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Anilene: Acute Exposure Guideline Levels
Pages 15-64

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From page 15...
... No reliable data on human exposures via the inhalation route were located. iThis document was prepared byAEGL Development Teammembers Robert Snyder and George Rodgers ofthe NationalAdvisory Committee on acute Exposure Guideline Levels for Hazardous Substances (NAC)
From page 16...
... It is believed that an intraspecies uncertainty factor of 10 is protective ofthe general population including susceptible individuals. The default uncertainty factors of 10 for each ofthe interspecies and intraspecies variabilities are also supported by the small database of information and the lack of reliable human inhalation studies.
From page 17...
... 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.
From page 18...
... 18 o on .= $ ¢ o o En ~ o ~ .En ~ .
From page 19...
... The primary effect of inhalation exposure to aniline vapor is the formation of methemogiobin in the RBCs. Hemolysis of the red cells and effects on the spleen occur following daily repeated or Tong-term exposures.
From page 20...
... , and Seger (1992) , the formation of methemogiobin concentrations of <15% are asymptomatic; methemogiobin levels exceeding ~ 5°/O ofthe circulating blood pigment result in cTinical cyanosis; and hypoxic symptoms including lethargy and semistupor are associated with serum levels of 55-60% or greater.
From page 21...
... 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 ~ h without serious disturbance.
From page 22...
... On the basis of inadequate human data and sufficient animal data, U.S.
From page 23...
... Reviews ofthe 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 ~ h without immediate or late sequalae, and 100 to ~ 60 ppm was the maximum concentration that could be inhaled for ~ h without serious disturbance. In studies of accidents with unknown exposure concentrations, methemogIobin levels of up to 72% were measured.
From page 24...
... were exposed to graded concentrations of aniline vapor for 4 h and observed for 14 ~ post-exposure (Carpenter et al.
From page 25...
... An initial weight loss at 24-72 h post-exposure was followed by a normal weight gain.
From page 26...
... were exposed to reagent grade aniline at concentrations of 0, 10, 30, 50, 100, or 150 ppm for ~ hid for 5 ~ or 12 hid for 4 ~ (Kim and CarIson 1986~. Exposure concentrations were achieved by passing air through a bottle containing aniline; concentrations were monitored continuously using a gas chromotograph.
From page 27...
... The Methemoglobin levels read from the original graph are approximately 10.5%, ~ 8%, 22%, 22%, and 23% at the 3-, 6-, 8-, 10-, and 12-h exposure durations, respectively. Following ~ or 12 h of exposure, recovery was rapid as shown in the graph (Figure I-1~.
From page 28...
... Hemolysis (decreased erythrocyte counts, splenic congestion, and hemosiderin deposition) was seen at 30 and 90 ppm at all exposure durations after the tenth exposure (time of onset could not be determined)
From page 29...
... EPA (l 994~. After the last exposure, methemoglobin levels were elevated in a dose-dependent manner: 17 ppm, 0°/O to 2.9% (no different from controls)
From page 30...
... However, because effects on development and reproduction arise after systemic uptake, oral administration of aniline can be considered for evaluating potential developmental and reproductive toxicity. Aniline (administered as aniline hydrochloride)
From page 31...
... 3.5. Carcinogenicity The National Cancer Institute conducted a bioassay of aniline hydrochloride for possible carcinogenicity using F344 rats and B6C3F, mice (NCI 19781.
From page 32...
... increase in fibrosarcomas or sarcomas NOS of either the spleen alone or multiple organs of the body cavity was observed in female rats. These incidences were statistically significant and associated with increased dietary concentrations of aniline hydrochloride.
From page 33...
... In a 2-y feeding study, daily ingestion of aniline hydrochloride produced increased sarcomas ofthe spleen in mate and female rats but not in mate or female mice. The sarcomas were of a rare type and appeared to be related to chronic administration of aniline.
From page 34...
... ) was added to samples of rat and human blood, blood from the human subjects produced less methemogiobin in the human subjects than in the rats (approximately 35% in human blood and 60% in rat blood)
From page 35...
... 4.4.1. Susceptible Subpopulations Infants are more sensitive to methemogiobin-generating chemicals than adults, as they have reduced levels of nicotine adenine dinucleotide (NADH, the cofactor (electron donor)
From page 36...
... A single oral administration of aniline hydrochloride to male SpragueDawley rats at 2 millimole per kilogram (mmole/kg) (259 mg/kg; presumably ~ 86 mg/kg of aniline)
From page 37...
... , and although the data are limited, methemogiobin formation increased by less than a factor of 2, i.e., was linear when comparing the 3- and 6-h exposure durations at a constant concentration of 100 ppm before reaching an asymptote at ~ h (Figure 1-1~. Based on the linear relationship between concentration and methemogiobin formation in the Kim and Carison (1986)
From page 38...
... , in citing older reports, listed 5 ppm as a maximum concentration considered safe for daily exposures but did not give the basis for their statement. No additional human data are available for the derivation of AEGL-1 values for aniline.
From page 39...
... it is believed that an intraspecies uncertainty factor of 10 is protective of infants. The uncertainty factors of 10 for each of the interspecies and intraspecies variabilities are dictated by the small database and the lack of reliable human inhalation studies.
From page 40...
... Although inhalation data for comparison purposes are not available, ingestion data suggest that humans may be considerably more sensitive to methemogiobin-forming chemicals than rats. Oral administration of aniline at 40 mg/kg to rats produced a maximum increase of ~ 6.6% in methemogiobin, whereas oral administration of 0.9 mg/kg to a human volunteer produced a maximum increase of 16.~%.
From page 41...
... It is believed that the intraspecies uncertainty factor of ~ 0 is protective of infants. Based on the linear relationship between methemogiobin formation and aniline concentration, the data were scaled to the relevant time periods using the relationship Cat x t= k and k = 720 ppm min.
From page 42...
... Henderson and Haggard (1943) cited human data in which a concentration of 100 to 160 ppm was the maximum concentration that could be inhaled for 1 h without serious disturbance.
From page 43...
... The American Industrial Hygiene Association (ATHA 1955) stated that 50-100 ppm could probably be tolerated for 60 min based on TABLE 1-11 Summary and Relationship of AEGL Valuesa Exposure Duration Classification 30min 1 h 4h 8h AEGL-1 16 ppm 8.0 ppm 2.0 ppm 1.0 ppm (Nondisabling)
From page 44...
... The ACGIH Threshold Limit Value (TLV) is intended for repeated daily exposure of the healthy adult worker and is not necessarily comparable to a single 8-h exposure.
From page 45...
... Data indicate that human infants are more sensitive to methemogiobin-generating chemicals than adults since they have reduced levels of nicotine adenine dinucleotide (NADH, the cofactor (electron donor) for methemogiobin reductase)
From page 46...
... The available data from oral bioassays with aniline suggest that a tumorigenic response may occur following long-term, repeated high-dose exposures that cause repetitive tissue damage in the spleen as a consequence of physioTogic adaptation to the chronic damage to erythrocytes (Bus and Popp 1987~. The AEGL values were not based on carcinogenicity in rats, because formation of methemogiobin was a more sensitive endpoint than induction of tumors of the spleen.
From page 47...
... 1982. 104-week chronic toxicity study in rats: Aniline hydrochloride.
From page 48...
... 1984. Splenic fibrosis and sarcomas in F344 rats fed diets containing aniline hydrochloride,p-chloroaniline, azobenzene, o-toluidine hydrochloride, 4,4'-sulfonyldianiline, or D & C red no.9.
From page 49...
... Standing Operating Procedures for Developing Acute Exposure Guideline Levels for airborne Chemicals. Washington, DC: National Academy Press.
From page 50...
... 1985. Teratologic and postnatal evaluation of aniline hydrochloride in the Fischer 344 rat.
From page 51...
... 1991. Effects of aniline hydrochloride in the mouse bone marrow micronucleus test after oral administration.
From page 53...
... Appendixes
From page 55...
... 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~.
From page 56...
... Because the cancer risk from a short-term exposure to aniline at the AEGL concentrations is estimated to be well below ~ in 10,000, even for individuals at a sensitive age, the AEGL values are based on the more stringent requirements for methemogiobin formation.
From page 57...
... Toxicity endpoint: Scaling: Methemoglobin level of 41% at exposure of 150 ppm for h C1 x t = k, based on the linear relationship between concentration of aniline and methemoglobin formation
From page 58...
... = 24 ppm 12 ppm = 3.0ppm 1.5 ppm ScaTing: Ci x t = k, based on the linear relationship between concen tration of aniline and methemoglobin formation Uncertainty factors: 10 for interspecies 10 for intraspecies Calculations: 250 ppml(IO x 10)
From page 59...
... 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.
From page 60...
... 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.
From page 61...
... Endpoint/Concenkation/Rationale: Administration of 150 ppm for ~ 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.
From page 62...
... 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.
From page 63...
... Oral administration of aniline to rats at 40 mg/kg produced a maximum increase of 16.6% in me/hemoglobin, 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)
From page 64...
... 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 AEGE values.


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