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Aniline1
Acute Exposure Guideline Levels

UPDATE OF ANILINE AEGLS

In Volume 1 of the series Acute Exposure Guideline Levels for Selected Airborne Chemicals (NRC 2000), acute exposure guideline level (AEGL) values were developed for 30 minutes (min) and 1, 4, and 8 hours (h). Since that time, AEGL values have also been developed for 10-min exposures. This document updates Volume 1 to include 10-min values. The Summary below is from Volume 1 and contains additional discussion to address the development of 10-min values.

SUMMARY

Aniline is an aromatic amine used chiefly by 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 hemoglobin in red blood cells, resulting in the formation of methemoglobin. The effect occurs 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.

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 Talmage of the Oak Ridge National Laboratory. 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 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, 2001).



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3 Aniline1 Acute Exposure Guideline Levels UPDATE OF ANILINE AEGLS In Volume 1 of the series Acute Exposure Guideline Levels for Selected Airborne Chemicals (NRC 2000), acute exposure guideline level (AEGL) values were developed for 30 minutes (min) and 1, 4, and 8 hours (h). Since that time, AEGL values have also been developed for 10-min exposures. This document updates Volume 1 to include 10-min values. The Summary below is from Vol- ume 1 and contains additional discussion to address the development of 10-min values. SUMMARY Aniline is an aromatic amine used chiefly by 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 hemoglobin in red blood cells, re- sulting in the formation of methemoglobin. The effect occurs following inhala- tion, 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 ar- rhythmia, and possibly death. 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 Talmage of the Oak Ridge National Laboratory. 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 concludes that the AEGLs developed in this document are scientifi- cally valid conclusions based on the data reviewed by the NAC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 115

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116 Acute Exposure Guideline Levels No reliable data on human exposures via the inhalation route were located. All AEGL values are based on a study in which rats were exposed to concentra- tions 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 ap- peared to be linear. Furthermore, the relationship between methemoglobin for- mation and time, between 3 and 8 h, was also linear when the aniline concentra- tion was held constant at 100 ppm. Methemoglobin reached an asymptote at 8 h. Based on the linear relationships between aniline concentration and methemo- globin formation and between methemoglobin formation and time at a constant aniline concentration, a linear relationship between concentration and exposure duration (C1 × t = k) was chosen for time-scaling aniline concentrations to the appropriate AEGL exposure durations. Although the key study (Kim and Carl- son 1986) used an 8-h exposure, methemoglobin measurements were taken at several time points during the study, and other studies with 4-h (E.I. du Pont de Nemours 1982; Pauluhn 2002) and 10-min exposures (Kakkar et al. 1992) sup- port the derived AEGL values. Thus, the 8-h AEGL values from the Kim and Carlson study were extrapolated back to 10 min. Following a 10-min exposure, the concentration of methemoglobin in blood is unlikely to reach steady state, as typically seen 6-8 h after the initiation of exposure. 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, 0.4-2.1%) to 22%. A review of the published data indicates that methemoglobin levels of 15-20% in humans result 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 lack 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 also used for intraspecies extrapolation. It is believed that an intras- pecies uncertainty factor of 10 is protective of the general population, including susceptible individuals. A default uncertainty factor of 10 for each of the inter- species and intraspecies variabilities is 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 relation- ship between concentration and exposure duration as related to methemoglobin formation. The AEGL-1 values are supported by the data of Pauluhn (2002) in which dogs exposed to 46 ppm for 4 h had the same methemoglobin concentra- tion (4.7%) as rats exposed to 50 ppm for 8 h (Kim and Carlson 1986; at 50 ppm, methemoglobin steady state in the blood is attained after several hours but prior to the full 8-h exposure).

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117 Aniline The AEGL-2 was based on the same study with rats in which a concentra- tion of 150 ppm for 8 h resulted in elevation of methemoglobin from a control value of 1-41%. This level of methemoglobin is associated with fatigue, leth- argy, 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 for the AEGL-1. 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 a >70% level of methemoglobin, the threshold for lethality according to Kiese (1974) and Seger (1992). The concentration of 250 ppm for 8 h was chosen as the threshold for lethality. 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 rationale as for the AEGL-1. Several studies with rats support the AEGL-3 values. A 10-min exposure to aniline at 15,302 ppm resulted in no clinical signs (Kakkar et al. 1992), and a 4-h exposure at 359 ppm (E. I. du Pont de Nemours 1982) resulted in severe toxic effects but no deaths. Dividing each of 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 study. Studies with repeated exposures of rats resulted in additional effects on the blood and spleen, but concentrations up to 87 ppm, 6 h/day, 5 days/week, for 2 weeks were not disabling or life- threatening. The derived AEGLs are listed in Table 3-1. Because aniline is absorbed through the skin in quantities sufficient to produce systemic toxicity, a skin no- tation 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 pun- gent but not necessarily unpleasant. TABLE 3-1 Summary of AEGL Values for Anilinea End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1b 48 ppm 16 ppm 8.0 ppm 2.0 ppm 1.0 ppm 22% methemoglobin: (nondisabling) (182 (61 (30 (7.6 (3.8 cyanosis (Kim and mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) Carlson 1986) AEGL-2 72 ppm 24 ppm 12 ppm 3.0 ppm 1.5 ppm 41% methemoglobin: (disabling) (274 (91 (46 (11 (5.7 lethargy (Kim and mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) Carlson 1986) (Continued)

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118 Acute Exposure Guideline Levels TABLE 3-1 Continued End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-3 120 ppm 40 ppm 20 ppm 5.0 ppm 2.5 ppm >70% (lethal) (456 (152 (76 (19 (9.5 methemoglobin: mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) lethality (extrapolated from data of Kim and Carlson 1986) a Cutaneous absorption of the neat material may occur, adding to the systemic toxicity. b The aromatic, amine-like odor of aniline will be noticeable by most individuals at these concentrations. REFERENCES E.I. du Pont de Nemours. 1982a. Inhalation median lethal concentration (LC50). OTS 84003A, Docket 878220239. E.I. du Pont de Nemours and Co., Inc., Wilmington, DE. Kakkar, P., S. Awasthi, and P.N. Viswanathan. 1992. Oxidative changes in brain of ani- line-exposed rats. Arch. Environ. Contam. Toxicol. 23(3):307-309. Kiese, M. 1974. Methemoglobinemia: A Comprehensive Treatise. Cleveland, OH: CRC Press. Kim, Y.C., and G.P. Carlson. 1986. The effect of an unusual workshift on chemical toxic- ity. II. Studies on the exposure of rats to aniline. Fundam. Appl. Toxicol. 7(1):144- 152. NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 2000. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 1. Washington, DC: National Academy Press. Pauluhn, J. 2002. Aniline-induced methemoglobinemia in dogs: Pitfalls of route-to-route extrapolations. Inhal. Toxicol. 14(9):959-973. Seger, D.L. 1992. Methemoglobin-forming chemicals. Pp. 800-806 in Hazardous Materi- als Toxicology: Clinical Principles of Environmental Health, J.B. Sullivan, and G.R. Krieger, eds. Baltimore, MD: Williams & Wilkins.