allyl alcohol interim dec 2008 v1

8/8/2019 Allyl Alcohol Interim Dec 2008 v1

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INTERIM 5: 12/2008

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ALLYL ALCOHOL(CAS Reg. No. 107-18-6)

INTERIM ACUTE EXPOSURE GUIDELINE LEVELS(AEGLs)

ForNAS/COT Subcommitte for AEGLs

December 2008


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INTERIM 5: 12/2008

INTERIM ACUTE EXPOSURE GUIDELINE LEVELS(AEGLs)

ALLYL ALCOHOL(CAS Reg. No. 107-18-6)

Oak Ridge National Laboratory, Managed and Operated by UT-Battelle, LLC, for the U.S. Department ofEnergy under contract number DE-AC05-00OR22725.


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PREFACE

Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for

Hazardous Substances (NAC/AEGL Committee) has been established to identify,review and interpret relevant toxicologic and other scientific data and develop AEGLsfor high priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits for the general public and areapplicable to emergency exposure periods ranging from 10 minutes to 8 hours. Threelevels C AEGL-1, AEGL-2 and AEGL-3 C are developed for each of five exposureperiods (10 and 30 minutes, 1 hour, 4 hours, and 8 hours) and are distinguished byvarying degrees of severity of toxic effects. The three AEGLs are defined as follows:

AEGL-1 is the airborne concentration (expressed as parts per million or

milligrams per cubic meter [ppm or mg/m3

]) of a substance above which it is predictedthat the general population, including susceptible individuals, could experience notablediscomfort, irritation, or certain asymptomatic, non-sensory effects. However, theeffects are not disabling and are transient and reversible upon cessation of exposure.

AEGL-2 is the airborne concentration (expressed as ppm or mg/m 3) of asubstance abovewhich it is predicted that the general population, including susceptible individuals, couldexperience irreversible or other serious, long-lasting adverse health effects or animpaired ability to escape.

AEGL-3 is the airborne concentration (expressed as ppm or mg/m3

) of asubstance above which it is predicted that the general population, including susceptibleindividuals, could experience life-threatening health effects or death.

Airborne concentrations below the AEGL-1 represent exposure levels that couldproduce mild and progressively increasing but transient and nondisabling odor, taste,and sensory irritation or certain asymptomatic, non-sensory effects. With increasingairborne concentrations above each AEGL, there is a progressive increase in thelikelihood of occurrence and the severity of effects described for each correspondingAEGL. Although the AEGL values represent threshold levels for the general public,including susceptible subpopulations, such as infants, children, the elderly, persons with

asthma, and those with other illnesses, it is recognized that individuals, subject tounique or idiosyncratic responses, could experience the effects described atconcentrations below the corresponding AEGL.


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ALLYL ALCOHOL INTERIM 5: 12/2008

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TABLE OF CONTENTS

PREFACE ....................................................................................................................... iii

LIST OF TABLES............................................................................................................vi

LIST OF FIGURES..........................................................................................................vi

EXECUTIVE SUMMARY................................................................................................vii

1. INTRODUCTION........................................................................................................ 1

2. HUMAN TOXICITY DATA.......................................................................................... 22.1. Acute Lethality.............................................................................................. 22.2. Nonlethal Toxicity ......................................................................................... 2

2.2.1 Acute studies ................................................................................... 2

2.2.2. Epidemiology Studies ..................................................................... 42.3. Developmental/Reproductive Effects............................................................ 42.4. Genotoxicity.................................................................................................. 42.5. Carcinogenicity ............................................................................................. 42.6. Summary ...................................................................................................... 4

3. ANIMAL TOXICITY DATA.......................................................................................... 43.1. Acute Lethality.............................................................................................. 4

3.1.1. Monkeys ......................................................................................... 43.1.2. Rats ................................................................................................ 53.1.3. Mice ................................................................................................ 7

3.1.4. Rabbits............................................................................................ 83.1.5. Guinea Pigs .................................................................................... 83.2. Nonlethal Toxicity ......................................................................................... 9

3.2.1. Rats ................................................................................................ 93.2.2. Mice .............................................................................................. 143.2.3. Dogs, Guinea Pigs, and Rabbits................................................... 15

3.3. Developmental/Reproductive Effects.......................................................... 153.4. Genotoxicity................................................................................................ 153.5. Carcinogenicity ........................................................................................... 153.6. Summary .................................................................................................... 16

4. SPECIAL CONSIDERATIONS................................................................................. 204.1. Metabolism and Mechanism of Toxicity...................................................... 204.2. Structure-Activity Relationships .................................................................. 224.3. Susceptible Populations ............................................................................. 224.4. Concentration-Exposure Duration Relationship.......................................... 23

5. DATA ANALYSIS FOR AEGL-1............................................................................... 235.1. Human Data Relevant to AEGL-1............................................................... 235.2. Animal Data Relevant to AEGL-1 ............................................................... 23


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5.3. Derivation of AEGL-1.................................................................................. 24

6. DATA ANALYSIS FOR AEGL-2............................................................................... 256.1. Human Data Relevant to AEGL-2............................................................... 256.2. Animal Data Relevant to AEGL-2 ............................................................... 25

6.3. Derivation of AEGL-2.................................................................................. 26

7. DATA ANALYSIS FOR AEGL-3............................................................................... 277.1. Human Data Relevant to AEGL-3............................................................... 277.2. Animal Data Relevant to AEGL-3 ............................................................... 277.3. Derivation of AEGL-3.................................................................................. 27

8. SUMMARY OF AEGLs............................................................................................. 298.1. AEGL Values and Toxicity Endpoints ......................................................... 298.2. Comparisons with Other Standards............................................................ 308.3. Data Adequacy and Research Needs ........................................................ 32

9. REFERENCES......................................................................................................... 34

APPENDIX A: Derivation of AEGL Values ................................................................... 39

APPENDIX B: ten Berge Analysis ................................................................................. 45

APPENDIX C: Derivation Summary for Allyl Alcohol AEGLs ....................................... 47


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LIST OF TABLES

1. Chemical and Physical Data ...................................................................................... 22. Summary of Sensory Response to Allyl Alcohol During 5-Minute Exposure .............. 33. Summary of Lethality Data in Rats Following Exposure to Allyl Alcohol..................... 6

4. Summary of Lethality Data in Mice Following Exposure to Allyl Alcohol .................... 75. Summary of Selected Clinical Observations in Rats Exposed to Allyl Alcohol up to 8

Hours.................................................................................................................. 106. Summary of Clinical Signs in Rats Exposed to Allyl Alcohol for 1, 4, or 8 Hours ..... 127. Summary of Selected Nasal Histopathological Findings in Rats Exposed to Allyl

Alcohol for 1, 4, or 8 Hours................................................................................. 138. Summary of Acute Lethal Inhalation Data in Laboratory Animals ............................ 189. Summary of Acute Nonlethal Inhalation Data in Laboratory Animals ....................... 1910. Summary of Repeat-Exposure Nonlethal Inhalation Data in Laboratory Animals... 2011. AEGL-1 Values for Allyl Alcohol ............................................................................ 2412. AEGL-2 Values for Allyl Alcohol ............................................................................. 26

13. AEGL-3 Values for Allyl Alcohol ............................................................................. 2914. Summary of AEGL Values for Allyl Alcohol ............................................................ 2915. Extant Standards and Guidelines for Allyl Alcohol.................................................. 31

LIST OF FIGURES

1. Category plot of human and animal toxicity data compared to AEGL values.. ......... 30


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EXECUTIVE SUMMARY

Allyl alcohol is a colorless liquid that is a potent sensory irritant. Signs of intoxicationfollowing inhalation exposure to allyl alcohol vapor include lacrimation, pulmonary

edema and congestion, and inflammation, hemorrhage, and degeneration of the liverand kidney. Human data were limited to voluntary exposures for short durations andgeneral statements about the symptoms following accidental occupational exposures tounknown concentrations of allyl alcohol for unspecified amounts of time. Animal dataincluded a current, detailed inhalation study in rats, studies in which lethality was theonly endpoint of interest, subchronic exposures, or single-exposure experiments inwhich only the RD 50 was measured.

The AEGL-1 values are based upon nasal irritation as indicated by reversible nasalinflammation observed histologically in rats 14 days after exposure to 51 ppm allylalcohol for 1 hour; 22 ppm for 4 hours, or 10 ppm for 8 hours (Kirkpatrick, 2008). These

values represent no effect levels for notable discomfort, as no clinical signs of nasalirritation were observed at these concentrations. A total uncertainty factor of 10 wasapplied. An intraspecies uncertainty factor of 3 and interspecies uncertainty factor of 3were applied because allyl alcohol is highly irritating and corrosive, and much of thetoxicity is likely caused by a direct chemical effect on the tissues; this type of port-of-entry effect is not expected to vary greatly among individuals or among species. For theAEGL derivation, the 1-, 4-, and 8-hour values were based upon the empirical data atthe respective durations. The default value of n = 3 was used to time scale the 1-hourAEGL-1 point of departure to 10 and 30 minutes. Although the effect of mild irritation isgenerally not scaled across time, the empirical data indicate a time-responserelationship for allyl alcohol-induced nasal irritation. The default value of n was used

instead of the n value derived from the rat lethality data because of the uncertainty inusing an n value derived from lethality to timescale the endpoint of mild irritation.

The AEGL-2 was obtained by dividing the AEGL-3 by 3. Two rats exposed to 51ppm for 8 hours developed severe, irreversible nasal lesions (Kirkpatrick, 2008). TheAEGL-2 values could be based on the highest no-effect level for irreversible nasalhistopathological lesions of 403 ppm for 1 hour, 102 ppm for 4 hours, and 21 ppm for 8hours; however, these concentrations are similar to the calculated LC 01 values used forthe AEGL-3 derivations. The data for irreversible nasal lesions were insufficient foranalyses by the ten Berge software or by benchmark dose because there is only onedata point with a non-zero response. No other empirical data meeting the definition of

an AEGL-2 endpoint were available; therefore, the AEGL-3 values were divided by 3 toprovide a reasonable estimate for AEGL-2 values.

The AEGL-3 values are based on the calculated LC 01 value in rats of 2600 ppm for10 minutes, 820 ppm for 30 minutes, 400 ppm for 1 hour, 93 ppm for 4 hours, and 45ppm for 8 hours. The LC 01 estimates were calculated using the ten Berge softwareprogram; data used in the analysis included the rat mortality data from Kirkpatrick(2008), Union Carbide and Carbon Corporation (1951), McCord (1932), and Smyth andCarpenter (1948) (see Appendix B). The ten Berge program estimated an n=0.95 for


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time scaling. An intraspecies uncertainty factor of 3 and interspecies uncertainty factorof 3 were applied because allyl alcohol is highly irritating and corrosive, and much of thetoxicity is likely caused by a direct chemical effect on the tissues; this type of port-of-entry effect is not expected to vary greatly among individuals or among species.

A level of distinct odor awareness (LOA), which represents the concentration abovewhich it is predicted that more than half of the exposed population will experience atleast a distinct odor intensity and about 10 % of the population will experience a strongodor intensity, could not be determined due to inadequate data. Although odorthresholds for allyl alcohol have been reported (1.4 ppm and 2.1 ppm), concurrent odorthreshold data for the reference chemical n-butanol (odor detection threshold 0.04 ppm)were not available.

The derived AEGL values are listed in the table.

SUMMARY OF AEGL VALUES FOR ALLYL ALCOHOL (ppm [mg/m 3])

Classification 10-min

30-min 1-hr 4-hr 8-hr Endpoint (Reference)

AEGL-1(Nondisabling)

9.3[23]

6.4[15]

5.1[12]

2.2[5.3]

1.0[2.4]

Slight nasal irritation inrats (Kirkpatrick, 2008)

AEGL-2(Disabling)

87[210]

27[65]

13[31]

3.1[7.5]

1.5[3.6]

AEGL 3/3

AEGL-3

(Lethality)

260

[630]

82

[200]

40

[97]

9.3

[23]

4.5

[11]

estimated LC 01 value in

rats calculated usingten Berge program;included rat mortalitydata from Kirkpatrick(2008), Union Carbideand CarbonCorporation (1951),McCord (1932), Smythand Carpenter (1948)


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1. INTRODUCTION

Allyl alcohol is a colorless liquid that is a potent sensory irritant. The chemical has apungent, mustard-like odor, with a reported odor recognition of 0.78 ppm (Dunlap et al.,1958) and odor detection threshold ranging from 1.4-2.1 ppm (AIHA, 1989). Primarily

used in the production of allyl esters for use in resins and plasticizers, allyl alcohol isalso used as an intermediate in the production of pharmaceuticals and other organicchemicals, as a fungicide and herbicide, in the production of glycerol, acrolein, and wargas, and as a flavoring agent (ACGIH, 1991; Budavari et al, 1996; Lington and Bevan,1994; Tabershaw et al., 1977). Allyl alcohol is produced from the isomerization ofpropylene oxide at a high temperature using a lithium phosphate catalyst (Lyondell,1994). Currently, there is only one producer of allyl alcohol in the United States(Lyondell, 2002). USITC (1995) stated that because there is only one U.S. producer,the data for production and sales quantities are not provided to avoid disclosure ofindividual company operations. TRI (2000) reported a total environmental release andoff-site waste transfer value of 2,593,952 pounds. Allyl alcohol is shipped by rail, truck,

and ship (Lyondell, 1994). The physicochemical data on allyl alcohol are presented inTable 1.

Vaporized and liquid allyl alcohol are intensely irritating to intact skin, eyes, andmucous membranes. Contact with the eye can produce corneal burns; direct skincontact can produce first- and second-degree burns and can induce epidermal necrosis.At sufficiently high concentrations, inhaled allyl alcohol can induce pulmonary edema

(Shell Chemical Corporation, 1957). Human data were limited to controlled studies withhuman volunteers; no lethality or epidemiology data on allyl alcohol exposure wereavailable. Studies addressing lethal and nonlethal toxicity of allyl alcohol in laboratoryanimals were available.

TABLE 1. Chemical and Physical Data

Parameter Value Reference

Molecular formula C 3H6O Budavari et al., 1996

Molecular weight 58.08 Budavari et al., 1996

CAS RegistryNumber

107-18-6 ACGIH, 1991

Physical state liquid Budavari et al., 1996

Color colorless Budavari et al., 1996

Synonyms 2-propen-1-ol, 1-propenol-3, vinylcarbinol

Budavari et al., 1996

Solubility miscible with water, alcohol,chloroform, ether, petroleum ether

Budavari et al., 1996


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Vapor pressure 23.8 mmHg at 25 EC17 torr at 20 EC

Lington and Bevan, 1994ACGIH, 1991

Vapor density(Air=1)

2.0 Parmeggiani, 1983

Specific gravity(water = 1)

0.8540 @ 20/4 EC Budavari et al., 1996

Melting point -50 EC Budavari et al., 1996

Boiling point 96-97 EC Budavari et al., 1996

Freezing point -129 E C Lyondell, 1994

Flash point 20.9 EC Lyondell, 1994

Conversionfactors

1 ppm = 2.42 mg/m 3 1 mg/m 3 = 0.413 ppm

NIOSH, 1994

2. HUMAN TOXICITY DATA2.1. Acute Lethality

No reported cases of death following exposure to allyl alcohol were found in thepublished literature.

2.2. Nonlethal Toxicity 2.2.1 Acute studies

Groups of five to seven volunteers, ranging in age from 19 to 39 years, wereexposed to allyl alcohol in an exposure room from one to three times a week for 5minutes over a total period of 50 days (Dunlap et al., 1958). The exposure room wascubical with approximately an 18,000 liter volume, and had a revolving fan for mixing thevapor in the room. The vapor was generated by flash vaporization of allyl alcohol usinga heat source. Five minutes of vaporization and equilibration were allotted beforevolunteers entered the room for the static exposure. It was not stated if the exposureconcentrations were calculated or measured concentrations. Volunteers wereApreconditioned at the beginning of the experiment by reviewing with them the differentsubjective sensations associated with a particular level of response... but the subject

was not aware of the nature of the material.@

During the static exposure at one-minuteintervals, they graded their responses to eye and nose irritation, olfactory recognition,central nervous system effects, and pulmonary effects as absent, slight, moderate,severe, or extreme (see Table 2). When reporting the results, however, the authorslisted the responses as only slight or moderate or greater, with the exception of eyeirritation. After each exposure, the eyes of each subject were visually inspected, andAphysical examination of the chest @ was made at the end of the day =s run or when thesubject noted subjective symptoms. Olfactory recognition was noted as at least slightby 5 of 6 subjects at the lowest concentration of 0.78 ppm, and became at least


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moderate at 6.25 ppm in 2 of 6 subjects. At concentrations of 12.5 ppm, moderate orgreater nose irritation was experienced by 4 of 7 volunteers, and all subjects expressednose irritation as moderate or greater at 25.0 ppm. Eye irritation was slight in 1 of 6 and1 of 7 individuals at 6.25 and 12.5 ppm, respectively, and was moderate or greater at 25ppm in 5 of 5 volunteers. The authors stated that the eye irritation at 25 ppm was

severe. It was not stated if responses varied with repeated exposure. Although notassociated with the controlled exposures of the volunteers, Dunlap et al. (1958)described symptoms in workers who were exposed to Amoderate @ concentrations of allylalcohol (range not given). The symptoms included lacrimation, retrobulbar pain, andblurred vision, which persisted for 24 to 48 hours after cessation of exposure. Nopermanent damage to the cornea was reported following exposure to unstatedconcentrations of allyl alcohol vapor.

Table 2. Summary of Sensory Response to Allyl Alcohol During 5-Minute Exposure

Olfactory Recognition a Eye Irritation a Nose Irritation a Conc.(ppm)

No.Subject

s AnyResponse

$ Moderate AnyResponse

$ Moderate AnyRespons

e

$ Moderate

0.78 6 5 1 0 0 2 0

6.25 6 5 2 1 0 3 1

12.5 7 6 1 1 0 7 4

25.0 5 3 1 5 5 b 5 5Source: Dunlap et al., 1958.b The numbers listed in the AAny Response @ column are for the number of volunteers showing any response atall; the A$ Moderate @ column represents those listing responses greater than Aslight @ b Response graded as severe

Ten volunteers were exposed to 2 ppm allyl alcohol for 1-3 minutes (Torkelson et al.,1959a). The volunteers went into a large chamber in groups of 2 or 3 once the desiredconcentration was obtained (methods in Torkelson et al., 1959b). Half of the volunteersreported a distinct odor but no irritation. McCord (1932) commented that workersexposed to allyl alcohol (concentration, duration, and exposure situation not reported)had signs and symptoms limited to severe irritation of the mucous membranes withedema and excessive secretions, conjunctivitis and lacrimation, and that exposure to 5ppm allyl alcohol would produce some irritation. One worker was reportedly temporarilyblinded by delayed corneal necrosis following exposure to the vapor, although thenature of the exposure was not provided (Smyth, 1956). Smyth stated that the primarytoxic effect following exposure to allyl alcohol vapor is irritation manifested by pulmonaryedema and disabling corneal injury.

Odor detection threshold values for allyl alcohol are reported by the AmericanIndustrial Hygiene Association (AIHA, 1989) as 1.4 ppm (3.3 mg/m 3) and 2.1 ppm (5mg/m 3). These values are based on two studies (Katz and Talbert, 1930; Dravnieks,1974) that were critiqued by the AIHA and graded as acceptable.


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2.2.2. Epidemiology Studies

Epidemiologic studies regarding human exposure to allyl alcohol were not availablein the literature searched.

2.3. Developmental/Reproductive Effects

No data are available regarding the developmental/reproductive toxicity of allylalcohol in humans.

2.4. Genotoxicity

No information on the genotoxicity of allyl alcohol in humans was available.

2.5. Carcinogenicity

No information on the potential carcinogenicity of allyl alcohol in humans wasavailable.

2.6. Summary

There were no reported cases of death following allyl alcohol exposure in humans,and no case reports of accidental work exposures. Volunteers exposed to allyl alcoholfor 5 minutes reported nose irritation at 12.5 ppm and severe eye irritation at 25 ppm.Workers exposed to moderate concentrations (range not given) were reported toexperience lacrimation, retrobulbar pain, and blurred vision. Accepted odor detectionthreshold values for allyl alcohol are 1.4- 2.1 ppm, and an odor recognition threshold of

0.78 ppm was reported.

3. ANIMAL TOXICITY DATA 3.1. Acute Lethality

3.1.1. Monkeys

One monkey (sex not given) exposed to 1000 ppm allyl alcohol died 4 hours into theexposure (McCord, 1932). Prior to death, the monkey was vomiting, had diarrhea, andappeared to be in severe pain. Necropsy revealed subcutaneous hemorrhage of theabdomen, petechial hemorrhage and inflammation of the intestine, a distendedgastrointestinal tract, and hemorrhage of the spleen and kidneys. Inflammation was

noted in the brain, meninges, and blood vessels, and the lungs showed edema withhemorrhagic exudate.


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3.1.2. Rats

Groups of five Crl:CD(SD) rats/sex were exposed by whole body inhalation to allylalcohol vapor at measured concentrations of 0, 51, 220, or 403 ppm for 1 hour; 0, 22,52, or 102 ppm for 4 hours; or 0, 10, 21, or 52 ppm for 8 hours (nominal concentrations

of 0, 50, 200, or 400 ppm for 1 hour; 0, 20, 50, or 100 ppm for 4 hours; or 0, 10, 20, or50 ppm for 8 hours) (Kirkpatrick, 2008). All animals survived to study terminationexcept for one male exposed to 52 ppm for 8 hours that died the day after exposure.The rat that died had severe ulceration and degeneration of olfactory epithelium, mildhemorrhage and edema in the lungs, moderate to severe erosion of the epithelium inthe larynx and trachea, and severe ulceration of the epithelium in the larynx. Furtherdetails may be found in Section 3.2.1.

To calculate inhalation LC 50 values for allyl alcohol in rats, groups of 6, male, Long-Evans rats were exposed to 40-2300 ppm allyl alcohol (individual concentrations notgiven) for 1, 4, or 8 hours in a cylindrical glass chamber with a capacity of 19.5 liters

(Dunlap et al., 1958). Airflow was set at 8.6 to 12.9 L/min. The authors failed tomention a concurrent control group, and analysis of allyl alcohol vapor in the chamberrevealed that concentrations ranged from 15 to 25% less than nominal. Vaporconcentrations were analyzed by drawing a sample of air through distilled water, addingbromine in acetic acid in the presence of mercapturic acetate as a catalyst, reducing theexcess bromine with iodide, and then titrating the iodine with thiosulfate. Animals wereobserved for at least 10 days following exposure. The uncorrected 1, 4, and 8 hourLC50 values were 1060, 165, and 76 ppm, respectively. Because Dunlap et al. (1958)were interested in comparing the results of allyl alcohol toxicity in rats, rabbits, and micefollowing various exposure routes [inhalation (rats), intragastric administration (rabbit,mouse, rat), intraperitoneal injection (mouse, rat), and percutaneous (rabbits)], signs of

toxicity and pathology were not separated for the various exposure routes. Therefore, itwas not clear if some signs of toxicity were specifically related to inhalation exposure, orif the signs were independent of the method of exposure. The general signs of toxicityreported in rats were lacrimation and tremors, with coma preceding death. Grossnecropsy findings in both rats and rabbits (findings not separated for each) includedpulmonary edema and congestion, visceral congestion, and discolored liver.Microscopic examination of rats and rabbits showed liver damage ranging from:Acongestion of the periportal sinusoids to periportal necrosis, central pallor to centralnecrosis, @ and rat kidneys were swollen and discolored. The idea that toxic signs andpathology changes are not dependent upon the exposure route of allyl alcohol wassupported by the published abstract by Dunlap and Hine (1955). It was stated that allyl

alcohol-induced lesions, such as necrosis, hemorrhage, and discoloration of the liver,discoloration of the kidneys, and congestion and hemorrhage of the intestines, did notvary with the route of administration. However, eye and nose irritation with profuselacrimation was specifically noted with the single 1-hour inhalation exposures in rats(concentrations not given), from which the 1-hour LC 50 value of 1060 ppm was derived(also reported in Dunlap et al., 1958).

Six Sherman rats (sex not specified) were exposed to 1000 ppm allyl alcohol vaporfor 1 hour (no details about exposure conditions provided) and observed for 14 days for


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mortality (Smyth and Carpenter, 1948). Four of the six exposed rats died. Exposureconcentration was not confirmed by analytical methods, and no controls were used.

McCord (1932) exposed rats (sex and strain not given) to several concentrations ofallyl alcohol vapor for various time periods. Six rats (strain and sex not given) exposed

to 1000 ppm allyl alcohol died 3 hours into an intended 7-hour exposure. Results of thenecropsy were not stated directly, but were said to be similar to the findings in themonkey (Section 3.1.1) and rabbits (Section 3.1.4) following allyl alcohol exposure.(The primary findings in the rabbits and monkey were hemorrhage in the lungs,intestinal tract, bladder, and kidneys.) Four rats exposed to 200 ppm allyl alcohol for 7hours/day died on the first or second day of exposure, and necropsy revealed similarfindings. Four of five rats exposed to 50 ppm allyl alcohol for 7 hours/day died afterapproximately 30 days of exposure (it is inferred from the study description thatexposures were conducted 7 days/week until termination). Necropsy information wasnot given. No changes were observed in any of the control animals (number andtreatment of controls not given).

Union Carbide and Carbon Corporation (1951) tabulated the mortality results ofinhalation toxicity studies of allyl alcohol in rats. No information was given aboutcontrols, method of exposure, strain or sex of rats, analytic verification of concentration,or period of observation following exposure. The mortality results of the studies arepresented in Table 3.

TABLE 3. Summary of Lethality Data in Rats FollowingExposure to Allyl Alcohol

Concentration(ppm)

Time (h) Deaths

200 1 0/10

1000 0.5 1/6

1000 1 4/6

1000 2 6/6

Source: Union Carbide and Carbon Corporation, 1951.

In a series of three experiments, groups of 10 Long-Evans male rats were exposedto 1, 2, 5, 20, 40, 60, 100, or 150 ppm allyl alcohol vapor for 7 hours/day, 5 days/week,for a total of 60 exposures, and control groups were exposed to air (Dunlap et al.,1958). Analyses of the vapor concentrations at 40 ppm and greater were within 10% ofnominal concentrations (information on the measured concentrations of the lowerexposure concentrations not provided). Animals were observed daily and weighedweekly. At 90 days, the survivors were killed by decapitation and necropsied. Liver,kidney, and lungs from all animals were weighed and examined microscopically, whilethe thyroid, heart, thymus, pancreas, spleen, adrenal, testis, bladder and brain fromevery other animal were preserved for microscopic examination. Exposure to 1, 2, 5,and 20 ppm allyl alcohol failed to produce any clinical signs of toxicity or abnormal gross


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or microscopic findings, although the animals in the 20 ppm group experienced asignificant reduction in body weight gain. Rats exposed to 150 ppm exhibited gasping,severe depression, nasal discharge, and eye irritation. All of the 150 ppm rats died: fourdied during the first exposure, two following the first exposure, two during the secondexposure, and two by the tenth exposure. The two rats surviving to the tenth exposure

were lethargic, had red-rimmed eyes, and lost a third of their original body weight.Necropsy revealed hemorrhagic livers, pale and spotted lungs, and bloatedgastrointestinal tracts. Slight congestion of the liver and lungs were found duringmicroscopic evaluation. Rats exposed to 100, 60 or 40 ppm had similar but less intensesigns, lesions, and microscopic findings. Six of the ten rats in the 100 ppm group diedby 46 exposures, and the remaining rats were accidentally killed on exposure day 56.Gasping and muzzle rubbing occurred during the first few exposures to 60 ppm butdisappeared thereafter, and persistent eye discharge was noted throughout theexperiment. This group had statistically increased liver and kidney weight, and onedeath was recorded (date not given). All signs of irritation in animals exposed to 40ppm resolved after the first few exposures, but lung weight was statistically increased at

necropsy.

A laboratory report by Shell Chemical Corp (1957) appears to be the same study asthat published by Dunlap et al. (1958). Rats were exposed to 1, 5, 10, 20, 40, 60, 100,or 150 ppm allyl alcohol for a total of 60 eight-hour exposures over 90 days (informationon strain, sex, and number not given) (Shell Chemical Corporation, 1957). No adverseeffects were noted in animals exposed to 20 ppm or less. Decreased growth and mildto moderate lung congestion were noted in the 40 ppm group. Animals in the 60 ppmgroup developed pulmonary congestion and increased kidney and lung weight, and 1/10animals died. All animals exposed to 100 ppm died after 32 exposures and ratsexposed to 150 ppm died after 2 exposures.

3.1.3. Mice

Union Carbide and Carbon Corporation (1951) tabulated the mortality results ofinhalation toxicity studies of allyl alcohol in mice. No information was given aboutcontrols, method of exposure, strain or sex of mice, analytic verification ofconcentration, or the period of observation following exposure. The results of thestudies are presented in Table 4.

TABLE 4. Summary of Lethality Data in Mice FollowingExposure to Allyl Alcohol

Concentration(ppm)

Time (h) Deaths

200 1 0/10

500 0.5 0/10

500 1 4/10

1000 1 6/10


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1000 2 8/10

1000 4 10/10

Source: Union Carbide and Carbon Corporation, 1951.

Groups of 10 mice (strain and sex not given) exposed to concentrations of 2450 to26,000 ppm allyl alcohol died within a time range of 165 to 24 minutes, respectively(Shell Chemical Corporation, 1957). Before dying convulsively, all animals developedspastic paralysis of the extremities, particularly of the hindlimbs. Necropsy revealedirritation and inflammation of the respiratory tract and irritation and congestion of theliver, kidneys, and spleen. All mice (10/10) exposed to 22,000 ppm for 10 minutes died(no other details provided). No deaths resulted when mice were exposed to 12,200ppm for 10 minutes, but all died when exposed for another 10 minute period (period ofobservation and time between exposures not given). When mice were exposed daily to2450 ppm allyl alcohol for 10 minutes, 10% of the animals died by three exposures, and30% were dead after nine exposures. Necropsy revealed irritation and inflammation ofthe respiratory tract and congestion of the gastrointestinal tract. Mice repeatedlyexposed to 2450 ppm allyl alcohol developed severe eye and nose irritation.

3.1.4. Rabbits

When two rabbits (strain and sex not given) were exposed to 1000 ppm allyl alcohol,one died 3.5 hours into the exposure, and the other died 4.25 hours into the exposure(McCord, 1932). During exposure, the rabbits had rales, and fluid dripped from theirnoses and mouths. Pulmonary hemorrhage, hemorrhage and inflammation of theintestinal tract, bladder, and kidneys, and gaseous distention of the gastrointestinal tractwere noted in both rabbits during necropsy. One rabbit also had hemorrhaging of theeyes, opaque sclerae, and inflamed genitalia. In a second experiment, three rabbitswere exposed to 200 ppm allyl alcohol for 7 hours/day. Labored and noisy breathingand discharge from the nose and mouth were observed within one hour of exposure.One rabbit convulsed and died after three days exposure, a second rabbit died after sixdays of exposure, and the third died after 18 days of exposure. The noisy and laboredbreathing and oral and nasal discharge continued with the exposures. Necropsy of theanimals revealed findings similar to those described above. In a third experiment, tworabbits were exposed to 50 ppm allyl alcohol for 7 hours/day. One rabbit died after 14exposures, and the second was killed after 28 exposures. Necropsy of the two rabbitsrevealed findings similar to those described above. No changes were observed incontrol animals (number and treatment of control not given).

Union Carbide and Carbon Corporation (1951) also tabulated the mortality results ofinhalation toxicity studies of allyl alcohol in rabbits. No information was given aboutcontrols, method of exposure, strain or sex of rabbits, analytic verification ofconcentrations, or the period of observation following exposure. The mortalitiesresulting from acute exposures are as follows: 0/10 exposed to 200 ppm for 1 hour; 0/4exposed to 500 ppm for 2 hours, and 4/4 exposed to 500 ppm for 4 hours. The reportalso made the claim that exposure to 3400 ppm for 2 to 5 minutes will cause necrosis ofthe cornea of rabbits, but these data were not included.


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3.1.5. Guinea Pigs

Four guinea pigs were individually exposed in a bell jar, with allyl alcohol present in apetri dish below the jar (Adams 1958). The exact exposure concentrations were

unknown. One exposed guinea pig started to exhibit signs of irritation within twominutes of exposure, with lacrimation and exophthalmos developing soon thereafter.When the animal was removed after 30 minutes of exposure, marked lacrimation andexudation of serous fluid from the nose and mouth was noted, and the exophthalmoswas pronounced. The guinea pig died 50 minutes post exposure from respiratoryfailure. A second guinea pig was exposed in the bell jar until death, which occurred at55 minutes of exposure. Clinical signs included exophthalmos, lacrimation, and oraland nasal serous fluid exudate. A third guinea pig was exposed to allyl alcohol for 20minutes. This animal also developed exophthalmos with lacrimation and nasaldischarge. The animal died of respiratory failure 5 hours post exposure. A fourthguinea pig was exposed for 15 minutes and developed the same clinical signs as the

others, but recovered and was still alive 6 days post exposure.

3.2. Nonlethal Toxicity3.2.1. Rats

Groups of three Crl:CD(SD) rats/sex were exposed by whole body inhalation to allylalcohol concentrations of 423 ppm or 638 ppm for 1 hour, 114 ppm for 4 hours, and 52ppm for 8 hours (Kirkpatrick, 2008). Animals were examined for clinical signs 30minutes into the exposure (all animals), 1 hour into the exposure (animals exposed for 4and 8 hours), 4 hours into the exposure (animals exposed for 8 hours), and within 1hour of post exposure (all animals). Animals were observed for 6 days post exposure

and then sacrificed without further examination. Animals were observed twice daily formortality, body weight was recorded prior to exposure and on post exposure day 5, andclinical examinations were performed daily. All animals survived to study termination,and no adverse effects on body weight were noted. Clinical signs included gaspingduring and after exposure, labored respiration during exposure, and red and/or clearmaterial around the mouth or nose and reddened fore- and hindlimbs after theexposure. The reddened limbs were considered an alcohol flush reaction caused by thepresence of the aldehyde metabolite, acrolein. One male exposed to 114 ppm for 1hour exhibited a slight gait impairment at 1 hour-post exposure; gait impairment was notnoted in any other animals. A summary of the incidence of selected clinical signs ispresented in Table 5.

Table 5. Summary of Selected Clinical Observations in Rats Exposed to Allyl


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Alcohol up to 8 Hours

1 hr 4 hr 8 hrObservation

423

ppm

638

ppm

114

ppm

52 ppm

Number animals 6 6 6 6

Gasping: Total animals affected30 min into exposure1 hr into exposure1 hr post exposureRecovery period

20200

21010

41130

33000

Labored respiration: Total animalsaffected

8 hr into exposureRecovery period

0NA

0

0NA

0

0NA

0

22

0

Reddened forelimbs: Total animalsaffected

1 hr post exposureRecovery period

000

440

660

330

Reddened hindlimbs: Total animalsaffected


000

330

660

440

Material around mouth/nose: Totalanimals affected


330

550

440

212

Source: Kirkpatrick, 2008

Groups of five Crl:CD(SD) rats/sex were exposed by whole body inhalation to allylalcohol vapor at measured concentrations of 0, 51, 220, or 403 ppm for 1 hour; 0, 22,52, or 102 ppm for 4 hours; or 0, 10, 21, or 52 ppm for 8 hours (nominal concentrationsof 0, 50, 200, or 400 ppm for 1 hour; 0, 20, 50, or 100 ppm for 4 hours; or 0, 10, 20, or

50 ppm for 8 hours) (Kirkpatrick, 2008). Chamber concentrations were measured bygas chromatography at approximately 30-minute intervals for the 1-hour exposure, and60-minute intervals for the 4- and 8-hour exposures. Observations for clinical signswere performed 30 minutes into the exposure (all exposures), 1 hour into the exposure,(4- and 8-hour exposures) and 4 hours into the exposure (8-hour exposure). Near theend of the exposure, the response to a loud noise stimulus was tested by striking thecage. Clinical examinations, involving handling and open field arena observations, wereperformed immediately after the exposure, within an hour post exposure, twice on theday 1, and once daily until terminal sacrifice at day 13. Body weight was recorded on


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days 0, 1, 6, and 13. At sacrifice on study day 14, blood was collected for analyses ofhematology and clinical chemistry parameters; a complete gross necropsy wasperformed; liver, kidney and lung weights were recorded; and selected tissues (kidneys,larynx, liver, lungs, nasal tissues, trachea, and gross lesions) were processed andexamined for histopathological changes. All animals survived to study termination

except for one male exposed to 52 ppm for 8 hours. The rat died the day afterexposure, and death was attributed to ulceration of the respiratory and olfactoryepithelium in the nasal passages, resulting in diminished breathing capacity, hypoxiaand death. In the remaining rats surviving to study termination, no exposure-relatedchanges were observed in body weight, hematology or clinical chemistry parameters, orduring gross necropsy or histopathological examination of the kidney, liver or lungs.

Summaries of clinical signs and histopathological changes in the nasal cavities ofrats exposed to allyl alcohol for 1, 4, or 8 hours are presented in Tables 6 and 7,respectively.

Exposure to 51, 220, and 403 ppm allyl alcohol for 1 hour produced gasping in only1 female rat exposed to 403 ppm at 30 minutes of exposure (Kirkpatrick, 2008). Theincidences of alcohol flushing and material around the mouth exhibited a concentration-related increase at 220 and 403 ppm. A clear concentration-related response was notestablished in the novel stimulus/arousal response findings. Histopathologicalexamination of the nasal cavity revealed reversible changes. The incidence of chronicinflammation was increased at 202 and 403 ppm. Although the incidences ofdegeneration of the olfactory epithelium, metaplasia of olfactory epithelium, andhemorrhage did not follow a definitive concentration-related response, they wereconsidered to be related to exposure because they were not present in control animals.

In the 4-hour exposures, 22 ppm allyl alcohol resulted in minimal clinical signs; onlyone animal exhibited material around the mouth (Kirkpatrick, 2008). Exposure to 52and 102 ppm for 4 hours produced a concentration-related increase in the number ofanimals exhibiting gasping, alcohol flushing, material around the mouth, and a reducedresponse to cage stimulus, and an increased incidence of yellow material around theurogenital area was observed 1 hour post exposure in females exposed to 102 ppm.Histopathological examination of the nasal cavity revealed reversible changes, includingdegeneration of the olfactory and respiratory epithelium, chronic inflammation, andgoblet cell hyperplasia.

In the 8-hour exposures, clinical effects were minimal at 10 and 21 ppm and

included a few rats with reddened forelimbs and/or hindlimbs and a few with materialaround the mouth, and one rat at each concentration with yellow material around theurogenital area; one rat exposed to 21 ppm had rales/increased respiration (Kirkpatrick,2008). Exposure to 52 ppm for 8 hours produced gasping, increased respiration, andred material around the mouth, yellow material around the urogenital area (3/10 rats),and killed one male rat (this rat had gasping, rales and red material around the nose 1hour post exposure; and rales and red material around the mouth and noseapproximately seven hours before death). Reddened forelimbs were present in only afew animals. The clinical signs were generally noted 1-hour post exposure, and were


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resolved by the end of the recovery period. A concentration-related increase in thenumber of animals with a reduced response to cage stimulus was noted at 21 and 52ppm. Histopathological examination of the nasal cavity of rats exposed to 10 or 21 ppmrevealed reversible changes including degeneration of the olfactory and respiratoryepithelium, chronic inflammation, and goblet cell hyperplasia. Exposure to 52 ppm

produced similar but generally more severe lesions. Two rats (including the one thatdied) developed severe irreversible changes. The rat that died had severe ulcerationand degeneration of olfactory epithelium, mild hemorrhage and edema in the lungs,moderate to severe erosion of the epithelium in the larynx and trachea, and severeulceration of the epithelium in the larynx. Another male rat had severe, irreversiblemetaplasia of olfactory epithelium and severe ulceration of olfactory epithelium, alongwith the degeneration and subacute inflammation seen in almost all high-concentration-group rats.


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TABLE 6. Summary of Clinical Signs in Rats Exposed to Allyl Alcohol for 1, 4, or 8 Hours

Concentration (ppm)

1 hr 4 hr Endpoint

0 51 220 403 0 22 52 102

n 10 10 10 10 10 10 10 10 10

Clinical signs; TotalGaspingRales/increased respirationReddened forelimbsReddened hindlimbsReddened earsRed/clear material around mouth

000000

001100

008703

109945

000000

000001

1 02203

6 07608

Clinical signs; 1-h post exposure:GaspingRales/increased respirationReddened forelimbsReddened hindlimbsReddened earsRed/clear material around mouth

000000

001100

008703

009945

000000

000001

1 02203

5 07608

Response to cage stimulusNo reactionSlight reactionEnergetic response (jump/vocalization)

280

0100

640

370

0100

0100

280

442

Source: Kirkpatrick, 2008


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TABLE 7. Summary of Selected Nasal Histopathological Findings in Rats Exposed to Allyl Alcohol for 1, 4, or 8 Hours

Concentration (ppm)

1 hr 4 hr Endpoint

0 51 220 403 0 22 52 102

n 10 10 10 10 10 10 10 10

Degeneration, olfactory epithelium (total)MinimalMildModerateSevereSevere, irreversible

0-----

202000

101000

320100

0-----

0-----

220000

10352 00

Inflammation, chronic and subacute (total)MinimalMild

Moderate

312

0

220

0

412

1

926

1

0--

-

724

1

713

3

806

2

Hyperplasia, goblet cell (total)MinimalMildModerate

1010

2110

2020

1010

0---

1010

5230

4112

Degeneration, respiratory epithelium (total)MinimalMildModerate

0---

0---

0---

0---

0---

0---

1100

2020

Metaplasia, olfactory epithelium (total)Mild

Severe, irreversible

0-

-

11

0

0-

-

0-

-

0-

-

0-

-

0-

-

0-

-Source: Kirkpatrick, 2008a Summary of number of animals with lesion taking into account all 6 nasal levels; grade for each lesion is the highest grade for any of thb Results for the rat that died are included; other effects in 52 ppm group males not in the Table include two with severe, irreversible ulcewith severe erosion of the olfactory epithelium


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3.2.2. Mice Groups of four male Ssc:CF-1 mice were exposed to 0.42, 2.00, 4.55, or 18.10 ppm

allyl alcohol for 30 minutes to determine the RD 50 for sensory irritation (Nielsen et al.,1984). RD 50 values represent the concentration of an airborne sensory irritant thatproduces a 50% reduction in the respiratory rate, the decreased respiratory rate being

caused by stimulation of the trigeminal nerve in the nasal mucosa. The animals wereplaced in a body plethysmograph attached to an exposure chamber such that theanimal =s head protruded into the chamber. Animals in the chambers were observed for5 to 15 minutes to establish a baseline respiratory rate before beginning exposure toallyl alcohol. An RD 50 value of 3.9 ppm (95% C.I.: 2.4-6.5 ppm) was determined basedon the maximum decrease in respiratory rate within the first 10 minutes of exposure,and another value of 4.8 ppm (95% C.I.: 2.7-10.2 ppm) was given for the mean for thelast 10 minutes (exposure during the last 21-30 minutes). The onset of decreasedrespiratory rate occurred rapidly, plateaued within 10 minutes of exposure, and quicklysubsided following termination of the exposure. Although studies investigatingintravenous administration of allyl alcohol demonstrated that conversion of allyl alcohol

to acrolein is required to produce systemic toxicity (Patel et al., 1983; Serafini-Cessi,1972), this study did not find evidence of such a conversion in that there was no delay inappearance, development, or resolution of the irritant response. However, no empiricaldata on allyl alcohol rates or extent of metabolism by pulmonary tract tissues werepresented. To determine if allyl alcohol produced pulmonary irritation at levelsproducing sensory irritation, concurrent exposures of tracheally cannulated mice to allylalcohol were performed. These exposures did not reveal any pulmonary irritationoccurring at the RD 50 concentration producing sensory irritation.

James et al. (1987) reported an RD 50 of 2.5 ppm allyl alcohol (2.0-3.2) for male ICRmice. Because the authors utilized allyl alcohol to verify their experimental system with

that of already published methods, no specific information about the generation of theallyl alcohol RD 50 was given. Thus, it is inferred that the method used was the same asthat given for the actual test compound, methylisocyanate vapor. Exposures wereperformed in glass exposure chambers, and vapor concentrations were measured by agas analyzer. Animals were observed in the chambers for 10 minutes to establish abaseline respiratory rate, and it is assumed the animals were then exposed to allylalcohol for 30 minutes.

Groups of ten male Swiss OF 1 mice were exposed to 2.4 or 6.4 ppm allyl alcohol for6 hours/day for 4 days; 6 hours/day for 9 days (5 consecutive days the first week, 4consecutive days the second week); or for 6 hours/day, 5 days/week for 2 weeks (Zissu,

1995). The target (nominal) concentrations were based on an RD 50 value of 1.6 ppm,and 3 times the RD 50 value of 4.8 ppm. Groups of 5 mice were used for controls.Histopathological examination of animals following the respective exposure durationsrevealed that lesions of the upper respiratory tract epithelium (hyperplasia, inflammatoryinfiltrates, and desquamation of epithelial cells) and olfactory epithelium (a slight loss ofisolated sensory cells) developed in the 2.4 and 6.4 ppm groups. The lesions weremost severe in the group exposed for 4 days, becoming less severe in the animalsexposed for longer periods. No pathologic changes were noted in the trachea or lungsof exposed animals. The target RD 50 of 1.6 was chosen from a published review (Bos


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et al., 1992) that summarized sensory irritation data for a large number of chemicals.The original reference (Muller and Greff, 1984) investigated the correlation betweenselected physio-chemical parameters and sensory irritation for four chemical groups.

3.2.3. Dogs, Guinea Pigs, and Rabbits

Groups of 12 male and 12 female rats, 9 male and 9 female guinea pigs, and 3 maleand 3 female rabbits were exposed to 7 ppm (range of 6.6-7.1 ppm) allyl alcohol vaporfor 28 seven-hour periods, to 2 ppm (range of 0.6-3.2 ppm) allyl alcohol vapor for 127-134 seven-hour periods, to control air, or were used as unexposed controls (Torkelsonet al., 1959a; methods reported in Torkelson et al., 1959b). One male and one femalebeagle dog each were exposed to 2 ppm allyl alcohol, air, or were used as unexposedcontrols. All exposures were conducted for 7 hours/day, 5 days/week. None of theanimals exposed to 7 ppm exhibited any clinical signs of toxicity or changes in body ororgan weight, but microscopic examination found mild and reversible liver and kidneydegeneration in almost all animals. Livers had dilation of the sinusoids, cloudy swelling,

and focal necrosis, and kidneys showed epithelial necrosis in the convoluted tubules,proliferation of the interstitial tissue, and changes similar to those seen inglomerulonephritis. Animals exposed to 2 ppm allyl alcohol vapor exhibited nomeasurable adverse effects as judged by clinical signs, mortality, body or organ weight,or gross and microscopic examination of tissues (noses not examined). (The specieswere not separated in this AEGL document because the species could not bedistinguished among the data provided).

3.3. Developmental/Reproductive Effects

No developmental/reproductive inhalation toxicity data concerning allyl alcohol were

found in the searched literature.


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3.4. Genotoxicity

Allyl alcohol tested mutagenic in cultured V79 cells using 6-thioguanine resistanceas the measure of mutagenicity (Smith et al., 1990). At doses of 1 and 2 u M, thenumber of mutants/10 6 survivors were 14 " 8 and 37 " 12, respectively, values similar

to those produced by acrolein (Smith et al., 1990). A positive test was obtained in amodified Ames assay (tester strain TA100) without metabolic activation (750revertants/ u mole), but the mutagenic activity was greatly reduced with metabolicactivation (approximately150 revertants/ u mole) (Lutz et al., 1982). It has beensuggested that bacterial alcohol dehydrogenase converts allyl alcohol to acrolein, whichmay be responsible for the mutagenic activity, and that the addition of the S9 mixinactivates acrolein by binding of the metabolite by the amino and sulfhydryl groupspresent in the mix (Lutz et al., 1982). Allyl alcohol tested positive for mutagenesis atconcentrations of 50-300 u g/plate in the Salmonella tester strain TA1535 in thepresence of hamster S9, but not in the presence of rat S9, and was cytotoxic at aconcentration of 500 g/plate (Lijinsky and Andrews, 1980). Allyl alcohol was not

mutagenic in strains TA1537, TA1538, TA98, or TA100 in the presence or absence ofrat or hamster S9 (Lijinsky and Andrews, 1980). Bignami et al. (1977) reported that allylalcohol failed to increase the numbers of revertants in Salmonella typhimurium strainsTA1535, TA100, TA1538, and TA98 (details not given), and allyl alcohol did not inducepoint mutations in Aspergillus nidulans .

3.5. Carcinogenicity

At this time, there are not enough data to provide a quantitative assessment of thecarcinogenic potential of allyl alcohol. Allyl alcohol has not been classified as tocarcinogenicity by the U.S. EPA or by IARC. No evidence of carcinogenicity was found

in a study in which male and female F344 rats were administered 300 mg allyl alcohol/Lin drinking water for 106 weeks, or when 20 male Syrian golden hamsters weregavaged with 2 mg allyl alcohol in corn oil once a week for 60 weeks (Lijinsky andReuber, 1987). The median time to death and incidence of tumors was comparable intreated animals compared to controls. Further details, such as body- and organ-weightchanges, were not provided in this study.

Although no data are available to assess the potential for allyl alcohol to causecancer, some of its metabolites are recognized carcinogens. The U.S. EPA (1991) hasclassified glycidaldehyde as a probable human carcinogen (B2) based upon anincreased incidence of malignant tumors in rats and mice following subcutaneous

injection of glycidaldehyde and of skin carcinomas following dermal application to mice.Acrolein is classified as a possible human carcinogen (C) based upon an increasedincidence of adrenal cortical adenomas in female rats exposed via drinking water, andthe carcinogenic potential of an acrolein metabolite (U.S. EPA, 1994).


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3.6. Summary

A summary of acute animal lethality data is found in Table 8, and summaries ofacute and repeat-exposure nonlethality data in animals are found in Tables 9 and 10,respectively.

Rats survived exposure to allyl alcohol at concentrations of 423 ppm or 638 ppm for1 hour, 114 ppm for 4 hours, or 52 ppm for 8 hours (Kirkpatrick, 2008). Clinical signs inall exposure groups included gasping during and after exposure, and material aroundthe mouth/nose and alcohol flushing after the exposure. Two rats exposed to 52 ppmfor 8 hours exhibited labored respiration during exposure. In another study, rats wereexposed to allyl alcohol vapor at concentrations of 51, 220, or 403 ppm for 1 hour; 22,52, or 102 ppm for 4 hours; or 10, 21, or 52 ppm for 8 hours (Kirkpatrick, 2008). Allanimals survived to study termination except for one male rat exposed to 52 ppm for 8hours. Reversible histopathological changes were observed in the nasal cavity ofexposed rats, and clinical signs included material around the mouth, alcohol flushing,

and gasping. Exposure to higher concentrations at each duration generally resulted inincreased incidences of clinical signs and histopathological changes in the nasal cavity.Other data on nonlethal, single inhalation exposures to allyl alcohol were limited to two

RD50 studies in mice, in which RD 50 values of 3.9 ppm and 2.5 ppm were given (Nielsenet al., 1984; James et al., 1987). A few studies investigating the effects of repeatedinhalation exposure in animals were available. One study found histopathologicallesions in the upper respiratory tract epithelium and olfactory epithelium of micefollowing exposure to 2.4 ppm for 6 hours/day for 4 days, and the lesions decreased inseverity in groups exposed for 9 days or 2 weeks (Zissu, 1995). Repeated inhalationexposures in rats to 1, 2, 5, or 20 ppm produced no gross toxicity, but repeatedexposures to 40 ppm resulted in transient irritation and increased lung weight (Dunlap et

al., 1958). Repeated inhalation exposure in rats, guinea pigs, rabbits, and dogsresulted in no measurable adverse effects following 28, seven-hour exposures to 2 ppm(Torkelson et al., 1959a). Rats, guinea pigs, and rabbits exposed to 7 ppm for 127-134seven-hour exposures exhibited only mild and reversible microscopic liver and kidneydamage.

Other acute animal toxicity animal data focused on lethality. Mice, rats, and rabbitssurvived exposure to 200 ppm for 1 hour; mice survived exposure to 500 ppm for 0.5hours, but not 1 hour; and rabbits survived a 2-hour but not a 4-hour exposure to 500ppm (Union Carbide and Carbon Corporation, 1951). Exposure to 1000 ppm for as littleas 0.5 hours up to 4 hours killed monkeys, mice, rats, and rabbits (McCord, 1932; Union

Carbide and Carbon Corporation, 1951; Smyth and Carpenter, 1948). The only LC 50 values available were based upon target concentrations, and were unreliable as Dunlapet al. (1958) stated that actual concentrations ranged from 15-25% less than targetconcentrations. The uncorrected LC 50 values in rats were 1060 ppm for 1 hour, 165ppm for 4 hours, and 76 ppm for 8 hours. Repeated exposures of rats to 60, 100, or150 ppm for 7 hours/day, 5 days/week, for 60 exposures resulted in mortality.


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No data were available regarding inhaled allyl alcohol as a developmental orreproductive toxicant. Allyl alcohol was genotoxic in prokaryotic systems. No relevantdata were available to assess the potential for inhaled allyl alcohol to cause cancer.

TABLE 8. Summary of Acute Lethal Inhalation Data in Laboratory Animals

SpeciesConc.(ppm)

ExposureTime (h) Effect Reference

Monkey 1000 4 1/1 died McCord, 1932

Mouse 200 1 0/10 died Union Carbide and Carbon Corporation,1951

Mouse 500 0.51

0/10 died4/10 died

Union Carbide and Carbon Corporation,1951

Mouse 1000 124

6/10 died8/10 died10/10 died


Mouse 22,00012,200

10 min2 x 10 min

10/10 died:10/10 died after second exp.

Shell Chemical Corporation, 1957

Rat 106016576

148

LC50 Dunlap et al., 1958; Dunlap and Hine, 1955

Rat 63842311452

1148

No deaths (n=6) Kirkpatrick, 2008

Rat 51220403

1 No deaths (n=10) Kirkpatrick, 2008

Rat 2252102

4 No deaths (n=10) Kirkpatrick, 2008

Rat 102152

8 0/10 died0/10 died1/10 died

Kirkpatrick, 2008

Rat 200 1 0/10 died Union Carbide and Carbon Corporation,1951

Rat 1000 0.51

2

1/6 died4/6 died

6/6 died


Rat 1000 1 4/6 died Smyth and Carpenter, 1948

Rat 100020050

32 x 7 h7h/d, 30 d

6/6 died during exposure4/4 died by end of 2ndexposure4/5 died

McCord, 1932

Rat 60100150

7h/d,5d/wk, for60 exp.

1/10 by 60 th exposure6/10 by 56 th exposure10/10 by 10 th exposure

Dunlap et al., 1958


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TABLE 8. Summary of Acute Lethal Inhalation Data in Laboratory Animals

Rabbit 200 1 0/10 died Union Carbide and Carbon Corporation,1951

Rabbit 500 24

0/4 died4/4 died


Rabbit 1000 3.54.25

1/1died1/1 died

McCord, 1932

TABLE 9. Summary of Acute Nonlethal Inhalation Data in Laboratory Animals

Species ExposureDuration

Conc.(ppm)

Effects References

Mouse 10 min 3.9 RD 50 Nielsen et al., 1984

Mouse 10 min 2.5 RD 50 James et al., 1987

Rat 1148

63842311452

Gasping, flushing a , material aroundmouth/noseGasping, material around mouth/noseGasping, flushing, material around mouth/noseGasping, labored respiration, flushing, materialaround mouth/nose

Kirkpatrick, 2008

51 Some flushing; Nose: olfactory degenerationand inflammation

220 Same as above (more affected), plus materialaround mouth/nose

Rat 1

403 Same as above (more affected), plus gasping,

Kirkpatrick, 2008

22 1 w/ material around mouth/nose; Nose:inflammation

52 Same as above (more affected) plus gasping,some flushing, reduced reaction; Nose:olfactory/respiratory degeneration

Rat 4

102 Same as above (more affected) plus Nose:respiratory degeneration

Kirkpatrick, 2008

10 1 w/ flushing; material around mouth/nose

21 Same as above (more affected) plus someincreased respiration and flushing; Nose:olfactory degeneration and inflammation

Rat 8

52 1/10 died; gasping; irreversible nasal histopath

Kirkpatrick, 2008

a Flushing characterized by reddened limbs/ears considered an alcohol flush reaction caused by the presenceof the aldehyde metabolite, acrolein


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TABLE 10. Summary of Repeat-Exposure Nonlethal Inhalation Data inLaboratory Animals

Species Exposure

Duration

Conc.(ppm)

Effects References

Mouse 6h/d, 4 d 2.4 Histopathological changes inupper respiratory tract epithelium(hyperplasia, inflammatoryinfiltrates, desquamation) andolfactory epithelium (slight loss ofisolated sensory cells)

Zissu, 1995

Rat 7h/d,5d/wk,60 exp.

12520

No observable adverse effectsNo observable adverse effectsNo observable adverse effectsReduced body weight gain

Dunlap et al.,1958

Rat 7h/d,5d/wk,for 90 d

40 Irritation (gasping, eye irritation,nasal discharge) disappeared afterfirst few exposures; increased lungweight

Dunlap et al.,1958

Rat 7 h/d,5d/wk,for 90 d

60 Irritation: gasping and muzzlerubbing first few exposures thatdisappeared thereafter; persistent

eye discharge; increased lung andkidney weight; 1/10 died after 4exp.

Dunlap et al.,1958

Rat, Guineapig, Rabbit

7h/d,5d/wk,127-134exp.

7 Liver lesions: degeneration,dilation of sinusoids, cloudyswelling, focal necrosisRenal lesions: degeneration,epithelial necrosis in convolutedtubules, proliferation of

Torkelson etal., 1959a

Rat, Guineapig, Rabbit,Dog

7h/d,5d/wk,28 exp.

2 No adverse effects Torkelson etal., 1959a


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4. SPECIAL CONSIDERATIONS 4.1. Metabolism and Mechanism of Toxicity

Signs of toxicity in animals following acute and repeated inhalation exposure to allylalcohol include lacrimation, pulmonary edema and congestion, gasping, alcohol

flushing, material around the nose and/or mouth, and labored breathing.Histopathological examination of rats following acute exposure to allyl alcohol revealednasal lesions which progressed in incidence and severity with increasing duration andconcentration, ultimately resulting in death due to reduced breathing capacity(Kirkpatrick, 2008). This is in contrast to the findings by McCord (1932) of pulmonarycongestion leading to edema and compensatory emphysema, with degeneration of thecells in the convoluted tubules of the kidney, liver, myocardium, ganglion cells of thespinal cord, and retina.

Attention has been focused on the mode of action by which oral or parenteral allylalcohol causes periportal necrosis in liver. It appears that this effect is more apt to

occur after oral, intraperitoneal, or intravenous administration. Studies on themechanism of allyl alcohol-induced liver necrosis and covalent binding to livermacromolecules disclosed that metabolism of allyl alcohol to the reactive metaboliteacrolein is required (Serafini-Cessi, 1972; Patel et al., 1983). This reaction is mediatedby the cytosolic liver enzyme alcohol dehydrogenase (ADH) in the presence of NAD +.The importance of ADH activity was exemplified in a study in which an ADH-negativestrain of deer mice was resistant to allyl alcohol toxicity, while the ADH-positive strain ofdeer mice exhibited dose-dependent necrosis of periportal regions of the liver andincreased plasma levels of lactate dehydrogenase, sorbitol dehydrogenase, and SGOTactivity 24 hours post i.p. exposure (Belinsky et al., 1985). Another study found that oldmale rats were more susceptible to allyl alcohol-induced hepatotoxicity than were

young, adult, male rats because old rats had increased ADH activity (Rikans andMoore, 1987). Acrolein can be detoxified to acrylic acid by further metabolism byaldehyde dehydrogenase or by conjugation with glutathione (GSH) (Rikans, 1987;Rikans and Moore, 1987). Depletion of glutathione can therefore enhance toxicity.Hormann et al. (1989) propose that inactivation of thiol groups is critical for allyl alcoholhepatotoxicity based on a study in which isolated rat hepatocytes exposed to allylalcohol exhibited an initial rapid depletion of glutathione, followed by an increase inmalondialdehyde, a decrease in protein sulfhydryl groups, and eventual loss ofmembrane integrity. When sulfhydryl compounds were added to the hepatocytes,however, hepatocytes were protected against cytotoxicity. Because mechanisticstudies have reported that allyl alcohol-induced hepatotoxicity is also oxygen

dependent, further experiments were conducted to elucidate which cell types areinvolved. It was determined that the presence of Kupffer cells is required to produceO2-dependent hepatic necrosis (Przbocki et al., 1992).

Because one primary route of allyl alcohol exposure is inhalation, Patel et al. (1980)compared the metabolism of allyl alcohol in lung and liver preparations from maleHoltzman rats. In the lungs, allyl alcohol was rapidly epoxidized to glycidol, and thenfurther metabolized to glycerol, most likely by the action of epoxide hydrase. Allylalcohol was not metabolized to the reactive metabolite acrolein because rat lungs do


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not contain appreciable ADH activity. Likewise, the amount of ADH activity in humanlungs is only a small percentage of the ADH activity in liver: one study reported humanlung ADH activity ranged from 1 to 8% of the ADH activity measured in liver (Moser etal., 1968). No study was available on the capability of rodent nasal and oral epithelialtissues to convert allyl alcohol to acrolein. It is currently not known if the parent alcohol

is a direct irritant, or if conversion to the acrolein metabolite is required to produceirritation. Liver preparations metabolized allyl alcohol to acrolein, acrylic acid,glycidaldehyde, and glyceraldehyde. It is not likely that much glycidol and glycerolwould be produced in the liver, as most of the hepatic allyl alcohol delivered dose wouldbe converted to acrolein.

No quantitative information was available on systemic absorption and distribution ofallyl alcohol following inhalation exposure. Although studies investigating intravenousadministration of allyl alcohol demonstrated that conversion of allyl alcohol to acroleinwas required to produce toxicity, the study by Nielsen et al. (1984) did not find evidenceof such a conversion occurring: there was no delay in the appearance, development, or

disappearance of the measured irritant response in mice. The in vitro study by Patel etal. (1980) demonstrated that the lungs will not metabolize allyl alcohol to the reactivemetabolite acrolein, and it is not known how much of the allyl alcohol will be distributedto the liver where the metabolic conversion will occur. The study investigating lungpathology in mice following repeated exposure to an RD 50 concentration did notinvestigate whether any pathologic changes had occurred in other organs such as theliver and kidney (Zissu, 1995). Therefore, it is not known if inhalation exposure to lowerconcentrations of allyl alcohol will produce toxicity confined in the lungs, or if somesystemic toxicity will also be produced. It should again be noted that subchronicexposure in rats, guinea pigs, and rabbits to 2 ppm allyl alcohol did not result in anymeasurable adverse effects (Torkelson, 1959a).

4.2. Structure-Activity Relationships

Groups of four male Ssc:CF-1 mice were exposed by inhalation to allyl acetate, allylalcohol, allyl ether, or acrolein to evaluate the sensory and pulmonary irritation ofpropene derivatives (Nielsen et al., 1984). The four propene derivatives did not varymuch in their ability to elicit sensory irritation as assessed by RD 50 measurements: theRD50 s were 2.9, 3.9, 5.0, and 2.9 ppm, respectively. However, when the potency wasexpressed in terms of the thermodynamic activity, acrolein was ten times more potentthan the other three derivatives. Further experiments in which tracheally cannulatedmice were exposed to the respective RD 50 concentrations of the propene derivatives did

not reveal any pulmonary irritation occurring at the RD 50 concentration.

A number of studies investigating a homologous series of nonreactive alcoholsdemonstrated that both the odor and nasal pungency thresholds and eye irritationthresholds in normosmics and nasal pungency thresholds in anosmics decreased withincreasing chain length (Cometto-Muniz and Cain, 1990; 1993; 1994; 1995). Althoughquantitative structure-activity relationship (QSAR) equations have been developed topredict nasal pungency, a condition of the equations is that the volatile organiccompounds must be nonreactive (Abraham et al., 1996; 1998). Allyl compounds are


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reactive and are specifically excluded. If one uses the algorithm to predict the potencyof a reactive compound, the predicted minimum potency will be less than the observedpotency.

4.3. Susceptible Populations

Exposure to high concentrations of inhaled allyl alcohol can produce pulmonarycongestion, edema and compensatory emphysema, so it is likely that those withpulmonary conditions would be at increased risk (McCord, 1932). Allyl alcohol exposurecan result in hepatotoxicity, so individuals with compromised liver function may also beat an increased risk. More specifically, variations in the amount of ADH or glutathionewill influence the extent of hepatotoxicity. This is due to the fact that allyl alcohol-induced hepatotoxicity is dependent on conversion of allyl alcohol to acrolein by ADH(Serafini-Cessi, 1972; Patel et al., 1983). Acrolein is then detoxified by furthermetabolism to acrylic acid by aldehyde dehydrogenase or by conjugation withglutathione (Rikans, 1987; Rikans and Moore, 1987). Hepatic damage can also be

influenced by bacterial infections, as demonstrated in a study reporting that allyl alcohol-treated rats pretreated with bacterial endotoxin experienced enhanced hepatic damagecompared to rats given allyl alcohol alone (Sneed et al., 1997).

4.4. Concentration-Exposure Duration Relationship

The experimentally derived exposure values are scaled to AEGL time frames usingthe concentration-time relationship given by the equation C n x t = k , where C =concentration, t = time, and k is a constant. The values of the exponent n generally arein the range of 1-3.5, and Ashould always be derived empirically from acute inhalationtoxicity experiments, in which both the concentration and exposure period are variables @

(ten Berge et al., 1986). For the AEGL-3 derivation, the LC 01 estimates at each AEGLtime frame were calculated by the ten Berge software program using all availableindividual rat mortality data (see Appendix B); the ten Berge program estimated ann=0.95 for time scaling. For the AEGL-1 derivation, the 1-, 4-, and 8-hour values werebased upon the empirical data at the respective durations. The default value of n = 3was used to time scale the 1-hour AEGL-1 point of departure to 10 and 30 minutes.Although the effect of mild irritation is generally not scaled across time, the empiricaldata indicate a time-response relationship for allyl alcohol-induced nasal irritation. Thedefault value of n was used instead of the n value derived from the rat lethality databecause of the uncertainty in using an n value derived from lethality to timescale theendpoint of mild irritation.

5. DATA ANALYSIS FOR AEGL-1 5.1. Human Data Relevant to AEGL-1

Human volunteers exposed to allyl alcohol for 5 minutes reported olfactoryrecognition at the lowest concentration of 0.78 ppm (5/6 subjects) (Dunlap et al., 1958).Nasal irritation was reported as slight in 2/6 subjects exposed to 0.78 ppm and 3/6

subjects exposed to 6.25 ppm for 5 minutes. Moderate or greater nasal irritation wasreported in 1/6 subjects exposed to 6.25 ppm for 5 minutes, by 4/7 volunteers exposed


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to 12.5 ppm, and in all five subjects exposed to 25 ppm. Slight eye irritation was notedby 1/6 and 1/7 individuals exposed to 6.25 or 12.5 ppm for 5 minutes, respectively,while severe eye irritation was reported by all five volunteers at 25 ppm for 5 minutes.The human data were not used for the AEGL derivation because of the extremely shortexposure duration and uncertainties in the exposure. Although humans reported severe

eye irritation at 25 ppm for 5 minutes, rats exposed to 600 ppm for 1 hour did not exhibitany signs of eye irritation (Dunlap et al., 1958; Kirkpatrick, 2008). It is possible that theeye irritation noted by the human volunteers was the result of acrolein contamination.

5.2. Animal Data Relevant to AEGL-1

Exposure to 51 ppm allyl alcohol for 1 hour, 22 ppm for 4 hours, or 10 ppm for 8hours produced reversible histopathological changes in the nasal cavity of rats,including degeneration of the olfactory epithelium, chronic inflammation, and goblet cellhyperplasia (Kirkpatrick, 2008). Clinical signs were limited to material around the mouth

and alcohol flushing. Exposure to higher concentrations at each duration resulted inincreased incidences of the histopathological changes in the nasal cavity, gasping, andreduced reaction to cage stimulus.

5.3. Derivation of AEGL-1

The AEGL-1 values are based upon nasal irritation as indicated by reversible nasalinflammation observed histologically in rats 14 days after exposure to 51 ppm allylalcohol for 1 hour; 22 ppm for 4 hours, or 10 ppm for 8 hours (Kirkpatrick, 2008). Thesevalues represent no effect levels for notable discomfort, as no clinical signs of nasal

irritation were observed at these concentrations. A total uncertainty factor of 10 wasapplied. An intraspecies uncertainty factor of 3 and interspecies uncertainty factor of 3were applied because allyl alcohol is highly irritating and corrosive, and much of thetoxicity is likely caused by a direct chemical effect on the tissues; this type of port-of-entry effect is not expected to vary greatly among individuals or among species. For theAEGL derivation, the 1-, 4-, and 8-hour values were based upon the empirical data atthe respective durations. The default value of n = 3 was used to time scale the 1-hourAEGL-1 point of departure to 10 and 30 minutes. Although the effect of mild irritation isgenerally not scaled across time, the empirical data indicate a time-responserelationship for allyl alcohol-induced nasal irritation. The default value of n was usedinstead of the n value derived from the rat lethality data because of the uncertainty in

using an n value derived from lethality to timescale the endpoint of mild irritation.

AEGL-1 values are presented in Table 11.


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TABLE 11. AEGL-1 Values for Allyl Alcohol [ppm(mg/m 3)]

Classification 10-min 30-min 1-hr 4-hr 8-hr

AEGL-1 9.3 (23) 6.4 (15) 5.1 (12) 2.2 (5.3) 1.0 (2.4)


Human volunteers exposed to allyl alcohol for 5 minutes reported slight nasalirritation in 2/6 subjects exposed to 0.78 ppm and 3/6 subjects exposed to 6.25 ppm(Dunlap et al., 1958). Moderate or greater nasal irritation was reported in 1/6 subjectsexposed to 6.25 ppm, by 4/7 volunteers exposed to 12.5 ppm, and in all five subjectsexposed to 25 ppm. Slight eye irritation was noted by 1/6 and 1/7 individuals exposedto 6.25 or 12.5 ppm for 5 minutes, respectively, while severe eye irritation was reportedby all five volunteers at 25 ppm for 5 minutes. The human data were not used for theAEGL derivation because of the extremely short exposure duration and uncertainties inthe exposure. Although humans reported severe eye irritation at 25 ppm for 5 minutes,rats exposed to 600 ppm for 1 hour did not exhibit any signs of eye irritation (Dunlap etal., 1958; Kirkpatrick, 2008). It is possible that the eye irritation noted by the humanvolunteers was the result of acrolein contamination.


Rats were exposed to allyl alcohol vapor at concentrations of 0, 51, 220, or 403 ppmfor 1 hour; 0, 22, 52, or 102 ppm for 4 hours; or 0, 10, 21, or 52 ppm for 8 hours(Kirkpatrick, 2008). In rats exposed to allyl alcohol for 1 hour, 51 ppm produced minimaleffects, and 220 ppm and 403 ppm resulted in concentration-related increases inalcohol flushing, material around the mouth, and chronic inflammation in the nasalcavity. Olfactory epithelium degeneration and goblet cell hyperplasia were present inone to three rats at all exposure concentrations, and one rat exposed to 403 ppmexhibited gasping during the exposure. In rats exposed for 4 hours, 22 ppm producedmaterial around the mouth in one rat, goblet cell hyperplasia in one rat, and chronicinflammation in the nasal cavity; 52 and 102 ppm generally resulted in concentration-related increases in alcohol flushing, material around the mouth, gasping, reducedresponse to cage stimulus, and olfactory and respiratory epithelium degeneration,chronic inflammation in the nasal cavity, and goblet cell hyperplasia. In the 8-hourexposures, clinical effects were minimal at 10 and 21 ppm (a few rats had alcoholflushing, material around the mouth, and one rat at each concentration had yellowmaterial around the urogenital area; one rat at 21 ppm had rales/increased respiration),while 52 ppm killed one rat. A concentration-related increase in the number of animalswith a reduced response to cage stimulus was noted at 21 and 52 ppm.Histopathological examination of the nasal cavity of rats exposed to 10 or 21 ppmrevealed reversible changes including degeneration of the olfactory and respiratoryepithelium, chronic inflammation, and goblet cell hyperplasia. Exposure to 52 ppmproduced similar but generally more severe lesions.


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Other inhalation data were not appropriate for an AEGL derivation. Because thestandard RD 50 testing protocol calls for the use of male Swiss-Webster mice only (Alarieet al., 1981; ASTM, 1991), the RD 50 values reported for allyl alcohol (Nielsen et al.,1984: male Ssc:CF-1 mice; James et al., 1987: male ICR mice; Zissu, 1995: male Swiss

OF 1 mice) were not appropriate to use as a basis for an AEGL derivation. Repeated 7-hour exposures of rats to 20, 40, or 60 ppm allyl alcohol resulted in no measurableadverse effects at 20 ppm, irritation which resolved after the first few exposures andincreased lung weight at 40 ppm, and irritation (gasping and muzzle-rubbing) whichdisappeared after the first few exposures, persistent eye discharge, and one death at 60ppm (Dunlap et al., 1958

6.3. Derivation of AEGL-2

Two rats exposed to 51 ppm for 8 hours developed severe, irreversible nasal lesions(Kirkpatrick, 2008). The AEGL-2 values could be based on the highest no-effect level

for irreversible nasal histopathological lesions of 403 ppm for 1 hour, 102 ppm for 4hours, and 21 ppm for 8 hours; however, these concentrations are similar to thecalculated LC 01 values used for the AEGL-3 derivations. The data for irreversible nasallesions were insufficient for analyses by the ten Berge software or by benchmark dosebecause there is only one data point with a non-zero response.

No other empirical data meeting the definition of an AEGL-2 endpoint wereavailable; therefore, the AEGL-3 values were divided by 3 to provide a reasonableestimate for AEGL-2 values.

AEGL-2 values are presented in Table 12.

TABLE 12. AEGL-2 Values for Allyl Alcohol [ppm(mg/m 3)]

Classification

10-min 30-min 1-hr 4-hr 8-hr

AEGL-2 87 (210) 27 (65) 13 (31) 3.1 (7.5) 1.5 (3.6)


No human data were relevant for the derivation of an AEGL-3. No reports of deathfollowing accidental exposure to allyl alcohol were found in the available literature.



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Group of five rats/sex were exposed to allyl alcohol vapor at concentrations of 0, 51,220, or 403 ppm for 1 hour; 0, 22, 52, or 102 ppm for 4 hours; or 0, 10, 21, or 52 ppmfor 8 hours (Kirkpatrick, 2008). All animals survived to study termination except for onemale rat exposed to 52 ppm for 8 hours. The rat died the day after exposure, and deathwas attributed to ulceration of the respiratory and olfactory epithelium in the nasal

passages, resulting in diminished breathing capacity, hypoxia and death. One othermale rat had irreversible nasal histopathological lesions. The histopathological changesthat were observed in the nasal cavities of all other exposed rats were consideredreversible. In a preliminary study by Kirkpatrick (2008), groups of three rats/sex wereexposed to allyl alcohol concentrations of 423 ppm or 638 ppm for 1 hour, 114 ppm for4 hours, and 52 ppm for 8 hours. All animals survived to study termination. Clinicalsigns in all exposure groups included gasping during and after exposure, and materialaround the mouth/nose and alcohol flushing after the exposure; two rats exp

allyl alcohol interim dec 2008 v1

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