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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 6
7
Iron Pentacarbonyl1
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.
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-
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 guideline reports (NRC 1993, 2001).
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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 susceptible 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 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, 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 corresponding AEGL.
SUMMARY
Iron pentacarbonyl is one of several iron carbonyls. It is formed by the interaction of carbon monoxide with finely divided iron. Iron pentacarbonyl is used in the manufacture of powdered iron cores for electronic components, as a catalyst and reagent in organic reactions, and as an antiknock agent in gasoline. Iron pentacarbonyl is pyrophoric in air (50 C auto ignition point), burning to ferric oxide.
Quantitative toxicity data and odor detection data for humans are unavailable. Qualitative descriptions of the signs and symptoms of iron pentacarbonyl exposure include giddiness and headache and occasionally dyspnea and vomiting. With the exception of dyspnea, these signs and symptoms are alleviated upon removal from exposure, but fever, cyanosis, and coughing may occur 12-36 h after exposure. This information could not be validated, and additional details were unavailable.
Animal data are limited to lethality findings in rats, mice, and rabbits. Based on the limited data available, the rat appears to be the most sensitive species as determined by the 30-min LC50 of 118 ppm and a 4-h LC50 of 10 ppm relative to the 30-min LC50 of 285 ppm for the mouse. For mice a 1.35-fold increase in the LC50 exposure concentration resulted in near 100% mortality for the same exposure duration, suggesting a steep exposure-response relationship for this species above the lethality threshold. Similarly, a 2.8-fold increase in exposure concentration (from 86 to 244 ppm) resulted in an increased mortality rate in rats from 4/12 to 11/12. No reproductive/developmental toxicity, genotoxicity, or carcinogenicity data are available for iron pentacarbonyl.
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Data were unavailable for determining the exponent n. 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 1 to 3.5 (ten Berge et al. 1986). In the absence of chemical-specific data, temporal scaling was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points.
Data consistent with AEGL-1 effects were limited to labored breathing and signs of irritation in rats exposed to 5.2 ppm for 4 h and no observable effects in rats exposed for 6 h/day to 1 ppm for 28 days. However, analysis of the overall dataset for iron pentacarbonyl indicated a very steep exposure-response curve with little margin between exposures producing no observable effects and those resulting in lethality. No AEGL-1 values were recommended.
Limited data in rats revealed that there is only a small margin between exposures causing little or no toxicity and those causing more severe effects and death. No effect was observed following exposure of rats to 1 ppm, for 6 h/day for up to 28 days, while a single exposure to 2.91 ppm for 6 h/day caused notable signs of toxicity and 10% mortality. The occurrence of deaths in laboratory species several days following cessation of exposure was considered in the derivation of the AEGL-2 values. In the absence of exposure-response data for serious and/or possibly irreversible effects, AEGL-2 values were developed by a 3-fold reduction in the AEGL-3 values. This 3-fold reduction was justified by the steep exposure-response relationship in rats, where there appears to be about a 3-fold difference between exposures that produce no lethality and those resulting in 50-100% lethality. The AEGL-2 values also reflect the application of an uncertainty factor of 3 for both interspecies variability and intraspecies variability as described for the development of AEGL-3 values.
Animal data consistent with the definition of AEGL-3 were limited to 30-min LC50 values for rats (118 ppm) and mice (285 ppm), a 45.5-min LClo value for rabbits (250 ppm), and a 4-h LC50 in rats (10 ppm). In addition to a 4-h LC50 value for rats, Biodynamics (1988) provided a 4-h LC16 estimate of 6.99 ppm and an estimated lethality threshold (4 h) of 5.2 ppm for male and female rats. Data from a study by BASF (1995), however, showed that a single 6-h exposure to 2.91 ppm resulted in 10% (1/10 rats) mortality and that a second exposure resulted in 50% mortality. Remaining rats, however, survived an additional 26 six-h exposures, while rats exposed to 1.0 ppm exhibited no clinical signs of toxicity. Using benchmark dose (BMD) analysis of the BASF data, a 6-h exposure to 1.0 ppm was selected as the point of departure for AEGL-3 derivation. A total uncertainty factor of 10 was applied. An uncertainty factor of 3 was applied to account for interspecies variability and is justified by the 2- to 3-fold variance observed for rats and mice and uncertainties in extrapolating to humans. An additional factor of 3 was applied to account for uncertainties regarding individual variability in the toxic response to iron pentacarbonyl. Additionally, iron pentacarbonyl exhibits a steep exposure-response relationship with little margin between minimal and lethal effects and little individual variability in the response of test animals. The AEGL values for iron pentacarbonyl are presented in Table 7-1.
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The AEGL-3 values are defensible when compared to the absence of a toxic response in rats following multiple exposures (6 h/day at 1 ppm for 28 days).
Neither quantitative nor qualitative data are available regarding the potential carcinogenicity of iron pentacarbonyl by any route of exposure. Therefore, a quantitative assessment of potential risk is not possible. Genotoxicity tests in several strains of Salmonella typhimurium were negative.
1.
INTRODUCTION
Iron pentacarbonyl is one of several iron carbonyls. It is formed by the interaction of carbon monoxide with finely divided iron, as shown below (Brief et al. 1967):
The reaction rate is proportional to the square of the carbon monoxide partial pressure. The presence of oxygen, carbon dioxide, and oxidizing gases retards the formation of iron pentacarbonyl.
TABLE 7-1 Summary of AEGL Values for Iron Pentacarbonyl
Classification
10 min
30 min
1 h
4 h
8 h
End Point (Reference)
AEGL-1 (nondisabling)
NR
NR
NR
NR
NR
Not recommended; insufficient data.
AEGL-2 (disabling)
0.077 ppm
0.61 mg/m3
0.077 ppm
0.61 mg/m3
0.060 ppm
0.48 mg/m3
0.037 ppm
0.30 mg/m3
0.025 ppm
0.20 mg/m3
Based on a 3-fold reduction in the AEGL-3 values.
AEGL-3 (lethal)
0.23 ppm
1.8 mg/m3
0.23 ppm
1.8 mg/m3
0.18 ppm
1.4 mg/m3
0.11 ppm
0.88 mg/m3
0.075 ppm
0.60 mg/m3
Estimated lethality threshold in rats (1.0 ppm determined by BMD analysis (BASF 1995). n = 1 or 3; uncertainty factor = 10 (3 for both interspecies variability, and individual variability).
Note: NR: not recommended. Numerical values for AEGL-1 are not recommended (1) because of the lack of available data and (2) because an inadequate margin of safety exists between the derived AEGL-1 and the AEGL-2. Absence of an AEGL-1 does not imply that exposure below the AEGL-2 is without adverse effects. Under ambient atmospheric conditions, iron pentacarbonyl may undergo photochemical decomposition to iron nonacarbonyl and carbon monoxide or burn to ferric oxide.
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Iron pentacarbonyl is used in the manufacture of powdered iron cores for electronic components, as a catalyst and reagent in organic reactions, and as an antiknock agent in gasoline (Sunderman et al. 1959; Budavari et al. 1989). Iron pentacarbonyl is pyrophoric in air (−15°C flashpoint; 50°C autoignition temperature), burning to ferric oxide (ACGIH 2001). It is also light sensitive, decomposing to iron nonacarbonyl and carbon monoxide (ACGIH 1991). Exposure of the general population to iron pentacarbonyl probably would be limited to pressurized releases at manufacturing sites utilizing this chemical intermediate.
Information regarding odor threshold is unavailable. Chemical and physical data for iron pentacarbonyl are shown in Table 7-2.
2.
HUMAN TOXICITY DATA
2.1.
Acute Lethality
Information regarding the lethal toxicity of iron pentacarbonyl is limited to statements by Stokinger (1994) that death may occur 4-11 days following exposure (exposure terms not provided). Pathologic findings may include pulmonary hepatization, vascular injury, and degeneration of the central nervous system. No further details are available regarding these qualitative descriptions.
TABLE 7-2 Chemical and Physical Data
Property
Descriptor or Value
Reference
Synonyms
Iron carbonyl; pentacarbonyl iron
Common name
Iron pentacarbonyl
ACGIH 2001; Budavari et al. 1989
Chemical formula
Fe(CO)5
Budavari et al. 1998
Molecular weight
195.90
Budavari et al. 1998
CAS Registry No.
13463-40-6
Budavari et al. 1998
Physical state
Liquid
Budavari et al. 1998
Solubility
Insoluble in water and dilute acids, soluble in most organic solvents
ACGIH 2001; Budavari et al. 1998
Vapor pressure
35 torr at 25°C
40 mm Hg at 30.3°C
ACGIH 2001; Brief et al. 1967
Density
1.46-1.52 at 20°C
ACGIH 2001
Boiling/melting point
103°C/−20°C
ACGIH 2001
Conversion factors in air
1 mg/m3 = 0.13 ppm
1 ppm = 8.0 mg/m3
ACGIH 2001
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2.2.
Nonlethal Toxicity
Information on the nonlethal toxicity of iron pentacarbonyl in humans is limited to qualitative descriptions provided by Stokinger (1994). Stokinger noted that the signs and symptoms of iron pentacarbonyl exposure are similar to those for nickel carbonyl and include giddiness and headache and occasionally dyspnea and vomiting, these effects being similar to those associated with metal fume fever. With the exception of dyspnea, these signs and symptoms are alleviated upon removal from exposure, but fever, cyanosis, and coughing may occur 12-36 h after exposure. No source was provided for validation of this information, and no further details were available.
2.2.1.
Epidemiologic Studies
No epidemiologic studies of iron pentacarbonyl toxicity are available.
2.3.
Reproductive/Developmental Toxicity
Data regarding the reproductive/developmental toxicity of iron pentacarbonyl in humans are not available.
2.4.
Genotoxicity
No human genotoxicity data for iron pentacarbonyl are currently available.
2.5.
Carcinogenicity
Information regarding the potential carcinogenicity of iron pentacarbonyl in humans is not available.
2.6.
Summary
Information regarding the toxicity of iron pentacarbonyl in humans is limited to unverifiable qualitative statements regarding signs and symptoms of exposure. Exposure terms relating to lethal or nonlethal effects are not available.
3.
ANIMAL TOXICITY DATA
3.1.
Acute Lethality
Acute lethality data are available for several laboratory species but are lim-
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ited to only a few older studies. These studies tend to lack details on the analytical techniques used for determining exposure concentrations.
3.1.1.
Rats
Sunderman et al. (1959) conducted toxicity studies in which male and female Wistar rats (130-180 g) were exposed for 30 min to iron pentacarbonyl at concentrations of 1.57, 2.08, 2.98, or 3.62 mg/L (equivalent to 204, 270, 387, or 470 ppm). There was no description of analytical methods regarding measurement of exposure atmospheres. A total of 20 rats were used in each exposure; three or four rats were exposed at a time. The exposure chamber consisted of an 11-L desiccator. Iron pentacarbonyl was dissolved in ethyl ether and injected into the desiccator via a Vigreux column and a motor-driven syringe. Airflow was set at 11 L/min. Mortality ratios were determined at 3 and 5 days postexposure and are shown in Table 7-3. The investigators estimated the 30-min LC50 as 0.91 mg/L (118 ppm) with a 95% confidence interval of 0.73-1.14 mg/L (95-148 ppm). There was no mention of test animal deaths occurring during or immediately following exposure.
Gage (1970) reported the results of inhalation studies on groups of four male and four female rats exposed to iron pentacarbonyl. Two 5.5-h exposures (on consecutive days) to 15 ppm produced lethargy, respiratory difficulty, 0.2-0.4% carboxyhemoglobin, and four deaths 3-4 days following exposure. Necropsy revealed pulmonary edema and congestion in the dead rats. One 5.5-h exposure to 33 ppm resulted in lethargy, respiratory difficulty, 4% carboxyhemoglobin, and three deaths one day following exposure. Necropsy findings again included pulmonary edema and congestion. The experiments utilized dynamic atmospheres (i.e., continuously generated and passed through the exposure chamber). The iron pentacarbonyl atmosphere was generated by injecting liquid test article (in petroleum ether) at a known rate into a metered stream of air. The iron pentacarbonyl test atmospheres were not verified by analytical techniques.
In an acute inhalation study conducted by Biodynamics for International Specialty Products, groups of 10 CD Sprague-Dawley rats (five/sex/exposure) were exposed to iron pentacarbonyl (0,5.2, 17, 28, or 60 ppm; 99.5% purity) for 4 h (Biodynamics 1988). A group of 10 rats exposed to clean air served as controls. Impinger samples of chamber air were taken every hour for 1 min and analyzed colorimetrically. For each exposure group, chamber concentrations varied (see Table 7-4), but the response was 100% lethality at analytical concentrations at or above 14 ppm and no lethality at or below 6.6 ppm. The results of this experiment are summarized in Table 7-4. The investigators calculated a 4-h LC50 of 10 ppm (both sexes combined, 95% confidence interval of 8.5-13 ppm). No deaths occurred at 5.2 ppm, but 100% mortality was observed for the remaining exposure groups. Deaths occurred at 1-8 days postexposure. For the 60-, 28-,
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TABLE 7-3 Lethal Toxicity of Iron Pentacarbonyl in Rats Exposed for 30 min
Exposure Concentration (ppm)
Mortality at 3 Days
Mortality at 5 Days
244
11/12
11/12
195
12/18
15/18
160
12/18
13/18
118
3/12
6/12
86
1/12
4/12
Source: Sunderman et al. 1959. Reprinted with permission; copyright 1959, American Medical Association.
TABLE 7-4 Mortality in Rats Exposed for 4 h to Iron Pentacarbonyl
Concentration (ppm)
Mortality (Number Dead/Number Exposed)
Nominal
Analytical (range)
Males
Females
Combined
Control
—
0/5
0/5
0/10
7.5
5.2 (4.1-6.6)
0/5
0/5
0/10
24
17 (14-20)
5/5
5/5
10/10
38
28 (19-38)
5/5
5/5
10/10
80
60 (55-64)
5/5
5/5
10/10
Source: Biodynamics 1988.
17-, and 5.2-ppm groups, the respective mortality ratios at postexposure day 5 were 6/10, 7/10, 9/10, and 0/10. Carboxyhemoglobin increased in a dose-related fashion (up to 11.6% increase in the high-dose group relative to controls) but was unaffected in the low-dose group. A lethality versus concentration plot provided in the study indicated that the 5.2-ppm concentration was near a lethality threshold. Gross pathology of rats that died spontaneously revealed red discoloration in several tissues (not specified) and pulmonary edema. The study authors indicated that this was consistent with animals that are not exsanguinated upon death and, therefore, could not be unequivocally considered treatment related.
A 28-day exposure study (consistent with good laboratory practice [GLP] and Organisation for Economic Co-operation and Development [OECD] guidelines) was conducted by BASF Aktiengesellschaft (BASF 1995) in which male and female Wistar rats (five/sex/exposure group) were exposed for 6 h/day, 5 days/week, to iron pentacarbonyl (99.5% purity) at concentrations of 0.1, 0.3, 1, 3, or 10 ppm (0, 0.1, 0.3, 1, 2.91, and 9.85 ppm analytical). A group of 10 rats exposed to clean air only served as controls. All of the rats in the 10-ppm exposure group died within 4 days of the first and only 6-h exposure (see Table 7-5). Prior to death, these rats exhibited clinical signs of piloerection, lassitude, red discharge (confirmed as blood) around the nostrils, and labored respiration. Five of 10 rats in the 3-ppm group were dead within 4 days after only two 6-h ex-
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TABLE 7-5 Mortality in Rats Exposed to Iron Pentacarbonyl for 6 h/Day for Up to 28 Days
Concentration (ppm)
Results
Test Groupa
Analytical
Mortality (Number Dead/Number Exposed)
Comments
0 control
–
0/10
No clinical signs
4
0.1 (0.1 ± 0.01)
0/10
No clinical signs
E
0.3 (0.3 ± 0.01)
0/10
No clinical signs
1
1 (1.00 ± 0.02)
0/10
No clinical signs
2
3 (2.91 ± 0.01)
5/10
One death after first exposure; 50% after two exposures; death occurred within 4 days
3
10 (9.85)
10/10
Dead or terminated in extremis after one exposure; deaths occurred within 3 days
aGroup designators as reported in BASF 1995.
posures. On days 4 and 5 the surviving rats exhibited piloerection and accelerated respiration, and on days 6 through 9 they still exhibited accelerated respiration. From day 10 to the end of the study, the rats exhibited no abnormal clinical signs. Moribund animals also exhibited impaired respiration and bloody discharge from the nostrils. Necropsy of these animals revealed severe pulmonary damage as well as damage to the spleen. None of the rats in the 0.1-, 0.3-, or 1-ppm groups exhibited any clinical signs even after 4 weeks of exposure, although some rats in the 1.0-ppm group were found (upon necropsy) to have increased absolute and relative lung weights. The investigators stated that this could possibly be treatment related. The mortality and exposure-response reported in this study are consistent with those of the previously described acute inhalation study by Biodynamics. The data from these studies suggest a steep exposure-response relationship and a lethality threshold of ~3-5 ppm for exposures of 4-6 h in duration.
3.1.2.
Mice
Sunderman et al. (1959) also conducted lethality studies using Swiss albino mice (18-20 g; gender not specified) using the same exposure system as described for the rat studies (se Section 3.1.1). Exposure concentrations over the 30-min exposure period were 1.57, 2.08, 2.98, and 3.62 mg/L (204, 270, 387, and 470 ppm). The investigators estimated the 30-min LC50 as 2.19 mg/L (285 ppm) with a 95% confidence interval of 1.91-2.51 mg/L (248-326 ppm). Results of this experiment are shown in Table 7-6.
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TABLE 7-6 Lethal Toxicity of Iron Pentacarbonyl in Mice Exposed for 30 min
Exposure Concentration (ppm)
Mortality at 3 Days
Mortality at 5 Days
470
16/20
20/20
387
15/20
17/20
270
8/20
9/20
204
5/20
5/20
Source: Sunderman et al. 1959. Reprinted with permission; copyright 1959, American Medical Association.
In addition to the experiments conducted to estimate an LC50, experiments were conducted to assess the effectiveness of antidotes (dithiocarb, dimercaprol, penicillamine, and CaNa2EDTA). For these experiments, groups of 10 albino Swiss mice (gender not specified) were exposed to 3.0 mg of iron pentacarbonyl/L (390 ppm) for 30 min. Lethality was assessed at 3 and 5 days postexposure. At 3 days postexposure, mice not receiving an antidote exhibited 50-90% mortality (Table 7-5). At 5 days postexposure, mice not given any antidote and exposed for 30 min to 390 ppm, exhibited 70-100% lethality (see Table 7-7). These data and the data from the LC50 experiments suggest a steep exposure-response curve (≈1.35-fold increase in the LC50 produces near 100% mortality) for this strain of mouse. Preliminary data indicated that CaNa2EDTA may have provided some protection against iron pentacarbonyl-induced toxicity.
3.1.3.
Rabbits
Armit (1908) reported that a 45.4-min exposure of rabbits (age, number, strain, and gender not specified) to 0.025 volume percent (≈250 ppm) of iron pentacarbonyl resulted in fatality. No further information is available regarding this finding. Stokinger (1981) cited an oral LD50 of 18 mg/kg and a dermal LD50 of 240 mg/kg for rabbits.
TABLE 7-7 Lethal Toxicity of Iron Pentacarbonyl (390 ppm) in Six Groups of Mice Exposed for 30 min
Mortality at 3 Days
Mortality at 5 Days
8/10
9/10
5/10
7/10
10/10
10/10
9/10
10/10
9/10
9/10
9/10
9/10
Source: Sunderman et al. 1959. Reprinted with permission; copyright 1959, American Medical Association.
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3.2.
Nonlethal Toxicity
Data on the nonlethal toxicity of iron pentacarbonyl in animals are limited to two unpublished studies regarding pathology in dead rats.
3.2.1.
Rats
Gage (1970) reported the results of inhalation studies on groups of four male and four female rats exposed to iron pentacarbonyl. One group receiving eighteen 5.5-h exposures to 7 ppm exhibited no overt signs of toxicity and necropsy findings were unremarkable. Exposures to higher concentrations (15 and 33 ppm) were lethal. As previously described, the experiments utilized dynamic atmospheres (i.e., continuously generated and passed through the exposure chamber) generated by injecting liquid test article (in petroleum ether) at a known rate into a metered stream of air. Iron pentacarbonyl concentrations were not verified by analytical techniques.
In a 4-h inhalation study reported by Biodynamics (1988), groups of five male and five female Sprague-Dawley CD rats were exposed (whole body) to iron pentacarbonyl at concentrations of 5.2, 17, 28, or 60 ppm (analytical concentration). A control group was exposed to clean air. With the exception of the 5.2-ppm group, all exposures resulted in 100% lethality within 9 days after exposure (mortality ratios at day 5 are noted in Section 3.1.1). Clinical signs during exposure were limited to decreased activity, closing of the eyes, and labored breathing. At 1-2 h postexposure, however, clinical observations for all treatment groups included labored breathing (not for the 5.2-ppm group), lacrimation, mucoid and bloody nasal discharge, salivation, hypothermia (60-ppm group only), and ano-genital staining. A slight exposure-related increase in carboxyhemoglobin levels was observed in males, especially at 1 h into the exposure, but tended to return to normal by the end of the exposure. Even rats in the 5.2-ppm group exhibited a slight increase in carboxyhemoglobin relative to unexposed controls [males: 3.7% (1 h) and 3.5% (4 h) versus 3.2% (1 h) and 3.3% (4 h) for controls; females: 3.0% (1 h) and 2.5% (4 h) versus 2.6% (1 h) and 3.2% (4 h) for controls]. Neurological examinations (gait, muscle tone, reflexes) revealed no findings in the 5.2-ppm group rats. At 1-2 h postexposure, rats in the 5.2-ppm group exhibited lacrimation, nasal discharge, and salivation at incidences similar to those of unexposed controls. Although gross pathology findings at terminal necropsy (postexposure day 15) of rats in the 5.2-ppm group revealed red lungs in a few rats and red turbinates in one male, the study authors indicated the treatment relationship of these findings to be equivocal.
In a 28-day inhalation exposure study (BASF 1995), groups of SPF-Wistar rats (five males and five females per group) were exposed (whole body) to iron pentacarbonyl (0, 0.1, 0.3, 1, 3, or 10 ppm), 6 h/day, for up to 28 days (analytical concentrations were 0, 0.1, 0.3, 1, 2.91, and 9.85 ppm). Although 50% and 100% lethality occurred in the 3-ppm and 10-ppm groups, respectively, no rats
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cOSHA PEL-TWA (Occupational Health and Safety Administration, Permissible Exposure Limits–Time Weighted Average) (OSHA 1993) is defined analogous to the ACGIH TLV-TWA but is for exposures of no more than 10 h/day, 40 h/week.
dOSHA PEL-STEL (Permissible Exposure Limits–Short-Term Exposure Limit) (OSHA 1993) is defined analogous to the ACGIH TLV-STEL.
eIDLH (Immediately Dangerous to Life and Health, National Institute of Occupational Safety and Health) (NIOSH 2003) represents the maximum concentration from which one could escape within 30 min without any escape-impairing symptoms or any irreversible health effects. By concurrence with OSHA PEL, no IDLH was established.
fNIOSH REL-TWA (National Institute of Occupational Safety and Health, Recommended Exposure Limits–Time Weighted Average) (NIOSH 2003) is defined analogous to the ACGIH TLV-TWA.
gNIOSH REL-STEL (Recommended Exposure Limits–Short-Term Exposure Limit) (NIOSH 2003) is defined analogous to the ACGIH-TLV-STEL.
hACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value–Time Weighted Average) (ACGIH 2001) is 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.
iACGIH TLV-STEL (Threshold Limit Value–Short-Term Exposure Limit) (ACGIH 2001) is defined as a 15-min TWA exposure which should not be exceeded at any time during the workday even if the 8-h TWA is within the TLV-TWA. Exposures above the TLV-TWA up to the STEL should not be longer than 15 min and should not occur more than four times per day. There should be at least 60 min between successive exposures in this range.
jMAK (Maximale Arbeitsplatzkonzentration [Maximum Workplace Concentration], Deutsche Forschungs-Gemeinschaft [German Research Association], Germany) (DFG 1999) is defined analogous to the ACGIH-TLV-TWA.
kMAK Spitzenbegrenzung (Kategorie II,2) (Peak Limit Category II,2) (DFG 1999) constitutes the maximum concentration to which workers can be exposed for a period up to 30 min, with no more than two exposure periods per work shift; total exposure may not exceed 8-h MAK.
lEinsatztoleranzwert (Action Tolerance Levels) (Vereinigung zur Förderung des deutschen Brandschutzes e.V. [Federation for the Advancement of German Fire Prevention]) constitutes a concentration to which unprotected firemen and the general population can be exposed to for up to 4 h without any health risks.
Note: NR: not recommended. Numerical values for AEGL-1 are not recommended (1) because of the lack of available data or (2) because an inadequate margin of safety exists between the derived AEGL-1 and the AEGL-2. Absence of an AEGL-1 does not imply that exposure below the AEGL-2 is without adverse effects. Under ambient atmospheric conditions, iron pentacarbonyl may undergo photochemical decomposition to iron nonacarbonyl and carbon monoxide or burn to ferric oxide.
response relationship for which there appeared to be little margin between exposures producing little or no toxicity and those resulting in lethal responses. The available studies also showed that the respiratory tract may be a primary target for the lethality of this chemical following inhalation exposure. Information re-
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garding the human experience was limited to inadequately validated qualitative descriptions of nonspecific responses.
The most notable research need is to provide definitive exposure-response data for nonlethal effects, thereby allowing for a more precise description of the exposure-response profile for iron pentacarbonyl, particularly in terms of AEGL-2 effects. AEGL-1 are not recommended due to the absence of data specific to response end points consistent with the AEGL-1 definition. Furthermore, available data suggest that there is little margin between these levels, thereby rendering development of AEGL-1 values tenuous and of questionable utility. Although LC50 data are available for two species, the overall database is insufficient to definitively determine the magnitude of species variability in the lethal response to inhaled iron pentacarbonyl.
9.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Iron pentacarbonyl. Pp. 806-807 in Documentation of the Threshold Limit Values and Biological Exposure Indices, 6th Ed. American Conference of Governmental Industrial Hygienists, Cincinnatti, OH.
ACGIH (American Conference of Governmental Hygienists). 2001. Documentation of the Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices, 7th Ed. American Conference of Governmental Hygienists, Cincinnatti, OH.
AIHA (American Industrial Hygiene Association). 1999. The AIHA Emergency Response Planning Guideline and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association, Fairfax, VA.
Armit, H.W. 1908. The toxicology of nickel carbonyl, Part II. J. Hyg. 8:565-600.
BASF. 1988. Report on the Study of Eisenpentacarbonyl in the Ames Test. BASF Department of Toxicology. EPA/OTS Doc # 0529732.
BASF. 1995. Study on the Inhalation Toxicity of Eisenpentacarbonyl as a Vapor in Rats -28 Day Test. BASF Department of Toxicology. EPA/OTS Doc # 89-950000244.
Biodynamics. 1988. An Acute Inhalation Toxicity Study of Iron Pentacarbonyl in the Rat. Final Report. EPA/OTS Doc ID 88-920001300.
Brief, R.S., R.S. Ajemian, and R.G. Confer. 1967. Iron pentacarbonyl: Its toxicity, detection, and potential for formation. Am. Ind. Hyg. Assoc. J. 28(1):21-30.
Budavari, S., M.J. O'Neil, A. Smith, and P.E. Heckelman, eds. 1989. Iron pentacarbonyl. P. 806 in The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 11th Ed. Rahway, NJ: Merck.
Budavari S, O'Neil, M.J., Smith, A., Heckelman, P.E., Kennedy, J.F., Eds. 1998. Iron pentacarbonyl. The Merck Index. 11th ed. Merck and Co., Whitehouse, NJ. p. 874.
Devasthali, S.D., V.R. Gordeuk, G.M. Brittenham, J.R. Bravo, M.A. Hughs, and L.J. Keating. 1991. Bioavailability of carbonyl iron: A randomized, double-blind study. Eur. J. Hematol. 46(5):272-278.
DFG (Deutsche Forschungsgemeinschaft). 1999. List of MAK and BAT Values 1999: Maximum Concentrations and Biological Tolerance Values at the Workplace. Commission for the Investigation of Health Hazards of Chemical Compounds in
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the Work Area. Report No. 35. Weinheim, Federal Republic of Germany: Wiley-VCH.
EPA (U.S. Environmental Protection Agency). 2002. Benchmark Dose Software Version 1.3.1. National Center for Environmental Assessment, U.S. Environmental Protection Agency.
Gage, J.C. 1970. The subacute inhalation toxicity of 109 industrial chemicals. Br. J. Ind. Med. 27(1):1-18.
Gordeuk, V.R., G.M. Brittenham, M. Hughes, L.J. Keating, and J.J. Opplt. 1987. High-dose carbonyl iron for iron deficiency anemia: A randomized double-blind trial. Am. J. Clin. Nutr. 46(6):1029-1034.
Haber, F. 1924. Zur Geschichte des Gaskrieges. Pp. 76-92 in Fünf Vorträge aus den Jahren 1920-1923. Berlin: J. Springer.
Huebers, H.A., G.M. Brittenham, E. Csiba, and C.A. Finch. 1986. Absorption of carbonyl iron. J. Lab. Clin. Med. 108(5):473-478.
NIOSH (National Institute for Occupational Safety and Health). 2004. Iron pentacarbonyl. In NIOSH Pocket Guide to Chemical Hazards. Publication No. 97-140. National Institute for Occupational Safety and Health, Public Health Service, U.S. Department of Health, Education and Welfare, Cincinnati, OH [online]. Available: http://www.setonresourcecenter.com/MSDS_Hazcom/NPG/npgd0345.html [accessed July 27, 2007].
NRC (National Research Council). 1985. Emergency and Continuous Exposure Guidance Levels for Selected Airborne Contaminants, Vol. 5. Washington, DC: National Academy Press.
NRC (National Research Council). 1993. Guidelines for Developing Community Emergency 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: National Academy Press.
Rinehart, W.E., and T. Hatch. 1964. Concentration-time product (CT) as an expression of dose in sublethal exposures to phosgene. Am. Ind. Hyg. Assoc. J. 25:545-553.
Stokinger, H.E. 1981. Metal carbonyls Mex(CO)y. Pp. 1792-1807 in Patty’s Industrial Hygiene and Toxicology, Vol. IIA. Toxicology, G.D. Clayton, and F.E. Clayton, eds. New York: John Wiley & Sons.
Stokinger, H.E. 1994. Metals. In: Clayton, G.D., Clayton, F.E., Eds., Patty’s Industrial Hygiene and Toxicology. John Wiley & Sons, New York. Pp. 1792-1807.
Sunderman, F.W., B. West, and J.F. Kincaid. 1959. A toxicity study of iron pentacarbonyl. AMA Arch. Ind. Health 19(1):11-13.
ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Hazard. Mater. 13: 301-309.
Warheit, D.B., M.C. Carakostas, M.A. Hartsky, and J.F. Hansen. 1991. Development of a short-term inhalation bioassay to assess pulmonary toxicity of inhaled particles: Comparisons of pulmonary responses to carbonyl iron and silica. Toxicol. Appl. Pharmacol. 107(2):350-368.
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APPENDIX A
Derivation of AEGL-1 Values
Quantitative data regarding responses consistent with the AEGL-1 definition were not available for acute inhalation exposure of humans or test animals to iron pentacarbonyl. Because of the lack of appropriate data, reliable AEGL-1 values could not be determined. Additionally, the exposure-response relationship and apparent extreme toxicity of iron pentacarbonyl following inhalation exposure in animals suggest little margin between exposures with little or no apparent effect and those causing lethality. Therefore, AEGL-1 values are not recommended. Absence of an AEGL-1 value does not imply that exposure below the AEGL-2 concentration is without adverse effects.
Derivation of AEGL-2 Values
Key study:
AEGL-2 values were derived by a 3-fold reduction in the AEGL-3 and therefore are also based on the data reported by BASF (1995).
Toxicity end point:
The AEGL-3 values were reduced by a factor of 3 as a threshold estimate for serious and/or irreversible effects. Comparison of the resulting values with available animal data affirms that the resulting values would be below those causing a lethal response and that they are consistent with the steep exposure-response relationship indicated by the animal data.
Scaling:
As per AEGL-3 development.
Uncertainty factors:
3 for uncertainties regarding interspecies variability as per AEGL-3 development.
3 for intraspecies variability as per AEGL-3 development.
Derivation of AEGL-3 Values
Key study:
BASF 1995.
Toxicity end point:
10% lethality following a single 6-h exposure of male and female rats to 2.91 ppm; 50% mortality following
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two 6-h exposures to 2.91 ppm. Data from an independent study (Biodynamics 1988) provided a 4-h LC50 of 10 ppm, a 4-h LC16 of 6.99 ppm, and an estimated 4-h lethality threshold of 5.2 ppm. The AEGL-3 point of departure (NOAEL for lethality) was estimated to be 1.0 ppm (6-h exposure) based on BMD analysis and evaluation of the available data (see Section 7.3).
Scaling:
Data were unavailable for determining the exponent “n.” 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 1 to 3.5 (ten Berge et al. 1986). In the absence of chemical-specific data, temporal scaling was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points.
(1.0 ppm)1 × 6 h = 6 ppm•h
(1.0 ppm)3 × 6 h = 6 ppm•h
Uncertainty factors:
3 for uncertainties regarding interspecies variability. Lethality data suggest some variability (approximately 2 to 3 fold based on data from Sunderman et al. 1959) among the laboratory species tested. Definitive data regarding a lethality threshold for humans exposed to iron pentacarbonyl are not available.
3 for intraspecies variability. The adjustment for this area of uncertainty was limited to 3 because the available toxicity data indicate that acute inhalation exposure to iron pentacarbonyl results in port-of-entry effects (i.e., airway and lungs) rather than systemic effects, and therefore variability in response due to dosimetric factors may be limited. Additionally, lethality in rats following acute inhalation exposure to iron pentacarbonyl exhibits a steep exposure-response relationship with little margin between minimal and lethal effects and little individual variability in the response of test animals.
10-min AEGL-3:
Due to uncertainties in extrapolating from a 6-h experimental time point to a 10-min AEGL-specific du
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ration, the 30-min AEGL-3 has been adopted as the 10-min AEGL-3.
10-min AEGL-3 = 0.23 ppm (1.8 mg/m3)
30-min AEGL-3:
C3 × 0.5 h = 6.0 ppm•h
C = 2.28 ppm
30-min AEGL-3 = 2.28 ppm/10 = 0.23 ppm
(1.8 mg/m3)
1-h AEGL-3:
C3 × 1 h = 6.0 ppm•h
C = 1.82 ppm
1-h AEGL-3 = 1.82 ppm/10 = 0.18 ppm
(1.4 mg/m3)
4-h AEGL-3:
C3 × 4 h = 6.0 ppm•h
C = 1.14 ppm
4-h AEGL-3 = 1.14 ppm/10 = 0.11 ppm
(0.88 mg/m3)
8-h AEGL-3:
C × 8 h = 6.0 ppm•h
C = 0.75 ppm
8-h AEGL-3 = 0.75 ppm/10 = 0.075 ppm
(0.60 mg/m3)
APPENDIX B
Time Scaling for Iron Pentacarbonyl AEGLs
The relationship between dose and time for any given chemical is a function of the physical and chemical properties of the substance and its unique toxicological and pharmacological properties. Historically, the relationship according to Haber (1924), commonly called Haber’s law or Haber’s rule (i.e., C × t = k, where C = exposure concentration, t = exposure duration, and k = a constant) has been used to relate exposure concentration and duration to effect (Rinehart and Hatch 1964). This concept states that exposure concentration and exposure duration may be reciprocally adjusted to maintain a cumulative exposure constant (k) and that this cumulative exposure constant will always reflect a specific quantitative and qualitative response. This inverse relationship of concentration and time may be valid when the toxic response to a chemical is equally dependent on the concentration and the exposure duration. However, an assessment by ten Berge et al. (1986) of LC50 data for certain chemicals revealed chemical-
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specific relationships between exposure concentration and exposure duration that were often exponential. This relationship can be expressed by the equation Cn × t = k, where n represents a chemical-specific, and even a toxic end point-specific, exponent. The relationship described by this equation is basically the form of a linear regression analysis of the log-log transformation of a plot of C versus t. ten Berge et al. (1986) examined the airborne concentration (C) and short-term exposure duration (t) relationship relative to death for approximately 20 chemicals and found that the empirically derived value of n ranged from 0.8 to 3.5 among this group of chemicals. Hence, the value of the exponent (n) in the equation Cn × t = k quantitatively defines the relationship between exposure concentration and exposure duration for a given chemical and for a specific health effect end point. Haber’s rule is the special case where n = 1. As the value of n increases, the plot of concentration versus time yields a progressive decrease in the slope of the curve.
Data were not available to derive an exposure concentration-exposure duration relationship (n) for propargyl alcohol. In the absence of chemical-specific data, 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 (NRC 2001).
Although exposure-response data for the same toxicity end point over multiple time periods were limited to several LC50 values, these data suggested a near-linear relationship. Therefore, the value of n was set at unity for the exponential temporal scaling equation, C1 × t = k.
APPENDIX C
ACUTE EXPOSURE GUIDELINES FOR IRON PENTACARBONYL
Derivation Summary for Iron Pentacarbonyl AEGLS
AEGL-1 VALUES
10 min
30 min
1 h
4 h
8 h
Not recommended
Not recommended
Not recommended
Not recommended
Not recommended
Key reference: Not applicable.
Test species/Strain/Number: Not applicable.
Exposure route/Concentrations/Durations: Not applicable.
Toxicity end point: Data unavailable for defining AEGL-1-specific end points.
Time scaling: Not applicable.
Concentration/Time selection/Rationale: Not applicable.
Uncertainty factors/Rationale: Not applicable.
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10 min
30 min
1 h
4 h
8 h
Not recommended
Not recommended
Not recommended
Not recommended
Not recommended
Modifying factor: Not applicable.
Animal-to-human dosimetric adjustments: Not applicable.
Comments: NR: not recommended. Numerical values for AEGL-1 are not recommended (1) because of the lack of available data, and (2) because an inadequate margin of safety exists between the derived AEGL-1 and the AEGL-2 values. Absence of an AEGL-1 value does not imply that exposure below the AEGL-2 concentration is without adverse effects.
AEGL-2 VALUES
10 min
30 min
1 h
4 h
8 h
0.077 ppm
0.077 ppm
0.060 ppm
0.037 ppm
0.025 ppm
Key reference: Not applicable; see AEGL-3.
Test species/Strain/Number: Rat/Wistar/5 males and 5 females per exposure group.
Exposure route/Concentrations/Durations: Not applicable; see AEGL-3.
Toxicity end point: 3-fold reduction in AEGL-3 values.
Time scaling: Cn × t = k, where n =1 or 3; as per AEGL-3 values.
Concentration/Time selection/Rationale: See procedure/rationale for AEGL-3.
Uncertainty factors/Rationale
Total Uncertainty Factor: 10 (as per AEGL-3 values).
Modifying factor: None applied
Animal-to-human dosimetric adjustments: None.
Data adequacy: Although definitive data were unavailable that described effects consistent with the AEGL-2 definition, a 3-fold reduction in AEGL-3 values was considered appropriate for development of AEGL-2 values. This approach is consistent with the available data demonstrating a steep exposure-response curve. Under ambient atmospheric conditions, iron pentacarbonyl may undergo photochemical decomposition to iron nonacarbonyl and carbon monoxide or burn to ferric oxide.
AEGL-3 VALUES
10 min
30 min
1 h
4 h
8 h
0.23 ppm
0.23 ppm
0.18 ppm
0.11 ppm
0.075 ppm
Key reference: BASF. 1995. Study on the inhalation toxicity of eisenpentacarbonyl as a vapor in rats—28 day test. BASF Department of Toxicology.
EPA/OTS Doc # 89-950000244.
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10 min
30 min
1 h
4 h
8 h
0.23 ppm
0.23 ppm
0.18 ppm
0.11 ppm
0.075 ppm
Test species/Strain/Number: Rat/Wistar/5 males and 5 females per exposure group.
Exposure route/Concentrations/Durations: 6-h inhalation exposure
Test Group
Exposure Concentration (ppm analytical)
0
clean air control
4
0.1 (0.1 ± 0.01)
E
0.1 (0.1 ± 0.01)
1
1 (1.00 ± 0.02)
2
3 (2.91 ± 0.01)
3
10 (9.85)
Toxicity end point: 10% mortality after one 6-h exposure to 2.91 ppm; 50% mortality following two 6-h exposures. A benchmark dose analysis of the BASF (1995) data provided an MLE LC01 of 1.9 ppm and a BMDL LC05 of 0.80 ppm.
Time scaling: Cn × t = k, where n =1 or 3. 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 1 to 3.5 (ten Berge et al. 1986). In the absence of chemical-specific data, temporal scaling was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points. Due to uncertainties in extrapolating from the 6-h point of departure to 10 min, the 30-min AEGL-3 was adopted as the 10-min value.
Concentration/Time selection/Rationale: A benchmark dose analysis of the BASF (1995) data provided an MLE LC01 of 1.9 ppm and a BMCL LC05 of 0.80 ppm. Due to insufficient data differentiating the MLE LC01 from the BMCL LC05, the more conservative BMCL LC05 value of 0.80 ppm would normally have been selected as the point of departure for the AEGL-3 estimation. However, because no deaths resulted from a 28-day exposure to 1 ppm, 1 ppm was considered a more reasonable point of departure than 0.8.
Uncertainty factors/Rationale:
Total uncertainty factor: 10
Interspecies:
3 to account for data deficiencies in species variability in the toxic response to iron carbonyl and for possible variability in toxicodynamics; exposures causing lethality in rats and mice varied by 2- to 3-fold.
Intraspecies:
3 to account for possible individual variability in the sensitivity to iron pentacarbonyl-induced toxicity. Adjustment of the AEGL-3 values by application of greater uncertainty was not considered necessary because the total uncertainty factor of 10 resulted in AEGL-3 values that were reasonable compared to the available acute exposure data and data from multiple-exposure
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10 min
30 min
1 h
4 h
8 h
0.23 ppm
0.23 ppm
0.18 ppm
0.11 ppm
0.075 ppm
animal studies. Additionally, lethality of rats following acute inhalation exposure to iron pentacarbonyl exhibits a steep exposure-response relationship with little margin between minimal and lethal effects and little individual variability in the response (Biodynamics 1988).
Modifying factor: None.
Animal-to-human dosimetric adjustments: None.
Data adequacy: The AEGL-3 values have been developed based on an estimate of the lethality threshold as determined by data available from a well-conducted GLP study. Under ambient atmospheric conditions, iron pentacarbonyl may undergo photochemical decomposition to iron nonacarbonyl and carbon monoxide or burn to ferric oxide.
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APPENDIX D
Category Plot for Iron Pentacarbonyl AEGLS
FIGURE 7-2 Category plot of animal toxicity data compared to AEGL values. Note that the above plot includes multiple exposure studies for which a single exposure was input into the plot (5.5 h/d for two days in rats (Gage 1970); 6h/d, 5d/wk for 28 days in rats (BASF 1995). No effect = No effect or mild discomfort. Discomfort = Notable transient discomfort/irritation consistent with AEGL-1 level effects. Disabling = Irreversible/long-lasting effects or an impaired ability to escape. Some lethality = Some, but not all, exposed animals died. Lethal = All exposed animals died.