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1 Acetone Cyanohydrin1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) (P.L. 92-463) of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished to identify, review, and interpret relevant toxicologic and other scientific data and develop 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-1, AEGL-2, and AEGL-3, as appropriate, will be developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and will be distinguished by varying degrees of severity of toxic effects. The recommended exposure levels are considered applicable to the general population, including infants and children and other individuals who may be sensitive or 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 1 This document was prepared by the AEGL Development Team composed of Peter Griem (Forschungs- und Beratungsinstitut Gefahrstoffe GmbH) and Chemical Managers Larry Gephart and Ernest V. Falke (National Advisory Committee [NAC] on Acute Ex- posure Guideline Levels for Hazardous Substances). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Expo- sure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guideline reports (NRC 1993, 2001). 13

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14 Acute Exposure Guideline Levels 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- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m³) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild and progressively increasing odor, taste, and sensory irrita- tion or certain asymptomatic, nonsensory effects. With increasing airborne con- centrations 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 AEGLs represent threshold levels for the general public, including sensitive subpopulations, it is recognized that certain individuals, sub- ject to idiosyncratic responses, could experience the effects described at concen- trations below the corresponding AEGL. SUMMARY Acetone cyanohydrin is a colorless to yellowish liquid with a characteris- tic bitter almond odor due to the presence of free hydrogen cyanide (HCN). The major use of acetone cyanohydrin is in the production of methacrylic acid and its esters; the latter are used for the production of plexiglass. Further uses of acetone cyanohydrin are in the production of acrylic esters, polyacrylic plastics. and synthetic resins, as well as in the manufacture of insecticides, pharmaceuti- cals, fragrances, and perfumes. Acetone cyanohydrin decomposes spontaneously in the presence of water to acetone and HCN. Fatalities and life-threatening occupational intoxication have been de- scribed after accidental inhalation, skin contact, and ingestion. Initial symptoms after mild exposure to acetone cyanohydrin range from cardiac palpitation, headache, weakness, dizziness, nausea, and vomiting to nose, eye, throat, and skin irritation. Acetone cyanohydrin behaves as its molar equivalent in cyanide both in vitro and in vivo. All the pharmacologic actions of cyanide result from cyanide’s reversible complex with the ferric (+3) state of mitochondrial cyto- chrome c oxidase also known as ferrocytochrome c oxygen oxidoreductase. Cessation of electron transport across the inner mitochondrial membrane results in inhibition of oxygen utilization and causes hypoxia and cellular destruction. Four studies exposed rats repeatedly to acetone cyanohydrin at about 10, 30, and 60 ppm for 6 h/day (d), 5 d/week (wk) for a total of 4 weeks (Monsanto

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15 Acetone Cyanohydrin 1986a; using groups of 10 male and 10 female rats), 10 weeks (Monsanto 1982b; using groups of 15 male rats) and 14 weeks (Monsanto 1986b; using groups of 15 male and 15 female rats) or for 6 h/d for 21 days (Monsanto 1982c; using groups of 15 female rats). Death was observed at 60 ppm after the first exposure in three animals of the Monsanto (1986a) study but not in subsequent exposures or in the other studies conducted under similar protocols. Preceding death, respiratory distress, prostration, convulsions, and tremors were obvious. In all studies, exposure at 60 and 30 ppm caused signs of irritation (red nasal discharge, clear nasal discharge, perioral wetness, and encrustations) during the first and subsequent weeks of exposure. At 10 ppm, red nasal discharge was not observed in one study (Monsanto 1986a); its incidence was not increased com- pared with the concurrent control group in two studies (Monsanto 1982b,c), but it was increased compared with the control group in the fourth study (Monsanto 1986b). No other signs of intoxication were reported in these four studies. The derivation of AEGL-1 values was based on the facts that acetone cya- nohydrin decomposes spontaneously to HCN and acetone and that local and systemic toxic effects of acetone cyanohydrin are due to free cyanide. Once ab- sorbed, a dose of acetone cyanohydrin behaves in a manner identical to that of its molar equivalent in absorbed free cyanide. It is appropriate to apply the AEGL-1 values (on a ppm basis) derived for HCN (NRC 2002) to acetone cya- nohydrin. This procedure is supported by similar values that would be derived on the basis of available acetone cyanohydrin studies in rats (derivation basis would be exposure at 9.2 ppm for 6 h/d, 5 d/wk for 4 weeks, which did not result in red nasal discharge [Monsanto 1986a]) using a total uncertainty factor of 10. The odor threshold of acetone cyanohydrin has not been firmly estab- lished. Shkodich (1966) published the odor threshold for acetone cyanohydrin in water (0.06 milligrams per liter [mg/L]). However, the odor would necessarily be the consequence of a mixed presentation of the HCN and acetone cyano- hydrin concentrations in air. Since no definitive reports on the odor threshold of acetone cyanohydrin were located in the literature, no level of distinct odor awareness (LOA) was derived. The derivation of AEGL-2 values was based on the facts that acetone cya- nohydrin decomposes spontaneously to HCN and acetone and that the systemic toxicity of acetone cyanohydrin is due to free cyanide. Once absorbed, a dose of acetone cyanohydrin behaves in a manner identical to that of its molar equiva- lent in absorbed free cyanide. It is appropriate to apply the AEGL-2 values (on a ppm basis) derived for HCN (NRC 2002) to acetone cyanohydrin. This proce- dure is supported by similar values that would be derived on the basis of avail- able acetone cyanohydrin studies in rats using a total uncertainty factor of 10 (derivation basis would be exposure at 29.9 ppm for 6 h/d, 5 d/wk for 4 weeks, which caused signs of irritation, while the next higher concentration produced respiratory distress, prostration, convulsions and tremors, Monsanto [1986a]). The derivation of AEGL-3 values was based on the facts that acetone cya- nohydrin decomposes spontaneously to HCN and acetone and that the systemic toxicity of acetone cyanohydrin is due to free cyanide. Once absorbed, a dose of

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16 Acute Exposure Guideline Levels acetone cyanohydrin behaves in a manner identical to that of its molar equiva- lent in absorbed free cyanide. It is appropriate to apply the AEGL-3 values (on a ppm basis) derived for HCN (NRC 2002) to acetone cyanohydrin. This proce- dure is supported by the close similarity of acetone cyanohydrin and HCN re- garding death in rats: Blank (1983) reported that 3 of 10 rats died after the first exposure to HCN at 68 ppm; the subsequent two exposures on the following days caused no additional deaths. This finding closely resembles that of Mon- santo’s (1986a) report of death of 3 of 20 animals after the first exposure to ace- tone cyanohydrin at 60 ppm (the actual exposure concentration on the first day might have been slightly higher than the average 59.6 ppm); no additional deaths were found in the 19 subsequent exposures. The derived values are listed in Table 1-1 below. 1. INTRODUCTION Acetone cyanohydrin is a colorless to yellowish liquid with a characteris- tic bitter almond odor due to the presence of free HCN (ACGIH 1996). The ma- jor use of acetone cyanohydrin is in the preparation of -methacrylic acid and its esters; the latter are used for the production of plexiglass. Further uses of ace- tone cyanohydrin are in the production of acrylic esters, polyacrylic plastics, and synthetic resins as well as an intermediate in the manufacture of insecticides, pharmaceuticals, fragrances, and perfumes (OECD 1997). About 0.5-1 million metric tons of acetone cyanohydrin is produced worldwide annually (IUCLID 2000) principally by reaction of HCN with acetone. Chemical and physical properties of acetone cyanohydrin are listed in Table 1-2. TABLE 1-1 Summary of AEGL Values for Acetone Cyanohydrina,b End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 2.5 ppm 2.5 ppm 2.0 ppm 1.3 ppm 1.0 ppm Application of (Nondisabling) (8.8 (8.8 (7.0 (4.6 (3.5 AEGL-1 values mg/m³) mg/m³) mg/m³) mg/m³) mg/m³) for HCN (NRC 2002) AEGL-2 17 ppm 10 ppm 7.1 ppm 3.5 ppm 2.5 ppm Application of (Disabling) (60 (35 (25 (12 (8.8 AEGL-2 values mg/m³) mg/m³) mg/m³) mg/m³) mg/m³) for HCN (NRC 2002) AEGL-3 27 ppm 21 ppm 15 ppm 8.6 ppm 6.6 ppm Application of (Lethal) (95 (74 (53 (30 (23 AEGL-3 values mg/m³) mg/m³) mg/m³) mg/m³) mg/m³) for HCN (NRC 2002) a Acetone cyanohydrin decomposes spontaneously in the presence of water to yield HCN and acetone. Therefore, both acetone cyanohydrin and HCN concentrations should be considered. b Cutaneous absorption may occur; direct skin contact with the liquid should be avoided.

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17 Acetone Cyanohydrin TABLE 1-2 Chemical and Physical Data for Acetone Cyanohydrin Parameter Data Reference Molecular formula (CH3)2C(OH)CN IUCLID 2000 Molecular weight 85,1 E.I. du Pont de Nemours and Co. 1998 CAS Registry Number 75-86-5 IUCLID 2000 Physical state Liquid E.I. du Pont de Nemours and Co. 1998 Color Colorless E.I. du Pont de Nemours and Co. 1998 Colorless to yellowish ACGIH 1996 Synonyms 2-Propanone cyanohydrin; 2-cyano- IUCLID 2000 2-propanol; 2-cyano-2- hydroxypropane; hydroxyisobutyronitrile; 2-methyl- lactonitrile; 2-hydroxy-2-methyl- propionitrile; Acetoncyanhydrin Vapor pressure 1.07 hPa at 20°C IUCLID 2000 0.8 mm Hg at 20°C E.I. du Pont de Nemours and Co. 1998 1 mm Hg at 25°C E.I. du Pont de Nemours and Co. 1998 1.6 hPa at 40°C Grybat et al. 2003 12.5 hPa at 72°C Grybat et al. 2003 0.932 g/cm3 at 19°C IUCLID 2000 Density 0.9267 g/cm3 at 25°C IUCLID 2000 Melting point −19°C to −20°C IUCLID 2000 Boiling point 81°C at 30.7 hPa IUCLID 2000 82°C at 23 mm Hg E.I. du Pont de Nemours and Co. 1998 95°C at 1013 hPa IUCLID 1996 (decomposition to acetone and HCN) Solubility Very soluble in water, alcohol and E.I. du Pont de Nemours and ether Co. 1998 Odor Characteristic bitter almond odor of ACGIH 1996 free HCN Explosive limits in air 2.2 % (LEL) to 12 % (UEL) IUCLID 2000 Conversion factors 1 ppm = 3.5 mg/m³ E.I. du Pont de Nemours and 1 mg/m³ = 0.28 ppm Co. 1998 Since the elimination reaction of HCN from acetone cyanohydrin is an en- dothermic reaction, the decomposition of acetone cyanohydrin is accelerated by heat. At temperatures of 120°C or higher, acetone cyanohydrin decomposes with

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18 Acute Exposure Guideline Levels the evolution of HCN (IUCLID 2000). Rather than acting as mere diluents, wa- ter and ethanol (especially in the presence of amines) exert specific dissociative effects on acetone cyanohydrin (Stewart and Fontana 1940). The very rapid breakdown of acetone cyanohydrin with moisture would present some chal- lenges in any accidental spill or release. Because acetone cyanohydrin breaks down so readily to HCN and the toxicity is due to HCN, both materials are pre- sent in a mixture and the ratio of the two could be rapidly changing. Therefore, both materials would need to be tracked to give an indication of the risk. Acetone cyanohydrin in air can be specifically determined using solid sor- bent sampling (samples should be stored water-free and frozen to avoid decom- position), elution with a water-free solvent (ethylacetate), and gas chroma- tographic analysis (Glaser and O‘Connor 1985; NIOSH 1985). Methods for total cyanide determination involving sampling in alkaline solutions or infrared spec- troscopy also are available (Singh et al. 1986). Electrochemical detectors for HCN and Draeger tubes for HCN will not detect acetone cyanohydrin. However, these devices can be used to detect HCN that will form rapidly in a case of ace- tone cyanohydrin release because of its decomposition to acetone and HCN. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality Although deaths have occurred from exposures to acetone cyanohydrin, specific exposure concentrations and exposure periods have not been reported (Sunderman and Kincaid 1953; NIOSH 1978; DECOS 1995; ACGIH 1996). Fatalities and life-threatening poisonings with clonic-tonic convulsions in work- ers have been described after inhalation (Krefft 1955) and skin contact (Sun- derman and Kincaid 1953; Thiess and Hey 1969) as well as after accidental in- gestion (Sunderman and Kincaid 1953). Following mild exposure to acetone cyanohydrin, patients presented with cardiac palpitation; headache; weakness; dizziness; nausea; vomiting; and nose, eye, throat, and skin irritation (Ballantyne and Marrs 1987; DECOS 1995). 2.2. Nonlethal Toxicity No relevant studies documenting nonlethal effects in humans after a single inhalation exposure to acetone cyanohydrin were located in the available litera- ture. Cases of intoxication in workers after dermal contact with acetone cyano- hydrin have been reported (Lang and Stintzy 1960; Zeller et al. 1969). Sunderman and Kincaid (1953) described at least three pumpers who lost consciousness during the packing operation of acetone cyanohydrin. The men recovered after they had been revived on exposure to fresh air and cleaning their hands. No permanent injury apparently occurred following these exposures. It had been noted that the pumpers usually had their hands covered with grease.

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19 Acetone Cyanohydrin When the employees had covered their hands, the effects of acetone cyano- hydrin were minimal, suggesting dermal penetration of acetone cyanohydrin as the principal route of exposure in these cases. The symptoms following mild exposure to acetone cyanohydrin were predominantly cardiac palpitation, head- ache, nausea, and vomiting. No details about the exposure conditions were re- ported. Oral exposure to acetone cyanohydrin may occur as a consequence of its liberation from linamarin, a cyanogenic glycoside found in cassava and other plant foodstuffs (Conn 1979). Linamarin is the common name given to a mole- cule composed of glucose and acetone cyanohydrin. Since toxic effects of lina- marin usually become evident only after long-term, low-dose exposure, toxicity data for linamarin are not considered relevant to AEGL development and thus are not presented here. Shkodich (1966) reported that according to a majority of people smelling and tasting acetone-cyanohydrin-containing water, the sensory threshold of smell for this substance is at a concentration of 0.06 mg/L and that of aftertaste is 0.48 mg/L. No experimental details were reported. 2.3. Developmental and Reproductive Toxicity No studies documenting potential developmental or reproductive toxicity of acetone cyanohydrin exposure in humans were located in the available litera- ture. 2.4. Genotoxicity No studies documenting the genotoxic potential of acetone cyanohydrin exposure in humans were located in the available literature. 2.5. Carcinogenicity No studies documenting the carcinogenic potential of acetone cyanohydrin exposure in humans were located in the available literature. 2.6. Summary Deaths associated with inhaled acetone cyanohydrin have occurred, but exposure concentrations are unknown. Likewise, airborne exposure concentra- tions for those who survived the initial acute intoxication were not provided, but in each instance, there was ample opportunity for skin absorption. No informa- tion on developmental or reproductive effects, genotoxicity, or carcinogenicity was located.

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20 Acute Exposure Guideline Levels 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality Lethality data are available for the rat; only one study reporting lethality in mice was located. The lethality data are summarized in Table 1-3. 3.1.1. Rats Smyth et al. (1962) exposed groups of six albino rats to acetone cyano- hydrin vapors that were produced by passing a 2.5-L/min-air-stream through a fritted glass disc immersed in 50 mL of acetone cyanohydrin. Doses were loga- rithmically distributed, differing by a factor of two (doses were not stated ex- plicitly). The observation period was 14 d. After exposure for 4 h, two of six rats were killed at 62.5 ppm and six of six rats were killed at 125 ppm. The maxi- mum time rats could be exposed to saturated vapor (about 1,300 ppm) without producing any deaths was 5 min. No other signs of toxicity were reported. Izmerov et al. (1982) reported an LC40 (concentration that is lethal for 40% of test organisms) of 185 mg/m³ (51.8 ppm) for 2 h in rats (no details re- ported). Sunderman and Kincaid (1953) using saturated vapors of commercially available acetone cyanohydrin reported that six of six rats died after 1.5 min. When the free HCN contained in the acetone cyanohydrin was removed by pre- cipitation with silver nitrate before exposure, the authors found that collapse occurred after an average time of 4 min and 50 % mortality after 10 min (the exact number of animals not stated). Monsanto (1986a) exposed groups of 10 female and 10 male Sprague- Dawley rats to acetone cyanohydrin at 0, 10, 30, or 60 ppm for 6 h/d, 5 d/wk for 20 exposure days (28 days in total). Concentrations in the exposure chamber were calculated by dividing the net amount of acetone cyanohydrin delivered to the chamber per unit time by the airflow per unit time and, in addition, measured by a Miran infrared analyzer (using the C-N triple bond frequency, which de- tects both acetone cyanohydrin and HCN) four times daily. For the total expo- sure period, mean analytic concentrations (± standard deviation [SD]) were de- termined as 9.2 ± 0.9, 29.9 ± 1.2, and 59.6 ± 1.4 ppm, respectively. In the highest exposure group, respiratory distress, tremors or convulsions or both, foaming at the mouth, and prostration were observed in four males following the first exposure. Three of the four animals died. No deaths occurred in the 29.9- ppm group (see section 3.2.4 for nonlethal effects). In three other studies con- ducted under similar protocols, no deaths were observed at 60 ppm for 6 h/d (Monsanto 1982b,c, 1986b) (see sections 3.2.1 and 3.3.1). The authors sug- gested that the differences between the 28-d study and the 14-week study (Mon- santo 1986b) were possibly due to the very steep dose-response for acetone

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21 Acetone Cyanohydrin TABLE 1-3 Summary of Acute Lethal Inhalation Data in Laboratory Animals Concentration Species (ppm) Exposure Time Effect Reference Rat Saturated vapor 1.5 min 6/6 animals died during Sunderman and (about 1,300 ppm) (time to death) exposure period; using Kincaid 1953 commercially available acetone cyanohydrin Rat Saturated vapor 10 min 6/6 animals died during Sunderman and (about 1,300 ppm) (time to death) exposure period; using Kincaid 1953 commercial acetone cyanohydrin with free HCN removed Rat 125 4h 6/6 animals died Smyth et al. 1962 Rat 62.5 4h 2/6 animals died Smyth et al. 1962 Rat 59.6 6 h/d, 5 d/wk, 3/20 animals died (deaths Monsanto 1986a 4 wk occurred after first exposure during which exposure to an elevated concentration may have occurred) Rat 58.6 6 h/d, 7 d/wk, No deaths in 24 animals Monsanto 1982c 21 d Rat 57.7 6 h/d, 5 d/wk, No deaths in 30 animals Monsanto 1986b 14 wk Rat 57.2 6 h/d, 5 d/w, No deaths in 15 animals Monsanto 1982b 48 d Rat 51.8 2h LC40 Izmerov et al. 1982 Mouse 574 2h LC50 Gabor et al. 1962 Mouse 19.6 2h LC30 Izmerov et al. 1982 cyanohydrin or to the normal variation in experimental animals of the same strain. Evaluation of the nominal and analytic concentrations revealed that the animals in the 60-ppm group may have been exposed to a slightly higher con- centration during the second half of the first day: the nominal concentration of 64.8 ppm for the first day was the highest of all days (mean for the other 19 ex- posure days was 60.4 ± 1.8 ppm), likewise, the last two analytic concentrations measured during the first day (55.5, 60.5, 63.5, and 63.5 ppm; mean 60.8 ± 3.8) were greater than those measured on all subsequent exposure days (the highest individual value for exposure days 2-20 was 61.5 ppm; mean for exposure days 2-20 was 59.5 ± 1.4 ppm).

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22 Acute Exposure Guideline Levels 3.1.2. Mice Gabor et al. (1962) exposed albino mice to different acetone cyanohydrin concentrations (0.5-3 mg/L [40-840 ppm]) for 2 h. Deaths were reported as 0 of 10 mice at 140 ppm, 0 of 10 at 280 ppm, 8 of 10 at 420 ppm, 18 of 44 at 560 ppm, 4 of 10 at 700 ppm, and 10 of 10 at 840 ppm. The authors found a 50% narcosis level at 1.65 mg/L (462 ppm) and calculated a LC50 of 2.05 mg/L (574 ppm). The mouse strain, analytic methods, and post-exposure observation period were not reported. Izmerov et al. (1982) reported an LC30 of 70 mg/m³ (19.6 ppm) for 2 h in mice (no details were reported). 3.2. Nonlethal Toxicity No studies were located that evaluated nonlethal consequences of acetone cyanohydrin after a single inhalation exposure. Studies using repeated inhalation exposure reported signs of irritation, such as red nasal discharge and perioral wetness. These data are summarized in Table 1-4. 3.2.1. Rats Monsanto (1986a) exposed groups of 10 female and 10 male Sprague- Dawley rats to mean acetone cyanohydrin concentrations of 9.2 ± 0.9, 29.9 ± 1.2, and 59.6 ± 1.4 ppm, respectively, for 6 h/d, 5 d/wk for 20 exposure days (28 days in total) (see section 3.1.1). Three of 20 animals that inhaled 59.6 ppm died after the first exposure. The three animals that died and another animal that sur- vived showed respiratory distress, prostration, tremors and/or convulsions (ob- served in three of the four animals), and foaming of the mouth (observed in two of the four animals). During the first week of exposure, red nasal discharge was reported in 0 of 20 control animals, 0 of 20 animals in the 10-ppm group, 4 of 20 animals in the 30-ppm group, and 2 of 20 animals in the 60-ppm group (the au- thors reported incidences of irritation only for whole weeks, but not for single days). Reduced (p > 0.05) body weight was found in the high-exposure group. No gross or microscopic lesions attributable to acetone cyanohydrin exposure were observed. Total serum protein was reduced in male rats at all exposure concentrations but only statistically significant in the mid- and high-exposure groups. Monsanto (1986b) conducted exposures of 15 female and 15 male Spra- gue-Dawley rats to acetone cyanohydrin at 0, 10, 30, or 60 ppm for 6 h/d, 5 d/wk for 14 weeks. Concentrations in the exposure chamber were calculated by dividing the net amount of acetone cyanohydrin delivered to the chamber per unit time by the airflow per unit time and, in addition, measured by a Miran

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TABLE 1-4 Summary of Nonlethal Signs of Acetone Cyanohydrin Exposure in Laboratory Animals Target [analytic] Species concentration (ppm) Exposure Time Effect Reference Rat 60 [57.2] 6 h/d, Red nasal discharge in 14/15 animals vs. 10/15 in controls and perioral Monsanto 1982b 5 d/wk, 48 d wetness/red stain in 8/15 animals vs. 2/15 in controls during first 10-d period; 15 males tested Rat 60 [58.6] 6 h/d, Red nasal discharge and encrustations during week 1 in 12/24 animals vs. Monsanto 1982c 7 d/wk, 21 d 6/24 controls; 24 females tested Rat 60 [59.6] 6 h/d, Respiratory distress, prostration, tremors and/or convulsions in 4/20, red Monsanto 1986a 5 d/wk,4 wk nasal discharge in 2/20 animals vs. 0/20 in controls during week 1; 3/20 males died after first day; 10 females and 10 males tested Rat 60 [57.7] 6 h/d, Bloodlike discharge about the nose in 20/30 animals vs. 6/30 in controls Monsanto 1986b 5 d/wk, 14 wk and clear nasal discharge in 2/30 animals vs. 0/30 in controls during week 1; no deaths occurred; 15 females and 15 males tested Rat 30 [28.5] 6 h/d, Red nasal discharge in 12/15 animals vs. 10/15 in controls and perioral Monsanto 1982b 5 d/wk, 48 d wetness/red stain in 4/15 animals vs. 2/15 in controls during first 10-d period; 15 males tested Rat 30 [30.4] 6 h/d, Red nasal discharge and encrustations during week 1 in 10/24 animals vs. Monsanto 1982c 7 d/wk, 21 d 6/24 controls; 24 females tested Rat 30 [29.9] 6 h/d, Red nasal discharge in 4/20 animals vs. 0/20 in controls during week 1; Monsanto 1986a 5 d/wk, 4 wk 10 females and 10 males tested Rat 30 [28.6] 6 h/d, Bloodlike discharge about the nose in 18/30 animals vs. 6/30 in controls Monsanto 1986b 5 d/wk, 14 wk and clear nasal discharge in 3/30 animals vs. 0/30 in controls during week 1; 15 females and 15 males tested Rat 10 [10.0] 6 h/d, Red nasal discharge during week 1 in 10/15 animals vs. 10/15 in Monsanto 1982b 5 d/wk, 48 d controls; 15 males tested (Continued) 23

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39 Acetone Cyanohydrin discussed in section 3.1.1, the actual exposure concentration on the first day might have been slightly higher than the average 59.6 ppm), and no additional deaths were found in the 19 subsequent exposures. The AEGL-3 values for acetone cyanohydrin are set at the same values (on a ppm basis) as the AEGL-3 values for HCN (NRC 2002). The values are listed in Table 1-8. 8. SUMMARY OF AEGLs 8.1. AEGL Values and Toxicity End Points The AEGL values for various levels of effects and various time periods are summarized in Table 1-9. They were derived using the following key studies and methods. The derivation of AEGL values was based on the facts that acetone cya- nohydrin decomposes spontaneously to HCN and acetone and that the local and systemic toxicity of acetone cyanohydrin is due to free cyanide. Once absorbed, a dose of acetone cyanohydrin behaves in a manner identical to that of its molar equivalent in absorbed free cyanide. It is appropriate to apply the AEGL values (on a ppm basis) derived for HCN (NRC 2002) to acetone cyanohydrin. All inhalation data are summarized in Figure 1-1. The data were classified into severity categories chosen to fit into definitions of the AEGL health effects. TABLE 1-8 AEGL-3 Values for Acetone Cyanohydrina AEGL 10 min 30 min 1h 4h 8h AEGL-3 27 ppm 21 ppm 15 ppm 8.6 ppm 6.6 ppm (95 mg/m³) (74 mg/m³) (53 mg/m³) (30 mg/m³) (23 mg/m³) a Acetone cyanohydrin decomposes spontaneously in the presence of water to yield HCN and acetone. Therefore, both acetone cyanohydrin and HCN concentrations should be considered. TABLE 1-9 Summary of AEGL Values for Acetone Cyanohydrina,b Classification 10 min 30 min 1h 4h 8h AEGL-1 2.5 ppm 2.5 ppm 2.0 ppm 1.3 ppm 1.0 ppm (Nondisabling) (8.8 mg/m³) (8.8 mg/m³) (7.0 mg/m³) (4.6 mg/m³) (3.5 mg/m³) AEGL-2 17 ppm 10 ppm 7.1 ppm 3.5 ppm 2.5 ppm (Disabling) (60 mg/m³) (35 mg/m³) (25 mg/m³) (12 mg/m³) (8.8 mg/m³) AEGL-3 27 ppm 21 ppm 15 ppm 8.6 ppm 6.6 ppm (Lethal) (95 mg/m³) (74 mg/m³) (53 mg/m³) (30 mg/m³) (23 mg/m³) a Acetone cyanohydrin decomposes spontaneously in the presence of water to yield HCN and acetone. Therefore, both acetone cyanohydrin and HCN concentrations should be considered. b Cutaneous absorption may occur; direct skin contact with the liquid should be avoided.

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Consistency of Data for Acetone Cyanohydrin 40 with Derived AEGL Values 1000.00 Human - No effect 100.00 Human - Discomfort Human - Disabling Animal - No effect Animal - Discomfort Animal - Disabling Animal - Some Lethality AEG L-3 Animal - Lethal 10.00 AEGL Concentration (ppm) AEG L-2 AEG L-1 1.00 0 60 120 180 240 300 360 420 480 Time (minutes) FIGURE 1-1 Categorical representation of acetone cyanohydrin inhalation data.

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41 Acetone Cyanohydrin The category severity definitions are “no effect,” “discomfort,” “disabling,” “le- thal,” “some lethality” (at an experimental concentration in which some of the animals died and some did not, this label refers to the animals that did not die), and “AEGL.” Note that the AEGL values are designated as triangles without an indication to their level. AEGL-3 values are higher than the AEGL-2 values, and the AEGL-2 values are higher than the AEGL-1 values. 8.2. Comparison with Other Standards and Criteria Standards and guidance levels for workplace and community exposures are listed in Table 1-10. 8.3. Data Adequacy and Research Needs Definitive exposure-response data for acetone cyanohydrin in humans are not available. Data from earlier animal studies were often compromised by un- certain quantitation of exposure atmospheres, small numbers of animals, and poor data presentation. Four more recent repeated inhalation exposure studies in rats sponsored by Monsanto Company utilized accurate and reliable methods for characterizing concentrations. However, repeat exposure studies were consid- ered of limited relevance for the derivation of AEGL values. TABLE 1-10 Extant Standards and Guidelines for Acetone Cyanohydrin Exposure Duration Guideline 10 min 30 min 1h 4h 8h AEGL-1 2.5 ppm 2.5 ppm 2.0 ppm 1.3 ppm 1.0 ppm AEGL-2 17 ppm 10 ppm 7.1 ppm 3.5 ppm 2.5 ppm AEGL-3 27 ppm 21 ppm 15 ppm 8.6 ppm 6.6 ppm WEEL (AIHA)a 5 ppm for 15 min 2 ppm TLV ceiling (ACGIH)b 4.7 ppm as cyanide REL ceiling (NIOSH)c 1 ppm a AHIA WEEL (American Industrial Hygiene Association, workplace environmental exposure level) (AIHA1999) represent workplace exposure concentrations to which, it is estimated, nearly all employees could be repeatedly exposed without adverse effects. WEELs are ex- pressed as time-weighted-average values for different time periods. b ACGIH TLV ceiling (American Conference of Governmental Industrial Hygienists, Thresh- old Limit Value) (ACGIH 1996) is defined as a 15-min TWA exposure concentration, which should not be exceeded at any time during the workday. Because acetone cyanohydrin behaves qualitatively and quantitatively both in vitro and in vivo exactly as does its molar equivalent in free cyanide, the TLV for acetone cyanohydrin is assigned to be identical to that for free HCN. c NIOSH REL ceiling (National Institute of Occupational Safety and Health, recommended exposure limits) (NIOSH 1978)is defined analogous to the ACGIH TLV ceiling. NIOSH based the value on the assumption that acetone cyanohydrin was approximately 18.3 times as toxic as acetonitrile by inhalation.

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42 Acute Exposure Guideline Levels With regard to toxic effects, the similarity between acetone cyanohydrin and HCN concerning both the mechanism of toxic effects and dose-response relationships was considered high enough to apply the AEGL-1, AEGL-2, and AEGL-3 values derived for HCN to acetone cyanohydrin on a part per million basis. In contrast to HCN, appropriate studies are not available for acetone cya- nohydrin in exposed workers for the derivation of AEGL-1 or in well-performed inhalation exposure studies evaluating neurotoxic or lethal effects for the deriva- tion of AEGL-2 and AEGL-3 values. However, the available results of studies in rats are in good agreement with HCN studies. LC50 studies for acetone cyano- hydrin performed according to good laboratory practice would strengthen the derived AEGL-3 values. It Because of the steep dose-response relationship, concentrations of AEGL-2 and AEGL-3 values differ only by a factor of 1.6 to 2.6, which could cause problems in regulatory applications of AEGL values especially when it is considered that uncertainties of measurements and dispersion (plume) calcula- tions can be in the same order of magnitude or even higher. 9. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1996. Acetone Cyanohydrin. Supplements to the Sixth Edition Documentation of the Threshold Limit Values and Biological Exposure Indices. American Conference of Govern- mental Industrial Hygienists, Cincinnati, OH. ACGIH (American Conference of Governmental Industrial Hygienists). 1997. Acetone. Supplements to the Sixth Edition Documentation of the Threshold Limit Values and Biological Exposure Indices. American Conference of Governmental Indus- trial Hygienists, Cincinnati, OH. AIHA (American Industrial Hygiene Association). 1999. The AIHA 1999 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. Fairfax, VA: AIHA Press. ATSDR (Agency for Toxic Substances and Disease Registry). 1990. Toxicological Pro- file for Acrylonitrile. U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA [online]. Available: http://www.atsdr.cdc.gov/toxprofiles/tp125-p.pdf [accessed May 19, 2008]. ATSDR (Agency for Toxic Substances and Disease Registry). 1994. Toxicological Pro- file for Acetone. U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA [online]. Available: http://www.atsdr.cdc.gov/toxprofiles/tp21-p.pdf [accessed May 19, 2008]. ATSDR (Agency for Toxic Substances and Disease Registry). 1997. Toxicological Pro- file for Cyanide (Update). U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA. Ballantyne, B., and T.C. Marrs, eds. 1987. Clinical and Experimental Toxicology of Cya- nides. Bristol, U.K.: Wright.

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43 Acetone Cyanohydrin Blanc, P., M. Hogan, K. Mallin, D. Hryhorczuk, S. Hessl, and B. Bernard. 1985. Cyanide intoxication among silver-reclaiming workers. J. Am. Med. Assoc. 253(3):367- 371. Blank, T.L. 1983. Inhalation Pilot Study of Hydrogen Cyanide Exposure in Sprague- Dawley Rats. Report No. MSL-2985. EPA OTS Submission 88-920007543. Mon- santo Company. Bonsall, J.L. 1984. Survival without sequelae following exposure to 500 mg/m3 of hy- drogen cyanide. Hum. Toxicol. 3(1):57-60. Casazza, J.P., M.E. Felver, and R.L. Veech. 1984. The metabolism of acetone in the rat. J. Biol. Chem. 259(1):231-236. Conn, E.E. 1979. Cyanogenic glycosides. Int. Rev. Biochem. 27:21-43. DECOS (Dutch Expert Committee on Occupational Standards). 1995. Acetone Cyano- hydrin: Health Based Recommended Occupational Exposure Limit. Prepared by Dutch Expert Committee on Occupational Standards, Health Council, to the Minis- ter for Health, Welfare, and Sports, the Minister and State Secretary for Social Af- fairs and Employment, The Hague: Gezondheidsraad. Dixon, M., and E.C. Webb. 1964. Pp. 337-340 in Enzymes, 2nd Ed. New York: Academic Press. E.I. du Pont de Nemours and Co. 1998. Acetone Cyanohydrin. E.I. du Pont de Nemours and Co., Haskell Laboratory, Newark, DE. El Ghawabi, S.H., M.A. Gaafar, A.A. El Saharti, S.H. Ahmed, K.K. Malash, and R. Fares. 1975. Chronic cyanide exposure: A clinical radioisotope and laboratory study. Br. J. Ind. Med. 32(3):215-219. Ellington, J.J., F.E. Stancil, and W.D. Payne. 1987. Measurement of Hydrolysis Rate Constants for Evaluation of Hazardous Waste Land Disposal, Vol. 1. Data on 32 Chemicals. EPA 600/3-86/043. NTIS PB87-140349. Environmental Research Laboratory, U.S. Environmental Protection Agency, Athens, GA. Gabor, S., C. Raucher, M. Leoca and R. Geleru. 1962. Experimental studies on the toxic- ity of some chemical substances used in the manufacturing or organic glass (plexi- glass) [in Rumanian]. Igiena 11:27-30. Gentry, P.R., T.R. Covington, H.J. Clewell, and M.E. Anderson. 2003. Application of a physiologically-based pharmacokinetic model for reference dose and reference concentration estimation for acetone. J. Toxicol. Environ. Health 66(23):2209- 2225. Gibson, Q.H., and C. Greenwood. 1963. Reactions of cytochrome oxidase with oxygen and carbon monoxide. Biochem. J. 86:541-554. Glaser, R.A., and P.F. O‘Connor. 1985. The analysis of air for acetone cyanohydrin using solid sorbent sampling and gas chromatography. Anal. Lett. 18(2):217-237. Grybat, A., S. Laue, R. Boelts, and K. Fischer. 2003. Experimental Determination of the Vapor-Liquid Equilibrium for the Binary Systems Acetone Cyanohydrine + Water and Acetone Cyanohydrine + Benzene. Laboratory for Thermophysical Properties GmbH, and University of Oldenburg. May 8, 2003. ICI (Imperial Chemical Co.). 1993. Kinetics for the Dissociation of Acetone Cyanohydrin in Water. Imperial Chemical Co., London, UK (as cited in OECD 1997). IUCLID (International Uniform Chemical Information Database). 2000. 2-hydroxy-2- methylpropionitrile (CAS No. 75-86-5). IUCLID Dataset. 2000 CD- room Ed. European Commission, European Chemicals Bureau [online]. Available: http://ecb.jrc.it/iuclid-datasheet/75865.pdf [accessed May 21, 2008].

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44 Acute Exposure Guideline Levels Izmerov, N.F., I.V. Sanotsky and K.K. Sidorov. 1982. Toxicometric Parameters of Indus- trial Toxic Chemicals under Single Exposure. Centre of International Projects, GKNT, Moscow. Johannsen, F.R., and G.J. Levinskas. 1986. Relationships between toxicity and structure of aliphatic nitriles. Fundam. Appl. Toxicol. 7(4):690-697. Kaplita, P.V., and R.P. Smith. 1986. Pathways for the bioactivation of aliphatic nitriles to free cyanide in mice. Toxicol. Appl. Pharmacol. 84(3):533-540. Kosugi, K., V. Chandramouli, K. Kumaran, W.C. Schumann, and B.R. Landau. 1986. Determinants in the pathways followed by the carbons of acetone in their conver- sion to glucose. J. Biol. Chem. 261(28):13179-13181. Krefft, S. 1955. Acetoncyanhydrin poisoning in man and animal; Experimental research on percutaneous toxicity of acetoanyhydrin [in German]. Arch. Gewerbepathol. Gewerbehyg. 14(2):110-116. Lang, J., and F. Stintzy. 1960. A case of slow poisoning by hydrocyanic acid caused by cyanhydrin acetone [in French]. Arch. Mal. Prof. 21:652-657. Leeser, J.E., J.A. Tomenson, and D.D. Bryson. 1990. A Cross-Sectional Study of the Health of Cyanide Salt Production Workers. Report No. OHS/R/2. ICI Central Laboratory, Macclesfield, Cheshire, UK. Lemberg, M.R. 1969. Cytochrome oxidase. Phys. Rev. 49(1):48-121. Magos, L. 1962. A study of acrylonitrile poisoning in relation to methaemoglobin-CN complex formation. Br. J. Ind. Med. 19(4):283-286. Marhold, J.V. 1972. Sborník Výsledkù Toxikologického Vysetrení Látek a Pripravkù. Praha: Institut pro výchovu vedoucích pracovníku chemického prumyslu. Monsanto. 1982a. Range-Finding Teratology Study in the Rat. Report No. IL-83-094. EPA/OPTS Public File No. 878216399. Monsanto Co., St. Louis, MO (as cited in IUCLID 2000). Monsanto. 1982b. Male Fertility Study of Sprague-Dawley Rats Exposed by Inhalation Route to Acetone Cyanohydrin. Report No. ML-82-144. Monsanto Co., St. Louis, MO. Monsanto. 1982c. Female Fertility Study of Sprague-Dawley Rats Exposed by Inhalation Route to Acetone Cyanohydrin. Report No. ML-82-125. Monsanto Co., St. Louis, MO. Monsanto. 1983. Teratology Study in Rats. Report No. IL-83-105. Monsanto Co., St. Louis, MO. EPA/OPTS Public file No. 878216401(as cited in IUCLID 2000). Monsanto. 1986a. One-Month Inhalation Toxicity of Acetone Cyanohydrin in Male and Female Sprague-Dawley Rats with cover letter dated 04-25-86. Report No. BN-81- 178. Monsanto Co., St. Louis, MO. Monsanto. 1986b. Three-Month Inhalation Toxicity of Acetone Cyanohydrin in Male and Female Sprague-Dawley Rats with cover letter dated 04-25-86. Report No. ML- 82-143. Monsanto Co., St. Louis, MO. NIOSH (National Institute for Occupational Safety and Health). 1978. Criteria for a Rec- ommended Standard: Occupational Exposure to Nitriles. NIOSH Publication 78- 212. U.S. Department of Health, Education, and Welfare, Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health [online]. Available: http://www.cdc.gov/niosh/78-212.html [accessed May 20, 2008]. NIOSH (National Institute of Occupational Safety and Health). 1985. NIOSH Manual of Analytical Methods (NMAM): Method 2506 Acetone Cyanohydrin. U.S. Depart- ment of Health, Education, and Welfare, National Institute of Occupational Safety and Health (as cited in DECOS 1995).

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45 Acetone Cyanohydrin NIOSH (National Institute of Occupational Safety and Health). 1996. Acetone. Docu- mentation for Immediately Dangerous to Life and Health Concentrations (IDLH): NIOSH Chemical Listing and Documentation of Revised IDLH Values [online]. Available: http://www.cdc.gov/niosh/idlh/67641.html [accessed May 23, 2008]. NRC (National Research Council). 1984. Acetone. Pp. 5-25 in Emergency and Continu- ous Exposure Guidance Levels for Selected Airborne Contaminants, Vol. 1. Wash- ington, DC: National Academy Press. NRC (National Research Council). 2000. Hydrogen cyanide. Pp. 330-365 in Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Vol. 4. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. NRC (National Research Council). 2002. Hydrogen cyanide. Pp. 211-276 in Acute Expo- sure Guideline Levels for Selected Airborne Chemicals, Vol. 2. Washington, DC: The National Academies Press. OECD (Organization for Economic Cooperation and Development). 1997. Acetone Cya- nohydrin. OECD Initial Assessment Reports for High Production Volume Chemi- cals, Including Screening Information Data Sets (SIDS), Vol. 4, Part 1. Geneva: United Nations Environment Programme Chemicals. November 1997 [online]. Available: http://www.chem.unep.ch/irptc/Publications/sidsidex/sidsidex.htm [ac- cessed May 23, 2008]. Rieders, F. 1971. Noxious gases and vapors. I. Carbon monoxide, cyanides, methemo- globin, and sulfhemoglobin. Pp. 1180-1205 in Drill’s Pharmacology in Medicine, 4th Ed, J. DiPalma, ed. New York: McGraw-Hill. Shkodich, P.E. 1966. Experimental determination of the maximum permissible concen- tration of acetone cyanohydrin in water basins [in Russian]. Gig. Sanit. 31(6):335- 341. Singh, H.B., N. Wasi, and M.C. Mehra. 1986. Detection and determination of cyanide - a review. Int. J. Environ. Anal. Chem. 26(2):115-136. Smith, L., H.C. Davies, and M.E. Nava. 1979. Kinetics of reaction of cytochrome c with cytochrome c oxidase. Pp. 293-304 in Cytochrome Oxidase, Developments in Bio- chemistry, Vol. 5, T.E. King, Y. Orii, B. Chance, and K. Okunuki, eds. Amster- dam: Elsevier/North-Holland Biomedical Press. Smyth, H.F., C.P. Carpenter, C.S. Weil, U.C. Pozzani, and J.A. Striegel. 1962. Range- finding toxicity data: List VI. Am. Ind. Hyg. Assoc. J. 23:95-107. Stannard, J.N., and B.L. Horecker. 1948. The in vitro inhibition of cytochrome oxidase by azide and cyanide. J. Biol. Chem. 172(2):599-608. Stewart, T.D., and B.J. Fontana. 1940. Effect of solvation upon the dissociation of ace- tone cyanohydrin. J. Am. Chem. Soc. 67(12):3281-3285. Sunderman, F.W., and J.F. Kincaid. 1953. Toxicity studies of acetone cyanohydrin and ethylene cyanohydrin. Arch. Ind. Hyg. Occup. Med. 8(4):371-376. Swinyard, E.A. 1975. Noxious gases and vapors: Carbon monoxide, hydrocyanic acid, benzene, gasoline, kerosene, carbon tetrachloride, and miscellaneous organic sol- vents. Pp. 900-911 in The Pharmacological Basis of Therapeutics, 5th Ed, L.S. Goodman, and A. Gilman, eds. New York: Macmillan. Thiess, A.M., and W. Hey. 1969. On the toxicity of isobutyronitrile and alpha- hydroxyisobutyronitrile (acetone cyanohydrin). Demonstration on 2 cases of poi- soning [in German]. Arch. Toxikol. 24(4):271-282.

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46 Acute Exposure Guideline Levels Willhite, C.C., and R.P. Smith. 1981. The role of cyanide liberation in the acute toxicity of aliphatic nitrieles. Toxicol. Appl. Pharmacol. 59(3):589-602. Wilson, J. 1987. Cyanide in human disease. Pp. 292-311 in Clinical and Experimental Toxicology of Cyanides, B. Ballantyne, and T.C. Marrs, eds. Bristol, UK: Wright. Wood, J.L., and S.L. Cooley. 1956. Detoxication of cyanide by cystine. J. Biol. Chem. 218(1):449-457. Zeller, H., H.T. Hofmann, A.M. Thiess, and W. Hey. 1969. Toxicity of nitriles (results of animal experiments and 15 years of experience in industrial medicine) [in Ger- man]. Zentralbl. Arbeitsmed. 19(8):225-238.

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47 Acetone Cyanohydrin APPENDIX A DERIVATION OF AEGL VALUES FOR ACETONE CYANOHYDRIN AEGL-1 VALUESa 10 min 30 min 1h 4h 8h 2.5 ppm 2.5 ppm 2.0 ppm 1.3 ppm 1.0 ppm Reference: The AEGL-1 values for acetone cyanohydrin are set at the same values (on a ppm basis) as the AEGL-1 values for HCN. NRC (National Research Council). 2002. Hydrogen cyanide. Pp. 211-276 in Acute Expo- sure Guideline Levels for Selected Airborne Chemicals, Vol. 2. Washington, DC: Na- tional Academy Press,. Test Species/Strain/Number: Not applicable. Exposure Route/Concentrations/Durations: Not applicable. Effects: Not applicable. End Point/Concentration/Rationale: Human data on acetone cyanohydrin relevant for the derivation of AEGL-1 are lacking. One study in rats (Monsanto 1986a) reported red nasal discharge (which was interpreted as a sign of local irritation in the upper respiratory tract) in 4/20 animals at 29.9 ppm and in 2/20 animals at 59.6 ppm, but not in control animals and in animals exposed at 9.2 ppm during the first week of repeated 6-h/d exposures. However, red nasal discharge was not consistently seen in any of the other Monsanto (1982b,c, 1986b) studies and, when present, was not always dose-responsive. In addition, control animals varied widely in terms of whether that end point was present. In light of the variability of the red nasal discharge in repeat studies, it seemed a poor end point on which to base the AEGL-1. Also, the repeat exposures used in the Monsanto studies were not appropriate for the derivation of AEGL-1 values. The pathogenesis of red nasal discharge in rats is not entirely clear. In the case of acetone cyanohydrin, it may be related to local tissue hypoxia leading to vasodilatation and subsequent extravasation of red blood cells, which could explain the lack of histopathologic findings. Red nasal discharge in rats occurs at the plexus antebrachii, which is very prominent in the rat. In the rat, extravasation of red blood cells visible as red nasal discharge is caused easily not only by locally acting chemicals but also by stress, dry air, or upper respiratory tract infections. The derivation of AEGL-1 values was based on the facts that acetone cyanohydrin decomposes spontaneously to HCN and acetone and that the systemic toxicity of acetone cyanohydrin is due to free cyanide. Once absorbed, a dose of acetone cyanohydrin behaves in a manner identical to that of its molar equivalent in absorbed free cyanide. It is appropriate to apply the AEGL-1 values (on a ppm basis) derived for HCN (NRC 2002) to acetone cyanohydrin. Uncertainty Factors/Rationale: Not applicable. Time Scaling: Not applicable. (Continued)

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48 Acute Exposure Guideline Levels AEGL-1 VALUES Continued 10 min 30 min 1h 4h 8h 2.5 ppm 2.5 ppm 2.0 ppm 1.3 ppm 1.0 ppm Modifying Factor: Not applicable. Animal to Human Dosimetric Adjustment: Not applicable. Data Quality and Support for AEGLs: Similar values would be derived on the basis of available acetone cyanohydrin studies in rats (derivation basis would be an exposure of 9.2 ppm for 6 h/d, 5 d/wk for 4 weeks that did not result in red nasal discharge [Monsanto 1986a]) using a total uncertainty factor of 10. a Acetone cyanohydrin decomposes spontaneously in the presence of water to yield HCN and acetone. Therefore, both acetone cyanohydrin and HCN concentrations should be considered. AEGL-2 VALUESa 10 min 30 min 1h 4h 8h 17 ppm 10 ppm 7.1 ppm 3.5 ppm 2.5 ppm Reference: The AEGL-2 values for acetone cyanohydrin are set at the same values (on a ppm basis) as the AEGL-2 values for HCN. NRC (National Research Council). 2002. Hydrogen cyanide. Pp. 211-276 in Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 2. National Academy Press, Washington, DC. Test Species/Strain/Sex/Number: Not applicable. Exposure Route/Concentrations/Durations: Not applicable. Effects: Not applicable. End Point/Concentration/Rationale: The derivation of AEGL-2 values was based on the facts that acetone cyanohydrin decomposes spontaneously to HCN and acetone and that the systemic toxicity of acetone cyanohydrin is due to free cyanide. Once absorbed, a dose of acetone cyanohydrin behaves in a manner identical to that of its molar equivalent in absorbed free cyanide. It is appropriate to apply the AEGL-2 values (on a ppm basis) derived for HCN (NRC 2002) to acetone cyanohydrin. Uncertainty Factors/Rationale: Not applicable. Modifying Factor: Not applicable. Animal to Human Dosimetric Adjustment: Not applicable. Time Scaling: Not applicable. Data Quality and Support for AEGLs: Very similar values would be derived on the basis of available acetone cyanohydrin studies in rats (derivation basis would be an exposure of 29.9 ppm for 6 h/d, 5 d/wk for 4 weeks that caused red nasal discharge as a sign of irritation, and the next higher concentration produced respiratory distress, prostration, convulsions, and tremors [Monsanto 1986a]) using a total uncertainty factor of 10. a Acetone cyanohydrin decomposes spontaneously in the presence of water to yield HCN and acetone. Therefore, both acetone cyanohydrin and HCN concentrations should be considered.

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49 Acetone Cyanohydrin AEGL-3 VALUESa 10 min 30 min 1h 4h 8h 27 ppm 21 ppm 15 ppm 8.6 ppm 6.6 ppm Reference: The AEGL-3 values for acetone cyanohydrin are set at the same values (on a ppm basis) as the AEGL-3 values for HCN. NRC (National Research Council). 2002. Hydrogen cyanide. Pp. 211-276 in Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 2. National Academy Press, Washington, DC. Test Species/Strain/Sex/Number: Not applicable. Exposure Route/Concentrations/Durations: Not applicable. Effects: Not applicable. End Point/Concentration/Rationale: The derivation of AEGL-3 values was based upon the facts that acetone cyanohydrin decomposes spontaneously to HCN and acetone and that the systemic toxicity of acetone cyanohydrin is due to free cyanide. Once absorbed, a dose of acetone cyanohydrin behaves in a manner identical to that of its molar equivalent in absorbed free cyanide. It is appropriate to apply the AEGL-3 values (on a ppm basis) derived for HCN (NRC 2002) to acetone cyanohydrin. Uncertainty Factors/Rationale: Not applicable. Modifying Factor: Not applicable. Animal to Human Dosimetric Adjustment: Not applicable. Time Scaling: Not applicable. Data Quality and Support for the AEGLs: Support comes from the close similarity of acetone cyanohydrin and HCN regarding death in rats: Blank (1983) reported that 3 of 10 rats died after the first exposure to HCN at 68 ppm, but the subsequent two exposures on the following days caused no additional deaths. This finding closely resembles that of Monsanto (1986a) reporting death of 3 of 20 animals after the first exposure to acetone cyanohydrin at 60 ppm (the actual exposure concentration on the first day might have been slightly higher than the average 59.6 ppm), and no additional deaths were found in the 19 subsequent exposures. a Acetone cyanohydrin decomposes spontaneously in the presence of water to yield HCN and acetone. Therefore, both acetone cyanohydrin and HCN concentrations should be considered.