9
Nickel Carbonyl1
Acute Exposure Guideline Levels

PREFACE

Under the authority of the Federal Advisory Committee Act (P.L. 92-463) of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop acute exposure guideline levels (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-2 and AEGL-3 levels, and AEGL-1 levels as appropriate, will be developed for each of five exposure periods (10 min, 30 min, 1 h, 4 h, 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 and 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 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.

1

This document was prepared by AEGL Development Team member Robert Young of Oak Ridge National Laboratory and Ernest Falke (Chemical Manager) of the National Advisory Committee on Acute Exposure Guideline Levels for Hazardous Substances (NAC). The NAC reviewed and revised the document, which was 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 data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993; 2001).



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9 Nickel Carbonyl1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (P.L. 92-463) of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop acute exposure guide- line levels (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-2 and AEGL-3 levels, and AEGL-1 levels as appropriate, will be developed for each of five exposure periods (10 min, 30 min, 1 h, 4 h, 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 and 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 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. 1 This document was prepared by AEGL Development Team member Robert Young of Oak Ridge National Laboratory and Ernest Falke (Chemical Manager) of the National Advisory Committee on Acute Exposure Guideline Levels for Hazardous Substances (NAC). The NAC reviewed and revised the document, which was 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 scientifi- cally valid conclusions based on data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993; 2001). 213

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214 Acute Exposure Guideline Levels 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 can produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic nonsensory effects. With increasing airborne concentrations above each AEGL, there is a progres- sive 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, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that certain individuals, subject to unique or idiosyncratic responses, could experience the effects described at concentrations below the correspond- ing AEGL. SUMMARY Nickel carbonyl, formed by the reaction of carbon monoxide with metallic nickel, is used in nickel refining, in the synthesis of acrylic and methacrylic es- ters, and for other organic synthesis. In air, nickel carbonyl rapidly decomposes to metallic nickel and carbon monoxide with a 50% decomposition at room tem- perature and total decomposition at 150-200 C. Its decomposition is inversely proportional to the concentration of carbon monoxide; in the absence of carbon monoxide, decomposition may occur in approximately 1 min. Thus, potential exposure to the parent nickel carbonyl is limited by its rapid conversion to air- borne metallic nickel. Human data are limited to case reports, primarily of nickel workers, that affirm the extreme toxicity of the compound. Definitive exposure terms are lack- ing in these reports. Available information suggests that there are very limited or no warning properties associated with exposure to nickel carbonyl. Significant signs and symptoms of toxicity are known to occur in the absence of recogniz- able odor. Human case studies have shown that a latency period often occurs between initial signs of toxicity and subsequent serious effects that may progress to death. The primary target of nickel carbonyl-induced acute toxicity appears to be the lungs, although extra pulmonary involvement also has been reported. The specific mechanism of toxicity is unclear but appears to involve damage to pul- monary tissue. Animal data are limited to lethality and developmental toxicity. Lethality values (LC50) are available for rats, mice, cats, and rabbits. Thirty-minute LC50

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215 Nickel Carbonyl values for these species range from 33.6 to 266 ppm. These lethality data indi- cate notable species variability in the lethal response to inhaled nickel carbonyl; smaller species are generally more sensitive. Developmental toxicity has been demonstrated in rats and hamsters following single 30-min (11.2-42 ppm, rats) or 15-min (8.4 ppm, hamsters) exposures of dams during gestation. In hamsters, developmental toxicity was observed in dams following lethal or near-lethal exposures. In rats, developmental toxicity was observed in offspring of dams that were exposed to nonlethal concentrations of nickel carbonyl. Because in- formation on the health status of the rat dams was not provided, it was not pos- sible to determine the relative maternal versus fetal sensitivity to nickel carbonyl challenge. Epidemiologic data do not support the contention that inhalation of nickel carbonyl is carcinogenic to humans. Studies of respiratory tract cancer in nickel workers suggest that nickel dusts, nickel sulfide, and nickel subsulfide may be more relevant than nickel carbonyl and that nickel carbonyl is not a likely causa- tive agent in the carcinogenicity observed in nickel refinery workers. Limited data for rats have provided equivocal evidence of pulmonary carcinogenicity following acute or long-term exposure to nickel carbonyl. Data are unavailable for a quantitative assessment of the carcinogenic potential of nickel carbonyl in humans or animals. Exposure-response data over multiple time periods are unavailable for nickel carbonyl, and empirical derivation of a temporal scaling factor (n) was not possible. The concentration-exposure time relationship for many irritant and systemically acting vapors and gases may be described by Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence of an empirically derived exponent (n), temporal scaling was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points. Neither human nor animal data are available for deriving AEGL-1 values. Both human and animal data affirm the extreme toxicity of nickel carbonyl. Published accounts of human exposures indicate that symptoms of toxicity can occur in the absence of olfactory or other sensory detection. Severe pulmonary edema and hemorrhage can follow initial asymptomatic exposures by as much as 12 h after exposure. Therefore, AEGL-1 values are not recommended. Teratogenicity and fetotoxicity findings in rats and hamsters following le- thal or near-lethal exposures have been reported. No human data are available that specifically identify effects consistent with AEGL-2. AEGL-2 values for nickel carbonyl were developed based on a 30-min exposure of mice to 2.17 ppm (Kincaid et al. 1953). A concentration-dependent lethal response was observed for exposures to 6.51-12.6 ppm, but the lowest concentration (2.17 ppm) resulted in no deaths. Exposure to 6.51 ppm resulted in the deaths of two of 15 mice, and a 30-min LC50 of ~9.4 ppm was estimated by the investigators. Although no histopathology examinations were performed on the mice in the 2.17-ppm group, Kincaid et al. and Barns and Denz (1951) reported findings of pleural effusion, severe pulmonary congestion, and pulmo-

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216 Acute Exposure Guideline Levels nary edema for rats that died following exposure to nickel carbonyl. Therefore, the 30-min exposure to 2.17 ppm was considered a reasonable estimate of an exposure that might cause pulmonary damage in the mouse (the most sensitive species tested) but not result in irreversible adverse effects. As shown by the multiple-exposure studies of Kincaid et al., repeated exposures of mice to this or greater concentrations did not result in a lethal response. Pulmonary damage appears to be a component in the continuum of the toxic response to nickel car- bonyl and an appropriate critical effect for AEGL-2 development. The available lethality data suggest that the mouse represents a sensitive species. Based on this and the analysis conducted by Kincaid et al. indicating an inverse relationship between lethality and body size, the interspecies uncertainty factor of 3 appears to be justified. Although intraspecies variability is difficult to assess based on available data, an uncertainty factor of 3 was applied with the assumption that neither the effects of nickel carbonyl on pulmonary tissues nor dosimetry would vary greatly among individuals. Occupational exposure data suggest that the AEGL-2 values are sufficiently protective. A modifying factor of 3 was applied in the development of the AEGL-2 values to account for data deficiencies re- garding AEGL-2 specific effects and the possibility of developmental toxicity. AEGL-3 values were derived based on an estimated lethality threshold in mice (3.17 ppm) exposed to nickel carbonyl for 30 min (Kincaid et al. 1953). Lethality data were available for several species (rats, mice, rabbits, and cats). A total uncertainty adjustment of 10 was applied (each uncertainty factor of 3 is the approximate logarithmic mean of 10, which is 3.16; hence, 3.16 × 3.16 = 10). Analysis of the available data indicated that the mouse was the most sensi- tive species and that larger species tended to be less sensitive. Because data from the most sensitive species were used and because the available LC50 values vary approximately 8-fold, the total uncertainty adjustment of 10 is weighted toward the uncertainty in individual sensitivity to nickel carbonyl exposure. Data are unavailable to definitively apportion the uncertainty adjustment between inter- and intraspecies. Limited data suggest the development of pulmonary tumors in rats inhal- ing nickel carbonyl. There are equivocal findings suggestive of a tumorigenic response following a single massive exposure of rats to nickel carbonyl. How- ever, a valid quantitative cancer risk assessment is not currently feasible for a single acute exposure. Although some nickel compounds (nickel subsulfide and nickel refinery dust) are considered human carcinogens based on animal data and epidemiological studies, other nickel compounds including nickel carbonyl are considered potential human carcinogens based on limited animal data. The human carcinogen classification is based on animal data and evaluations of epi- demiologic data showing an increased risk of pulmonary and sinonasal cancers in nickel refinery workers with exposure to nickel refinery dust, which is pri- marily nickel subsulfide (EPA 1991). No quantitative carcinogen risk assess- ment has been conducted for nickel carbonyl due to deficiencies in the available data. Evaluations of epidemiological studies by Doll (1984) and CEC (1990) concluded that nickel carbonyl was an unlikely contributor to the increased risk

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217 Nickel Carbonyl of sinonasal cancers in the nickel refinery workers. Therefore, cancer risk was not the basis for AEGL development. The AEGL values and toxicity end points are summarized in Table 9-1. 1. INTRODUCTION Nickel carbonyl, formed by the reaction of carbon monoxide with metallic nickel, is used in nickel refining, in the synthesis of acrylic and methacrylic es- ters, and for other organic syntheses (Antonsen 1978; Budavari et al. 1996). Ad- ditionally, the compound is used in vapor deposition plating to increase the du- rability of injection molds for automotive parts (EPA 2002). Although frequently listed as a site-limited intermediate, on-site storage by some users have listed up to 900 pounds of nickel carbonyl (EPA 2002). Upon heating to 200° C, nickel carbonyl decomposes to pure nickel and carbon monoxide, a re- action referred to as the Mond process (Goyer 1991). In air at room temperature, 50% of nickel carbonyl rapidly decomposes to nickel and carbon monoxide. At temperatures of 150-200°C, 100% degradation may occur (Vuopola et al. 1970). The rate of decomposition is inversely dependent on the carbon monoxide con- centration; in the absence of carbon monoxide, nickel carbonyl will completely decay in about 1 min (Stedman et al. 1980). An odor threshold of 0.5-3 ppm has been reported for humans but not validated (AIHA 1989). Some inhaled nickel carbonyl is eliminated via expired air, the remainder may dissociate to Ni0, sub- sequently oxidized to Ni (II) and released into the blood serum, where it may bind to albumin and nickel-binding substances and be cleared via the kidneys. Nickel carbonyl will, however, damage Type I and Type II alveolar cells of the lungs and may induce pulmonary edema and chemical pneumonitis. Physico- chemical data for nickel carbonyl are shown in Table 9-2. TABLE 9-1 Summary of AEGL Values for Nickel Carbonyl (ppm [mg/m3]) Classification 10 min 30 min 1h 4h 8h End Point (Reference) AEGL-1 NR NR NR NR NR NR (nondisabling) AEGL-2 0.10 0.072 0.036 0.0090 0.0045 NOAEL for severe (disabling) (0.69) (0.50) (0.25) (0.063) (0.031) pulmonary damage in mice; 2.17 ppm, 30 min (Kincaid et al. 1953). AEGL-3 0.46 0.32 0.16 0.040 0.020 Estimated mouse lethality (lethal) (3.2) (2.2) (1.1) (0.27) (0.14) threshold (LC01 of 3.17 ppm; (Kincaid et al. 1953). Note: Numerical values for AEGL-1 are not recommended because of the lack of avail- able data. Absence of an AEGL-1 does not imply that exposure below the AEGL-2 is without adverse effects. Abbreviations: NR, not recommended; NOAEL, no-observed-adverse-effect level.

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218 Acute Exposure Guideline Levels TABLE 9-2 Physical and Chemical Data Property Descriptor or Value Reference Synonyms Nickel tetracarbonyl Budavari et al. 1996 Common name Nickel carbonyl Chemical formula C4NiO4 Budavari et al. 1996 Molecular weight 170.73 Budavari et al. 1996 CAS Registry No. 13463-39-3 Budavari et al. 1996 Physical state Liquid Budavari et al. 1996 Vapor pressure Antonsen 1978 28.7 kPa at 20°C Sax and Lewis 1989 400 mm at 25.8°C Density Budavari et al. 1996 1.318 at 17°C Boiling/melting point Budavari et al. 1996 43°C/−19.3°C Solubility Miscible with organic Antonsen 1978; Budavari et solvents, soluble to about al. 1996 5,000 parts in water. 1 mg/m3 = 0.14 ppm Conversion factors in air 1 ppm = 6.9 mg/m3 2. HUMAN TOXICITY DATA 2.1. Acute Lethality Nickel carbonyl is known to exhibit extreme toxicity in humans following acute exposure (Antonsen 1978; Budavari et al. 1996; Sunderman 1989; Goyer 1991). Nickel carbonyl is generally considered the most toxic form of nickel (Ellenhorn 1997) and upon inhalation produces both respiratory tract and sys- temic effects (Shi 1994a). Individuals poisoned by acute exposure to nickel car- bonyl exhibit immediate and delayed effects (Kincaid et al. 1953). The acute lethality of nickel carbonyl in humans is well documented (Sunderman 1989; Kurta et al. 1993; Ellenhorn 1997). Lethality appears to be attributed to neu- rologic and respiratory effects (Sunderman 1989; Kurta et al. 1993). Several reports are available that document lethal exposure to nickel car- bonyl. Sunderman (1989) reported on the exposure of over 100 workers to nickel carbonyl at a Port Arthur, Texas, petroleum refining facility. Thirty-one experienced acute signs and symptoms of toxicity (headache, sternal and epigas- tric pain, nausea, vomiting, chest constriction, shortness of breath, hacking and unproductive cough, extreme weakness, fatigue), and two subsequently died. Case-specific data were not reported, but pneumonitis, respiratory difficulties (cough, shortness of breath, chest constriction) and neurological signs (convul- sions, confusion) were associated with those individuals with severe or lethal

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219 Nickel Carbonyl poisoning. It was noted that the signs and symptoms of poisoning could be cate- gorized as immediate or delayed (latency of 1-5 days). The onset of severe symptoms varied from 10 h to 6 days. Convalescence was protracted and the administration of 2,3-dimercaptopropanol was attributed with saving the lives of some of the victims. Kincaid et al. (1956) estimated the human LC50 as 3 ppm, and Vuopola et al. (1970) noted that atmospheric concentrations of 30 ppm of nickel carbonyl are probably immediately fatal to humans. The limited acute lethality values for inhalation exposure of humans to nickel carbonyl are summarized in Table 9-3. 2.2. Nonlethal Toxicity Shi (1986) reported on 179 cases of nonlethal occupational exposure to nickel carbonyl. Exposure times varied from 2 h. The report was primarily a qualitative analysis of the documented exposures. No specific expo- sure concentration or exposure duration data were provided regarding the signs and symptoms discussed, and therefore there were no data useful for derivation of AEGL values. Exposures were categorized as mild, moderate, or severe based on many clinical signs and symptoms. The onset of signs and symptoms varied from a few minutes to several hours to as long as a week following exposure and included respiratory system, nervous system, digestive tract, and cardiovascular effects. In analyzing the toxic responses in the 179 cases, Shi (1994a) found that there was an immediate stage lasting 4-5, followed by a remission of approxi- mately 12 h that may extend to 2-3 days. The immediate phase was character- ized by neurologic disorders and upper-airway irritation, while the delayed phase was generally characterized by chest pain, cough and dyspnea, palpitation, fever, leukocytosis, and some X-ray abnormalities (irregular linear shadow, ex- pansion and increased density of the hilus, diffuse irregular nodular mottling or patchy shadows). The delayed onset of toxicity is consistent with what is ob- served in animal models. Sunderman (1992) provided information on the results of a study involv- ing 156 male workers accidentally exposed to nickel carbonyl at the Toa Gosei Chemical plant in Nagoya, Japan. Of the workers exposed, 137 exhibited symp- toms of poisoning, but no fatalities occurred, due in part to treatment of the workers with Antabuse and Dithiocarb (diethyldithiocarbamate). Exposure terms were unavailable, but the report served to identify major medical findings for the exposed workers. These included abnormal liver function, renal insufficiencies, skin lesions, abnormal densities in pulmonary x-rays, and symptoms of encepha- lopathy. An acute case of nickel carbonyl poisoning involving inhalation and der- mal exposure was reported by Kurta et al. (1993). Although exposure terms were unavailable, the report provided a clinical picture of nickel carbonyl poi- soning and its outcome following antidote therapy with disulfiram and diethyl-

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220 Acute Exposure Guideline Levels TABLE 9-3 Acute Lethality of Nickel Carbonyl in Humans Acute Lethality Value Reference 30-min LC50: 3 ppm (Estimated) Kincaid et al. 1956 30 ppm: Immediately Fatal (Estimated) Vuopola et al. 1970 dithiocarbamate. Twenty-four hours after the exposure, urinary nickel levels were 172 µg/dL (normal is <5 µg/dL). The 46-year-old subject initially experi- enced headache, chest pains, shortness of breath, and weakness. The subject was aggressively treated with oxygen and other supportive and prophylactic therapy (e.g., antibiotics) as well as disulfiram and diethyldithiocarbamate. An 18-day hospital stay was required, but upon discharge pulmonary function was still moderately impaired. In a report by Sunderman (1990) on clinical management of nickel car- bonyl poisoning with Dithiocarb, reference was made to the inability of human subjects to detect low concentrations of nickel carbonyl. Results of experiments in which six human subjects smelled “whiffs” of 0-5 ppm of nickel carbonyl (no specific exposure durations were provided) were highly variable, with some individuals acknowledging detection of the compound and others being unaware of any odor. The results suggested that nickel carbonyl is unlikely to be detected at low concentrations, especially by those unfamiliar with it. 2.2.1. Epidemiologic Studies Shi et al. (1986) conducted a study in which serum monoamine oxidase (SMAO) activity and electroencephalograms (EEGs) were evaluated in male and female nickel carbonyl workers. Group A contained 42 workers (average age, 36.2) with 10-20 years of work; Group B had 36 individuals (average age, 29.1) with 2-8 years of work; and Group C included 40 individuals (average age, 28.4) with no possible exposure to nickel carbonyl. It was noted that the average concentration of nickel carbonyl in the work area was 0.007-0.52 mg/m3 (equivalent to 0.0009-0.073 ppm). Results of the study revealed statistically sig- nificant (t-test) decreases in SMAO activity with longer exposure durations. Incidences of abnormal EEGs were significantly increased with longer exposure durations. Although these findings demonstrate nonlethal effects following long- term, low-level exposure to nickel carbonyl, extrapolation to acute exposure situations would be uncertain. More recently, Shi (1994b) conducted a study of lung function in workers occupationally exposed to nickel carbonyl for 2-20 years. The study groups in- cluded workers exposed to nickel carbonyl over 18.6 years (men), 16.6 years (women), 2.5 years (men), or 3.8 years (women). The nickel carbonyl concentra- tion at the workplace, as determined by gas chromatography, ranged from 0.007 to 0.52 mg/m3 (0.00098-0.072 ppm). Unexposed workers served as controls. For

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221 Nickel Carbonyl male workers exposed for more than 14 years and for female workers exposed for more than 10 years, statistically significant (p < .05 to p < .001) alterations in several lung function measures were noted. For those workers exposed for lesser durations, considerably fewer parameters were altered. Although inadequate for the derivation of AEGL values, the results of this study show that long-term exposure to nickel carbonyl at concentrations of 0.00098-0.072 ppm may affect respiratory function but are not life threatening. 2.3. Reproductive/Developmental Toxicity Data regarding the reproductive/developmental toxicity of nickel carbonyl in humans were not available. 2.4. Genotoxicity Decheng et al. (1987) analyzed data from workers occupationally exposed to nickel carbonyl and found no increase in the frequency of chromosomal aber- rations but that nickel carbonyl appeared to act synergistically with cigarette smoke in increasing the frequency of sister chromatid exchange in peripheral lymphocytes. Cytogenetic measurements were evaluated by Shi (1992) in 64 workers (19-48 years old) exposed to nickel carbonyl (0.0043-0.026 mg/m3; 0.0006- 0.0036 ppm) over a period of 10 years. Compared to unexposed workers, the incidences of chromosomal anomalies in peripheral lymphocytes were signifi- cantly increased (p < .01 to p < .05). Anomalies included “teratogenized” cells, chromatic aberrations, chromosomal aberrations, breakage and deletion, sister chromatid exchanges, and increased micronuclei frequency. An increase in dy- skaryotic cells in the sputum was also found to be significant (p < .01) in work- ers exposed to nickel carbonyl compared to unexposed workers. 2.5. Carcinogenicity In an unpublished study (cited in Morgan 1992) using data from the Cly- dach, Wales, refinery, pulmonary cancer deaths in a group of 69 men occupa- tionally exposed to nickel carbonyl vapor did not exceed those of unexposed workers based on an age-specific status (see Table 9-4). It was not specified if the analysis was adjusted for cigarette smoking or other confounding factors, and definitive exposure data were not available. IARC (1987) considers nickel and nickel compounds as Group 1 carcino- gens (sufficient evidence in humans and animals) and U.S. Environmental Pro- tection Agency (EPA) has classified both nickel subsulfide and nickel refinery

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222 Acute Exposure Guideline Levels TABLE 9-4 Mortality Data for 69 Workers Occupationally Exposed to Nickel Carbonyl (1933-1964) SMRa Disease Group Expected Observed All causes 35.8 38 106 Pulmonary cancer 3.9 6 152 a Standard mortality ratio; p > .05. dust as human carcinogens (EPA 1991). These assessments are based primarily on epidemiologic data showing an increased risk of pulmonary and sinonasal cancers in nickel refinery workers exposed to nickel refinery dust (which is pri- marily nickel subsulfide). Nickel carbonyl is considered a potential human car- cinogen, although a quantitative assessment has not been conducted due to in- sufficient data (EPA 1991). However, Doll (1984) and CEC reported that nickel carbonyl was considered an unlikely contributor to the increased risk of sinona- sal cancers in the nickel refinery workers. The CEC (1990) concluded that “the available epidemiological studies suggest that the toxicologic properties of nickel tetracarbonyl do not include the potential to cause cancer.” 2.6. Summary The human health effects of inhaled nickel carbonyl have been summa- rized by Sunderman (1989) and Shi (1994a). Nickel carbonyl is generally con- sidered to be one of the most toxic industrial chemicals. A thorough assessment of the exposure response to nickel carbonyl is complicated by the often asymp- tomatic delay between initial, mild toxic effects and delayed serious effects that may result in fatal outcomes. Sunderman and co-workers summarized the vari- ous signs and symptoms of 350 individuals poisoned by nickel carbonyl. Imme- diate effects that usually resolved upon removal from exposure included head- ache, dizziness, sternal and epigastric pain, nausea, and vomiting. Effects that followed a 1- to 5-day latency included chest constriction, chills, shortness of breath, muscle pains, weakness, gastrointestinal disorders, convulsions, delir- ium, and death. Although some forms of nickel are known and suspected car- cinogens, the carcinogenic potential of nickel carbonyl in humans is equivocal and no quantitative data are currently available. Although specific exposure response data for human health effects are not available, the severity of acute nickel carbonyl poisoning paralleled increases in urinary nickel (Shi 1994a), and correlations between urinary nickel and expo- sure severity have been determined (Sunderman and Sunderman (1958). For mild, moderately severe, and severe exposures, initial 8-h urinary nickel values were 10 µg/100 mL but 50 µg/100 mL, respectively.

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223 Nickel Carbonyl 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality Inhalation lethality data are available for several species. Although data from some reports were only semiquantitative and lacked detail, other reports provided definitive data from well-conducted studies. 3.1.1. Rats In experiments with rats, Barnes and Denz (1951) examined the lethality of nickel carbonyl exposure and the effects of subsequent treatment with 2,3- dimercaptopropanol (British Anti-Lewisite). In this study, groups of 10-76 al- bino rats (sex and strain not specified) were exposed to nickel carbonyl for peri- ods of 5-30 min (ct of 17 × 103 to 70 × 103 mg•min/m3; equivalent to 2,380- 9,800 ppm•min). Nickel carbonyl concentrations were estimated by chemical analysis and, although capable of detecting nickel concentrations of 1-2 µg, may lack the precision of later reports in which concentrations were determined by gas chromatographic techniques. Only a range of exposure periods and ct values were provided by the authors (17-23 × 103, 29-38 × 103, 43-58 × 103, and 70 × 103 mg•min/m3; equivalent to 2,380-3,220, 4,060-5,200, 6,020-8,120, and 9,800 ppm•min, respectively). Mortality in these four exposure groups was 65%, 77%, 84%, and 100%, respectively. Exposed rats exhibited initial postexposure inac- tivity, followed by apparent recovery. At about 12 h postexposure, the condition of the rats deteriorated, followed by death 18-150 h after exposure. Necropsy findings revealed marked pleural effusion and extensive pulmonary edema. The concentrations reported in this study appear to be extremely high when com- pared to other experimental data. Kincaid et al. (1953) conducted acute lethality studies in several species, including rats. In these experiments, groups of 6-21 Wistar rats (gender not specified) were exposed to nickel carbonyl vapor at concentrations of 0.17, 0.20, 0.38, 0.45, or 0.50 mg/L for 30 min (equivalent to 23.8, 28.0, 53.2, 63.0, and 70 ppm, respectively). The report provided detailed information regarding the ex- posure protocol as well as generation and measurement of the experimental at- mosphere. Adjustments were made to account for decomposition of the nickel carbonyl. Results of the experiment with rats are shown in Table 9-5. Using probit analysis, a 30-min LC50 of 0.24 mg/L (33.6 ppm) was estimated. The rats were observed for 0.2 h to 6 days after exposure. It was reported that deaths usually occurred 2-3 days after termination of exposure. Animals that died im- mediately exhibited severe pulmonary congestion and pulmonary edema. In rats that survived for several days, extensive pneumonitis was observed. In experiments to study the efficacy of dimercaprol in the treatment of nickel carbonyl poisoning, control rats (those not receiving the dimercaprol) were exposed for 30 min to nickel carbonyl at concentrations of 0.20, 0.40, or

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249 Nickel Carbonyl APPENDIX A Derivation of AEGL-1 Values Quantitative data regarding responses consistent with the AEGL-1 defini- tion were not available for acute inhalation exposure to nickel carbonyl. Avail- able data indicate that toxic effects in humans may occur in the absence of de- tection. Because of the lack of appropriate data, AEGL-1 values could not be determined and, due to the extreme toxicity of nickel carbonyl and the docu- mented latency between relatively asymptomatic exposures and severe toxicity, are not recommended. Absence of an AEGL-1 value does not imply that expo- sure below the AEGL-2 concentration is without adverse effects. Derivation of AEGL-2 Values Key study: Kincaid et al. 1953. Toxicity end point: Estimated threshold for pulmonary damage in mice exposed to 2.17 ppm for 30 min. Scaling: Exposure-response data over multiple time periods are unavailable for nickel carbonyl, and empirical derivation of a scaling factor (n) was not possible. The concentration exposure-time relationship for many irritant and systemically acting vapors and gases may be described by Cn × t = k, where the ex- ponent n ranges from 0.8 to 3.5. In the absence of an empirically derived exponent (n), and to obtain con- servative and protective AEGL values, temporal scal- ing was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points. (2.17 ppm)1 × 0.5 h = 1.09 ppm h (2.17 ppm)3 × 0.5 h = 5.1 ppm3 h Uncertainty factors: 3 for interspecies variability. The available lethality data suggest that the mouse represents a sensitive species. Based on available lethality data and the analysis conducted by Kincaid et al. (1953) indicat- ing an inverse relationship between lethality and body size (see Section 4.4.1.), the interspecies uncer- tainty factor of 3 appears to be justified.

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250 Acute Exposure Guideline Levels 3 for intraspecies variability. Although intraspecies variability is difficult to assess based on available data, an uncertainty factor of 3 was applied with the assumption that neither the effects of nickel carbonyl on pulmonary tissues nor dosimetry would vary greatly among individuals. Additionally, the occupa- tional exposure data reported by Shi et al. (1994b) suggest that the AEGL-2 values are sufficiently pro- tective. Modifying factor: A modifying factor of 3 was applied to account for data deficiencies regarding AEGL-2 specific effects and to account for the possible developmental toxic effects. C3 × 0.167 h = 5.1 ppm3⋅h 10-min AEGL-2: C = 3.1 ppm 10-min AEGL-2 = 3.1 ppm/30 = 0.10 ppm (0.69 mg/m3) C1 × 0.5 h = 1.09 ppm⋅h 30-min AEGL-2: C = 2.17 ppm 30-min AEGL-2 = 2.17 ppm/30 = 0.072 ppm (0.50 mg/m3) C1 × 1 h = 1.09 ppm⋅h 1-h AEGL-2: C = 1.03 ppm 1-h AEGL-2 = 1.09 ppm/30 = 0.036 ppm (0.25 mg/m3) C1 × 4 h = 1.09 ppm⋅h 4-h AEGL-2 C = 0.27 ppm 4-h AEGL-2 = 0.27 ppm/30 = 0.0090 ppm (0.063 mg/m3) C1 × 8 h = 1.09 ppm⋅h 8-h AEGL-2: C = 0.136 ppm 8-h AEGL-2 = 0.136 ppm/30 = 0.0045 ppm (0.031 mg/m3)

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251 Nickel Carbonyl Derivation of AEGL-3 Values Key study: Kincaid et al. 1953 Toxicity end point: Estimated 30-min lethality threshold in mice: 3.17 ppm, using the mouse lethality data from Sunderman et al. (1980) and the method of Litchfield and Wil- coxon (1949) (see Appendix D). Cn × t = k (ten Berge 1986). Data were unavailable Scaling: for determining the exponent n. The concentration- exposure time relationship for many irritant and sys- temically acting vapors and gases may be described by Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence of an empirically derived exponent (n), and to obtain con- servative and protective AEGL values, temporal scal- ing was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points. (3.17 ppm)1 × 0.5 h = 1.58 ppm⋅h (3.17 ppm)3 × 0.5 h = 15.93 ppm3⋅h Uncertainty factors: Total uncertainty adjustment of 10 (each uncertainty factor of 3 is the logarthimic mean of 10, which is 3.16; hence, 3.16. × 3.16 = 10). Lethality data from the smallest and, according to Kincaid et al. (1953), the most sensitive species was used for development of the AEGL-3. For this reason, and because the available LC50 values vary approximately 8-fold, the total uncertainty adjustment of 10 is weighted toward the uncertainty in individual sensitivity to nickel car- bonyl exposure. Data are unavailable to definitively apportion adjustment between inter- and intraspecies uncertainty. C3 × 0.5 h = 15.93 ppm3⋅h 10-min AEGL-3: C = 4.57 ppm 10-min AEGL-3 = 4.57 ppm/10 = 0.46 ppm (3.2 mg/m3)

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252 Acute Exposure Guideline Levels C1 × 0.5 h = 1.58 ppm⋅h 30-min AEGL-3: C = 3.17 ppm 30-min AEGL-3 = 3.17 ppm/10 = 0.32 ppm (2.2 mg/m3) C1 × 1 h = 1.58 ppm⋅h 1-h AEGL-3: C = 1.58 ppm 1-h AEGL-3 = 1.58 ppm/10 = 0.16 ppm (1.1 mg/m3) C1 × 4 h = 1.59 ppm⋅h 4-h AEGL-3: C = 0.398 ppm 4-h AEGL-3 = 0.398 ppm/10 = 0.040 ppm (0.27 mg/m3) C1 × 8 h = 1.59 ppm⋅h 8-h AEGL-3: C = 0.198 ppm 8-h AEGL-3 = 0.198 ppm/10 = 0.020 ppm (0.14 mg/m3) APPENDIX B CARCINOGENICITY ASSESSMENT FOR NICKEL CARBONYL CANCER ASSESSMENT OF NICKEL CARBONYL Quantitative data regarding the carcinogenicity of nickel carbonyl in hu- mans and laboratory species are unavailable, and therefore neither a cancer slope factor nor unit risk can be derived. The available evidence does not support a definitive assessment of cancer risk in humans for a single once-in-a-lifetime acute exposure. Epidemiologic data do not support the contention that inhalation of nickel carbonyl is carcinogenic to humans. Based on inadequate human data and limited data in animals, EPA (2003) categorizes nickel carbonyl as B2 (po- tential human carcinogen), while the IARC (1987) specifically states that nickel carbonyl was considered unlikely to be involved in causing cancers among nickel refinery workers.

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253 Nickel Carbonyl APPENDIX C DETERMINATION OF LETHALITY THRESHOLDS Mouse lethality data: Kincaid et al. (1953) (see Table 9-8). Expected Dose (ppm) Mortality Observed, % Expected, % Observed Chi-Square 2.170 0/12 0 (0.30) 0.21 0.09 0.0004 −3.13 6.510 2/15 13.33 16.46 0.0071 7.840 3/10 30.00 29.83 0.17 0.0000 −4.82 8.680 10/29 34.48 39.30 0.0097 −1.68 9.800 10/20 50.00 51.68 0.0011 −7.86 10.900 12/22 54.55 62.41 0.0264 12.600 10/10 100 (92.20) 75.14 17.06 0.1558 Values in parentheses are corrected for 0 or 100 percent. Total = 0.2005. LC50 = 9.642(8.609 − 10.800)* Slope = 1.49(1.37 − 1.63)* *These values are 95 percent confidence limits. Total animals = 118. Total doses = 7. Animals/dose = 16.86. Chi-square = total chi-square × animals/dose = 3.3800. Table value for Chi-square with 5 degrees of freedom = 11.0700. LC84 = 14.398. LC16 = 6.457 Expected Lethal Concentration Values (ppm) LC0.1 1.814 LC1.0 3.174 LC5.0 4.731 LC10 5.668 LC25 7.392 LC50 9.642 LC75 12.577 LC90 16.404 LC99 29.296

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254 Acute Exposure Guideline Levels Rat lethality data: Kincaid et al. (1953) (see Table 9-6). Observed Expected Dose (ppm) Mortality Observed, % Expected, % Chi-Square 67.000 19/30 94.00 89.13 4.87 0.0245 67.000 9/10 90.00 89.13 0.87 0.0008 −10.66 105.000 24/30 80.00 90.66 0.1342 168.000 30/30 100 (94.30) 92.05 2.25 0.0069 266.000 30/30 100 (94.30) 93.22 1.08 0.0018 266.000 10/10 100 (94.30) 93.22 1.08 0.0018 Values in parentheses are corrected for 0 or 100 percent: Total = 0.1700. LC50 = 0.246(0.057 − 1.062)* Slope = 82.91(0.00 − 450639439.54)*. *These values are 95 percent confidence limits. Total animals = 140. Total doses = 6. Animals/dose = 23.33. Chi-square = Total chi-square × animals/dose = 3.9672. Table value for chi-square with 4 degrees of freedom = 9.4900. LC84 = 20.398: LC16 = 0.003 Expected Lethal Concentration Values (ppm) LC0.1 0.000 LC1.0 0.000 LC5.0 0.000 LC10 0.000 LC25 0.013 LC50 0.246 LC75 4.596 LC90 85.860 LC99 511.48

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255 Nickel Carbonyl APPENDIX D ACUTE EXPOSURE GUIDELINE LEVELS FOR NICKEL CARBONYL Derivation Summary for Nickel Carbonyl AEGLS AEGL-1 VALUES 10 min 30 min 1h 4h 8h NR NR NR NR NR Key reference: NA Test species/Strain/Number: NA Exposure route/Concentrations/Durations: NA Toxicity end point: NA Time scaling: NA Concentration/Time selection/Rationale: NA Uncertainty factors/Rationale Total uncertainty factor: NA Modifying factor: NA Animal to human dosimetric adjustments: NA Data adequacy: Quantitative data regarding responses consistent with the AEGL-1 definition were not available for acute inhalation exposure to nickel carbonyl, and therefore AEGL-1 values are not recommended (NR). Available data indicate that toxic effects in humans may occur in the absence of detection. Because of the lack of appropriate data, AEGL-1 values could not be determined and, due to the extreme toxicity of nickel carbonyl and the documented latency between relatively asymptomatic exposures and severe toxicity, are not recom- mended. Absence of an AEGL-1 value does not imply that exposure below the AEGL-2 concentrations are without adverse effects. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 0.10 ppm 0.072 ppm 0.036 ppm 0.0090 ppm 0.0045 ppm Key reference: Kincaid, J.F., J.S. Strong, and F.W. Sunderman. 1953. Nickel poisoning. 1. Experimental study of the effects of acute and subacute exposure to nickel carbonyl. Arch. Ind. Hyg. Occup. Med. 8:48-60. Test species/Strain/Number: albino mice; gender and strain not specified Exposure route/Concentrations/Durations: inhalation, 2.17 ppm 30 min Toxicity end point: Exposure to 2.17 ppm for 30 min caused no deaths and was considered a NOAEL for severe damage pulmonary tissue. Exposure to 6.51 ppm resulted in the death of 2/15 mice. Although no pathology examinations were performed on the mice, lethal exposure of rats to nickel carbonyl caused (Continued)

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256 Acute Exposure Guideline Levels AEGL-2 VALUES Continued 10 min 30 min 1h 4h 8h 0.10 ppm 0.072 ppm 0.036 ppm 0.0090 ppm 0.0045 ppm Toxicity end point (continued): severe pulmonary edema, pulmonary conges- tion, and pleural effusion. It is assumed that mice (most sensitive species) ex- posed to 2.17 ppm for 30 min would exhibit some effects on pulmonary tissue. Pulmonary damage appears to be a component in the continuum of the toxic response to nickel carbonyl and an appropriate critical effect for AEGL-2 devel- opment. The 30-min exposure to 2.17 ppm was considered a point-of-departure representative of a NOAEL for AEGL-2 effects. Time scaling: Exposure-response data over multiple time periods are unavail- able for nickel carbonyl, and empirical derivation of a scaling factor (n) was not possible. The concentration exposure time relationship for many irritant and systemically acting vapors and gases may be described by Cn × t = k, where the exponent, n, ranges from 0.8 to 3.5. In the absence of an empirically derived exponent n, and to obtain conservative and protective AEGL values, temporal scaling was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points. Concentration/Time selection/Rationale: Groups of 15 mice exposed for 30 min to 2.17, 6.51, 7.84, 8.68, 9.80, 10.9, or 12.6 ppm. A concentration-dependent lethal response was observed for exposures to 6.51-12.6 ppm, but the lowest exposure (2.17 ppm) resulted in no deaths. Exposure to 6.51 ppm resulted in the death of 2/15 mice. The 2.17 ppm exposure for 30 min was considered a NOAEL for severe damage to pulmonary tissue. Uncertainty factors/Rationale: Total uncertainty: 10 Interspecies: An uncertainty factor of 3 was applied to account for inter- species variability. The available lethality data suggest that the mouse represents a sensitive species. Based on available lethality data and the analysis conducted by Kincaid et al. (1953) indicating an inverse relationship between lethality and body size (see Section 4.4.1.), the interspecies uncer- tainty factor of 3 appears to be justified. Intraspecies: An uncertainty factor of 3 was applied with the assumption that neither the effects of nickel carbonyl on pulmonary tis- sues nor dosimetry would vary greatly among individuals. The occupational exposure data reported by Shi et al. (1994b) suggest that the AEGL-2 values are sufficiently pro- tective. Modifying factor: 3; the overall dataset for nickel carbonyl is deficient regarding nonlethal effects of nickel carbonyl inhalation. Therefore, a modifying factor of 3 was applied in the development of the AEGL-2 values to account for these (Continued)

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257 Nickel Carbonyl AEGL-2 VALUES Continued 10 min 30 min 1h 4h 8h 0.10 ppm 0.072 ppm 0.036 ppm 0.0090 ppm 0.0045 ppm Modifying factor (continued): deficiencies and the possibility of developmental toxic effects reported by Sunderman and colleagues. Animal to human dosimetric adjustments: None applied; insufficient data. Data adequacy: Data regarding AEGL-2 specifics effects are lacking. The AEGL-2 is based on an estimated threshold for severe pulmonary damage with considerations based on selection of a sensitive species and a critical effect and point of departure appropriate for AEGL-2 development. The data deficiencies have been acknowledged by application of a modifying factor. AEGL-3 VALUES 10 min 30 min 1h 4h 8h 0.46 ppm 0.32 ppm 0.16 ppm 0.040 ppm 0.020 ppm Key reference: Kincaid et al. 1953. Test species/Strain/Number: 10-20 albino mice (age, gender and strain not specified) Exposure route/Concentrations/Durations: Inhalation (whole-body exposure) exposure to 2.17, 6.51, 7.84, 8.68, 9.80, 10.9, or 12.6 ppm for 30 min Toxicity end point: Lethality; LC01 estimated by method of Litchfield and Wil- coxon (1949) Concentration (ppm) Response (Number 2.17 Dead/Number Exposed) 6.51 7.84 8.68 9.80 10.9 12.6 0-min LC01 estimated at 3.17 ppm was used as the determinant of AEGL-3. Time scaling: Exposure-response data over multiple time periods are unavail- able for nickel carbonyl, and empirical derivation of a scaling factor (n) was not possible. The concentration-exposure time relationship for many irritant and systemically acting vapors and gases may be described by Cn × t = k, where the exponent, n, ranges from 0.8 to 3.5. In the absence of an empirically derived exponent n, and to obtain conservative and protective AEGL values, temporal scaling was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the Cn × t = k equation (ten Berge et al. 1986). Concentration/Time selection/Rationale: Estimated 30-min LC01 (3.17 ppm) (Continued)

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258 Acute Exposure Guideline Levels AEGL-3 VALUES Continued 10 min 30 min 1h 4h 8h 0.46 ppm 0.32 ppm 0.16 ppm 0.040 ppm 0.020 ppm Uncertainty factors/Rationale: Total Uncertainty Factor: 10 (Each uncertainty factor of 3 is the approximate logarithmic mean of 10, which is 3.16; hence, 3.16. × 3.16 = 10. Lethality data from the smallest and the most sensitive species were used for development of the AEGL-3. For this reason, and because the available LC50 values vary ap- proximately 8-fold, the total uncertainty adjustment of 10 is weighted toward the uncertainty in individual sensitivity to nickel carbonyl exposure. Data are un- available to definitively apportion adjustment between inter- and intraspecies uncertainty. Modifying factor: None. Animal to human dosimetric adjustments: None applied; insufficient data. Data adequacy: The AEGL-3 values were based on a reasonable estimate of the lethality threshold in a sensitive species. The key study was properly designed and conducted.

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APPENDIX E CATEGORY PLOT FOR NICKEL CARBONYL AEGLS Chemical Toxicity - TSD All Data Nickel Carbonyl Human - No Effect 1000 Human - Discomfort 100 Human - Disabling 10 Animal - No Effect Animal - Discomfort 1 ppm Animal - Disabling 0 AEGL-3 Animal - Some Lethality AEGL-2 0 Animal - Lethal AEGL 0 0 60 120 180 240 300 360 420 480 Minutes FIGURE 9-1 Chemical toxicity; TSD all data, nickel carbonyl. 259