduction work force 22 from 1940 to 1977. The chief cause of death ofinterest to the researchers was malignant 23 neoplasms ofthe brain since previous studies seem to indicate that employees ofthe 24 refining and chemical industry are subjectto a higher risk ofbrain cancer. Other 25 causes ofdeath were not considered. A further restriction imposed by the researchers on this 26 cohort involved geography and residence, i.e., observed deaths due to a brain tumor were 27 confined to those who were residents ofa fear-county area surrounding the Texas plant. This 28 led the researchers to generatethree sets ofexpected rates from which to calculateexpected 29 deaths. The first (method A) involved the assumption that none of the cohort members had 30 moved from the four-county areaand that each was at risk ofdeath from a brain tumor from 31 the time of first exposure throughthe end ofthe exposureperiodor his death, whichever

August 1990 8-3 DRAFT - DO NOT QUOTE OR CITE 1 came first (person-years). Two other estimates considered that the subjects had migrated 2 outside of the fear-county«f area. In the first of these estimates (method B), person-years were 3 assumed tocease accumulating on the last day of employment. In the second case 4 (method Q expected deaths, calculated in four distinct lengths ofemployment categories, 5 were obtained by multiplying the expected deaths, determined in the first method by the 6 fraction of the number of those persons with malignant neoplasms residing only inthe 7 four-county study area to the total number ofmalignant neoplasms found in all members of

8 the cohort. 9 Altogether some 25 brain tumor deaths were found in this cohort. Included with these 10 deaths were both benign and malignant (nature unspecified) neoplasms ofthe brain and central 11 nervous system. Only 5deaths fell into the latter two categories. Presumably the rates that 12 were used to calculate expected deaths must have also included deaths in these two categories 13 as well, although not explicitly stated. Under the three* different methods described above 14 43.0, 19.7, or 22.9 brain tumor deaths, respectively, would have been expected. Although 15 adjustment method A railed to show any trend, adjustment methods Band Crevealed an 16 increased risk of brain tumors with increasing employment for the segment of the cohort that 17 began work prior to 1945. No statistical analyses were done because ofthe authors 18 uncertainty regarding the handling of asample cohort from amuch larger population. Under 19 adjustment method B, standard mortality ratios (SMRs) were 65, 175, 86, and 214 for 20 persons employed under one year, e&e to four years, feeto 19 years, and 20 years or more. 21 In the group employed for 20 or more years there were 16 observed deaths compared to 22 9.4 expected using this method B. Since these excesses were mostly confined to aperiod of 23 employment prior to 1945 the authors concluded that those hired before 1945 were probably 24 subject to an increased risk ofbrain cancer although no statistical analyses were run since the 25 authors did not know how tocalculate significance based on sample data. 26 Aside from the feet that the authors* main purpose appears to have been to demonstrate 27 the efficacy ofavariation in arather well established methodological design, there has been 28 no effort to tie the slight suggested excesses ofbrain cancer into any likely occupational 29 exposure. The authors' only reference to any possible exposure is astatement, general in 30 nature, that populations employed in the petroleum refining and chemical industries may be at

August 1990 8-4 DRAFT-DONOTQUOTEORCITE 1 increased risk ofdeveloping brain tumors. Presumably they planned to leave the 2 identification ofetiologic agentsto laterresearchers. 3 It seemsthat the authors could have avoided the whole problemof small numbersin the 4 study results ifthey hadbeen morejudicious in their selection of methodologies. The idea of 5 reducing the size ofa cohortto manageable proportions is laudable. However, there are 6 already rather well established ways ofgoing about this thathave been pioneered by the 7 National Institute for Occupational Safety and Health. Taking a systematic random sample of 8 all those employees who ever worked at the plantimplies that the researcher intends to make 9 inferences about the population as a whole concerning maybecertain health conditions that 10 might exist in the plant. But ifthe purpose is to identifycertain agents or departments it 11 might be better to look for commonalities in the individual cases and then define a cohort 12 consisting of only those who have greatest potential for exposure to those commonalities. 13 The shotgun approach utilizedby these authors is inappropriate to identify single agents 14 responsible for an excess in the risk ofa disease. As a result, this paper fells short in its 15 ability to identify any plant department or agent responsible for the suggested excess ofbrain

16 lesions. 17 A second study (Bond et al., 1983) wasundertaken as a sequel to the studythat 18 identified an excess numberofbrain tumorsin the chemical plantin Texas (Reeve et al., 19 1983). Bond and associatesAexamined the brain tumors identified in the study by Reeve and *•*** 20 co-worker^, refined the case definition, conducted amore vigorous case ascertainment, and *" 21 increased the total numberofnet cases of "primary intercranial neoplasms" from 25 to 28. 22 They then conducted a case-control study ofbrain tumors utilizing two matched comparison 23 groups; the purpose of which was to identify a likelyetiologic agent, but nothing specific. 24 Control group A (4 per each case) was selected from all white male noncancerdeaths known 25 to the company. They were matched on thebasis of age at death and year ofdeath. The 26 second control group (group B) was selected from whitemalemembers ofthe 5 percent 27 sample for all eligible cohort employees that formed the basis ofthe original cohort mortality 28 study (Reeve et al., 1983). Cases were matched with controls on the basisofage and 29 duration of employment at the plant. 30 The authors found that the agents to which both cases and controlshad the greatest 31 potential for exposure were chlorine, hydrogen chloride, and sulfur dioxide. Although the

August 1990 8-5 DRAFT-DONOTQUOTEORCITE 1 risk of brain tumors from exposure to all 3 of these agents was elevated when compared with 2 the first control group (A), none were statistically significant. When the second control 3 group (B) was utilized, however, not even the suggestion of an elevated risk appeared. One 4 explanation for the nonsignificant elevated risk seen in control group A isthe lack of test 5 sensitivity since it was based upon small numbers. If all cases of brain cancer had been 6 enumerated from the plant sample, company records, deaths recorded in the4 county area 7 surrounding the plant, and unsolicited reports to the National Institute for Occupational Safety 8 and Health it may have been possible toincrease the power enough todetect arisk. On the 9 other hand, as was pointed out by the author, duration of employment at the plant may have 10 been aconfounder that produced an excess when not adequately controlled for inthe analysis. 11 In feet, when the authors evaluated the length of employment in control group A (employees 12 from the 5 percent sample) they found that the mean length ofemployment was an average of 13 41 man-months longer than that of the cases. They attribute this toa bias introduced from 14 inclusion of greater numbers of skilled laborers in control group A who just happen to have a 15 much longer service (<20 years) with the company. These workers were mainly located in 16 the magnesium department and consequentiy an odds ratio of 1.93 (borderline significant) was 17 found for this department. 18 In addition to controlling for length of employment arequirement should have been 19 considered that a minimum latent period also be stipulated inthe analysis and the brain cancer 20 deaths beevaluated accordingly. Ofnote is the large number of cases (17) listed whose 21 minimum lapse oftime since initial employment was over 20 years. Exposure variable 22 comparisons ofcases with matched controls should have been done for those with 20 or more 23 years oflatency. In feet, 24 ofthe 28 cases were diagnosed with brain cancer more than 24 10years after initial employment 25 Besides the problem with latency there is the problem with the small sample sizes 26 introduced by taking only a5 percent sample ofthose who worked there. A better approach 27 to keep the cohort size manageable might have been to just specify in the definition a 28 requirement that aminimum length ofemployment be achieved before agiven employee be 29 included in the cohort. This would also help to insure that only the niaximally exposed 30 employees be studied. In terms ofwhether or not this study implicated some etiologic agent,

August 1990 8-6 DRAFT-DONOTQUOTEORCITE 1 it fails because of the deficiencies outlined above and ofcourse it also fails to evaluate 2 mortality for othersite-specific cancers from exposure to chlorine or hydrogen chloride. 3 In a latercase-control study, Bond et al. (1985b) identified 26 casesofrenal cancer in 4 former employeesof the sameTexas petrochemical plantpreviously studied by Bond et al. 5 (1983) and Reeve et al. (1983). Only 5 ofthe renal cancer deaths occurring in this group 6 were found as partofthe 5 percentsamplediscussed in the earlier studies. The remaining 7 21 caseswere found as the result ofan intensiveeffort on the partof the company by 8 matching the mortality files ofthe Texas Bureau ofVital Statistics and the M. D. Anderson 9 Hospital andTumor Institute in the 5 county area surrounding the plant. 10 Just as in the earlier study by Bond et al. (1983), two control groups were selected for 11 comparison purposes similar to the control groups of the earlier study ofbrain cancer with 12 certain differences as follows. In control group A, referents were selected from all white 13 male decedents who were partof the samerandom samplethat was chosen earlier minus those 14 who died from cancer. Four controls were matched on the basis ofdate of birth and duration 15 ofemployment. A total of92 decedents were chosen in this manner. 16 The second control group (group B) was selected from the same5 percent sample but 17 without restrictions on vital status. Matching was 4 to 1 on the basis ofdate ofbirth, date of 18 hire, and date oftermination. A total of98 individuals werechosen this way. In neither 19 control group was a 4 to 1 matching possible for every case, however. OcU& r

August 1990 8-7 DRAFT-DONOTQUOTEORCITE 1 these5 workerswere also exposed to asbestos, phenol-formaldehyde resins, tung oil, cell 2 putty, Cab-O-Sil, benzene-sulfonyl chloride, trichloroacetic vinyl-ester resin, and 3 MEK-peroxide. Hence, it wouldbe impossible to determine whichofthe agents above was 4 the one that caused the excess in renal cancer. 5 This studyhas several problems not the least ofwhichis the likelihood thatnot all cases 6 ofrenal cancer in this plant population areenumerated in the-24 cases studied by the author 7 due to the unusual manner in which renal cancer cases were identified. More of them may 8 remain unidentified simply because conventional methods for determining vital status were 9 followed. Furthermore, a simple cohort mortality study might have been the more 10 appropriate choice ofa methodology to be utilized rather than thecase-control method. That 11 this is probably thebetter procedure has apparently been recognized by the current authors. 12 In summary it appears that an apparent excess of renal cancer in the employees who 13 worked in the cell maintenance areaofchlorine productionof this company cannot be 14 attributed to exposure to chlorine because of thelikelihood ofmultiple exposures occurring in 15 workers in that area. As a result, this study cannot be said to provide evidence of a causal 16 relationship between exposure to chlorine and an excess riskofrenal cancer. 17 Another cohort mortality study (Bond et al., 1985a) wascompleted on the 5 percent 18 systematic random sample of all present and past white male employees of the petrochemical 19 plant in Texas that was suspected of being associated with ahigh risk of brain cancer. The 20 initial purpose of the sample was to provide an estimate of the extent of brain cancer tobe 21 found in this plant but later it was decided that this sample could also provide a device for 22 determining directions for additional research on cause-specific mortality. Ultimately this 23 base-line data source provided the material from which several case control studies (Reeve 24 et al., 1983; Bond et al., 1983; Bond et al., 1985b) were derived. 25 Cause-specific mortality was analysed by duration of employment and date of hire. 26 These data provided the basis for developing a surrogate for exposure. Significant excess 27 risks of mortality were found due tototal cancer (71 observed, 55.5 expected), ill-defined 28 conditions (8 observed, 3.3 expected), and all external causes of death (57 observed, 29 40.7 expected). Jn addition, excess cancer mortality was primarily due to significant excess 30 cancer risks of kidney cancer (5 observed, 1.4 expected) and lung cancer (29 observed, 31 17.0 expected) and a nonsignificant excess risk of pancreatic cancer (7 observed,

August 1990 8-8 DRAFT-DONOTQUOTEORCITE 1 3.0 expected). Whentheanalysis was narrowed to onlythose whohad achieved a minimum 2 of 15 years follow-up, only lung cancer remained statistically significant (26 observed, 3 14.8 expected). With theadded requirement that a minimum of 15 years service mustbe 4 achieved, cancer ofthe kidney and lung cancer remained statistically significant as follows: 5 2 persons died with kidney cancer butonly 0.3 were expected and 6 former employees with 6 lung cancer died whileonly 2.3 were expected. 7 The authors mentioned that many chemical agents were present in this plantduring its. 8 operation, i.e., chlorine, caustic, ethylene, ethylene glycol, ethylene dichloride, ethylene 9 dibromide, carbon tetrachloride, styrene, perchlorethylene, plus many organic and inorganic 10 chemicals. Apparently some40,000 persons had beenemployed in this plant from 1940 to

11 1977. 12 A major problemwith this study is the fact that it is a random sampleof the total 13 employed population at this plant in Texas. This limits its utility for identifying causes of 14 death that need to be researched further becausethe power to detect significantcause-specific 15 mortality is of necessity reduced. Approximately 45.6 percent ofthe sample consisted of 16 employees with a duration ofemploymentless than one year. If the authors were concerned 17 with the problem of following a cohortofimmense size it would have been more appropriate 18 to limit the size by selecting only those members ofthe cohort who could be expected to have 19 the greatest potential for exposure, i.e., those members who had worked the longest at the 20 plantand consequently the group most likely to manifested health effects if, in fact, any exist. 21 The authors, in what appears to be a display ofhindsight, assure the reader that they intend to 22 do just that in their discussion section. They statetheir intention to do an "expanded 23 mortality study ofall employeeswith one or more years ofcompany service." 24 In any case, the authors concluded thatit was beyond the scopeofthe study to look for 25 cause-specific agents responsible for me excesses thatwere seen. They do speculate, 26 however, that certain confounders, i.e, smokingand/orregion ofresidence, may have hadan 27 influence. By regionofresidence is meantregional differences in healthcaredelivery, death 28 certification practices, lifestyle factors, or "other" environmental exposures. 29 In conclusion, it would appearthat there is a suggestion ofan association ofcertain 30 cause-specific mortality with employment at this plantbut that it is not possibleto determine

August 1990 8-9 DRAFT-DONOTQUOTEORCITE 1 from this study whether itis due to confounders or to some agent in the workplace. This 2 study is inadequate to conclude that chlorine or hydrogen chloride are responsible. 3 Since there are no adequate epidemiological studies or animal carcinogenicity studies for 4 chlorine and hydrogen chloride inthe present data base, these compounds are classified as 5 Group D, "not classifiable as to human carcinogenicity," based on the weight-of-evidence 6 approach in the current EPA guidelines for carcinogen risk assessment.

August 1990 8-10 DRAFT-DONOTQUOTEORCITE 8.3 REFERENCES

4 Albert, R. E.; SeUakmnar, A R.; Laskin, S.; Kuschner, M.; Nelson, N.; Snyder, C. A. (1982) Gaseous 5 formaldehyde andhydrogen chloride induction ofnasal cancer in the rat JNCI J. Natl. Cancer Inst 68: 6 597-603. 7 8 Bond, G. G.; Cook, R. R.; Wight, P. C; Flores, G. H. (1983) A case-control studyofbrain tumor mortality 9 at a Texas chemical plant JOM J. Occup. Med. 25: 377-386. 10 11 Bond, G. G.; Reeve, G. R.; Ott, M. G.; Waxweiler, R. J. (1985a) Mortality amonga sampleofchemical 12 company employees. Am. J. Ind. Med. 7: 109-121. 13 14 Bond, G. G.; Shellenberger, R. J.; Flores, G. H.; Cook, R. R.; Fishbeck, W. A. (1985b) A case-control study 15 of renalcancermortality at a Texas chemical plant Am. J. Ind. Med. 7: 123-139. 16 17 dimming, R. B. (1978) The potential for increased mutagenic riskto thehuman population due to the products 18 ofwater chlorination. In: Jolley, R. L., ed. Water chlorination: environmentalimpact and health effects, 19 volume 1, proceedings ofthe conference; October 1975; Oak Ridge, TN. Ann Arbor, MI: Ann Arbor 20 Science Publishers, Inc.; pp. 229-241. 21 22 Dolara, P.; Ricci, V.; Burrini, D.; Griffini, O. (1981) Effect ofozonation and chlorination on the mutagenic 23 potential ofdrinking water. Bull. Environ. Contain. Toxicol. 27: 1-6. 24 25 Douglas, G. R.; Bell, R. D. L.; Liu, V. W.; Kamra, O. P. (1982) Mutagenic activity of chlorination-stage pulp 26 and paper mill effluents in a battery of mammalian mutagenicity assays. Environ. Mutagen. 4: 397-398. 27 28 Druckrey, H. (1968) Chloriertes Trinkwasser, Toxizitaets-Pruerungen an Ratten ueber sieben Generationen 29 [Chlorinated drinking water, toxicity studies in seven generations of rats]. Food Cosmet Toxicol. 30 6: 147-154. 31 32 Ehrenbeig, L.; Gustaffsson, A.; Lundqvist, U. (1956) Chemically induced mutation and sterility in barley. Acta 33 Chem. Scand. 10: 492-494. 34 35 Fisher, N.; Hutchinson, J. B.; Berry, R.; Hardy, J.; Ginocchio, A. V. (1983) Long-term toxicity and 36 carcinogenicity studies ofcake made from chlorinated flour: 1. studies in rats. Food Chem. Toxicol. 37 21:427-434. 38 39 Kutzman, R. S. (1983) A study of Fischer-344 rats subchronically exposed to 0, 0.5, 1.5, or 5.0 ppm chlorine. 40 Upton, NY: Brookhaven National Laboratory, National Toxicology Program; pp. 1-3; interagency 41 agreement no. 222-Y01-ES-9-0043. 42 43 Lee, E. G.-H.; Mueller, J. C; Walden, C. C; Stich, H. (1981) Mutagenic properties of pulp mill effluents. 44 Pulp Pap. Can. 82: T149-T154. 45 46 Meier, J. R.; Lingg, R. D.; Bull, R. J. (1983) Formation ofmutagens following chlorination ofhumic acid: a 47 model for mutagen formation duringdrinking watertreatment Mutat Res. 118: 25-41. 48 49 Mickey, G. H.; Holden, H., Jr. (1971) Chromosomal effects of chlorine on mammalian cells in vitro. EMS 50 Newsl. 4: 39-41. 51

August 1990 8-11 DRAFT-DONOTQUOTEORCITE 1 National Research Council. (1976) Chlorine and hydrogen chloride. Washington, DC: Committee on Medical 2 and Biological Effects ofEnvironmental PoUutants; EPA report no. EPA/600/1-76-020. Available from: 3 NTTS, Springfield, VA; PB-253196/0. 4 5 Rannug, U.; Jenssen, D.; Rarnel, C; Eriksson, K.-E.; Kringstad, K. (1981) Mutagenic effects of effluents from 6 chlorine bleaching of pulp. J. Toxicol. Environ. Health 7; 33-47. 7 8 Reeve, G. R.; Bond, G. G.; Lloyd, J. W.; Cook, R. R.; Waxweiler, R. J.; Fishbeck, W. A (1983) An 9 investigation ofbrain tumors among chemical plant employees using asample-based cohort method. JOM 10 J. Occup. Med. 25: 387-393. 12 SeUakumar, A. R.; Snyder, C. A; Solomon, J. J.; Albert, R. E. (1985) Carcinogenicity offormaldehyde and 13 hydrogen chloride inrats. Toxicol. Appl. Pharmacol. 81: 401-406. 1514 Shih, K. L.; Lederberg, J. (1976) Effects of chloramine on Bacillus subtUis deoxyribonucleic acid. J. Bactenol. 16 125:934-945. 18 Stover, E. L.; Cimmung, R. B.; Lee. N. E.; Jolley, R. L. (1983) Chlorine vs ozone at Marlborough, 19 Massachusetts: dismfection and mutagenic activity screening. In: Jolley, R. L.; Brungs, W. A.; Cotruvo, 20 J. A; Dimming, R. B.; Mattice, J. S.; Jacobs, V. A, eds. Water cWorination: environmental impact 21 and health effects, volume 4, book 2, environment, health, and risk, proceedings ofthe fourth 22 conference; October 1981; Pacific Grove, CA Ann Arbor, MI: Arm Arbor Science Publishers, Inc.; 23 PP- 1249-1260. OA.25 U.S. Environmental Protection Agency. (1985) Health assessment document for chloroform. Research Triangle 26 Park NO Office ofHealth and Environmental Assessment, Environmental Criteria and Assessment 27 Office; EPA report no. EPA-600/8-84-004. Available from: NTTS, Springfield, VA; PB86-105004. 2928 Zoeteman, B. C. J.; Hnd.ec, J.; de Greef. E.; Kool, H. J. (1982) MiUagenic activity associated_™th 30 by-products of drinking water dismfection by chlorine, chlonae dioxide, ozone and UV-inadiation. EHP 31 Environ. Health Ferspect 46: 197-205.

August 1990 8-12 DRAFT - DO NOT QUOTE OR CTTE i 9. REGULATIONS AND STANDARDS

2

3 4 9.1 CHLORINE 5 The National Institute for Occupational Safety and Health (1976) recommended a 6 15-minute ceiling concentration of0.5 ppm (1.5 mg/m3) for chlorine in workplace air. The 7 Occupational Safety and Health Administration (OSHA) established a ceiling permissible 8 exposure limit of 1ppm (3 mg/m3) for the gas. The American Conference of Governmental 9 Industrial Hygienists (ACGIH) recommended a tentative 8-hour time weighted average 10 threshold limit value of 0.5 ppm (1.5 mg/m3) for chlorine and a 15-minute short-term 11 exposure threshold limit value of 1ppm (3 mg/m3) (American Conference of Governmental 12 Industrial Hygienists, 1987). These recommendations were based on chroniceffects noted in 13 the lung and digestive system (American Conference ofGovernmental Industrial Hygienists, 14 1986b). 15 The TWA value in Switzerland is 0.5 ppm (1.5 mg/m3) and the MIC value in the USSR 16 is0.3 ppm (1 mg/m3) (International Labor Organization, 1980). The National Research 17 Council (1973) panel on chlorine seta short-term public exposure limit (STPL) of 1.0 ppm 18 for 10 minutes or 0.5 ppm for 30 minutes; this was based on minimum irritation and not 19 health hazard. The same committee set public emergency limits (PELs) of3 ppm for a 20 10-minute exposure and 2 ppm (5.8 mg/m3) for a30 or 60 minute exposure. These levels 21 were based on strong odor and irritation of mucous membranes.

22

23

24 9.2 HYDROGEN CHLORIDE 25 . The Occupational Safety and Health Administration $9&restablished a ceiling 26 permissible exposure limit for hydrogen chloride of 5 ppm (7 mg/m3). American Conference 27 ofGovernmental Industrial Hygienists (1986a) also recommended a ceiling threshold limit 28 value of5 ppm, the concentration presumed to be the borderline for severe irritation effects 29 yet sufficiently low to prevent toxic injury from exposure(American Conferenceof 30 Governmental Industrial Hygienists, 1986b). The National Research Council Subcommittee 31 on HC1 recommended a short-term public exposure limit (STPL) of 4 ppm (6 mg/m3) for

August 1990 9-1 DRAFT-DONOTQUOTEORCITE 1 10 minutes and 2ppm (3 mg/m3) for 30 or 60 minutes. Similarly, public emergency limits 2 (PELs) of 7ppm (10 mg/m3) for 10 minutes and 3ppm (5 mg/m3) for 30 or 60 minutes have 3 been established (GEOMET Technologies, Inc., 1981).

August 1990 9-2 DRAFT - DO NOT QUOTE OR CTIE 9-3 REFERENCES

4 American Conference of Governmental Industrial Hygienists. (1986a) TLVs: threshold limit values for chemical 5 substances in the work environment adopted by ACGIH with intended changes for 1986-1987. 6 Cincinnati, OH: American Conferenceof Governmental Industrial Hygienists; pp. 12, 20. 7 8 American Conference of Governmental Industrial Hygienists. (1986b) Documentation of the thresholdlimit 9 values and biological exposure indices, 5th ed. Cincinnati, OH: American Conference of Governmental 10 Industrial Hygienists, Inc.; pp. 117, 313. 11 12 American Conference of Governmental Industrial Hygienists. (1987) TLVs: thresholdlimit values and biological 13 exposure indices for 1987-1988. Cincinnati, OH: American Conference of Governmental Industrial 14 Hygienists; p. 40. 15 16 Code of Federal Regulations. (1989) Air contaminants-permissibleexposure limits. C. F. R. 29: §1910.1000, 17 table Z-l-A. 18 19 GEOMET Technologies, Inc. (1981) Hydrogen chloride: report 4, occupational hazard assessment. Cincinnati, 20 OH: U.S. Department of Healthand Human Services, National Institute for Occupational Safetyand 21 Health; NIOSH contract no. 210-79-0001. Available from: NTIS, Springfield, VA; PB83-105296. 22 23 International Labor Organization. (1980) Occupational exposure limits for airborne toxic substances. 2nd ed. 24 Geneva, Switzerland. 25 26 National Institute for Occupational Safety and Health. (1976) Criteria for a recommended standard ... 27 occupational exposure to chlorine. Cincinnati, OH: U.S. Department of Health, Education, and Welfare, 28 NIOSH publication no. 76-170. Available from: NTIS, Springfield, VA; PB-266367/2. 29 30 National Research Council. (1973) Guides for short-term exposures of the public to air pollutants. Vm. Guide 31 for chlorine. Washington, DC: U.S. Environmental Protection Agency; report no. NAS/ACT/P-628.9. 32 Available from: NTIS, Springfield, VA; PB-244339.

August 1990 9-3 DRAFT - DO NOT QUOTE OR CITE CHLORINE/HYDROGEN CHLORIDE ADDITIONS Eighty-two patients were treated at a hospital after accidental exposure to chlorine gas from a leaking Industrial unit. All Patients suffered from watering eyes9 sneezing, cough, retrosternal burning, sputum, and dyspnea. Of 82 persons treated, 62 underwent spirometry and 56 underwent flexible fiber optic bronchoscopy on days 2 through 7 postexposure. In a follow-up study of 14 of the chorine exposed victims, nonsmokers were asymptomatic 2 weeks postexposure. Smokers continued to have sputum and were dyspnea 6 months after the exposure. There was also a greater obstructive ration (FEV./FVC; 62.2 ± 10.55 versus 78.55 + 5.24 percent) 6 months following exposure. However, according to the authors, these patients were not symptoraatlcally worse nor was 1t likely that they suffered additional lung damage since they had preexisting lung disease. It was estimated that the subjects were exposed to 30 ppm (87 mg/m3) chlorine. The length of the exposure was not given (Abhyankar et al., 1989).

Givan et al. (1989) reported on a 3 month old, previously healthy female child, who was exposed to chlorine when an Industrial accident occurred near her home. The child had mild respiratory distress with audible wheezing 30 minutes postexposure. Chest radiograph on admission to the hospital was normal. Approximately 2 hours after arrival the child became agitated and tachypnelc and began coughing up clear, foamy sputum. The patient's condition Improved following treatment. However, 1 year after exposure a chest radiograph showed mild hyperinflation and she remained under treatment because of reoccurring coughing and wheezing episodes. The authors concluded that chlorine exposure 1n Infants results in acute respiratory illness that appears to resolve very slowly.

Pherwanl et al. (1989) reported on changes In pulmonary function 1n school children 14 to 15 days following exposure to chlorine from an accidental release. Eighty-four children ages 9 to 17, 60 males and 24 females, were examined for changes 1n VC, FVC, FEV„ FEV7FVC, W1EF, PEFR, and FEF^. Eighty-four age, sex, and height matched children from an ongoing study of pulmonary function measurements in normal children served as controls. There was a statistically significant (p >0.005) decrease in VC, FVC, FEV„ PEFR, and FEF* in the chorine exposed children. The authors reported that there was also another accidental chlorine release on one of the test days.

In another case of accidental exposure to chlorine gas, 88 people, ages 21 to 60 years, were admitted to the hospital with dyspnea, coughing, irritation of the throat and eyes, headaches, giddiness, chest pain, and abdominal discomfort after being exposed to 66 ppm chlorine for almost 1 hour. Pulmonary function test 48 hours postexposure revealed respiratory incapacitation in 62 of the exposed Individuals. Beginning on day 5 postexposure, 56 of the exposed were subjected to bronchoscopy. Of the 56 individuals examined, 12 showed signs of chronic bronchitis, 28 had scattered hemorrhagic spots under the bronchial mucosa, and 7 showed signs of bronchial erosion (Shroff et al., 1988). Cytopathologlc features from bronchial brushing were determined on 28 patients 5 days postexposure. According to the authors, the most significant finding was that termed "Irritation forms" of bronchial epithelial cells. These cells had a rounding of the cytoplasmic borders with a hint of terminal end plates bearing cilia, the nuclei had evidence of chromatolysis, dense nuclear membranes, and pseudonucleoli. In 15 smears there were multinucleated syncytial respiratory epithelial cells with terminal end plates with degenerating cilia. Nonpigmented alveolar macrophages with vacuolated cytoplasm in sheets were noted in 9 smears. Varying degrees of basal-cell and goblet cell hyperplasia with polymorphonuclear leukocytes, alveolar macrophages, and erythrocytes In the background. Proliferating fibroblasts and capillary fragments exhibiting endothelial lining were seen in 7 smears from mucosal erosions. Bronchial brushing were obtained from 7 patients with persistent cough and respiratory distress 15 days postexposure. There were abundant polymorphonuclear,leukocytes, erythrocytes, and pigmented and nonpigmented alveolar macrophages against a necrotic background. There were also fragments of proliferating fibroblasts and hyperplastic basal cells and few columnar epithelial and goblet cells. Bronchial brushing obtained from these same patients 25 days postexposure showed occasional fibrotic fragments, mononuclear cells, pigments and nonpigmented alveolar macrophages, and ciliated columnar and goblet epithelial cells. The authors hypothesized that these patients are at risk of developing obi Iterative bronchiolitis at a later date as a result of the chlorine exposure (Shroff et al., 1988).

*•*