3
Monochloroacetic Acid1
Acute Exposure Guideline Levels

PREFACE

Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). AEGL-1, AEGL-2, and AEGL-3, as appropriate, will be developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and will be distinguished by varying degrees of severity of toxic effects. It is believed that the recommended exposure levels are applicable to the general population, including infants and children and other individuals who may be sensitive or susceptible. The three AEGLs have been defined as follows:


AEGL-1 is the airborne concentration (expressed as parts per million [ppm] or milligrams per cubic meter [mg/m3]) of a substance above which it is

1

This document was prepared by the AEGL Development Team composed of Peter Griem (Forschungs- und Beratungsinstitut Gefahrstoffe GmbH) and Chemical Manager Ernest V. Falke (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guideline reports (NRC 1993, 2001).



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3 Monochloroacetic Acid1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). AEGL-1, AEGL-2, and AEGL-3, as appropriate, will be developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and will be distinguished by varying degrees of severity of toxic effects. It is believed that the recommended exposure levels are applicable to the general population, in- cluding infants and children and other individuals who may be sensitive or sus- ceptible. The three AEGLs have been defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million [ppm] or milligrams per cubic meter [mg/m3]) of a substance above which it is 1 This document was prepared by the AEGL Development Team composed of Peter Griem (Forschungs- und Beratungsinstitut Gefahrstoffe GmbH) and Chemical Manager Ernest V. Falke (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then re- viewed by the National Research Council (NRC) Committee on Acute Exposure Guide- line Levels. The NRC committee has concluded that the AEGLs developed in this docu- ment are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guideline reports (NRC 1993, 2001). 135

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136 Acute Exposure Guideline Levels predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m³) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m³) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild and progressively increasing odor, taste, and sensory irrita- tion or certain asymptomatic, nonsensory effects. With increasing airborne con- centrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold levels for the general public, including sensitive subpopulations, it is recognized that certain individu- als, subject to idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL. SUMMARY Monochloroacetic acid (MCAA) is a colorless crystalline material, which is highly soluble in water and soluble in organic solvents. Its vapor pressure at room temperature is moderate with reported values between 0.2 hectopascals (hPa) (crystalline substance) and 10 hPa (solution in water). MCAA has a pun- gent odor. MCAA is produced by chlorination of acetic acid or hydrolysis of tri- chloroethylene (also known as trichloroethene) using sulfuric acid. The world production capacity was estimated at 362,500 metric tons/year in 1987. MCAA or its sodium salt, sodium monochloroacetate, are used primarily in the indus- trial production of carboxymethyl-cellulose, herbicides, and thioglycolic acid as well as in the production of plastics, pharmaceuticals, flavors, cosmetics, and other organic chemicals. MCAA is an acid (pKa, 2.85) and, therefore, can cause eye and skin irrita- tion upon contact with a diluted MCAA solution and can cause skin corrosion and conjunctival burns upon contact with more concentrated solutions. The sys- temic toxicity of MCAA is caused by inhibition of enzymes of the glycolytic pathway and the tricarboxylic acid cycle. This metabolic blockage damages or- gans with a high-energy demand, such as heart, central nervous system (CNS), and muscles, and leads to metabolic acidosis due to the accumulation of lactic acid and citric acid in the body.

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137 Monochloroacetic Acid No studies are available reporting severe toxic effects in humans after in- halation exposure to MCAA. Mortality was reported in a child after oral uptake of 5-6 milliliters (mL) of an 80% MCAA solution (Rogers 1995). Several lethal accidents have been reported, in which workers were dermally exposed to hot liquid MCAA. An inadequately described study reported an irritation threshold of 1.48 ppm (Maksimov and Dubinina 1974); no respiratory tract irritation, ef- fects on lung function parameters, or irritation of skin and mucous membranes were reported for more than 33 workers potentially exposed to MCAA concen- trations between <0.13 ppm for 3 h and 0.31 ppm for 7 h (Clariant GmbH, un- published material, 2000). The only animal study reporting lethal effects after inhalation exposure was an inadequately described study in which an LC50 (concentration with 50% lethality) of 46.8 ppm for 4 h was reported for rats (Maksimov and Dubinina 1974). Several studies report lethal effects after oral exposure with LD50 values mostly between 50 and 200 mg/kg for rats, mice and guinea pigs. In a single inhalation experiment on rats, eye squint and slight lethargy were observed dur- ing exposure to an analytic concentration of 66 ppm for 1 h (Dow Chemical Co. 1987). In an inadequately reported study, an irritation threshold in rats of 6.16 ppm and a no-observed-effect level (NOEL) for histologic changes in the respi- ratory tract in rats and guinea pigs of 1.5 ppm after 4 months have been reported (Maksimov and Dubinina 1974). No relevant studies of adequate quality were available for the derivation of the AEGL-1. Therefore, AEGL-1 values were not recommended because of in- sufficient data. Due to the lack of an adequately performed study reporting an odor threshold for MCAA, no level of distinct odor awareness (LOA) was de- rived. The AEGL-2 was based on a single inhalation study of MCAA in rats (Dow Chemical Co. 1987) in which eye squint and lethargy were observed in rats exposure to 66 ppm for 1 h. A total uncertainty factor of 10 was used. An uncertainty factor of 3 was applied for interspecies variability (1) because the effect level was considered below that of an AEGL-2, (2) because the available data on acute oral lethality do not point at a large interspecies variability for more severe (lethal) effects, and (3) because of the limited toxicodynamic vari- ability, as the enzymes inhibited by MCAA do not vary considerably within and between species. An uncertainty factor of 3 was applied for intraspecies variabil- ity because of the limited toxicokinetic variability with respect to local effects and because of the limited toxicodynamic variability with respect to systemic effects, as the enzymes inhibited by MCAA do not vary considerably within and between species. The other exposure duration-specific values were derived by time scaling according to the dose-response regression equation Cn × t = k, using the default of n = 3 for shorter exposure periods and n = 1 for longer exposure periods, due to the lack of suitable experimental data for deriving the concentra- tion exponent. No relevant studies of adequate quality were available for the derivation of the AEGL-3 value. Therefore, due to insufficient data and the uncertainties of a

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138 Acute Exposure Guideline Levels route-to-route extrapolation, AEGL-3 values were not recommended. The AEGLs are summarized in Table 3-1. 1. INTRODUCTION MCAA is a colorless crystalline material, which is highly soluble in water and soluble in organic solvents. MCAA is produced by chlorination of acetic acid or hydrolysis of tri- chloroethylene using sulfuric acid (BUA 1994). (1) The chlorination of acetic acid is carried out in liquid phase at temperatures between 85° and 120°C. Ace- tic anhydride and acetylchloride may be used as catalysts. The chlorination product contains considerable amounts of acetic acid and dichloroacetic acid. Purification takes place either by selective dechlorination of dichloroacetic acid and subsequent distillation, or by recrystallization from suitable solvents (ECB 2005). (2) Trichloroethylene and sulfuric acid are heated to 130-140°C in the reactor. A mixture of trichloroethylene and sulfuric acid is continuously fed to the bottom of the reactor. The chloroacetic acid and sulfuric acid are permitted to overflow into a cascade, where the chloroacetic acid is distilled at 20 mm Hg, and the sulfuric acid is recycled. The hydrolysis of trichloroethylene yields high- purity MCAA, but has the disadvantage of utilizing a relatively more expensive starting material (ECB 2005). The world production capacity was estimated at 362,500 metric tons/year in 1987 (KEMI 1994). Europe produced about 145,000 metric tons in 1999 (ECB 2005), and the United States produced about 39,000 metric tons in 1989 (OECD 1996). Imports into the United States comprised about 17,000 metric tons of chloroacetic acids in 2003 (USITA 2004). The TRI database (DHHS 2008) lists 17 sites in the United States where production and use of MCAA causes emissions to the air. TABLE 3-1 Summary of AEGL Values for Monochloroacetic Acida End Point Classification 10 min 30 min 1h 4h 8h (Reference) N.R.b AEGL-1 N.R. N.R. N.R. N.R. Insufficient data (Nondisabling) AEGL-2 12 ppm 8.3 ppm 6.6 ppm 1.7 ppm 0.83 ppm Eye squint and (Disabling) (47 (33 (26 (6.7 (3.3 lethargy in rats mg/m³) mg/m³) mg/m³) mg/m³) mg/m³) (Dow Chemical Co. 1987) AEGL-3 N.R. N.R. N.R. N.R. N.R. Insufficient data (Lethal) a Skin contact with molten MCAA or MCAA solutions should be avoided; dermal penetration is rapid, and fatal intoxications have been observed when 10% or more of the body surface was involved. b Not recommended because of insufficient data.

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139 Monochloroacetic Acid MCAA is pumped in molten form (about 80°C) or as 80% aqueous solu- tion through pipes on industrial sites and is also transported in molten form in tank trucks and rail tank cars between industrial sites (ECETOC 1999; ECB 2005). Therefore, an inhalation exposure during accidental releases cannot be ruled out (ECETOC 1999), although no case of severe intoxication by inhalation has been published in the literature. MCAA or its sodium salt, sodium monochloroacetate, are used primarily in the industrial production of carboxymethylcellulose, herbicides, thioglycolic acid as well as in the production of plastics, pharmaceuticals, flavors, cosmetics, and other organic chemicals (KEMI 1994; ECB 2005). Haloacetic acids, including MCAA, are a group of chemicals that are formed along with other drinking-water disinfection byproducts (e.g., triha- lomethanes) when chlorine or other disinfectants used to control microbial con- taminants in the water react with naturally occurring organic and inorganic mat- ter in water. Depending on the amount of bromide in the source water, varying amounts of chlorinated, brominated, and mixed bromochlorohaloacetic acids are produced. EPA (63 Fed. Reg. 69390 [1998]) published the stage 1 Disinfec- tants/Disinfection Byproducts Rule to regulate a group of five haloacetic acids at a maximum contaminant level of 0.06 mg/L (60 ppb) annual average. A very small inhalation exposure might result from this water contamination. Xu and Weisel (2003) measured an aerosol-bound concentration of haloacetic acids at 6.3 nanograms (ng)/m³ during showering with water containing haloacetic acids at 250 µg/L. Chemical and physical properties of MCAA are listed in Table 3-2. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality Deaths after inhalation of MCAA have not been reported in the literature (ECETOC 1999). Lethal effects have occurred after oral intoxication and after dermal exposure to hot, liquid MCAA (BUA 1994; IUCLID 1996; ECETOC 1999). Some of these incidences are described in the following paragraphs. Feldhaus et al. (1993) and Rogers (1995) reported a case study of a fatal acute oral exposure. A 5-year old girl was accidentally given 5-6 mL of an 80% MCAA-containing wart remover. One and one- half hours after exposure, she developed refractory ventricular tachycardia, pulmonary edema, and acidemia. The patient died 8 h after ingestion despite medical intervention. An autopsy revealed diffuse gastric erosions, fatty infiltration of the liver, and pulmonary and cerebral edema. The postmortem MCAA concentration in serum was 100 mg/L as determined by gas chromatography and mass spectroscopy. The expo- sure corresponds to an oral dose of about 200-240 mg/kg (see section 7.1). Fatal cases and life-threatening poisonings in workers have been described after skin contact (BUA 1994; IUCLID 1996): Christofano et al. (1970) reported

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140 Acute Exposure Guideline Levels TABLE 3-2 Chemical and Physical Data for MCAA Parameter Data Reference Molecular formula ClCH2-COOH (C2H3ClO2) NTP 1992 Molecular weight 94.5 g/mol NTP 1992 CAS Registry 79-11-8 NTP 1992 Number Physical state Solid NTP 1992 Color Colorless NTP 1992 Synonyms Chloroacetic acid; monochloroethanoic OECD 1996; Greim acid; chloroethanoic acid; 1998 Monochloressigsäure; Chlorethansäure Vapor pressure 0.1 mm Hg (at 20°C) Dow Chemical Co. 1987 ca. 0.2 hPa (crystalline substance at 20°C) Greim 1998 1 hPa (at 20°C) IUCLID 1996 10 hPa (solution in water at 20°C) IUCLID 1996 1 mm Hg (at 43°C) Weast 1984 4.4 hPa (liquid at 65°C) IUCLID 1996 8.23 mm Hg (at 80°C) Dow Chemical Co. 1987 10 mm Hg (at 81°C) Weast 1984 40 mm Hg (at 109.2°C) Weast 1984 100 mm Hg (at 130.7°C) Weast 1984 400 hPa (at 169°C) Weast 1984 Density 1.58 g/cm³ (solid) OECD 1996 13,707 g/cm³ (liquid) Melting point 63°C (-crystalline form, common form) Weast 1984 56.2°C (-crystalline form) 52.5°C (-crystalline form) Boiling point 187.8°C (-crystalline form) Weast 1984 187.9°C (-crystalline form) 187.8°C (-crystalline form) Solubility Very soluble in water (4,210 g/L at 20°C); IUCLID 1996; BG soluble in methanol, ethanol, acetone, ether, Chemie 1993; Weast dioxane, DMF, DMSO 1984 2.85 Weast 1984 Acidity, pKa Odor Pungent odor ICPS & CEC 1994 Explosive limits in No data air 1 ppm = 3.92 mg/m3 (at 1,013 hPa, 25°C) Conversion factors BG Chemie 1993 1 mg/m3 = 0.26 ppm (at 1,013 hPa, 25°C) a case, in which about 10% of the body surface was contaminated with warm MCAA solution. Although the contaminated skin was immediately rinsed with water for more than 1 h, first-grade burns, anxiety, restlessness, and shock de- veloped, followed by death about 10 h after the accident. Ruty et al. (1988) re-

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141 Monochloroacetic Acid ported on the case of a 47-year-old worker, who had pressurized, molten (about 90°C) MCAA squirted on both legs. Although the legs were immediately rinsed with water, 6% of the body area showed first-grade burns. Four hours after the accident, nausea, vomiting, cardiovascular shock, unconsciousness, and coma developed. Arrhythmia, hypotension, and severe metabolic acidosis were found. The patient was treated with ethanol, an effective antidote for fluoroacetic acid intoxications. His symptoms ameliorated after 24 h, and the patient returned to work 3 months later. Kulling et al. (1992) reported the case of a 38-year-old man who was splashed with an 80% MCAA solution on 25-30% of his body surface. On admission to hospital 1 h after the accident, he had epidermal and dermal superficial burns and showed slight disorientation. One hour later, he developed agitation, cardiac failure and coma. He later developed severe metabolic acido- sis, rhabdomyolysis, renal insufficiency, and cerebral edema and died on day 8 after the accident because of severe CNS damage. 2.2. Nonlethal Toxicity Clariant GmbH (unpublished material, 2000) reported that routine medical examinations of workers of two plants, producing MCAA and sodium monochloroacetate, respectively, revealed no respiratory tract irritation, effects on lung-function parameters, or irritation of skin and mucous membranes. The number of potentially exposed workers was 33 in one plant and not stated for the other. Concentrations of MCAA and sodium monochloroacetate, respectively, were measured at individual workplaces about every 1 to 2 years between 1991 and 2000. Measurements were carried out either as area or personal sampling by drawing a defined volume of air through a 0.01-mol/L sodium hydroxide solu- tion during a time period between 275 and 430 min followed by ion chromatog- raphy analysis. Results are given in Table 3-3. Maksimov and Dubinina (1974) and Rodionova and Ivanov (1979) re- ported an irritation threshold for humans of 5.7 mg/m³ (1.48 ppm) (for this study, an exposure time of 1 min was stated in Izmerov et al. [1982]). The ex- perimental details were not described by the authors. An odor threshold of 0.01 ppm cited from an unpublished correspondence from Dow Chemical Co. was reported by AIHA (1993). Oelert and Florian (1972) cited an odor threshold of 0.045 ppm; however, the authors did not state whether this value was taken from the literature or whether and how they meas- ured the odor threshold. Knapp (1923) reported a case in which occupational exposure to MCAA had resulted in severe damage of the cornea (keratitis traumatica), but did not provide details of the exposure. Morrison and Leake (1941) reported that daily oral exposure for 60 days to 300 mL of a 0.05% MCAA solution in water did not result in adverse effects in three human volunteers. The exposure corresponds to an oral dose of about 2.1 mg/kg/day (d) (see section 6.1).

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142 Acute Exposure Guideline Levels TABLE 3-3 Results of Monochloroacetic Acid Measurements at Workplace Number of Workers and Exposure Time Workplace Individual MCAA Concentrations Measured Per Workshift Plant Situation Between 1991 and 2000 SMCA Area of Area sampling; 1 person for 1 h production rollers for 1, <1, <1, 1, 1, 1, 1 mg/m³ (MCAA measured) production (0.26, <0.26, <0.26, 0.26, 0.26, 0.26, of MCAA 0.26 ppm) flakes SMCA Filling of Personal sampling; Max. 4 persons production MCAA <1, 1.2, 1, <1, 1 mg/m³ (MCAA measured) for 7 h flakes (<0.26, 0.31, 0.26, <0.26, 0.26 ppm) SMCA SMCA Area sampling; 1 person for 1 h production mixer 0.81, 0.89 mg/m³ (SMCA measured) (0.21, 0.23 ppm) SMCA Filling of Personal sampling; 1 person for 6 h production bags with 0.49, 0.45, <0.40 mg/m³ (SMCA measured) SMCA (0.13, 0.12, <0.10 ppm) MCAA Round and Personal sampling; 8 persons for 3 h production sampling <1, <1, <1,<1,<1, <1, <1, <1,<1,<1, 0.8, <0.5, men work <0.5, <0.5, <0.5, <0.5, <0.5 mg/m³ (MCAA area in five measured) buildings (<0.26, <0.26, <0.26, <0.26, <0.26, <0.26, <0.26, <0.26, <0.26, <0.26, 0.21, <0.13, <0.13, <0.13, <0.13, <0.13, <0.13 ppm) Abbreviations: SMCA; sodium monochloroacetate; MCAA, monochloroacetic acid. Source: Adapted from Clariant GmbH, upublished material, 2000. 2.3. Reproductive and Developmental Toxicity No studies documenting developmental or reproductive effects of MCAA in humans were identified (IUCLID 1996; MEDLINE and TOXLINE search, No- vember 2003). 2.4. Genotoxicity No studies documenting genotoxic effects of MCAA in humans were identified (IUCLID 1996; Greim 1998; MEDLINE and TOXLINE search, Novem- ber 2003). 2.5. Carcinogenicity No studies documenting carcinogenic effects of MCAA in humans were identified (IUCLID 1996; Greim 1998; MEDLINE and TOXLINE search, Novem- ber 2003).

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143 Monochloroacetic Acid 2.6. Summary No studies are available on severe toxic effects in humans after inhalation exposure to MCAA. An inadequately described study reported an irritation threshold of 1.48 ppm (Maksimov and Dubinina 1974; Rodionova and Ivanov 1979); no respiratory tract irritation, effects on lung-function parameters or irri- tation of skin and mucous membranes were reported for more than 33 workers potentially exposed to MCAA concentrations at less than 0.13 ppm for 3 h and at 0.31 ppm for 7 h (Clariant GmbH, unpublished material, 2000). Mortality of a child was reported after oral uptake of 5-6 mL of an 80% MCAA solution (Feldhaus et al. 1993; Rogers 1995). Several lethal accidents were reported in which workers were dermally exposed to hot liquid MCAA or aqueous MCAA solutions (BUA 1994; IUCLID 1996; ECETOC 1999). 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality Several studies are available that report oral lethal doses of MCAA in dif- ferent animal species. The oral lethality data are summarized in Table 3-4. Only one study was found that reported lethal effects after inhalation exposure. 3.1.1. Nonhuman Primates In a metabolic study, Dow Chemical Co. (1976) administered MCAA in- travenously to one male rhesus monkey. The animal was given 75 mg/kg on day 1 and 200 mg/kg on day 2. It died 2 h after the second dose. No signs of toxicity other than vomiting were reported; the cause of death remained undetermined. (Note: The study would be ethically unacceptable today.) 3.1.2. Rats Maksimov and Dubinina (1974) observed no deaths in albino rats exposed to MCAA vapor at 5 mg/m³ (1.3 ppm). (The authors stated that this was the maximum achievable vapor concentration at 20°C.) When MCAA was heated to 95°C and rats were exposed to the condensed aerosol, the authors reported an LC50 of 180 (146-221) mg/m³ (46.8 ppm) for 4 h (exposure duration taken from Izmerov et al. 1982). The experimental details were not described by the au- thors. Hoechst AG (1979a) administered 1% (weight/volume[w/v]) solutions of MCAA in water to groups of 10 female Wistar rats that were deprived of food for 16 h before and 2 h after gavage. The post-exposure observation period was

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TABLE 3-4 Summary of Acute Oral Lethal Doses in Laboratory Animals 144 Species Dose (mg/kg) Study Type/Size Type of MCAA solution Signs and Symptoms Reference No details reported Anorexia, ruminal atony, diarrhea, Dalgaard-Mikkelsen and Cattle 100 1 animal fibrillar muscle twitchings, survived Rasmussen 1961 1 animal Colic, diarrhea, generalized muscle 150 twitching, dyspnea, death after 9 h Rabbit 90 Neutralized solution Apathy Woodard et al. 1941 LD50 (no details reported) Guinea pig 79.8 Neutralized solution Apathy Woodard et al. 1941 LD50 (10 animals/group) Rat 102 Non-neutralized solution Central nervous system effects, death Berardi 1986 LD50 (4 rats/group) in water after 1-4 h Rat 90.4 1% solution in water Restlessness, crouching, balance Hoechst AG 1979a LD50 (10 rats/group) disturbance, prone position, passiveness, drowsiness, incomplete eyelid closure, discharge from the eyes and dyspnea Rat 76.2 Neutralized solution Apathy Woodard et al. 1941 LD50 (5-20 rats/group) Rat 55 10% non-neutralized Not reported Maksimov and LD50 Dubinina 1974 (no details reported) solution in water 580 10% neutralized solution LD50 (no details reported) Mouse 260 Non-neutralized solution Immobility, ataxia, slight tremors, Berardi and Snyder1983 LD50 (8-10 mice/group) labored respiration, death after 3-6 h Mouse 255 Neutralized solution Apathy Woodard et al. 1941 LD50 (10 mice/group)

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Mouse 165 No details reported Respiratory paralysis Morrison and LD50 (no details reported) Leake 1941 Christiansen and Goose 50 2 animals No details reported No symptoms Dalgaard-Mikkelsen 1961 Same animals, Incoordination, seizures, death after 75 2 wk later 4-6 h 145

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Consistency of Data for Monochloroacetic Acid with Derived AEGL Values 100.00 Human - No effect Human - Discomfort 10.00 Human - Disabling Animal - No effect Animal - Discomfort Animal - Disabling Animal - Some Lethality AEGL - 2 Animal - Lethal AEGL 1.00 Concentration (ppm) 0.10 0 60 120 180 240 300 360 420 480 Time (minutes) FIGURE 3-2 Categorical representation of all MCAA inhalation data. 167

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168 Acute Exposure Guideline Levels TABLE 3-9 Extant Standards and Guidelines for Monochloroacetic Acid Exposure Duration Guideline 10 min 30 min 1h 4h 8h AEGL-1 N.R. N.R. N.R. N.R. N.R. AEGL-2 12 ppm 8.3 ppm 6.6 ppm 1.7 ppm 0.83 ppm AEGL-3 N.R. N.R. N.R. N.R. N.R. REL-TWA (AIHA)a 0.26 ppm 1 mg/m³ STEL (AIHA)b 1.0 ppm (4 mg/m³) for 15 min MAK (Germany)c 1.0 ppm MAC-Peak Category 1.0 ppm (The Netherlands)d (4 mg/m³) a AIHA TWA (American Industrial Hygiene Association 1993) is defined as the time-weighted average concentration for a normal 8-h workday and a 40-h workweek, to which nearly all workers may be repeatedly exposed, day after day, without adverse effect. b AIHA STEL (American Industrial Hygiene Association 1984) (AIHA 1993) is defined as a 15-min TWA exposure that should not be exceeded at any time during the workday. c MAK (maximale Arbeitsplatzkonzentration [maximum workplace concentration]) (Deutsche Forschungsgemeinschaft [German Research Association]) is defined analogous to the ACGIH Threshold Limit Value–time-weighted average (TLV-TWA). The peak category is 1; MCAA has a skin notation (BMAS 2000). d MAC (maximaal aanvaarde concentratie [maximal accepted concentration–peak category]) (MSZW 2004) is defined analogous to the AIHA TWA. Abbreviation: N.R., not recommended. 8.3. Data Adequacy and Research Needs Definitive, high-quality studies assessing health effects of MCAA after single or repeated inhalation exposure in humans or experimental animals are not available. Due to insufficient data, AEGL-1 and AEGL-3 values were not derived. The derivation of AEGL-2 was based on a single 1-h inhalation exposure study on rats using a single concentration. Single inhalation exposure studies focusing on lethal effects in animals and irritative effects in animals and humans would allow for more precisely de- fining the thresholds for the three AEGLs. 9. REFERENCES AIHA (American Industrial Hygiene Association). 1993. Monochloroacetic Acid. Work- place Environmental Exposure Levels. American Industrial Hygiene Association, Fairfax, VA.

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169 Monochloroacetic Acid Berardi, M.R. 1986. Monochloroacetic Acid Toxicity in the Mouse Associated with Blood-Brain Barrier Damage. Ph.D. Dissertation. Rutgers, State University of New Jersey, New Brunswick, NJ. Berardi, M., and R. Snyder 1983. Toxicity and pharmacokinetics of monochloroacetic acid. Pharmacologist 25:228 (as cited in BG Chemie 1993). Berardi, M.R., R. Snyder, R.S. Waritz, and K.R. Cooper. 1987. Monochloroacetic acid toxicity in the mouse associated with blood-brain barrier damage. Fundam. Appl. Toxicol. 9(3):469-479. BG Chemie (Berufsgenossenschaft der Chemischen Industrie). 1993. Monochlores- sigsäure. Toxikologische Bewertungen Nr. 23. Berufsgenossenschaft der Chemis- chen Industrie, Heidelberg. Bhat, H.K., M.F. Kanz, G.A. Campbell, and G.A. Ansari. 1991. Ninety day toxicity study of chloroacetic acids in rats. Fundam. Appl. Toxicol. 17(2):240-253. Bhunya, S.P., and P. Das. 1987. Bone marrow chromosome aberration and sperm abnor- mality in mice in vivo induced by monochloroacetic acid (MCA). Chromsome Inf. Serv. (42):28-30. BIBRA (The British Industrial Biological Research Association). 1997. Toxicity Profile: Chloroacetic Acid. TNO BIBRA International Ltd., Carshalton, Surrey, UK. BMAS (Bundesministerium für Arbeit und Soziales). 2000. Grenzwerte in der Luft am Arbeitsplatz. TRGS 900. In Gefahrstoffe: Kommentar zu Chemikaliengesetz und Gefahrstoffverordnung, Band 2, Lieferung 4/00, M. Nöthlichs, ed. Berlin, Ger- many: Erich Schmidt. Bryant, B.J., M.P. Jokinen, S.L. Eustis, M.B. Thompson, and K.M. Abdo. 1992. Toxicity of monochloroacetic acid administered by gavage to F344 rats and B6C3F1 mice for up to 13 weeks. Toxicology 72(1):77-87. BUA (Beratergremium für Umweltrelevante Altstoffe). 1994. Monochloressigsäure, Na- triummonochloracetat, BUA-Stoffbericht 127. Stuttgart: Hirzel. Christiansen, M., and S. Dalgaard-Mikkelsen. 1961. Toxic effects of monochloroacetic acid on geese. Acta Pharmacol. Toxicol. 18:179-182 (as cited in BG Chemie 1993). Christofano, E.E., J.P. Frawley, H.L. Reed, and K.L. Keplinger. 1970. Skin exposure to monochloroacetic acid. Am. Ind. Hyg. Assoc. J. 31(2):35. Dalgaard-Mikkelsen, S., and F. Rasmussen. 1961. Toksiciteten af monokloracetat for kvaeg. Nord. Vet. Med. 13:271-279. Daniel, F.B., M. Robinson, J.A. Stober, N.P. Page, and G.R. Olson. 1991. Ninety-day toxicity study of sodium monochloroacetate in Sprague-Dawley rats. Toxicology 67(2):171-185. DeAngelo, A.B., F.B. Daniel, B.M. Most, and G.R. Olson. 1997. Failure of mono- chloroacetic acid and trichloroacetic acid administered in the drinking water to produce liver cancer in male F344/N rats. J. Toxicol. Environ. Health 52(5):425- 445. DHHS (U.S. Department of Health and Human Services). 2008. Chloroacetic Acid (79- 11-8). TRI Release: 2004. TOXMAP, Specialized Information Services. National Institutes of Health, U.S. Department of Health and Human Services [online]. Available: http://toxmap.nlm.nih.gov/toxmap/main/index.jsp [accessed June 9, 2008]. Dow Chemical Co. 1976. Study of Monochloroacetic Acid: Pharmacokinetics, Metabo- lism and Potential Antidotes. Dow Chemical Company, Midland, MI. Dow Chemical Co. 1987. Monochloroacetic Acid: An Acute Vapor Inhalation Limit Study with Fischer 344 Rats. Dow Chemical Company, Midland, MI.

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170 Acute Exposure Guideline Levels ECB (European Chemicals Bureau). 2005. Monochloroacetic Acid (MCAA). CAS No: 79-11-8. EINECS No: 201-178-4. Summary Risk Assessment Report. Institute for Health and Consumer Protection, European Chemicals Bureau, Ispra, Italy [online]. Available: http://ecb.jrc.it/DOCUMENTS/Existing-Chemicals/RISK_ ASSESSMENT/SUMMARY/mcaasum320.pdf [accessed June 9, 2008]. ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals). 1999. Monochloroacetic Acid (CAS No. 79-11-8) and its Sodium Salt (CAS No. 3926- 62-3). Joint Assessement of Commodity Chemicals No. 38. European Centre for Ecotoxicology and Toxicology of Chemicals, Brussels, Belgium [online]. Avail- able: http://staging.idweaver.com/ECETOC/Documents/JACC%20038.pdf [ac- cessed June 16, 2008]. Elf Atochem. 1995. Acute Intravenous Toxicity in Male Rats with Monochloroacetic Acid. CIT study No. 12052 TAR (as cited in ECETOC 1999). EPA (U.S. Environmental Protection Agency). 1988. Recommandations for and Docu- mentation of Biological Values for Use in Risk Assessment. EPA/600/6-87/008. Environmental Criteria and Assessment Office, Office of Health and Environ- mental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Cincinnati, OH. February 1988 [online]. Available: http:// cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=34855 [accessed June 10, 2008]. Feldhaus, K., D. Hudson, D. Rogers, R.S. Horowitz, J. Brent, R.C. Dart, and H. Gomez. 1993. Pediatric fatality associated with accidental oral administration of monochloroacetic acid (MCA). Vet. Hum. Toxicol. 35:344. Greim, H., ed. 1998. Monochloressigsäure. In Gesundheitsschädliche Arbeitsstoffe: Toxikologisch-arbeitsmedizinische Begründungen von MAK-Werten, Loseblatt- samm-lung 26. Lfg. Weinheim: WILEY-VCH Verlag. Hercules. 1969a. Acute Vapor Inhalation Toxicity Study on Monochloroacetic Acid. IBT report No. N7789 (as cited in ECETOC 1999). Hercules. 1969b. Acute Vapor Inhalation Toxicity Study on Monochloroacetic Acid. IBT report No. N7646 (as cited in ECETOC 1999). Hayes, F.D., P.J. Gehring, and J.E. Gibson. 1972. Studies on the acute toxicity of monochloroacetic acid in rats. Toxicol. Appl. Pharmacol. 22(2)303 (Abstract No. 76). Hayes, F.D., R.D. Short, and J.E. Gibson. 1973. Differential toxicity of monochloroace- tate, monofluoroacetate, and monoiodoacetate in rats. Toxicol. Appl. Pharmacol. 26(1):93-102. Hoechst AG. 1979a. Akute orale Toxizität von Monochloressigsäure VA 2308 an weiblichen Ratten. Report No. 232/79, Hoechst AG, Pharma Forschung Toxikolo- gie (as cited in ECOTOC 1999). Hoechst AG. 1979b. Akute orale Toxizität von Monochloressigsäureäthylester an weib- lichen Ratten. Report No. 237/79. Hoechst AG, Pharma Forschung Toxikologie. 29.5.1979. Hoechst AG. 1979c. Akute orale Toxizität von Monochloressigsäuremethylester an weib- lichen Ratten. Unpublished report No. 139/79. Hoechst AG, Pharma Forschung Toxikologie. 30.3.1979. Hoechst AG. 1979d. Akute subcutane Toxizität von Monochloressigsäure VA 2308 an weiblichen Ratten. Report No. 233/79. Hoechst AG, Pharma Forschung Toxikolo- gie (as cited in ECETOC 1999). Hoechst AG. 1979e. Haut- und Schleimhautverträglichkeit von Monochloressigsäure VA 2308 an Kaninchen. Report No. 235/79. Hoechst AG, Pharma Forschung Toxiko- logie (as cited in ECETOC 1999).

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171 Monochloroacetic Acid Hoechst AG. 1988a. Monochloressigsäuremethylester Inhalation im strömenden Gemisch an männlichen und weiblichen SPF-Wistar-Ratten - 4 h - LC 50. Unpublished re- port No. 88.0041. Hoechst AG, Pharma Forschung Toxikologie und Pathologie. 7.3.1988. Hoechst AG. 1988b. Chloressigsäuremethylester - Subakute Inhalation (20 Applikationen in 28 Tagen) an SPF-Wistar Ratten. Unpublished report No. 88.0233. Study con- ducted for Berufsgenossenschaft der chemischen Industrie, by Hoechst AG, Pharma Forschung Toxikologie und Pathologie. 13.4.1988. Hoechst AG. 1988c. Natriummonochloracetat. Prüfung der akuten dermalen Toxizität and der Wistar-Ratte. Report No. 151/88. Hoechst AG, Pharma Forschung Toxiko- logie und Pathologie (as cited in ECETOC 1999). Hoechst AG. 1988d. Natriummonochloracetat. Prüfung auf Augenreizung am Kaninchen. Report No. 88.0109. Hoechst AG, Pharma Forschung Toxikologie und Pathologie (as cited in ECETOC 1999). IPCS /CEC (International Programme on Chemical Safety and the Commission of the European Communities). 1994. Chloroacetic acid. ICSC: 0235. International Chemical Safety Cards. International Programme on Chemical Safety and the Commission of the European Communities [online]. Available: Http://www.cdc. gov/niosh/ipcsneng/neng0235.html [accessed June 10, 2008]. IUCLID (International Uniform Chemical Information Database), 1996. Data Set, CD- ROM, 1st Ed. European Commission, European Chemicals Bureau, Joint Research Centre, Ispra, Italy. Izmerov, N.F., I.V. Sanotsky, and K.K. Sidorov. 1982. Toxicometric Parameters of In- dustrial Toxic Chemicals under Single Exposure. Centre of International Projects, GKNT, Moscow. Johnson, P.D., B.V. Dawson, and S.J. Goldberg. 1998. Cardiac teratogenicity of tri- chloroethylene metabolites. J. Am. Coll. Cardiol. 32(2):540-545. Kaphalia, B.S., H.K. Bhat, M.F. Khan, and G.A. Ansari. 1992. Tissue distribution of monochloroacetic acid and its binding to albumin in rats. Toxicol. Ind. Health 8(1- 2):53-61. KEMI (Kemikalieninspektionen). 1994. SIDS Dossier on the OECD HPV Chemical Monochloroacetic Acid (MCA). Kemikalieninspektionen, National Chemicals In- spectorate, Solna, Sweden. Knapp, P. 1923. Zur Frage der Keratitis traumatica infolge Einwirkung von Gasen. Schweizerische medizinische Wochenschrift 4, 702 (as cited in OECD 1996) Kulling, P., H. Andersson, K. Boström, L.A. Johansson, B. Lindström, and B. Nyström. 1992. Fatal systemic poisoning after skin exposure to monochloroacetic acid. J. Toxicol. Clin. Toxicol. 30(4): 643-652. Maksimov, G.G., and O.N. Dubinina. 1974. Materials of experimental substantiation of maximally permissible concentration of monochloroacetic acid in the air of pro- duction area [in Russian]. Gig. Tr. Prof. Zabol. 9:32-35. Mitroka, J.G. 1989. Monochloroacetic Acid Lethality in the Rat in Relation to Lactic Acid Accumulation in the Cerebrospinal Fluid. Ph.D. Dissertation, Rutgers, State University of New Jersey, New Brunswick, NJ. Morrison, J.L., and C.D. Leake. 1941. Monochloroacetic acid as a food and beverage stabilizer. Univ. Calif. Pub. Pharmacol. 1:397-421 (as cited in NTP 1992). MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst 2004: Monochloorazijnzuur. Den Haag: SDU Uitgevers [online]. Available: http://www.lasrook.net/lasrookNL/maclijst2004.htm [accessed Oct. 24, 2008].

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172 Acute Exposure Guideline Levels NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. NTP (National Toxicology Program). 1992. Toxicology and Carcinogenesis Studies of Monochloroacetic Acid (CAS No. 79-11-8) in F344/N Rats and B6C3F1 Mice. Technical Report No. 396. NIH 92-2851. U.S. Department of Health and Human Services, Public Health Service, National Institute of Health, National Toxicology Program, Research Triangle Park, NC. OECD (Organization for Economic Cooperation and Development). 1996. Chloroacetic Acid (79-11-8). Pp. 118-124 in Screening Information Data Set (SIDS) for High Production Volume Chemicals, Vol. III, Part 3. Geneva: United Nations Environ- ment Programme Chemicals [online]. Available: http://www.chem.unep.ch/ irptc/sids/OECDSIDS/79118.pdf [accessed June 13, 2008]. Oelert, H.H., and T. Florian. 1972. Detection and evaluation of odor nuisance from diesel exhaust gases. Staub Reinhalt. Luft 32(10):20-31. Rodionova, R.P., and N.G. Ivanov. 1979. Comparison of the level of irritant properties of industrial toxins [in Russian]. Tok. Nov. Prom. Khim. Vesh. 15:58-63;145-150 (as cited in ECOTOC 1999). Rogers, D.R. 1995. Accidental fatal monochloroacetic acid poisoning. Am. J. Forensic Med. Pathol. 16(2):115-116. Rozman, K.K. 2000. The role of time in toxicology or Haber‘s c × t product. Toxicology 149(1):35-42. Ruty, J., R.J. Millischer, J.C. Contassot, M. Vincenti, and J. Jouglard. 1988. Monoch- loroacetic acid: A report of systemic poisoning from percutaneous absorption. Pp. 145-148 in Occupational Health in the Chemical Industry: 22th ICOH (Interna- tional Commission on Occupational Health)-Congress, September 27-October 2, 1987, Sydney, Australia. Copenhagen, Denmark: World Health Organization. Smith, K.M., J.L. Randall, E.J. Read, and J.A. Stober. 1990. Developmental effects of chloroacetic acid in the Long-Evans rat. Teratology 41(5):593 (Abstract P164). Torkelson, T.R., C.D. Kary, M.B. Chenoweth, and E.R. Larson. 1971. Single exposure of rats to the vapors of trace substances in methoxyflurane. Toxicol. Appl. Pharma- col. 19(1):1-9. USITA (U.S. International Trade Administration). 2004. Industry Trade Data and Analy- sis. U.S. International Trade Administration, U.S. Department of Commerce [online]. Available: http://ita.doc.gov/td/industry/otea/trade-detail/Latest-Decemb er/Imports/29/291540.html van Hinsbergh, V.W.M., and M. Vermeer. 1994. Toxicity of Monochloroacetic Acid on Human Endothelial Cells and Rat Heart Mitochondria: Third interim report. Gaubius Laboratory TNO-GP, Leiden, The Netherlands (as cited in Greim 1998). Weast, R.C., ed. 1984. CRC Handbook of Chemistry and Physics: A Ready-Reference Book of Chemical and Physical Data, 64th Ed. Boca Raton: CRC Press. Woodard, G., S.W. Lange, K.W. Nelson, and H.O. Calvery. 1941. The acute oral toxicity of acetic, chloroacetic, dichloroacetic and trichloroacetic acids. J. Ind. Hyg. Toxi- col. 23(2):78-82. Yllner, S. 1971. Metabolism of chloroacetate-1-14C in the mouse. Acta Pharmacol. Toxi- col. 30(1-2):69-80.

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173 Monochloroacetic Acid Xu, X., and C.P. Weisel. 2003. Inhalation exposure to haloacetic acids and haloketones during showering. Environ. Sci. Technol. 37(3):569-576.

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174 Acute Exposure Guideline Levels APPENDIX A TIME-SCALING CALCULATIONS FOR AEGLS AEGL-2 VALUES Key study: Dow Chemical Co. 1987 Toxicity end point: Rats were exposed for 1 hat an analytic MCA concentration of 66 ppm, no other concentrations were tested. During exposure all rats squinted and appeared slightly lethargic. Scaling: C³ × t = k for extrapolation to 30 min and 10 min k = 66³ ppm³ × 1 h = 287,496 ppm³-h C × t = k for extrapolation to 8 h and 4 h k = 66 ppm × 1 h = 66 ppm-h Uncertainty factors: Combined uncertainty factor of 10. 3 for interspecies variability 3 for intraspecies variability Calculations: 10-min AEGL-2 C³ × 0.167 h = 287,496 ppm³-h C = 119.85 ppm 10-min AEGL-2 = 119.85 ppm/10 = 12 ppm (47 mg/m³) 30-min AEGL-2 C³ × 0.5 h = 287,496 ppm³-h C = 83.15 ppm 30-min AEGL-2 = 83.15 ppm/10 = 8.3 ppm (33 mg/m³) 1-h AEGL-2 C = 66 ppm 1-h AEGL-2 = 66 ppm/10 = 6.6 ppm (26 mg/m³) 4-h AEGL-2 C × 4 h = 66 ppm-h C = 16.50 ppm 4-h AEGL-2 = 16.50 ppm/10 = 1.7 ppm (6.7 mg/m³) 8-h AEGL-2 C × 8 h = 66 ppm-h C = 8.25 ppm 8-h AEGL-2 = 8.25 ppm/10 = 0.83 ppm (3.3 mg/m³)

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175 Monochloroacetic Acid APPENDIX B ACUTE EXPOSURE GUIDELINES FOR MONOCHLOROACETIC ACID Derivation Summary for Monochloroacetic Acid AEGL-1 VALUES 10 min 30 min 1h 4h 8h Not Not Not Not Not recommended recommended recommended recommended recommended Reference: Not applicable. Test Species/Strain/Number: Not applicable. Exposure Route/Concentrations/Durations: Not applicable. Effects: Not applicable. End Point/Concentration/Rationale: No definitive study was available for the derivation of AEGL-1 values. The human irritation threshold reported by Maksimov and Dubinina (1974) was inadequately described and, therefore, was not considered an adequate basis for the derivation of AEGL-1 values. The report by Clariant GmbH (unpublished material 2000) was not considered an adequate basis because the depth of the routine medical examination was not reported and the time point of the examination was not linked to an actual exposure assessment. Moreover, the exposure assessment using about one to two measurements per year was considered insufficient. Therefore, due to insufficient data, AEGL-1 values were not recommended. Uncertainty Factors/Rationale: Not applicable. Modifying Factor: Not applicable. Animal to Human Dosimetric Adjustment: Not applicable. Time Scaling: Not applicable. Data Adequacy: Adequate human or animal data relevant for the derivation of AEGL-1 values are not available. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 12 ppm 8.3 ppm 6.6 ppm 1.7 ppm 0.83 ppm Key Reference: Dow Chemical Company. 1987. Monochloroacetic acid: An acute vapor inhalation limit study with Fischer 344 rats. Unpublished report, Dow Chemical Company, Midland, USA. Test Species/Strain/Sex/Number: Rat/Fischer 344/6 female and 6 male. Exposure Route/Concentrations/Durations: Inhalation/66 ppm (analytic concentration)/1 h (Continued)

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176 Acute Exposure Guideline Levels AEGL-2 VALUES Continued 10 min 30 min 1h 4h 8h 12 ppm 8.3 ppm 6.6 ppm 1.7 ppm 0.83 ppm Effects: During all exposures, all rats (12/12) showed eye squint and slight lethargy. While in the text the expression “slight lethargy” is used, “lethargy” is used in the corresponding table. “The observations [prior to and after exposure] included an evaluation of fur, eyes, mucous membranes, and respiration. Behavior pattern and nervous system activity was also assessed by specific observation for tremors, convulsions, salivation, lacrimation, and diarrhea, as well as slight lethargy and other signs of altered central nervous system function.” During the 2-week observation period, MCAA-exposed rats lost weight initially (day 2) and regained weight during the remainder period (days 4-15). Gross pathologic examination of rats revealed no exposure-related effects. End Point/Concentration/Rationale: For the derivation of AEGL-2 values, the study in rats by Dow Chemical Co. (1987) was used because it was the only relevant inhalation study available. Exposure of rats to 66 ppm for 1 h resulted in eye squint and in some lethargy, which might be interpreted as an effect on the central nervous system, but no severe effects. There is some uncertainty as to the exposure because of the large discrepancy between the nominal exposure concentration of 964 ppm and the analytically measured exposure concentration of 66 ppm. The authors did not discuss whether recrystallization of MCAA took place completely outside the exposure chamber (that is, before the air stream entered the chamber) or whether uptake of recrystallized MCAA by routes other than inhalation (e.g., dermal and oral uptake after deposition on the hair) might have occurred. In case of an additional exposure, the measured air concentration of 66 ppm and be regarded as a conservative exposure assumption. The AEGL-2 values were based on a 1-h exposure to 66 ppm. Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 3, because (1) the effect level was considered below that of an AEGL-2, (2) because the available data on acute oral lethality do not point at a large interspecies variability for more severe (lethal) effects, and (3) because of the limited toxicodynamic variability as the enzymes inhibited by MCAA do not vary considerably within and between species. Intraspecies: 3, because of the limited toxicokinetic variability with respect to local effects and limited toxicodynamic variability with respect to systemic effects since the enzymes inhibited by MCAA do not vary considerably within and between species. Modifying Factor: Not applicable. Animal to Human Dosimetric Adjustment: Insufficient data. Time Scaling: The exposure duration-specific values were derived by time scaling according to the dose-response regression equation Cn × t = k, using the default of n = 3 for shorter exposure periods and n = 1 for longer exposure periods, due to the lack of suitable experimental data for deriving the concentration exponent. Data Adequacy: The only available single inhalation study in animals was used for the derivation of AEGL-2 values. In this study, neither different exposure concentrations nor different exposure durations were used. The derived values are supported by an older subchronic toxicity study in humans who had daily oral exposures to MCAA.

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177 Monochloroacetic Acid AEGL-3 VALUES 10 min 30 min 1h 4h 8h Not Not Not Not Not recommended recommended recommended recommended recommended Reference: Not applicable. Test Species/Strain/Sex/Number: Not applicable. Exposure Route/Concentrations/Durations: Not applicable. Effects: Not applicable. End Point/Concentration/Rationale: For the derivation of AEGL-3 values, no relevant and well-documented LC50 studies were available. Although oral lethality data in animals are available, they were not used as a basis for derivation of AEGL values because of the uncertainty regarding local effects of MCAA in the respiratory tract. Several mechanistic aspects point at a possible role of local effects: (1) MCAA has a pKa of 2.85 and thus is a strong acid, which may cause irritation and local tissue damage by its acidity alone; (2) MCAA can bind to sulfhydryl groups, for example, those of reduced glutathione, and may thus cause lung damage through glutathione depletion; and (3) during inhalation exposure, local concentrations of MCAA in the respiratory tract could cause local tissue damage by enzyme inhibition already in doses lower than those required for systemic effects in oral studies. Experimental findings support a possible local effect on the respiratory tract: (1) the available inhalation studies report effects on the respiratory tract, and (2) MCAA causes severe local damage to skin and eyes. Unfortunately, in the only LC50 study located in the literature (Maksimov and Dubinina, 1974), data presentation is inadequate. Because pathologic findings were not reported, it remains unknown whether rats died from local lung tissue destruction or from systemic toxicity (that is, acidosis affecting CNS or heart). Inhalation studies using MCAA esters were not considered relevant for the derivation of AEGL-3 values; compared with MCAA, local effects of its esters are less likely, because (1) the esters are not acidic and thus do not cause local effects by lowering the tissue pH value; and (2) local effects due to glutathione binding or enzyme inhibition can be expected to be smaller because the esters have to get hydrolyzed enzymatically to free MCAA first. Although quantitative data for the hydrolysis are lacking, it is likely that due to its rapid distribution in the body, much of the deposited ester will enter systemic circulation before it is hydrolyzed, and thus the concentration of MCAA in respiratory tract tissue is likely to be much smaller during inhalation exposure to MCAA esters than during MCAA exposure. Due to the inadequate presentation of the only LC50 available (Maksimov and Dubinina 1974) and the uncertainties of a route-to-route extrapolation, AEGL-3 values were not recommended. Uncertainty Factors/Rationale: Not applicable. Modifying Factor: Not applicable. Animal to Human Dosimetric Adjustment: Not applicable. Time Scaling: Not applicable. Data Adequacy: Adequate animal data relevant for the derivation of AEGL-3 values are not available.