1

Aniline1
Acute Exposure Guideline Levels

SUMMARY

ANILINE is an aromatic amine used chiefly in the chemical industry in the manufacture of dyes, dye intermediates, rubber accelerators, antioxidants, drugs, photographic chemicals, isocyanates, herbicides, and fungicides. Production of aniline oil in 1993 was approximately 1 billion pounds. The primary effect of an acute exposure to aniline is the oxidation of the hemoglobin in red blood cells (RBCs), resulting in the formation of methemoglobin. The effect may occur following inhalation, ingestion, or dermal absorption. In conjunction with methemoglobinemia, chronic exposures or exposures to high concentrations may produce signs and symptoms of headache, paresthesia, tremor, pain, narcosis/coma, cardiac arrhythmia, and possibly death.

No reliable data on human exposures via the inhalation route were located.

1  

This document was prepared by AEGL Development Team members Robert Snyder and George Rodgers of the National Advisory Committee on Acute Exposure Guideline Levels for Hazardous Substances (NAC) and Sylvia Talmadge of the Oak Ridge National Laboratory. The NAC reviewed and revised the document, which was then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NAC and are consistent with the NRC guidelines reports (NRC 1993; NRC in press).



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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 1 Aniline1 Acute Exposure Guideline Levels SUMMARY ANILINE is an aromatic amine used chiefly in the chemical industry in the manufacture of dyes, dye intermediates, rubber accelerators, antioxidants, drugs, photographic chemicals, isocyanates, herbicides, and fungicides. Production of aniline oil in 1993 was approximately 1 billion pounds. The primary effect of an acute exposure to aniline is the oxidation of the hemoglobin in red blood cells (RBCs), resulting in the formation of methemoglobin. The effect may occur following inhalation, ingestion, or dermal absorption. In conjunction with methemoglobinemia, chronic exposures or exposures to high concentrations may produce signs and symptoms of headache, paresthesia, tremor, pain, narcosis/coma, cardiac arrhythmia, and possibly death. No reliable data on human exposures via the inhalation route were located. 1   This document was prepared by AEGL Development Team members Robert Snyder and George Rodgers of the National Advisory Committee on Acute Exposure Guideline Levels for Hazardous Substances (NAC) and Sylvia Talmadge of the Oak Ridge National Laboratory. The NAC reviewed and revised the document, which was then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NAC and are consistent with the NRC guidelines reports (NRC 1993; NRC in press).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 All acute exposure guideline level (AEGL) values are based on a study in which rats were exposed to aniline at concentrations of 0, 10, 30, 50, 100, or 150 parts per million (ppm) for 8 or 12 h (Kim and Carlson 1986). The only reported effect was methemoglobin formation. The relationship between aniline concentration and methemoglobin formation appeared to be linear. Furthermore, at a constant concentration (100 ppm), the formation of methemoglobin between 3 and 8 h was basically linear, reaching an asymptote at 8 h. Based on the linear relationship between aniline concentration and methemoglobin formation and between methemoglobin formation and time at a constant aniline concentration, a linear relationship between concentration and exposure duration (C1×t=k, where C=exposure concentration, t=exposure duration, and k=a constant) was chosen for time-scaling aniline concentrations to the appropriate AEGL exposure durations. The AEGL-1 was based on an exposure of rats to a concentration of 100 ppm for 8 h, which resulted in elevation of methemoglobin from a control value of 1.1% (range, 0.4% to 2.1%) to 22%. A review of the published data indicates that methemoglobin levels of 15–20% in humans results in clinical cyanosis but no hypoxic symptoms. Although inhalation data for comparison purposes are not available, oral ingestion data suggest that humans may be considerably more sensitive to methemoglobin-forming chemicals than rats. Therefore, a default uncertainty factor of 10-fold was used for interspecies extrapolation (NRC 1993). Several sources also indicate that newborns may be more sensitive to methemoglobin-forming chemicals than adults. Because of the absence of specific quantitative data on sensitive human subpopulations and the fact that there are data suggesting greater susceptibility of infants, a default uncertainty factor of 10-fold was used for intraspecies extrapolation (NRC 1993). It is believed that an intraspecies uncertainty factor of 10 is protective of the general population including susceptible individuals. The default uncertainty factors of 10 for each of the interspecies and intraspecies variabilities are also supported by the small database of information and the lack of reliable human inhalation studies. The data were scaled across time using C1×t=k because of data indicating a linear relationship between concentration and exposure duration as related to methemoglobin formation. The AEGL-2 was based on the same study with rats in which a concentration of 150 ppm for 8 h resulted in elevation of methemoglobin from a control value of 1.1% to 41%. This level of methemoglobin is associated with fatigue, lethargy, exertional dyspnea, and headache in humans and was considered the threshold for disabling effects. Since the same mode of action applies to AEGL-2 effects, the 150-ppm concentration was divided by a combined uncertainty factor of 100 and scaled across time using the same reasons and relationships as those used for the AEGL-1 above.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 Data on concentrations of aniline inducing methemoglobin levels at the threshold for lethality were not available. Based on the fact that the relationship between the concentration of aniline and methemoglobin formation is linear, the dose-response curve from the study on which the AEGL-1 and AEGL-2 values were based was extrapolated to a concentration resulting in >70% formation of methemoglobin, the threshold for lethality. The concentration of 250 ppm for 8 h was chosen as the threshold for lethality, according to Kiese (1974) and Seger (1992). Since the same mode of action applies to AEGL-3 effects, the 250-ppm concentration was divided by a combined uncertainty factor of 100 and scaled across time using the same reasons and relationships as those used for the AEGL-1 above. Several studies with rats support the AEGL-3 values. A 10-min exposure to aniline at 15,302 ppm resulted in no toxic effects, and a 4-h exposure at 359 ppm resulted in severe toxic effects but no deaths. Dividing these values by a total uncertainty factor of 100 and scaling across time using C1×t=k results in values similar to those derived from the Kim and Carlson (1986) study. Studies with repeated exposures of rats resulted in additional effects on the blood and spleen, but concentrations up to 87 ppm, 6 h/d, 5 d/w for 2 w were not disabling or life-threatening. The derived AEGLs are listed in Table 1–1. Because aniline is absorbed through the skin in quantities sufficient to induce systemic toxicity, a skin notation was added to the summary table. The reported odor threshold for aniline ranges from 0.012 to 10 ppm. Therefore, the odor of aniline will be noticeable by most individuals at the AEGL-1 concentrations. The odor is somewhat pungent but not necessarily unpleasant. 1. INTRODUCTION Aniline is an aromatic amine used in the manufacture of dyes, dye intermediates, rubber accelerators, and antioxidants. It has also been used as a solvent, in printing inks, and as an intermediate in the manufacture of pharmaceuticals, photographic developers, plastics, isocyanates, hydroquinones, herbicides, fungicides, and ion-exchange resins. It is produced commercially by catalytic vapor phase hydrogenation of nitrobenzene (Benya and Cornish 1994; HSDB 1996). Production of aniline oil was listed at approximately 1 billion pounds in 1993 (U.S. ITC 1994). Chemical and physical properties are listed in Table 1–2. Aniline may be absorbed following inhalation, ingestion, and dermal exposures. The inhalation toxicity of aniline was studied in several animal species, but only one study that utilized multiple exposure concentrations for sublethal effects was located. Data from human studies lack specific details or exposures

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 TABLE 1–1 Summary of AEGL Values for Anilinea Classification 30 min 1 h 4 h 8 h Endpoint (Reference) AEGL-1b (Nondisabling) 16 ppm (61 mg/m3) 8.0 ppm (30 mg/m3) 2.0 ppm (7.6 mg/m3) 1.0 ppm (3.8 mg/m3) 22% Methemoglobin—cyanosis (Kim and Carlson 1986) AEGL-2 (Disabling) 24 ppm (91 mg/m3) 12 ppm (46 mg/m3) 3.0 ppm (11 mg/m3) 1.5 ppm (5.7 mg/m3) 41% Methemoglobin—lethargy (Kim and Carlson 1986) AEGL-3 (Lethal) 40 ppm (152 mg/m3) 20 ppm (76 mg/m3) 5.0 ppm (19 mg/m3) 2.5 ppm (9.5 mg/m3) >70% Methemoglobin—lethality (extrapolated from data of Kim and Carlson 1986) aCutaneous absorption of the neat material may occur, adding to the systemic toxicity. bThe aromatic, amine-like odor of aniline will be noticeable by most individuals at these concentrations. Abbreviations: ppm, parts per million; mg/m3, milligrams per cubic meter.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 TABLE 1-2 Chemical and Physical Data Parameter Value Reference Synonyms Benzenamine, aniline oil, phenylamine, aminobenzene, aminophen, arylamine Budavari et al. 1996, Benya and Cornish 1994 Molecular formula C6H5NH2 Benya and Cornish 1994 Molecular weight 93.13 Budavari et al. 1996 CAS Registry No. 62–53–3 HSDB 1996 Physical description Colorless oily liquid (freshly distilled); darkens on exposure to air and light Budavari et al. 1996 Solubility in water 1 g in 28.6 mL Budavari et al. 1996 Vapor pressure 15 mm Hg at 77°C 7.6 torr at 20°C 0.67 mm Hg at 25°C Benya and Cornish 1994 ACGIH 1991 U.S. EPA 1987 Vapor density (air=1) 3.22 Benya and Cornish 1994 Density (water=1) 1.002 (20/4°C) Benya and Cornish 1994 Melting point –6.3°C Benya and Cornish 1994 Boiling point 184–186°C Budavari et al. 1996 Odor aromatic amine-like pungent, oily NIOSH 1997 U.S. EPA 1992 Odor threshold 0.012 to 10 ppm 0.5 ppm 1.0 ppm U.S. EPA 1992 DOT 1985 Billings and Jones 1981 Conversion factors 1 ppm=3.8 mg/m3 1 mg/m3=0.26 ppm ACGIH 1991 were oral or percutaneous to the liquid or an aniline dye. The primary effect of inhalation exposure to aniline vapor is the formation of methemoglobin in the RBCs. Hemolysis of the red cells and effects on the spleen occur following daily repeated or long-term exposures. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No information on acute lethal concentrations for humans by the inhalation route was located. According to Bodansky (1951) and Kiese (1974), methemo-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 globin (the primary effect of inhalation exposure) levels above 85% may be lethal if treatment is not initiated. Seger (1992) cites a concentration of >70% as a potentially lethal level. Deaths of adults have occurred from ingestion, and infant deaths have occurred from absorption of aniline from diapers stenciled with ink containing aniline (Gosselin et al. 1984). Incidences of aniline intoxication in infants attributed to aniline dye through dermal exposure are numerous: (Graubarth et al. 1945; Kagan et al. 1949; Etteldorf 1951; Pickup and Eeles 1953; Ramsay and Harvey 1959; Smith 1992). In one study, most of the infants were visibly cyanotic and methemoglobin levels in these infants ranged from 30% to 60% (Etteldorf 1951). Complete recovery followed treatment with methylene blue. In a summary of these and several other reports, an overall infant mortality of 5–10% was reported (Gosselin et al. 1984). 2.2. Nonlethal Toxicity The reported odor threshold for aniline ranges from 0.012 to 10 ppm (Table 1–2). Although the odor may be somewhat pungent, no adverse effects are predicted to occur at the odor threshold. With increasing concentrations of aniline, exposure can cause headaches, methemoglobinemia, paresthesias, tremor, pain, narcosis/coma, cardiac arrhythmia, and possibly death (Benya and Cornish 1994). However, according to Bodansky (1951), Kiese (1974), and Seger (1992), the formation of methemoglobin concentrations of <15% are asymptomatic; methemoglobin levels exceeding 15% of the circulating blood pigment result in clinical cyanosis; and hypoxic symptoms including lethargy and semistupor are associated with serum levels of 55–60% or greater. Signs and symptoms associated with methemoglobin formation are summarized in Table 1–3. In sampling data from 18 workplace sites provided by the Occupational Safety and Health Administration (OSHA 1997), measurable concentrations were present in 3 of 18 samples; these concentrations were 0.070, 0.14, and 0.177 ppm. 2.2.1. Experimental Studies Two papers cited older data. However, symptoms at specific concentrations were not defined in the summary papers and details of the studies were not available. Flury and Zernik (1931) cited the following human data: a concentration of approximately 130 ppm was tolerated for 1/2 to 1 h without immediate or late sequalae and a concentration of 40–53 ppm was tolerated for 6 h without

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 TABLE 1–3 Signs and Symptoms Associated with Methemoglobin Concentrations in Humans Methemoglobin Concentration (%) Signs and Symptoms 1.1 Normal level 1–15 None 15–20 Clinical cyanosis (chocolate brown blood); no hypoxic symptoms 30 Fatigue; recovery without treatment 20–45 Anxiety, exertional dyspnea, weakness, fatigue, dizziness, lethargy, headache, syncope, tachycardia 45–55 Decreased level of consciousness 55–70, ~60 Hypoxic symptoms: semistupor, lethargy, seizures, coma, bradycardia, cardiac arrhythmias >70 Heart failure from hypoxia, High incidence of mortality >85 Lethal   Sources: Kiese 1974; Seger 1992. distinct symptoms. Henderson and Haggard (1943) cited the following data: a concentration of 5 ppm was considered safe for daily exposure, concentrations of 7 to 53 ppm produced slight symptoms after several hours, and 100 to 160 ppm as the maximum concentration that could be inhaled for 1 h without serious disturbance. The statements by Henderson and Haggard were based on several studies including those of Flury and Zernik (1931). 2.2.2. Epidemiology Studies No epidemiology studies in which exposure concentrations were measured were identified in the available literature. 2.2.3. Accidents No accidental inhalation exposures to aniline in which concentrations were known were identified in the available literature. However, methemoglobin levels were measured after accidental exposures to liquid aniline or aromatic

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 nitro or amino compounds (Hamblin and Mangelsdorff 1938; Mangelsdorff 1956). In these occupational exposures, methemoglobin levels reached 50–72%; the subjects were cyanotic and complained of headache, dizziness, and weakness. In some cases, oxygen therapy was instituted and intravenous dextrose solutions were administered; in one case, methylene blue was administered intravenously. Regardless of whether or not treatment was given, the half-life of methemoglobin ranged between 3 and 10 h following cessation of exposure, and levels were below 10% in less than 20 h. No deaths occurred. 2.3. Developmental and Reproductive Effects No developmental and reproductive toxicity data on humans concerning aniline were identified in the available literature. 2.4. Genotoxicity In an in vitro assay with cultured human fibroblasts, aniline produced only marginal increases in sister chromatid exchanges at the highest dose tested, 10 mM; whereas two metabolites of aniline, 2-aminophenol and N-phenylhydroxylamine, doubled the frequency of sister chromatid exchanges at the highest tested nontoxic concentration, 0.1 mM (Wilmer et al. 1981). 2.5. Carcinogenicity Historically, bladder tumors have been associated with exposures in the aniline dye industry. However, conclusive evidence for any one particular exposure could not be obtained in these studies since the workers were exposed to many chemicals within the same work area. For example, Case et al. (1954) investigated the incidence of bladder tumors among British workers in the chemical dye industry. In addition to aniline, the workers were exposed to other aromatic amines, including α- and β-naphthylamine, benzidine, and auramine. Although exposures could not be quantified, there was insufficient evidence to suggest that aniline was a cause of bladder cancers. More recent studies indicate that β-naphthylamine, 4-aminodiphenyl, 4-nitrodiphenyl, 4,4'-diaminodiphenyl, or o-toluidine may be involved in increased cancers in the dye industry (Ward et al. 1991; Benya and Cornish 1994). On the basis of inadequate human data and sufficient animal data, U.S. EPA (1994) in their Integrated Risk Information System (IRIS) classified aniline as

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 B2, a probable human carcinogen. The International Agency for Research on Cancer has classified the evidence for carcinogenicity of aniline in humans as inadequate and in animals as limited (IARC 1987). Based on a high-dose feeding study with rats (NCI1978), the National Institute for Occupational Safety and Health (NIOSH 1997) considers aniline and its homologues occupational carcinogens; however, OSHA (1995) has not classified aniline as an occupational carcinogen. ACGIH (1999) categorized aniline as A3, a confirmed animal carcinogen with unknown relevance to humans. Animal feeding studies (NCI 1978; CIIT 1982) indicate that aniline may be a very weak carcinogen in male and female rats (i.e., 3,000 and 2,000 ppm dietary threshold in the two studies, respectively) but not in male or female mice. Animal studies are summarized in Section 3.5 and a quantitative cancer risk assessment is performed in Appendix A. 2.6. Summary Human toxicity data are limited to secondary citations. Because these citations provided no experimental details, they cannot be considered reliable. Deaths have occurred from aniline ingestion and skin absorption, but doses were unknown. Reviews of the older literature indicate that a concentration of 5 ppm was considered safe for daily exposures, concentrations of 7 to 53 ppm produced slight symptoms after several hours, a concentration of 40 to 53 ppm was tolerated for 6 h without distinct symptoms, a concentration of 130 ppm may be tolerated for 0.5 to 1 h without immediate or late sequalae, and 100 to 160 ppm was the maximum concentration that could be inhaled for 1 h without serious disturbance. In studies of accidents with unknown exposure concentrations, methemoglobin levels of up to 72% were measured. Recoveries occurred with a minimum of medical intervention following cessation of exposure. There is no conclusive evidence from studies of cancers in dye workers that aniline is the causative agent. Two known metabolites of aniline induced sister chromatid exchange in the single study with cultured human fibroblasts. No studies on possible reproductive or developmental effects in humans associated with aniline exposures were located. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality Acute lethality data are summarized in Table 1–4 and discussed below.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 TABLE 1–4 Summary of Acute Lethal Inhalation Data in Laboratory Animalsa Species Concentration (ppm) Exposure Time Effect Reference Rat 839b 4 h LC50 E.I.du Pont de Nemours 1982a Rat 478c 4 h LC50 E.I.du Pont de Nemours 1982a Rat 250d 4 h Approximate LC50 Carpenter et al. 1949 Rat 550 8 h 82% mortality Comstock and Oberst 1952, as cited in Oberst et al. 1956 Mouse ~175 7 h LC50 von Oettingen et al. 1947 aLC50 (lethal concentration for 50% of the animals) values were obtained 14 d post-exposure (Carpenter et al. 1949; E.I.du Pont de Nemours 1982a). bHead-only exposure. cWhole-body exposure. dConcentrations not measured. 3.1.1. Rats Six Sherman rats (gender not specified) were exposed to graded concentrations of aniline vapor for 4 h and observed for 14 d post-exposure (Carpenter et al. 1949). The concentration that killed approximately half of the rats (exact number not stated) was 250 ppm. Concentrations were based upon empirical calculation and were not measured. An 8-h exposure to 550 ppm killed 82% of an unreported number of rats (Comstock and Oberst 1952, as cited in Oberst et al. 1956). Methemoglobinemia was the only pathologic change cited; no further details were reported. Groups of 10 8-w-old Crl:CD rats were exposed to various concentrations of aniline vapor/aerosol for 4 h (E.I.du Pont de Nemours 1982a). The atmospheres were generated by passing nitrogen over liquid aniline in a heated flask. The vapor/aerosol was diluted with humidified (45%) and oxygen-enriched (21%) air; the temperature of the exposure chamber was maintained at 27°C. Air samples were analyzed by gas chromatography. Two routes of exposure, head-only, using wire mesh restrainers, and whole-body, were compared to assess the significance of skin absorption and restraint on mortality. LC50 (lethal concentration for 50% of the animals) values for head-only and whole-body exposures were 839 ppm (95% confidence limit (CL), 802–882 ppm) and

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 TABLE 1–5 Mortality of Rats Exposed to Aniline via Head-Only or Whole-Body Exposures for 4 h Head-Only Exposures Whole-Body Exposures Concentration (ppm) Mortality Concentration Mortality 681 0/10 359 0/10 790 2/10 400 2/10 834 5/10 453 4/10 896 8/10 530 7/10   786 10/10   Source: E.I.du Pont de Nemours 1982a. 478 ppm (95% CL, 442–540 ppm), respectively. The lower value for whole-body exposure suggests significant dermal absorption. Mortality at each exposure concentration is listed in Table 1–5. All deaths occurred by d 4 post-exposure. "Signs observed during exposures by both routes were similar and included cyanosis, prostration, tremors, pallor, clear to reddish-brown eye, mouth, and nasal discharges, corneal clouding, tachypnea, and hair loss" (E.I.du Pont de Nemours 1982a). The severity of the signs was generally dose-related. An initial weight loss at 24–72 h post-exposure was followed by a normal weight gain. 3.1.2. Mice A 7-h LC50 for the mouse of approximately 175 ppm was reported by von Oettingen et al. (1947). Deaths occurred at all tested concentrations, which ranged from approximately 115 to 390 ppm; however, analytical determinations (both colorimetric and spectrophotometric) of calculated concentrations showed substantial variations, ranging from 49% to 81% of calculated concentrations. The discrepancy between calculated and analyzed values was probably due to condensation of aniline on the sides of the exposure chamber. The authors stated that the actual lethal values probably were within the range of the calculated and analyzed concentrations. In that case, the 7-h LC50 value for the mouse lies within the range of 175 to 288 ppm. Mice exposed to aniline became restless and cyanotic (ears and tails), and their eyes showed signs of irritation. Tremors, followed by convulsions and then depression, preceded death. Histologic examinations revealed hepatic fatty infiltrations.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 This page in the original is blank.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 APPENDIX A CARCINOGENICITY ASSESSMENT FOR ANILINE No inhalation slope factor is available for aniline, and the available inhalation studies did not examine the endpoint of carcinogenicity. Based on the chronic oral administration of aniline hydrochloride to CD-F rats (CIIT 1982), U.S. EPA in its Integrated Risk Information Systems (IRIS) has estimated an oral slope factor of 5.7×10P–3/mg/kg/d (U.S. EPA 1994). In that study, spleen tumor incidences in rats administered 0, 200, 600, or 2,000 ppm in the diet were 0/64, 0/90, 1/90, and 31/90, respectively. Aniline also has genotoxic action. The inhalation slope factor can be estimated by dividing the oral slope factor by 70 kg and multiplying by the inhalation rate of 20 m3/d: Inhalation slope factor=oral slope factor×1/70 kg×20 m3/d =5.7×10–3/mg/kg/d×1/70 kg×20 m3/d =1.6×10–3/mg/m3. To convert to a dose or concentration of aniline that would cause an excess cancer risk of 10–4 (a virtually safe dose), the risk is divided by the slope factor: dose=risk/slope dose=(risk of 1×10–4)/(1.6×10–3 (mg/m3)–1) =6.3×10–2 mg/m3. To convert a 70-y exposure to a 24-h exposure, the virtually safe dose is multiplied by the number of days in 70 yr: 24-h exposure=6.3×10–2 mg/m3×25,600 d =1,613 mg/m3. To adjust for uncertainties in assessing potential cancer risks for short-term exposures under the multistage model, the 24-h exposure is divided by an adjustment factor of 6 (Crump and Howe 1984). (1,613 mg/m3)/6=269 mg/m3 (71 ppm). The 24-h exposure can be converted to the shorter AEGL time points: 24-h exposure=269 mg/m3 (71 ppm) 8-h exposure=806 mg/m3 (212 ppm)

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 4-h exposure=1,613 mg/m3 (425 ppm) 1-h exposure=6,451 mg/m3 (1698 ppm) 30-min exposure=12,900 mg/m3 (3395 ppm). For 10–5 and 10–6 risk levels, the 10–4 values are reduced by 10-fold and 100-fold, respectively. Because the cancer risk from a short-term exposure to aniline at the AEGL concentrations is estimated to be well below 1 in 10,000, even for individuals at a sensitive age, the AEGL values are based on the more stringent requirements for methemoglobin formation.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 APPENDIX B DERIVATION OF AEGL VALUES Derivation of AEGL-1 Key study: Kim and Carlson (1986) Toxicity endpoint: Methemoglobin level of 22% at exposure of 100 ppm for 8 h Scaling: C1×t=k, based on the linear relationship between concentration of aniline and methemoglobin formation Uncertainty factors: 10 for interspecies 10 for intraspecies Calculations: 100 ppm/(10×10)=1 ppm C1×t=k 1 ppm×480 min=480 ppm·min 30-min AEGL-1: 480 ppm·min/30 min=16 ppm 1-h AEGL-1: 480 ppm·min/60 min=8.0 ppm 4-h AEGL-1: 480 ppm·min/240 min=2.0 ppm 8-h AEGL-1: 480 ppm·min/480 min=1.0 ppm Derivation of AEGL-2 Key study: Kim and Carlson (1986) Toxicity endpoint: Methemoglobin level of 41% at exposure of 150 ppm for 8 h Scaling: C1×t=k, based on the linear relationship between concentration of aniline and methemoglobin formation

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 Uncertainty factors: 10 for interspecies 10 for intraspecies Calculations: 150 ppm/(10×10)=1.5 ppm C1×t=k 1.5 ppm×480 min=720 ppm·min 30-min AEGL-1: 720 ppm·min/30 min=24 ppm 1-h AEGL-1: 720 ppm·min/60 min=12 ppm 4-h AEGL-1: 720 ppm·min/240 min=3.0 ppm 8-h AEGL-1: 720 ppm·min/480 min=1.5 ppm Derivation of AEGL-3 Key study: Kim and Carlson (1986) Toxicity endpoint: Projected methemoglobin level of 70–80% at exposure of 250 ppm for 8 h Scaling: C1×t=k, based on the linear relationship between concentration of aniline and methemoglobin formation Uncertainty factors: 10 for interspecies 10 for intraspecies Calculations: 250 ppm/(10×10)=2.5 ppm C1×t=k 2.5 ppm×480 min=1,200 ppm·min 30-min AEGL-1: 1,200 ppm·min/30 min=40 ppm 1-h AEGL-1: 1,200 ppm·min/60 min=20 ppm 4-h AEGL-1: 1,200 ppm·min/240 min=5.0 ppm 8-h AEGL-1: 1,200 ppm·min/480 min=2.5 ppm

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 APPENDIX C DERIVATION SUMMARY FOR ACUTE EXPOSURE GUIDELINE LEVELS FOR ANILINE (CAS No. 62–53–3) AEGL-1 Values-Aniline 30 min 1 h 4 h 8 h 16 ppm 8.0 ppm 2.0 ppm 1.0 ppm Key reference: Kim, Y.C., and G.P.Carlson. 1986. The effect of an unusual workshift on chemical toxicity. II. Studies on the exposure of rats to aniline. Fundam. Appl. Toxicol. 7:144–152 Test Species/Strain/Number: Adult male Sprague-Dawley rats, 5/exposure group Exposure Route/Concentrations/Durations: Inhalation: 0–150 ppm for 8 h Effects: Concentration (ppm) Methemoglobin Formation (%)a   0 1.1 (0.4–1.7)   10 1.1 (0.4–1.7)   30 1.6   50 4.7   100 22   150 41 aValues are estimates from data presented as graphs. Endpoint/Concentration/Rationale: The only effect of aniline administration was formation of methemoglobin. Administration of 100 ppm for 8 h to rats resulted in elevation of methemoglobin to 22% but no hypoxic signs. A review of the literature revealed that methemoglobin levels of 15–20% in humans result in clinical cyanosis but no hypoxic symptoms. This effect was considered to be mild and reversible and, therefore, within the definition of the AEGL-1. The 8-h exposure to 100 ppm was chosen as the basis for the AEGL-1 calculations. Uncertainty Factors/Rationale: Total uncertainty factor: 100 Interspecies: 10—A review of oral administration studies suggested that humans may be considerably more sensitive to methemoglobin formation than rats. Oral administration of aniline to rats at 40 mg/kg produced a maximum increase of 16.6% in methemoglobin, whereas oral administration of 0.9 mg/kg to a human volunteer produced a maximum increase of 16.1%.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 Intraspecies: 10—Infants are more sensitive to methemoglobin-generating chemicals than adults, because they have reduced levels of nicotine adenine dinucleotide (NADH, the cofactor (electron donor) for methemoglobin reductase), and a high concentration of fetal hemoglobin in their erythrocytes (fetal hemoglobin is more oxidizable than adult hemoglobin) (Seger 1992). Modifying Factor: Not applicable Animal to Human Dosimetric Adjustment: Not applied; insufficient data. Time Scaling: Cn×t=k, where n=1 and k=480 ppm·min; based on the linear relationship between concentration and methemoglobin formation (Kim and Carlson 1986) Data Adequacy: The key study was well designed, conducted, and documented. Values were presented graphically. Supporting data were sparse, probably because aniline is not a vapor at room temperature, and poisonings have involved contact with the liquid. Although human data are sparse, it is believed that a total uncertainty factor of 100 is protective of human health. Because aniline is absorbed through the skin, which increases the systemic toxicity, direct skin contact with the liquid would be additive and result in onset of adverse effects at airborne concentrations below the respective AEGL values. Therefore, direct skin contact with the liquid should be avoided.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 AEGL-2 Values-Aniline 30 min 1 h 4 h 8 h 24 ppm 12 ppm 3.0 ppm 1.5 ppm Key reference: Kim, Y.C., and G.P.Carlson. 1986. The effect of an unusual workshift on chemical toxicity. II. Studies on the exposure of rats to aniline. Fundam. Appl. Toxicol. 7:144–152 Test Species/Strain/Sex/Number: Adult male Sprague-Dawley rats, 5/exposure group Exposure Route/Concentrations/Durations: Inhalation: 0–150 ppm for 8 h Effects: Concentration (ppm) Methemoglobin Formation (%)a   0 1.1 (0.4–1.7)   10 1.1 (0.4–1.7)   30 1.6   50 4.7   100 22   150 41 aValues are estimates from data presented as graphs. Endpoint/Concentration/Rationale: Administration of 150 ppm for 8 h to rats resulted in elevation of methemoglobin to 41% with no reported toxic signs. A review of the literature revealed that methemoglobin levels of 30–45% in humans are associated with fatigue, lethargy, exertional dyspnea, and headache. These signs and symptoms were considered the threshold for disabling effects. The 8-h exposure to 150 ppm was chosen as the basis for the AEGL-2 calculations. Uncertainty Factors/Rationale: Total uncertainty factor: 100 Interspecies: 10—A review of oral administration studies suggested that humans may be considerably more sensitive to methemoglobin formation than rats. Oral administration of aniline to rats at 40 mg/kg produced a maximum increase of 16.6% in methemoglobin, whereas oral administration of 0.9 mg/kg to a human volunteer produced a maximum increase of 16.1%. Intraspecies: 10—Infants are more sensitive to methemoglobin-generating chemicals than adults, because they have reduced levels of nicotine adenine dinucleotide (NADH, the cofactor (electron donor) for methemoglobin reductase), and a high concentration of fetal hemoglobin in their erythrocytes (fetal hemoglobin is more oxidizable than adult hemoglobin) (Seger 1992). Modifying Factor: Not applicable

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 Animal to Human Dosimetric Adjustment: Not applied; insufficient data Time Scaling: Cn×t=k, where n=1 and k=720 ppm·min; based on the linear relationship between concentration and methemoglobin formation (Kim and Carlson 1986) Data Adequacy: The key study was well designed, conducted, and documented. Values were presented graphically. Supporting data were sparse, probably because aniline is not a vapor at room temperature, and poisonings have involved contact with the liquid. Although human data are sparse, it is believed that a total uncertainty factor of 100 is protective of human health. Because aniline is absorbed through the skin, which increases the systemic toxicity, direct skin contact with the liquid would be additive and result in onset of adverse effects at airborne concentrations below the respective AEGL values. Therefore, direct skin contact with the liquid should be avoided.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 AEGL-3 Values-Aniline 30 min 1 h 4 h 8 h 40 ppm 20 ppm 5.0 ppm 2.5 ppm Key reference: Kim, Y.C., and G.P.Carlson. 1986. The effect of an unusual workshift on chemical toxicity. II. Studies on the exposure of rats to aniline. Fundam. Appl. Toxicol. 7:144–152 Test Species/Strain/Sex/Number: Adult male Sprague-Dawley rats, 5/exposure group Exposure Route/Concentrations/Durations: 0–150 ppm for 8 h Effects: Concentration (ppm) Methemoglobin Formation (%)a   0 1.1 (0.4–1.7)   10 1.1 (0.4–1.7)   30 1.6   50 4.7   100 22   150 41 aValues are estimates from data presented as graphs. Endpoint/Concentration/Rationale: Because the exposures did not result in effects consistent with the definition of an AEGL-3, the concentration vs percent hemoglobin formation data presented by the authors was graphed and projected to a methemoglobin level of 70–80%, which was considered the threshold for lethality in humans. This value was approximately 250 ppm. An 8-h exposure to 250 ppm was chosen as the basis for the AEGL-3 calculations. Uncertainty Factors/Rationale: Total uncertainty factor: 100 Interspecies: 10—A review of oral administration studies suggested that humans may be considerably more sensitive to methemoglobin formation than rats. Oral administration of aniline to rats at 40 mg/kg produced a maximum increase of 16.6% in methemoglobin, whereas oral administration of 0.9 mg/kg to a human volunteer produced a maximum increase of 16.1%. Intraspecies: 10—Infants are more sensitive to methemoglobin-generating chemicals than adults, because they have reduced levels of nicotine adenine dinucleotide (NADH, the cofactor (electron donor) for methemoglobin reductase), and a high concentration of fetal hemoglobin in their erythrocytes (fetal hemoglobin is more oxidizable than adult hemoglobin) (Seger 1992). Modifying Factor: Not applicable

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume1 Animal to Human Dosimetric Adjustment: Not applied; insufficient data Time Scaling: Cn×t=k, where n=1 and k=1,200 ppm·min; based on the linear relationship between concentration and methemoglobin formation (Kim and Carlson 1986) Data Adequacy: The key study was well designed, conducted, and documented. Values were presented graphically. Supporting data were sparse, probably because aniline is not a vapor at room temperature and poisonings have involved contact with the liquid. Although human data are sparse, it is believed that a total uncertainty factor of 100 is protective of human health. Because aniline is absorbed through the skin, which increases the systemic toxicity, direct skin contact with the liquid would be additive and result in onset of adverse effects at airborne concentrations below the respective AEGL values. Therefore, direct skin contact with the liquid should be avoided.