EPA/600/8-90/033
September 1989
\,
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR BENZYL ALCOHOL
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION ABENCY
CINCINNATI, OH 45268
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I
TECHNICAL REPORT DATA
(Fltate nod Instructions on the reverse before completing)
FREPORT NO.
'EPA/600/8-90/033
3. RECIPIENT'S ACCESSION NO.
PB91-213694
4. TITLE AND SUBTITLE
Health and Environmental Effects Document for
Benzyl Alcohol
7. AUTNOR(S)
5. REPORT DATE
«. PERFORMING ORGANIZATION CODE
8. PERFORMING ORGANIZATION REPORT NO.
. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
117CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
13. TYPE OF REPORT AND PERIOD COVERED
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
C incinnati. OH 45268
14. SPONSORING AGENCY CODE
EPA/600/22
IS. SUPPLEMENTARY NOTES
I bO
*
16. ABSTRACT
Health and Environmental Effects Documents (HEEDS) are prepared for the Office of
Solid Waste and Emergency Response (OSWER). This document series is intended to
pport listings under the Resource Conservation and Recovery Act (RCRA) as well as
provide health-related limits and goals for emergency and remedial actions under
e Comprehensive Environmental Response, Compensation and Liability Act (CERCLA).
Both published literature and information obtained from Agency Program Office files
are evaluated as they pertain to potential human health, aquatic life and environmen-
tal effects of hazardous waste constituents.
Several quantitative estimates are presented provided sufficient data are
available. For systemic toxicants, these include Reference Doses (RfDs) for chronic
and subchronic exposures for both the inhalation and oral exposures. In the case of
suspected carcinogens, RfDs may not be estimated. Instead, a carcinogenic potency
factor, or q^*, is provided. These potency estimates are derived for both oral and
inhalation exposures where possible. In addition, unit risk estimates for air and
drinking water are presented based on inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxicity and carcinogenicity are
derived. The RQ is used to determine the quantity of a hazardous substance for
which notification is required in the event of a release as specified under CERCLA.
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS
c. COSATI Field/Group
ptSTRIBUTtON STATEMENT
'Public
19. SECURITY CLASS (This Report/
Unclassified
21. NO. OF PAGES
105
20. SECURITY CLASS (Thispage)
Unclassified
22. PRICE
EPA Fora 2220-1 (R*v. 4-77) PMKVIOUI COITION i* OBCOLETE
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ORD CLEARANCE FORM
1. EPA Report No 2. Series 3 Lab/Office Draft No 4. Co
EPA/600/8 ECAO-Cin-G075 . D v
SA. Original Document Title:
Health and Environmental Effects Document for Benzyl Alcohol
>B Final Document Title, if changed:
i. Authors), Affiliation, and Address (identify
EPA authors with Lab/Office)
10 OU/Obj./PPA/Project/Deliverable Output No.
D109 Y105
11. Technical Information (Program) Manager
Signature^- Dafe
Signature of sender (if other than TI(P|M) DatetoCERI
insfe ^wp*==^iLi
(jpcumtfnf manager *f * / /
^L/,//^,7, ,.,
Branrp [Jiipf/
,r-i-rX.X^,
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DISCLAIMER
This document has been reviewed 1n accordance with the U.S. Environ-
mental Protection Agency's peer and administrative review policies and
approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document series
Is Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
Information obtained for Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. Ihe literature searched for 1n this document
and the dates searched are Included In "Appendix: Literature Searched."
Literature search material Is current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document Is sent to the Program Officer (OSMER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include: Reference doses
(RfDs) for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD, Is an estimate of an
exposure level which would not be expected to cause adverse effects when
exposure occurs during a limited time Interval I.e., for an Interval which
does not constitute a significant portion of the Hfespan. This type of
exposure estimate has not been extensively used, or rigorously defined as
previous risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfDs 1s the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfDs are not estimated. Instead,
a carcinogenic potency factor, or q-j* (U.S. EPA, 1980a) 1s provided.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
.are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxldty and carclno-
genldty are derived. The RQ Is used to determine the quantity of a
hazardous substance for which notification Is required 1n the event of a
release as specified under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). These two RQs (chronic toxldty
and carclnogenlclty) represent two of six scores developed (the remaining
four reflect IgnHabllity, reactivity, aquatic toxldty, and acute mammalian
toxlclty). Chemical-specific RQs reflect the lowest of these six primary
criteria. The methodology for chronic toxldty and cancer based RQs are
defined 1n U.S. EPA, 1984 and 1986a, respectively.
111
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EXECUTIVE SUMMARY
Benzyl alcohol Is a colorless liquid with a mild aromatic odor (Rlngk
and Thelmer, 1981). It Is soluble In most organic solvents such as chloro-
form, ether, glycerol and alcohol, and Is moderately soluble In water (Sax
and Lewis, 1987). Benzyl alcohol Is usually produced commercially by the
catalytic hydrolysis of benzyl chloride, although reduction of benzole add
or benzole acid derivatives Is also feasible (Rlngk and Thelmer, 1979).
Chemical Dynamics Corporation, ICI Amerlcal Holdings Inc. (Agricultural
Products Group) and Kalama Chemical Inc. currently manufacture benzyl
alcohol (SRI, 1988; USITC 1987, 1988); a large proportion Is used 1n flavor-
Ings and fragrances (SRI, 1988). Benzyl alcohol 1s also used In development
of color photographic film, as a solvent for dyestuffs. Inks and cosmetics
and 1n the preservation of parenteral drugs and medical syrups, ointments
and aerosols (Rlngk and Thelmer, 1979; Sax and Lewis, 1987).
In the atmosphere, benzyl alcohol probably exists almost entirely In the
vapor phase (Elsenrelch et al., 1981). Apparently, the gas-phase reaction
with photochemically produced hydroxyl radicals 1s the primary atmospheric
degradation pathway (half-life of -2 days) (Atkinson, 1985). Wet deposition
may also occur. The reactions both with ozone and with direct photochemical
degradation are not expected to be Important fate processes.
In water, the dominant fate process Is probably mlcroblal degradation.
Benzyl alcohol rapidly degraded 1n water under aerobic (Belly and Goodhue,
1976; Dore et al.. 1975; Shelton and Tledje, 1984; Urano and Kato, 1986) and
anaerobic (Balba et al., 1981; Horowitz et al., 1982) conditions In the
laboratory. Photolysis, hydrolysis, volatilization to the atmosphere and
1v
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chemical oxidation are all expected to be slow processes In water. Adsorp-
tion to sediment and suspended organic matter, as well as bloaccumulatlon 1n
fish and aquatic organisms, are probably not Important fate processes.
Benzyl alcohol occurs naturally In some foods (Coleman et al., 1981;
Oumont and Adda, 1978; Ho et al., 1983; K1nl1n et al., 1972; Takeoka et al.,
1988}. It 1s also a man-made compound used predominantly In flavorings and
fragrances, household remedies and other common household products (Rlngk
and Thelmer, 1979; Sax and Lewis, 1987). Although quantitative Information
Is lacking, available data suggest that the general population may be
exposed to benzyl alcohol primarily by Inhalation. Exposure can also occur
by Ingestlon and dermal contact during the use of products 1n which 1t 1s
contained.
Benzyl alcohol can be released to the environment by various pathways.
Primary sources of release Include wastewater emissions from Us manufac-
ture, formulation and use In commercial products (Dagon, 1973; Keith, 1976),
effluent from sewage treatment plants (Ellis et al., 1982; Gossett et al.,
1983) and landfill leaching (Albalges et al., 1986; Harmsen, 1983). Benzyl
alcohol was detected In Incinerator emissions and exhaust of gasoline and
«
dlesel engines (Hampton et al., 1982; Mulawa and Cadle, 1981; Selzlnger and
D1m1tr1ades, 1972; James et al., 1984).
Benzyl alcohol was considerably more toxic to bluegllls (LC5Q = 10
mg/J.) and tidewater sllversldes (LC5Q = 15 mg/a) In a study by Dawson
et al. (1977) than It was to fathead minnows (LC5{J =, 460 mg/ft) In a
study by Mattson et al. (1976). These differences may be species-related,
but the fact that two low values were reported 1n one study and one high
value was reported 1n another study suggests that differences In experi-
mental procedures between studies could have affected the results. An
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LC50 of 646 mg/t was reported 1n golden orfe (Kn1e et al., 1983), but
lack of details prevented assessment of this study. No effects were
reported In larval sea lamprey (Applegate et al., 1957), blueglll, goldfish
or trout (Hollls and Lennon, 1954; Wood, 1954) acutely exposed to 5 mg/Ji
of benzyl alcohol 1n screening-type studies. Among Invertebrates, an EC5Q
of 400 mg/a. was reported for Daphnla Immobilization (Knle et al., 1983),
and LDgQ values of 105-160 l/hectare were reported 1n mosqultos
(Slnnlah. 1983). Among algae, the EC value for effects on photosynthe-
sis and nltrogenase activity exceeded 100 nig/8. In all five species tested
(Stratton and Corke, 1982). The EC5Q for reduced growth was 2600 mg/l
1n one species (Knle et al., 1983). Effects In bacteria were reported at
concentrations ranging from 71.4-5083 mg/l (Kaiser et al., 1987; Knle et
al., 1983; Valshnav, 1986). In studies of terrestrial organisms 1t was
found that 131 mg/l of benzyl alcohol Inhibited spore germination 1n fungi
(Wilson et al., 1987) and that LD5_ values were 100 mg/kg bw or more In
two species of birds (Schafer et al., 1983).
No data were found regarding the extent and rate of absorption of benzyl
alcohol from Inhalation exposures. Benzyl alcohol has been shown to be
*
rapidly absorbed from orally administered doses In rabbits (D1ack and Lewis,
1928; Bray et al., 1951, 1958) and man (Snapper et al., 1924). An 1n vitro
study of percutaneous penetration of 14C-benzyl alcohol Indicated that a
major portion of the compound remained 1n the stratum corneum of the
epidermal layer of human skin.
No Information was found regarding distribution of benzyl alcohol
following Inhalation or oral exposures. In dogs, the calculated apparent
volume of distribution suggested that the major portion of Intravenously
administered benzyl alcohol was distributed In the tissues (Klmura et al.,
1971).
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Metabolism of benzyl alcohol Involves rapid oxidation to benzole add
using a benzaldehyde Intermediate. Benzole add 1s further metabolized to
hlppuMc add, which 1s excreted In the urine 1n both animals and man (Bray
et al., 1951. 1958; D1ack and Lewis, 1928; Stekol, 1939; HcCloskey et al.,
1986; Snapper et al., 1924). Ring labeled 14C-benzyl alcohol was shown to
form 14C-phenol In guinea pig liver mlcrosomes where there was no mlcro-
somal metabolism of benzole add (Sloane, 1965).
In humans, the Immature Hver and kidney of preterm Infants appear to
have a reduced capacity to metabolize benzyl alcohol by glyclne conjugation
(LeBel et al., 1988). No differences were detected In the pattern of
metabolism,between adult and neonatal mice (McCloskey et al., 1986). Small
Increases In the dose resulted In disproportionate plasma levels, Indicating
that benzyl alcohol was eliminated by saturable kinetics.
In soil, benzyl alcohol displays high mobility and readily leaches
through soil {Brlggs, 1981; Southworth and Keller, 1986; Swann et al.,
1983). H1crob1al degradation In soil may occur; however, conclusive data
were not located 1n the available literature. Volatilization from dry soil
to the atmosphere may be an Important fate process; however. It Is probably
*
not an Important process 1n wet soils.
No Information was located regarding the subchronlc or chronic exposure
to benzyl alcohol by Inhalation. Systemic effects from a 16-day gavage
study using male and female F344/N rats and B6C3F1 mice at doses of 0, 125,
250, 500, 1000 and 2000 mg/kg given 5 days/week Included Increased mortality
and lethargy In both spedes at doses >1000 mg/kg, mean body weights 18%
lower than controls 1n male rats receiving 1000 mg/kg, unusual bleeding 1n
male rats and mice at >1000 mg/kg, and rough hair coats In male rats at the
500 and 1000 mg/kg level, 1n female rats at the 250 and 500 mg/kg level. In
vll
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male mice at >500 mg/kg and In female mice at >1000 mg/kg (NTP, 1988). No
hlstopathologlcal effects attributable to treatment were noted 1n either sex
of either species. Effects on rats and mice from 91-day treatment at doses
of 0. 50, 100, 200, 400 and 800 mg/kg given 5 days/week were similar to the
shorter-term experiment. There was Increased mortality at the highest
dosage In male rats and female mice (and possibly female rats); other deaths
were attributed to the gavage procedure. Signs of neurotoxldty followed
dosing at the 800 mg/kg level In rats and mice, but this was considered an
acute effect. Mean body weights of the highest dosage rats of both sexes
and the female mice receiving >400 mg/kg were slightly lower than controls.
Hale rats at the 800 mg/kg level exhibited hlstopathologlcal effects of the
hippocampus, thymus, kidney, skeletal muscle, as well as unusual bleeding;
females rats at this dose also showed necrosis of the hippocampus. No
hlstopathologlcal effects attributable to treatment were seen In the mice.
Chronic oral studies consisted of the NTP-sponsored 103-week gavage
studies using rats and mice (NTP, 1988), and a developmental toxlclty and
reproduction study using mice by Nazelden (1983). In the NTP (1988) study,
rats and mice of both sexes were given doses of 0, 200 and 400 mg/kg and 0,
100 and 200 mg/kg, respectively, administered 5 days/week for 2 years.
Survival of the female rats at both dose levels was significantly lower than
that of vehicle controls. However, many of the deaths were judged to be
gavage-related, and not compound-related. The higher Incidence of
accidental death In the dosed animals 1s likely a result of the combined
effect of the gavage procedure simultaneous with the neurotoxlc effect of
the compound. High-dose male rats had a higher Incidence of epithelial
hyperplasla of the forestomach, and a squatnous cell papHloma was seen In
one male rat In the high- and low-dose groups. In female mice, survival 1n
V111
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the high-dose group was significantly higher than In controls after the 74th
week. Survival was not different between other groups of either sex.
Although mice were treated with lower doses of benzyl alcohol, they stm
appear to be the less sensitive species, since there were no lexicologically
significant effects even at the 200 mg/kg dose, which did produce systemic
effects In the rats.
In acute studies, rats died within 14 days after exposure to 1000 ppm
(4422 mg/m3) of benzyl alcohol for 8 hours (Smyth et al., 1951). Single
oral dose LD5Qs In animals range from -1000-2000 mg/kg (Jenner et al.,
1964; Graham and Kulzenga, 1945). The average survival time of cats was 22
hours from one 20 ml application of 100% benzyl alcohol to their shaved
backs (Graham and Kulzenga, 1945). Cats have a pronounced sensitivity to
drugs containing benzene rings that 1s due, In part, to a relative defi-
ciency 1n their ability to detoxify xenoblotlcs by glucuronlc acid conjuga-
tion (Wllcke, 1984). An acute dermal LD5Q of <5.0 ma/kg was reported
for guinea pigs (Jones, 1967). Benzyl alcohol has been reported to cause
severe eye problems following Us use In ocular surgery (Grant, 1974), some
dermal Irritation to rabbits and humans (Motoyosh! et al., 1979), hyper-
*
sensitivity reactions (Grant et al., 198?; Shmunes, 1984; Wilson et al.,
1986) and contact allergies 1n humans (Fisher, 1975; Edwards, 1981;
Lazzarlnl, 1982; Shojl, 1983; Van Joost et al., 1985).
A higher Incidence of preterm Infant mortality resulted from Intravascu-
lar and Intramuscular administration of drugs containing benzyl alcohol as a
preservative, so that dosages averaged 191 mg/kg/day (Brown et al., 1982).
No Information was found regarding carclnogenlclty from Inhalation
exposure to benzyl alcohol. A 2-year gavage study using rats and mice with
doses of 0, 200 and 400 mg/kg, and 0, 100 and 200 mg/kg, respectively, was
negative for carclnogenlclty under the conditions of the study (NTP, 1988).
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Benzyl alcohol was negative 1n reverse mutation assays with S. typhl-
murlum. with and without metabolic activating systems, (Mortelmans et al.,
1986; Florin et al., 1980; Rogan et al.. 1986; Ishldate et al., 1984), and
1n tests with E_. coll WP2 uvrA, but 1t caused DNA damage 1n a rec assay with
B. subtmis (Kuroda et al., 1984; Yoo, 1986). It was negative In an micro-
nucleus test 1n ddY mice (Hayashl et al., 1988), In mammalian cell culture
(Ishldate et al., 1988), and did not Induce DNA damage 1n human alveolar
cells (Waters et al., 1982). In the mouse L5178Y/tk*X~ lymphoma forward
mutation assay, results were equivocal (McGregor et al., 1988).
In a reproductive and developmental toxlclty study, gavaged doses of 750
mg/kg/day given to pregnant mice for gestation days 7-14 resulted 1n lower
mean Utter and pup weights, and signs of maternal toxlclty Including lower
mean body weights and Increased mortality (Hazelden, 1983; Hardln et al.,
1987).
As data regarding the subchronlc and chronic toxlclty and carclnogenlc-
1ty of Inhalation exposure to benzyl alcohol were not available, It was not
possible to derive RfDs or q*s for this route of exposure. There was
equivocal evidence of carclnogenldty In mice exposed to benzyl alcohol by
gavage for 2 years. Therefore, benzyl alcohol was classified In Group D -
not classifiable as to human carclnogenldty. A subchronlc oral RfD of 1.0
mg/kg/day was derived based on the NOAEL of 200 mg/kg, 5 days/week for 13
weeks in the NTP (1988) subchronlc rat study. A chronic oral RfO of 0.3
mg/kg/day was derived based on the LOAEL of 200 mg/kg 5 days/week for 2
years In the NTP (1988) study. An RQ of 1000 was derived, also based on the
LOAEL of 200 mg/kg 5 days/week In the NTP (1988) chronic study.
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. CHEMICAL AND PHYSICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 3
2. ENVIRONMENTAL FATE AND TRANSPORT 4
2.1. AIR 4
2.1.1. Reaction With Hydroxyl Radicals 4
2.1.2. Reaction WHh Ozone 4
2.1.3. Physical Removal Processes 4
2.1.4. Photolysis 4
2.2. HATER. 4
2.2.1. Hydrolysis 4
2.2.2. Oxidation 4
2.2.3. Photolysis 5
2.2.4. Mlcroblal Degradation 5
2.2.5. B1oconcentrat1on 6
2.2.6. Adsorption 6
2.2.7. Volatilization 6
2.3. SOIL 6
2.3.1. Mlcroblal Degradation 6
2.3.2. Adsorption/Leaching 7
2.3.3. Volatilization 7
2.4. SUMMARY 7
3. EXPOSURE 8
3.1. HATER 8
3.2. FOOD 8
3.3. INHALATION 9
3.4. DERMAL 9
3.5. OTHER 9
3.6. SUMMARY 9
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TABLE OF CONTENTS (cont.)
4. ENVIRONMENTAL TOXICOLOGY 11
4.1. AQUATIC TOXICOLOGY 11
4.1.1. Acute Toxic Effects on Fauna 11
4.1.2. Chronic Effects on Fauna 12
4.1.3. Effects on Flora 13
4.1,4. Effects on Bacteria 13
4.2. TERRESTRIAL TOXICOLOGY 14
4.2.1. Effects on Fauna 14
4.2.2. Effects on Flora 14
4.3. FIELD STUDIES 14
4.4. AQUATIC RISK ASSESSMENT 14
4.5. SUMMARY 16
5. PHARMACOKINETCS 19
5.1. ABSORPTION 19
5.2. DISTRIBUTION 20
5.3. METABOLISM 20
5.4. EXCRETION. 23
5.5. SUMMARY 24
6. EFFECTS 26
6.1. SYSTEMIC TOXICITY 26
6.1.1. Inhalation Exposure 26
6.1.2. Oral Exposure 26
6.1.3. Other Relevant Information 30
6.2. CARCINOGENICITY 34
6.2.1. Inhalation 34
6.2.2. Oral 34
6.2.3. Other Relevant Information 35
6.3. MU1AGENICITY 35
6.4. DEVELOPMENTAL TOXICITY 37
6.5. OTHER REPRODUCTIVE EFFECTS 37
6.6. SUMMARY 39
7. EXISTING GUIDELINES AND STANDARDS 42
7.1. HUMAN 42
7.2. AQUATIC 42
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TABLE OF CONTENTS (cont.)
Page
8. RISK ASSESSMENT 43
8.1. CARCINOGENICITY 43
8.1.1. Inhalation 43
8.1.2. Oral 43
8.1.3. Other Routes 43
8.1.4. Weight of Evidence 43
8.1.5. Quantitative Risk Estimates . . . 43
8.2. SYSTEMIC TOXIC1TY 44
8.2.1. Inhalation Exposure 44
8.2.2. Oral Exposure 44
9. REPORTABLE QUANTITIES 47
9.1. BASED ON SYSTEMIC 70X1C11Y 47
9.2. BASED ON CARCINOGENICITY 49
10. REFERENCES 52
APPENDIX A: LITERATURE SEARCHED 70
APPENDIX B: SUMMARY TABLE FOR BENZYL ALCOHOL 73
APPENDIX C: DOSE/DURATION RESPONSE GRAPH(S) FOR EXPOSURE TO
BENZYL ALCOHOL 74
xin
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LIST OF TABLES
No. Title Page
9-1 Oral Toxlclty for Benzyl Alcohol 48
9-2 Composite Scores for Orally Administered Benzyl Alcohol ... 50
9-3 Benzyl Alcohol: Hlnlmum Effective Dose (MED) and
Reportable Quantity (RQ) 51
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LIST OF ABBREVIATIONS
BCF
bw
CAS
CS
ONA
EEG
61
GMAV
GHCV
HPLC
K
Koc
Kow
LD50
LOAEL
MED
MNPCE
MTO
.NOAEL
PCE
ppm
RfD
RQ
SPF
THOD
v/v
Bloconcentratlon factor
Body weight
Chemical Abstract Service
Composite score
Deoxyrlbonuclelc acid
Electroencephalogram
Concentration effective to SOX of recipients
(and all other subscripted concentration levels)
Gastrointestinal
Genus mean acute value
Genus mean chronic value
High-performance liquid chromatography
Partition coefficient
So1l/sorpt1on coefficient
Octanol/water partition coefficient
Concentration lethal to 5054 of recipients
(and all other subscripted concentration levels)
Dose lethal to 50% of recipients
Lowest-observed-adverse-effect level
Minimum effective dose
NUronucleated polychromatic erythrocytes
Maximum tolerated dose
No-observed-adverse-effect level
Polychromatic erythrocytes
Parts' per million
Reference dose
Reportable quantity
Specific pathogen free
Theoretical oxygen demand
Volume per volume
xv
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Benzyl alcohol 1s also known as a-hydroxy toluene, benzene methanol,
phenylcarblnol and hydroxymethyl benzene (Chemllne, 1989; CAS, 1989; SANSS,
1989). The structure, CAS number, molecular weight and empirical formula
for benzyl alcohol are as follows:
CAS Registry number: 100-51-6
Empirical formula: C-.HD0
/ o
Molecular weight: 108.13
1.2. CHEMICAL AND PHYSICAL PROPERTIES
Benzyl alcohol 1s a colorless liquid with a mild aromatic odor (Rlngk
and Thelmer, 1979). In Us purest state, H has the distinct odor of a
rose. It Is soluble In most organic solvents such as chloroform, ether,
glycerol and alcohol (Rlngk and Thelmer, 1979; Sax and Lewis, 1987}.
Selected physical properties of benzyl alcohol are as follows:
Melting point: -15.3°C Weast et al., 1988
Boiling point: 205.3°C .Weast et al., 1988
Density: 1.0419 g/mi Weast et al., 1988
Vapor Pressure 0.11 mm Hg Rlddlck et al., 1986
at 25°C:
Water Solubility 40.00 g/l Rlngk and Thelmer. 1979
at 25'C:
Log Kow: 1.10 Hansch and Leo, 1985
0269d -1- 11/01/89
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Flash point:
Conversion factor
at 25°C:
105°C
1 ppm = 4.40 mg/m3
Sax and Lewis, 1987
Benzyl alcohol Is readily esterlfled with a variety of organic adds In
the presence of an acid catalyst. It can be readily oxidized to the
corresponding aldehyde, and under vigorous conditions, It can be oxidized to
benzole acid. Benzyl alcohol can also be catalytlcally hydrogenated,
producing toluene (Rlngk and Thelmer, 1979).
1.3. PRODUCTION DATA
Benzyl alcohol Is commercially prepared by the alkaline hydrolysis of
benzyl chloride using sodium carbonate (Rlngk and Thelmer, 1979). Benzyl
alcohol can also be prepared by the hydrolysis of benzyl chloride using
other catalysts, by the Grlgnard or related metalatlon reactions with benzyl.
chloride and by the reduction of benzole acid, benzole acid derivatives or
benzaldehyde. During 1977, 24 U.S. manufacturing plants produced 115-1150
thousand pounds of benzyl alcohol (TSCAPP, 1989}. The primary manufacturing
site was Monroe Chemical, Inc., Eddystone, DE. Current U.S. manufacturers
of benzyl alcohol are Chemical Dynamics Corp., South Plalnfleld, NJ; ICI
Agricultural Products Group, Edison, NJ; and Kalama Chemicals, Inc.,
Seattle, MA (SRI, 1988; USITC, 1987, 1988). More current U.S. production
data were not located In the available literature cited In Appendix A.
1.4. USE DATA
Benzyl alcohol 1s used 1n photographic developers for color films, as a
degreaslng agent In rug cleaners and as a solvent for dyestuffs, ballpoint
pen Inks, cellulose esters, casein, waxes, etc. It Is also used to preserve
aqueous and oily parenteral drugs In cough syrups, ointments, Insect
ointments and repellents, dermatologlcal aerosol sprays, and ophthalmic,
0269d
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11/01/89
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burn and dental solutions. Cosmetics such as nail lacquers and hair dyes
contain benzyl alcohol, as well. The aliphatic esters of benzyl alcohol are
used In flavorings, fragrances, soaps and perfumes (Rlngk and Thelmer, 1979;
Sax and Lewis, 1987).
1.5. SUMMARY
Benzyl alcohol 1s a colorless liquid with a mild aromatic odor (R1ngk
and Thelmer, 1979). It Is soluble In most organic solvents such as chloro-
form, ether, glycerol and alcohol, and 1s moderately soluble In water (Sax
and Lewis, 1987). Benzyl alcohol 1s usually produced commercially by the
catalytic hydrolysis of benzyl chloride, although reduction of benzole add
or benzole add derivatives Is also feasible (Rlngk and Thelmer, 1979).
Three companies currently manufacture benzyl alcohol (SRI, 1988; USITC 1987,
1988); a large proportion Is used In flavorings and fragrances (SRI, 1988).«
Benzyl alcohol Is also used In development of color photographic film, as a
solvent for dyestuffs, Inks and cosmetics and 1n the preservation of
parenteral drugs and medical syrups, ointments and aerosols (Rlngk and
Thelmer, 1979; Sax and Lewis, 1987).
0269d -3- 11/01/89
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Based on a vapor pressure of 0.11 mrn Hg at 25°C (Rtddlck et al., 1986),
benzyl alcohol ts expected to exist almost entirely 1n the vapor phase In
the ambient atmosphere (Elsenrelch et al., 1981).
2.1.1. Reaction with Hydroxyl Radicals. Using the method of Atkinson
(1985), the half-life for the gas-phase reaction of benzyl alcohol with
photochemically produced hydroxyl radicals In the atmosphere can be
estimated at 2 days, based on a calculated rate constant of S.llxlO"15
cm3/molecule-sec and an average atmospheric hydroxyl radical concentration
of 5xl05 molecules/cm3. This process Is probably the most Important
atmospheric fate process for benzyl alcohol.
2.1.2. Reaction with Ozone. Benzyl alcohol 1s not susceptible to oxlda-*
tlon by ozone In the atmosphere (Atkinson, 1985; U.S. EPA, 1987).
2.1.3.' Physical Removal Processes. Based on Its water solubility, 40
g/a (R1ngk and Thelmer, 1979), benzyl alcohol may undergo dissolution Into
clouds and subsequently be removed from the atmosphere In precipitation.
2.1.4. Photolysis. The direct photochemical degradation of benzyl
alcohol 1n the atmosphere Is not expected to be an Important fate process.
2.2. WATER
2.2.1. Hydrolysis. Benzyl alcohol probably does not undergo hydrolysis
since 1t contains no hydrolyzable functional groups (Lyman et al., 1982).
2.2.2. Oxidation. Based on the experimentally determined rate constant
for the reaction of benzyl alcohol with alkylperoxy radicals, 2.4 a/mol-s
(Hendry et al., 1974), and an estimated alkylperoxy concentration In water
of lxlO~» mol/4 (Mill et al., 1980), the half-life for this reaction 1s
0269d
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9 years. The half-life for the reaction of benzyl alcohol with photocheml-
cally produced hydroxyl radicals 1n water can be estimated at -100 days
using an experimentally determined rate constant of 8.4xlQ» a/mol-s
(Dorfman and Adams, 1973) and a optimal hydroxyl radical concentration of
IxlCT17 mol/l In natural waters (Mill et al., 1980).
2.2.3. Photolysis. No reaction was observed during a 4-hour sunlight
Irradiation of benzyl alcohol In water (Draper and Crosby, 1983). Thus,
direct photochemical degradation of benzyl alcohol 1n water Is probably not
an Important fate process.
2.2.4. Mlcroblal Degradation. Benzyl alcohol underwent 60.8% degradation
In a 5-day test using a sewage sludge Inoculum under aerobic conditions
(Belly and Goodhue, 1976). In a screening test, benzyl alcohol underwent
>75% aerobic degradation within 8 weeks using a sewage sludge Inoculum*
(Shelton and Tledje, 1984). Benzyl alcohol (100 mg/it) underwent 79% and
87% degradation after 5.4 and 8.3 days, respectively, under aerobic condi-
tions using a sewage seed (Urano and Kato, 1986). In a 5-day test, benzyl
alcohol underwent 33% biological THOD using a sewage Inoculum (Core et al.,
1975). These studies suggest rapid aerobic blodegradatlon 1n environmental
waters.
Benzyl alcohol underwent fast blodegradatlon after a 2-month acclimation
period under anaerobic conditions using a salt marsh sediment Inoculum
(Balba et al., 1981). Anaerobic blodegradatlon for benzyl alcohol using a
sludge seed from two different waste treatment plants was complete within 2
weeks (Horowitz et al., 1982). However, the sampling frequency was not
reported; thus, It Is not clear at what rate benzyl alcohol underwent
degradation.
0269d -5- 11/01/89
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2.2.5. B1oconcentrat1on. The BCF for benzyl alcohol Is 4.04, based on
the log KOW> 1.81 (Hansch and Leo, 1985). The regression equation, log
BCF e 0.76 log K - 0.23, was used In this determination {Lyman et al.,
1982). This value suggests that concentration In fish and aquatic organisms
Is not an Important fate process.
2.2.6. Adsorption. Based on experimental K values In soil that
ranged from <5-16 (Brlggs, 1981; Southworth and Keller, 1986), adsorption to
sediment and suspended organic material Is not expected to be an Important
fate process.
2.2.7. Volatilization. Based on benzyl alcohol's water solubility, 40
g/8, at 25°C (R1ngk and Thelmer, 1979), and Us vapor pressure of
4.1xl(T» mm Hg 40 g/l at 25°C (Rlddlck et al., 1986), a Henry's Law
constant of 3.91xlO~7 atm mVmolecule at 25°C can be calculated (Lyman*
et al., 1982). Using the bond method of Mine and Hookerjee (1975), a
Henry's Law constant of 2.28xlO~7 atm mVmolecule at 25°C can be
obtained. These values suggest that volatilization of benzyl alcohol from
water Is not an Important fate process. The estimated volatilization
half-life from a model river 1 m deep, flowing 1 m/sec, with a wind velocity
of 3 m/sec Is 97 days, based on the smaller of the above Henry's Law
constants (Lyman et al., 1982).
2.3. SOIL
2.3.1. M1crob1al Degradation. Pertinent data regarding the degradation
of benzyl alcohol 1n soil were not located In the available literature cited
In Appendix A. Bacteria obtained from soil and grown on phenol or toluene
degraded benzyl alcohol (Chambers et al., 1963; Claus and Walker, 1964;
Kramer and Doetsch, 1950). In water, blodegradatlon of benzyl alcohol would
probably occur rapidly under both aerobic and anaerobic conditions, suggest-
ing rapid blodegradatlon In soil.
0269d
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2.3.2. Adsorption/Leaching. Experimental K values for benzyl alcohol
range from <5-26.9 (BMggs, 1981; Southworth and Keller, 1986), suggesting
high mobility 1n soil for benzyl alcohol (Swann et al., 1983}
2.3.3. Volatilization. The relatively high vapor pressure for benzyl
alcohol, 0.11 mm Hg at 25°C (R1dd1ck et al., 1986), suggests that volatili-
zation from dry soil Is an Important fate process. However, volatilization
from moist or wet soil may not be significant.
2.4. SUMMARY
In the atmosphere, benzyl alcohol probably exists almost entirely In the
vapor phase (Elsenrelch et al., 1981). Apparently, the gas-phase reaction
with photochemically produced hydroxyl radicals is the primary atmospheric
degradation pathway (half-life of -2 days) (Atkinson, 1985). Wet deposition
may also occur. The reactions both with ozone and with direct photochemical1
degradation are not expected to be Important fate processes.
In water, the dominant fate process 1s probably microblal degradation.
Benzyl alcohol rapidly degraded In water under aerobic (Belly and Goodhue,
1976; Core et al., 1975; Shelton and Tledje, 1984; Urano and Kato, 1986) and
anaerobic (Balba et al., 1981; Horowitz et al., 1982) conditions In the
laboratory. Photolysis, hydrolysis, volatilization to the atmosphere and
chemical oxidation are all expected to be slow processes In water. Adsorp-
tion to sediment and suspended organic matter, as well as bloaccumulatlon In
fish and aquatic organisms, are probably not Important fate processes.
In soil, benzyl alcohol displays high mobility and readily leaches
through soil (Brlggs, 1981; Southworth and Keller, 1986; Swann et al.,
1983). Microblal degradation In soil may occur; however, conclusive data
were not located 1n the available literature. Volatilization from dry soil
to the atmosphere may be an Important fate process; however, It Is probably
not an Important process In wet soils.
0269d -7- 11/01/89
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3. EXPOSURE
Benzyl alcohol results from both natural and anthropogenic activity. It
Is found In various foods and Is used In a wide range of applications.
Primary sources of release Include losses In wastewater and fugitive
emissions during Us commercial manufacture and formulation.
The National Occupational Exposure Survey estimated that 203,108 workers
are exposed to benzyl alcohol (NIOSH, 1984). Based on the available
monitoring and use data, the general population apparently would be exposed
to benzyl alcohol by Inhalation, dermal .contact and Ingestlon during the use
of common household products In which It 1s contained. Minor exposure can
occur through the Ingestlon of food In which benzyl alcohol occurs naturally.
3.1. NATER
Quantitative monitoring data for benzyl alcohol In water are limited.
Benzyl alcohol was Identified In wastewater effluent from the photographic
processing Industry (Dagon, 1973) and Kraft paper mills In 6/8 samples at
<0.013 mg/i (Keith, 1976). Benzyl alcohol was qualitatively Identified In
secondary effluent from wastewater treatment plants (Ellis et a!., 1982).
The effluent from a Los Angeles County wastewater treatment plant contained
500 yg/i of benzyl alcohol (Gossett et al., 1983).
Benzyl alcohol was detected In leachate from a Barcelona, Spain,
sanitary landfill (Albalges et al., 1986) and from a municipal refuse
disposal site In the Netherlands (Harmsen, 1983).
3.2. FOOD
Benzyl alcohol 1s a volatile flavor component of baked potatoes (Coleman
et al., 1981), Beaufort (Gruyere) cheese (Dumont and Adda, 1978), bacon (Ho
et al., 1983) and roasted filberts (Klnlln et al., 1972). It Is also a
0269d
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volatile component of blended nectarines, but was not Identified In a head-
space analysis of the Intact fruit {Takeoka et al., 1988). These monitoring
data Indicate that the general population can be exposed to small amounts of
benzyl alcohol by Ingesting these foods; however, quantitative Information
Is not available.
3.3. INHALATION
Pertinent data regarding the ambient concentration of benzyl alcohol In
the atmosphere were not located In the available literature cited In
Appendix A. Benzyl alcohol was found In the gaseous effluent from four
waste Incinerators (James et al., 1984} and In gasoline and dlesel engine
exhaust (Hampton et al., 1982; Mulawa and Cadle, 1981; Selzlnger and
Dlmltrlades, 1972).
3.4. DERMAL
Pertinent data regarding dermal exposure to benzyl alcohol were not
located In the available literature cited In Appendix A. Benzyl alcohol 1s
used In perfumes, ointments, ophthalmic and burn solutions, Insect ointments
and repellents, dermatologlcal aerosol sprays, cosmetics and the preserva-
tion of aqueous and oily parenteral drugs (R1ngk and Thelmer, 1979; Sax and
Lewis, 1987). Use of these products results In dermal exposure.
3.5. OTHER
Benzyl alcohol Is also used 1n flavorings, cough syrups and dental
solutions (R1ngk and Thelmer, 1979; Sax and Lewis, 1987). Exposure to
benzyl alcohol may occur during the use of these products.
3.6. SUMMARY
Benzyl alcohol occurs naturally In some foods (Coleman et al., 1981;
Dumont and Adda, 1978; Ho et al., 1983; Klnlln et al., 1972; Takeoka et al.,
1988). It Is also a man-made compound used predominantly 1n flavorings and
0269d -9- 11/01/89
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fragrances, household remedies and other common household products (Rlngk
and Thelmer, 1979; Sax and Lewis, 1987). Although quantitative Information
1s lacking, available data suggest that the general population may be
exposed to benzyl alcohol primarily by Inhalation. Exposure can also occur
by Ingestlon and dermal contact during the use of products In which It Is
contained.
Benzyl alcohol can be released to the environment by various pathways.
Primary sources of release Include wastewater emissions from Its manufac-
ture, formulation and use In commercial products (Oagon, 1973; Keith, 1976),
effluent from sewage treatment plants (Ellis et al., 1982;. Gossett et a!.,
1983) and landfill leaching (Albalges et al., 1986; Harmsen, 1983). Benzyl
alcohol was detected In Incinerator emissions and exhaust of gasoline and
dlesel engines (Hampton et al., 1982; Mulawa and Cadle, 1981; Selzlnger and'
Dlmltrlades, 1972; James et al., 1984).
0269d
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by benzyl alcohol of 400 mg/a. An ECQ of 300 mg/a and an EC10Q
4. ENVIRONMENTAL TOXICOLOGY
4.1. AQUATIC TOXICOLOGY
4.1.1. Acute Toxic Effects on Fauna. Two tests of benzyl alcohol
toxldty have been performed In freshwater Invertebrates. Knle et al.
(1983) reported an EC for Immobilization of water fleas, Daphnla magna.
-""" "
Of
500 mg/a were also reported. No experimental details were provided.
Sinnlah (1983) studied the acute toxldty of benzyl alcohol to mosquito eggs
and larvae. Eggs of Aedes aegyptl and Aedes scutellarls. 5-14 days old and
Immersed In hay Infusion, were exposed to various concentrations of benzyl
alcohol for 24-72 hours. Water temperature was kept between 25 and 27°C.
Results were similar In eggs of both species, with LD5Q values of 160
a/hectare. Tests were also done using larvae and pupae. LD5Q values of*
105-110 a/hectare were reported In first Instar larvae. Third and fourth
Instar larvae were less sensitive, with LD5Q values of 126-129 a/hec-
tare. Concentrations <500 a/hectare failed to produce mortality In pupae.
LC5Q values have been calculated for several species of freshwater
fish. The acute toxldty of benzyl alcohol to fathead minnows, Plmephales
promelas. was determined by Mattson et al. (1976). Juvenile fathead
minnows, ranging 1n age from 4-8 weeks and 1n length from 1.1-3.1 cm, were
exposed to benzyl alcohol In a static nonrenewal test. The temperature of
the water varied between 18 and 22°C. Twenty fish (two groups of 10) were
tested at each of 3-5 nominal concentrations. The 1-, 24-, 48-, 72- and
96-hour LC5Q values were 770, 770, 770, 480 and 460 mg/a, respectively.
Toxldty was much higher In blueglll sunflsh, Lepomls macrochlrus. In a
static acute test conducted by Dawson et al. (1977). Blueglll, which varied
from 33-75 mm In length, were exposed to nominal concentrations of 5-56 ppm
0269d -11- 11/01/89
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(mg/l) of benzyl alcohol for 96 hours at 23°C. The 96-hour LC5Q was 10
ppm (mg/l). Kn1e et al. (1983) reported an LC5Q of 646 mg/t 1n golden
orfe, Leudscus Idus. The LCn was 630 . mg/i and the LC,__ was 662
U ' IUU
mg/i. No experimental details of this study were provided.
Several toxldty screening studies have been conducted In freshwater
fish. Larval sea lampreys, Petromyzon marlnus. varying 1n length from
7.5-12.5 cm, were exposed to 5 mg/l of benzyl alcohol for 24 hours under
static conditions at 13°C {Applegate et al., 1957). No effects were seen In
the two lampreys tested. Exposure to 5 mg/fi. of benzyl alcohol did not
have toxic effects on blueglll sunflsh, Lepomls macrochlrus. goldfish,
Carasslus auratas. or trout, Sal mo trutta. In similar studies (HolUs and
Lennon, 1954; Wood, 1954). In one study, benzyl alcohol was forcefed to
carPt Cyprlnus carplo. at doses of 127-136 mg/kg bw using gelatin capsules'
(Loeb and Kelly, 1963). The fish, which weighed an average of 1.4 kg, were
placed In 18°C running spring water for observation. No effects were noted
after 48 hours 1n the three fish tested.
One study of the acute toxlclty of benzyl alcohol to a marine species
was located In the literature. Tidewater sllversldes, Henldla beryl Una.
ranging In length from 40-100 mm, were exposed to nominal concentrations of
10-32 ppm (mg/i) benzyl alcohol under static conditions at 20°C (Dawson et
al., 1977). The 96-hour LC5Q was estimated to be 15 ppm (mg/H).
4.1.2. Chronic Effects on Fauna.
4.1.2.1. TOXICITY Pertinent data regarding the effects of chronic
exposure of aquatic fauna to benzyl alcohol were not located In the
available literature cited In Appendix A.
4.1.2.2. BIOACCUMULATION/BIOCONCENTRATION - Pertinent data regarding
the bloaccumulatlon/bloconcentratlon potential of benzyl alcohol In aquatic
fauna were not located In the available literature cited In Appendix A.
0269d
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4.1.3. Effects on Flora.
4.1.3.1. TOXICITY The effects of benzyl alcohol on photosynthesis,
nHrogenase activity and growth In algae were studied by Stratton and Corke
(1982). Blue-green algae, Anabaena Inaequalls, Anabaena cyllndrlca and
Anabaena varlabllls. and green algae, Chlorella pyrenoldosa and Scenedesmus
quadrlcauda. were tested. The 3-hour EC5Q for photosynthetlc effects,
measured by uptake of 14C02 from NaH14C03, was >100 ppm (mg/i) In
all five species. The 5-hour EC,-n for Inhibition of nHrogenase activity,
measured by acetylene reduction, 1n A. Inaequalls and A. cyllndrlca also
exceeded 100 ppm (mg/l). Growth, calculated from absorbance values, was
unaffected by 12- to 14-day exposures to benzyl alcohol concentrations of 10
ppm (mg/8.) In any of these species. A second study of the effects of
benzyl alcohol on algae was conducted on Haematocqcc^us, pluv.1a11s by Knle et%
al. (1983). The EC5Q for reduced growth was 2600 mg/8. 1n this study.
No experimental details were provided.
4.1.3.2. BIOCONCENTRATION -- Pertinent data regarding the bloconcen-
tratlon potential of benzyl alcohol In aquatic flora were not located 1n the
available literature cited In Appendix A.
4.1.4. Effects on Bacteria. A few studies have Investigated the toxldty
of benzyl alcohol to bacteria. The acute toxldty of benzyl alcohol to
Photobacterlum phosphoreum was measured by Kaiser et al. (1987) using the
Hlcrotox test. The 30-mlnute EC for light reduction In the bacterial
suspensions was 0.66 mM (71.4 mg/8,). Effects were produced at higher
concentrations 1n other studies. A cell multiplication test was conducted
In Pseudomonas putlda by Knle et al. (1983). The EC1Q for effects of
benzyl alcohol was 658 mg/l. Valshnav, (1986) Investigated the effect of
benzyl alcohol on the blodegredatlon rate of a mixed mlcroblal culture. The
ECcg for rate reduction was 0.047 mol/l (5083 mg/i).
0269d -13- 11/01/89
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4.2. TERRESTRIAL TOXICOLOGY
4.2.1. Effects on Fauna. The acute oral toxlclty of benzyl alcohol was
determined In two species of birds (Schafer et al., 1983). Birds were
trapped 1n the wild and held 1n captivity for 2-6 weeks before testing.
Benzyl alcohol was administered by gavage In propylene glycol. The LD.
was 100 mg/kg In redwing blackbirds and >100 mg/kg In starlings.
4.2.2. Effects on Flora. The effect of benzyl alcohol on fungus spore
germination was studied by Wilson et al. (1987). This chemical Inhibited
spore germination In both Mon111n1a fructlcola and Botrytls clnerea at a
concentration of 125 yl/8, (131 mg/a). Other studies of benzyl
alcohol's effects on terrestrial flora were not located.
4.3. FIELD STUDIES
Pertinent data regarding the effects of benzyl alcohol on flora and*
fauna In the field were not located In the available literature cited In
Appendix A.
4.4. AQUATIC RISK ASSESSMENT
The lack of an adequate quantity of pertinent data regarding the effects
of exposure of aquatic fauna and flora to benzyl alcohol precluded the
development of a freshwater criterion (U.S. EPA/OWRS, 1986). Available data
are displayed In Figure 4-1. Although studies on Daphnla and mosqultos were
available, these were not used because study details were not provided for
the former, and results were reported 1n nonstandard units for the latter.
Additional data required for the development of a freshwater criterion
Include the results of acute assays with a salmonld fish species, planktonlc
and benthlc crustaceans, an Insect, a nonarthropod and nonchordate species
and an Insect or species from a phylum not previously represented. The
development of a freshwater criterion also requires data from three chronic
toxldty tests and one bloconcentratlon study.
0269d
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TEST TYPE
Family
*1
Chordate (Salmonid-f ish)
#2
Chordate (warmwater fish)
#3
Chordate (fish or amphibian)
#4
Crustacean (planktonic)
*5
Crustacean (benthic)
#6
Insectan
*7
non-Arthropod/-Chordate
#8
New Insectan or phylum
representative
#9
Algae
#10
Vascular plant
GMAVa
(mg/L)
NA
10*>
460°
NA
NA
NA
NA
NA
NA
NA
GMCVa
(mg/L)
NA
NA
NA
NA
NA
NA
NA
NA
>100d
NA
BCFa
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA-Not available
bLCso for bluegHI sunflsh, Lepomis macrochirus
cLCso for fathead minnow, Plmephales promelas
"ECso for effects on photosynthesis and nitrogenase activity In the
blue-green alga, Anabaena Inaeoualls
FIGURE 4-1
Organization Chart for Listing GHAVs, GMCVs and BCFs Required to Derive
Numerical Water Quality Criteria by the Method of U.S. EPA/OURS (1986) for
the Protection of Freshwater Aquatic Life from Exposure to Benzyl Alcohol
0269d
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The lack of pertinent data regarding the effects of exposure of aquatic
fauna and flora to benzyl alcohol precluded the development of a saltwater
criterion (U.S. EPA/OWRS, 1986). Available data are shown In Figure 4-2.
Additional data required for the development of a saltwater criterion
Include the results of acute assays with a chordate species, a nonarthropod
and nonchordate species, a mysld or panaeld crustacean, three additional
nonchordate species and one other species of marine fauna. The development
of a saltwater criterion also requires data from three chronic toxlclty
tests, one test on a species of algae or vascular plant and one bloconcen-
tratlon study.
I
4.5. SUMMARY
Benzyl alcohol was considerably more toxic to bluegllls (LC = 10
mg/i} and tidewater sllversldes (LC5Q = 15 mg/i) In a study by Dawson*
et al. (1977) than It was to fathead minnows (LC = 460 rng/i) In a
study by Mattson et al. (1976). These differences may be species-related,
but the facts that two low values were reported In one study and one high
value was reported 1n another study suggest that differences In experimental
procedures could have affected the results. An LC5Q of 646 mg/a. was
reported In golden orfe (Kn1e et al., 1983), but lack of details prevented
assessment of this study. No effects were reported In larval sea lamprey
(Applegate et al., 1957), blueglll, goldfish or trout (HolUs and Lennon,
1954; Wood, 1954) acutely exposed to 5 mg/8. of benzyl alcohol 1n
screening-type studies. Among Invertebrates, an EC of 400 mg/l was
reported for Daphnla Immobilization (Knle et al., 1983), and LO^g values
of 105-160 a/hectare were reported In mosqultos (Slnnlah, 1983). Among
algae, the EC values for effects on photosynthesis and nltrogenase
activity exceeded 100 mg/a 1n all five species tested (Stratton and Corke,
0269d
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Family
HI
Chordate
#2
Chordate
«3
non-Arthropod/-Chordate
14
Crustacean (Mysid/Panaeid)
#5
non-Chordate
#6
non-Chordate
*7
non-Chordate
#8
Other
#9
Algae
#10
Vascular plant
aNA = Not available
bLCcn for tidewater sllverslde,
GMAVa
(mg/L)
15*
NA
NA
NA
NA
NA
NA
NA
NA
NA
Menldla berylUna
TEST TYPE
GMCVa
-------
1982). The EC5Q for reduced growth was 2600 mg/8, In one species (Knle
et al., 1983). Effects 1n bacteria were reported at concentrations ranging
from 71.4-5083 mg/l (Kaiser et al., 1987; Kn1e et al., 1983; Valshnav,
1986). Studies of terrestrial organisms showed that 131 mg/i of benzyl
alcohol Inhibited spore germination In fungi (Wilson et al., 1987) and that
L05Q values were >100 mg/kg bw In two species of birds (Schafer et al.,
1983).
0269d
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5. PHARHACOKINETICS
5.1. ABSORPTION
Pertinent data regarding the extent and rate of absorption of benzyl
alcohol from Inhalation exposure were not located In the available
literature cited 1n Appendix A.
Benzyl alcohol administered orally by stomach tube to rabbits In a 450
mg/kg dose was rapidly absorbed, as measured by urinary excretion of
hlppurlc acid at 65.7 and 72.8% of the dose at 6 and 24 hours, respectively
(Olack and Lewis, 1928). A 1000 mg dose of an aqueous suspension given to a
r-abbH by stomach tube was similarly absorbed by the excretion of 8254 of the
dose as either glucuronldes or ether-soluble acids (Bray et al., 1951). In
another gavage study 1n rabbits, compounds found In the urine after 24 hours
accounted for 98% of a 250 mg/kg dose of benzyl alcohol, Indicating rapid*
absorption of the compound (Bray et al., 1958). Humans also were found to
absorb a major portion of a 1500-2000 mg dose given orally, as shown by the
excretion of 74-88% of the dose as hlppurlc acid {Snapper et al., 1924).
In an J[n vitro study of the percutaneous penetration of 14C-labeled
benzyl alcohol In human autopsy skin (Menczel and Malbach, 1970), absorption
was measured In an absorption cell as the percent of dose applied to the
epidermal layer of the skin that was found In the normal saline dermal
perfusate after 5 days. Benzyl-7-l4C-alcohol (2.7 mg) was dissolved In 50
pi benzene. The amount of benzyl alcohol that diffused through the skin
ranged from 4.45-32.74%, with the variation thought to be related to the
thickness of the dermal layer. A large proportion of the benzyl alcohol
remained In the epidermal layer of skin, even after the 5-day experimental
period. The ratio of dermal to epidermal retention was generally <1 (mean
of 0.76 for five experiments). In a study using the same methods (Henczel
0269d -19- 11/01/89
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and Malbach, 1972), the dermal/saline solution equilibrium concentration of
benzyl-7-14C-alcohol ranged from 0.232-0.270, and conformed well with the
K of 0.254. The stratum corneum retained the major portion of benzyl
alcohol that was partitioned Into the epidermis.
5.2. DISTRIBUTION
Pertinent data regarding the distribution of benzyl alcohol following
Inhalation or oral exposure were not located In the available literature
cited In Appendix A.
Klmura et al. (1971) administered benzyl alcohol In Intravenous doses of
52 and 105 mg/kg to unanesthetlzed beagles of both sexes. The plasma
half-life was -1.5 hours. The calculated apparent volume of distribution,
11 I/kg, suggested that the major portion of the drug was distributed In
the tissues.
5.3. METABOLISM
A number of older studies reported that benzyl alcohol was rapidly
oxidized to benzole acid, which was then conjugated with glyclne and
excreted by the kidney as hlppurU acid 1n animals and man (Snapper et al.,
1924; Olack and Lewis, 1928; Stekol, 1939). Conjugation of benzole with
glydne Is catalyzed by glydne acyltransferase In the mitochondria!
fraction of the liver (Lebel et al., 1988).
Several studies of benzyl alcohol metabolism from oral administration
have been performed with rabbits. Olack and Lewis (1928) administered
benzyl alcohol to male rabbits by stomach tube (448-450 mg, expressed as
equivalent dose of benzole acid/kg bw) and found that It was rapidly
oxidized to benzole add and excreted In the urine as hlppurlc add,
accounting for 65.754 and 72.8X of the dose at 6 and 24 hours, respectively.
0269d
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Administration of 450 mg/kg sodium benzoate to the rabbits resulted In
similar recoveries, which Indicated that the oxidation of benzyl alcohol to
benzole acid occurred at least as rapidly as the formation and elimination
of hlppuHc acid. A rabbit given 1000 mg of an aqueous benzyl alcohol
suspension by stomach tube excreted 8254 of the dose as either glucuronldes
(2454 of excreted amount) or ether-soluble adds (76% of excreted amount);
however, when doses of 500-1600 mg were administered with glyclne, the
glucuronlde fraction dropped to 2-9%, and the ether-soluble fraction
Increased to 91-98% of the excreted dose (Bray et al., 1951). When the
Initial rate of benzyl alcohol conversion was greater than the maximum rate
of glyclne conjugation, benzole add was found In the blood. Bray et al.
(1958) Investigated the metabolism of benzyl alcohol (suspended 1n water)
administered by stomach tube to rabbits In doses of 250 mg/kg. The*
compounds found In urine after 24 hours, as a percent of the dose (means of
4-6 experiments), were 2% mercapturlc add, 74% glyclne conjugates, 8%
copper-reducing material (as glucuronlc acid) and 14% glucoslduronlc acid,
accounting for 98% of the dose. Humans on a pure milk and flour diet given
1500-2000 mg orally of benzyl alcohol excreted 74-88% of the dose as
hlppurlc add (Snapper et al., 1924),
HcCloskey et al. (1986) gave Intraperltoneal Injections of 500-1100
mg/kg of benzyl alcohol (10% In peanut oil, v/v) to adult CD-I male mice.
Benzyl alcohol appeared In the plasma within minutes of administration at
levels of 11.0-208.4 g/roi. Significant levels of benzaldehyde, an Inter-
mediate In the oxidation, were also found 1n plasma of mice 5 minutes after
doses of benzyl alcohol >700 mg/kg were administered. Benzaldehyde plasma
concentrations of 4.2-15.0 g/mi resulted from doses of 700-1100 mg/kg,
with no benzaldehyde detected In the plasma following doses <700 mg/kg.
0269d -21- 11/01/89
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Neither benzyl alcohol nor benzaldehyde was found In the plasma of control
mice Injected with either saline or peanut oil. At 4 hours after 1ntraper1-
toneal Injection of adults and neonates with benzyl alcohol at 1000 mg/kg,
plasma levels were 60-70 vg/ma for benzyl alcohol and 15-16 yg/ma.
for benzaldehyde In both age groups. No differences were detected In the
pattern of metabolism between mature and neonatal mice. Pretreatment of the
mice with pyrazole, an Inhibitor of alcohol dehydrogenase and the enzyme
responsible for the conversion of benzyl alcohol to benzaldehyde, Increased
levels of benzyl alcohol IR the plasma. Pretreatment of the mice with
dlsulflram, which Inhibits aldehyde dehydrogenase, the enzyme Involved 1n
the conversion of benzaldehyde to benzole acid, markedly Increased plasma
benzaldehyde levels to 3 times that of controls.
In metabolism studies of subcutaneously administered benzyl alcohol, two'
rabbits Injected with 1000 mg of benzyl alcohol excreted 300-400 mg of
hlppurlc add 1n the urine after 24 hours (Stekol, 1939). Stekol (1939)
Injected three rats subcutaneously with 500 mg/kg bw benzyl alcohol and
found that the substance Isolated from pooled 48-hour urine samples was
hlppurlc add (percent of dose not specified).
In a study of benzyl alcohol metabolism and elimination, 14 term (8
male, 6 female) and 9 preterm (5 male, 4 female) neonates received Intra-
venous or Intramuscular loading doses of phenobarbltal containing benzyl
alcohol (Lebel et al., 1988). Benzole add accumulated In the serum more In
preterm Infants than In term Infants, as determined by 10-fold higher
normalized peak level when measured by HPLC (p<0.001). Also, preterm
Infants were found to have greater percentages of benzole add and less
hlppurlc add 1n the urine after doses of benzyl alcohol than term Infants.
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It has been suggested that the Immature livers or kidneys of preterm Infants
may have a reduced capacity to detoxify by glyclne conjugation the amount of
benzole add produced from the oxidation of benzyl alcohol.
Gershanlk et al. (1982) administered benzyl alcohol (0.9%) to neonates
at a level of 99-234 mg/kg. The compound was found In the serum at a mean
concentration of 1.QUO.13 mmol/i. Mean benzole acid and hlppurlc acid
concentrations In the urine were 0.377^0.119 and 1.469_tQ.25 mmol/a,
respectively. In Infants that had not received benzyl alcohol, benzole add
and hlppurlc acid were found 1n the urine at much lower levels (0.029+0.009
and 0.765-0.089 mmol/!., respectively).
An in vitro metabolism study using guinea pig liver mlcrosomes (Sloane,
1965) showed that 14C-phenol could be formed from 14C-benzyl alcohol
(ring-labeled); there was no mlcrosomal metabolism of benzole add (In the'
presence of NAOPH) to phenol.
5.4. EXCRETION
Orally administered benzyl alcohol Is converted to benzole add, which
Is then conjugated with glydne and excreted 1n the urine as hlppurlc add
In animals and man (Snapper et al., 1924; Dlack and Lewis, 1928). In the
study by Dlack and Lewis (1928), 450 mg of benzyl alcohol administered to
male rabbits by stomach tube was accounted for as hlppurlc add In the urine
at 65.7 and 72.8% of the dose at 6 and 24 hours, respectively. Doses of 250
mg/kg administered to rabbits by gavage were recovered In the urine after 24
hours as (percent of dose): 2% mercapturlc add, 74% glyclne conjugates, 8%
copper-reducing material (as glucuronlc add) and 14% glucoslduronlc acid,
accounting for 98% of the dose (Bray et al., 1958). A dose of 1000 mg given
by stomach tube to one rabbit was excreted as either glucuronldes (24% of
excreted amount) or ether-soluble adds (76% of excreted amount), accounting
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for 8254 of the dose, while glydne administered with 500-1600 mg of benzyl
alcohol resulted In the glucuronlde fraction dropping to 2-9% and the
ether-soluble fraction rising to 91-98% of the excreted material (Bray et
a!., 1951). Humans given 1500-2000 mg of benzyl alcohol orally while on a
pure milk and flour diet excreted 74-88% of the dose as hlppurlc add
(Snapper et al., 1924).
Following Intraperltoneal Injections of benzyl alcohol In peanut oil to
adult and neonatal mice, McCloskey et al. (1986) suggested that benzyl
alcohol was eliminated by saturable kinetics, so that small Increases In
dosages would result 1n disproportionate levels In the plasma.
Subcutaneously administered benzyl alcohol, In dosages of 1000 mg given
in three portions 2 hours apart to rabbits, was recovered in the urine as
300-400 mg of hlppurlc acid after 24 hours (Stekol, 1939).
5.5. SUMMARY
No data were found regarding the extent and rate of absorption of benzyl
alcohol from Inhalation exposures. Benzyl alcohol was rapidly absorbed from
orally administered doses In rabbits (Dlack and Lewis, 1928; Bray et al..
1951, 1958) and man (Snapper et al., 1924). An hi vitro study of percuta-
neous penetration of 14C-benzyl alcohol Indicated that a major portion of
the compound remained in the stratum corneum of the epidermal layer of human
skin.
No Information was found regarding distribution of benzyl alcohol
following inhalation or oral exposure. In dogs, the calculated apparent
volume of distribution suggested that the major portion of Intravenously
administered benzyl alcohol was distributed In the tissues (Kimura et al.,
1971).
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Metabolism of benzyl alcohol Involves rapid oxidation to benzole add
using a benzaldehyde Intermediate. Benzole acid Is further metabolized to
hlppurlc acid, which Is excreted In the urine In both animals and man (Bray
et al., 1951, 1958; Dlack and Lewis, 1928; Stekol, 1939; HcCloskey et al.,
1986; Snapper et al., 1924). Ring-labeled 14C-benzyl alcohol was shown to
form 14C-phenol 1n guinea pig liver mlcrosomes where there was no
mkrosomal metabolism of benzole add (Sloane, 1965).
In humans, the.Immature livers and kidneys of preterm Infants appear to
have a reduced capacity to metabolize benzyl alcohol by glyclne conjugation
(Lebel et al., 1988). No differences were detected In the pattern of
metabolism between adult and neonatal mice {HcCloskey et al., 1986). Small
Increases In the dose resulted In disproportionate plasma levels, Indicating
that benzyl alcohol was eliminated by saturable kinetics.
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposure. Workers occupational1y exposed for an
undetermined duration to a high vapor concentration of a mixture containing
benzyl alcohol, benzene and ester solvents reported temporary headaches,
vertigo, nausea, diarrhea and weight loss (Treon and Staslk, 1983).
6.1.1.1. SUBCHRONIC Pertinent data regarding toxlclty from
subchronk Inhalation exposure of benzyl alcohol were not located 1n the
available literature cited In Appendix A.
6.1.1.2. CHRONIC Pertinent data regarding toxlclty from chronic
Inhalation exposure of benzyl alcohol were not located 1n the available
literature dted In Appendix A.
6.1.2. Oral Exposure.
6.1.2.1. SUBCHRONIC In 16-day and 13-week studies, F344/N rats and
B6C3F1 mice were gavaged with technical-grade benzyl alcohol (99X pure)
suspended In corn oil (NTP, 1988). In the shorter experiment, groups of
five males and five females of each species, 8 weeks old at the start of the
study, were administered 0 (vehicle only), 125, 250, 500, 1000 and 2000
mg/kg 5 days/week for 12 doses. (Animals In the 125 rag/kg dose groups were
unintentionally administered a 10-fold higher dose on days 8 and 9 of
treatment.) Animals were observed twice dally and were weighed Initially
and once a week. All animals were necropsled at the conclusion of the
study, and hlstologlc examinations were performed on three male and two
female rats and four male mice In the 500 mg/kg dose group and on three
female mice In the 1000 mg/kg dose group. All rats In the 2000 mg/kg dose
group and 2/5 males and 3/5 females In the 1000 mg/kg dose group died before
completion of the study. At the end of the study, mean body weight of the
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male rats In the 1000 mg/kg dose group was 1854 lower than that of the
controls. Rats receiving the two highest dosages were lethargic and had
blood around the nose and mouth and In the urinary and gastrointestinal
tracts; these rats also had hemorrhages under the skin. Hales In the 500
and 1000 mg/kg dose groups, and females In the 250 and 500 mg/kg dose
groups, had rough hair coats. There were no hlstopathologlc effects
attributable to treatment In any rats at any dosage level.
Effects In mice from the 16-day gavage study were similar to those found
In rats. All mice at the 2000 mg/kg level, and 1/5 males and 2/5 females at
the 1000 mg/kg dosage level, died before completion of the study. Male mice
receiving 500, 1000 and 2000 mg/kg and female mice receiving 1000 and 2000
mg/kg benzyl alcohol were lethargic and had rough hair coats. At necropsy,
blood was found In the urinary bladder of mice 1n the 1000 and 2000 mg/kg.
dose groups. Hlstopathologlc effects attributable to treatment were not
found In any mice at any dosage level.
In the 13-week studies, groups of 10 male and 10 female rats and mice
were dosed with 0 (vehicle only), 50, 100, 200, 400 and 800 mg/kg of benzyl
alcohol 5 days a week for the duration of the experiment. Rats were 7-8
weeks old and mice were 7-9 weeks old when placed on the study. Animals
were observed twice dally, weighed Individually at the beginning and end of
the study and weighed as groups once a week during the study. Moribund
animals were sacrificed. All animals were necropsled; those In the control
groups and the 800 mg/kg treatment groups were examined h1stopatholog1cally.
Microscopic examinations of the brains were performed on animals in the 400
mg/kg treatment groups of both species and on all mice that died before
termination of the study. Following dosing by gavage, 8/10 male rats admin-
istered 800 mg/kg and one given 200 mg/kg died; four of the deaths at the
0269d -27- 11/01/89
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highest dose were attributed to the gavage procedure. In the female rats,
one vehicle control, one In the 400 mg/kg dose group and two in the 800
mg/kg dose group died after being dosed; all deaths except one at the
highest dose were accidental. Following treatment, rats of both sexes In
the 800 mg/kg dose group showed signs of neurotoxldty Including staggering,
labored breathing and lethargy; at the end of the study, they had mean body
weights lower than that of vehicle controls (7% lower for males, 5% lower
for females). Five of 10 males 1n this dose group had blood around the nose
and mouth after 8 weeks of treatment. At this dose level, hlstopathologlc
effects attributable to treatment Included necrosis of the dentate gyrus of
the hippocampus In 9/9 males and 7/7 females. Skeletal muscle necrosis
(5/10), thymlc congestion, hemorrhage and atrophy (8/10) and nephrosls 1n
the kidney (6/9) were also observed In male rats at this highest dosage*
level.
In mice, no deaths were observed In the control groups, In the two lower
dosage groups in males or In the 200 mg/kg dose group In females; one or two
deaths were seen in the other dosage groups, but the only deaths not related
to the gavage procedure were of two females In the high-dose group. Final
mean body weights were 5 and 8% less than those of vehicle controls 1n the
400 and 800 mg/kg female dose groups, respectively; all other groups had
mean body weights within 5% of controls. In the first 2 weeks of the study,
male and female mice staggered after receiving the 800 mg/kg dosage. No
hlstopathologlc effects attributable to treatment were seen In the mice.
All groups had some mice with a chronic Interstitial pneumonia, which is
characteristic of a Sendai Infection.
6.1.2.2. CHRONIC --Two-year toxicology and carcinogenesis studies on
benzyl alcohol were conducted using groups of 50 male and 50 female F344/N
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rats and 86C3F1 mice (NTP, 1988). Technical-grade benzyl alcohol (99% pure)
mixed In corn oil was administered by gavage 5 days/week for 103 weeks to
rats In dosages of 0 (vehicle control), 200 and 400 mg/kg, and to mice In
dosages of 0, 100 and 200 mg/kg. Although mice In the 100 and 200 mg/kg
treatment groups were unintentionally dosed with 375 and 750 mg/kg
a-methylbenzyl alcohol for 4 days during week 80, no adverse effects were
noted. Animals were 8-9 weeks old when treatment began. Animals were
observed twice a day; they were weighed Initially, then once a week for 12
weeks and once a month thereafter. All animals were necropsled, and hlsto-
loglc examinations on a number' of organs and tissues were performed on all
female rats and on male rats and mice In the vehicle control and high-dose
groups, male rats and mice that died before the 22nd month and male rats and
mice with gross lesions. The pituitary gland and testes were examined In'
low-dose male rats; the adrenal gland, brain, kidney, liver and lung were
examined In low-dose male mice; and the brain, liver, spleen and uterus were
examined In low-dose female mice.
Survival of the benzyl alcohol-treated female rats at both dose levels
was significantly lower than that of the vehicle controls, the low-dose
group after week 71 and the high-dose group after week 50. However, many of
the deaths In the treated rats, but considerably fewer 1n the controls, were
related to the gavage procedure. Respectively, accidental and nonacddental
deaths In groups of 50 control, low- and high-dose female rats were 1, 13,
17, 16, 13 and 20. Survival of control and treated male rats and mean body
weights for all rats within sex groups were generally comparable throughout
the study. No clinical signs that could be attributed to the treatment were
observed. Rats In control and treated groups at both dose levels exhibited
swelling In the cervical region, pink eyes and red exudate around the eyes,
0269d -29- 11/01/89
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signs of slalodacryoadenltls, which was confirmed In sentinel animals. Rats
In the high-dose groups showed an Increased Incidence of cataracts (males:
control, 2/50; low dose, 3/50; high dose, 23/50; females: 2/50, 2/50, 16/50)
and retinal atrophy (males: 1/50, 3/50, 24/50, females: 1/50. 3/50, 20/50),
but this was attributed to those animals being housed In the cages on the
top racks, permitting greater exposure to fluorescent lighting. High-dose
male rats also had a higher Incidence of epithelial hyperplasla of the fore-
stomach (control, 0/48; low dose, 0/19; high dose, 4/50). Benzyl alcohol-
treated rats that died before completion of the study had an Increased
Incidence of hemorrhage and foreign material 1n the respiratory tract.
Dose-related effects in the respiratory tracts of males Included Increases
In acute Inflammation In the nasal tract, hemorrhages In the larynx and
edema In the lungs. Higher Incidences of hemorrhage and foreign material In'
the lungs were seen In both male and female dosed rats.
In female mice, survival was significantly lower In the control group
than In the high-dose group after the 74th week. Survival did not differ
between other groups of either sex. High-dose male and female mice had an
Increased Incidence of corpora amylacea (males: control, 15/49; low dose,
21/48; high dose, 22/50; females: 14/50, 15/48, 25/50), although this was
noted to be "a common, spontaneously occurring lesion." High-dose male mice
had an Increased Incidence of lung congestion, and low-dose male and female
mice had an Increased Incidence of foreign material In the lungs; neither of
these effects was statistically significant.
6.1.3. Other Relevant Information. In an acute Inhalation study reported
by Smyth et al. (1951), six rats (strain and sex not specified) were exposed
to 1000 ppm benzyl alcohol for 8 hours and observed for 14 days. Three of
the six rats died. The maximum time that rats could be exposed to saturated
vapors of benzyl alcohol without death resulting was 2 hours.
0269d
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Single oral dose LD5Qs (Intubated) of 2080 and 1040 mg of benzyl
alcohol/kg bw were reported for rats (20 animals) and rabbits (9 animals),
respectively (Graham and Kulzenga, 1945). Within 30 minutes of dosing, both
rats and rabbits became prostrate until they died. Intubated benzyl alcohol
resulted In acute oral <-D50s of 1230 mg/kg (95% confidence Intervals of
1130-1330) 1n rats from a 100% solution and 1580 mg/kg (95% confidence
Intervals of 1410-1770} In mice from a 25% solution In corn oil (Jenner et
al., 1964). In the rats, death occurred within 1 hour to 4 days; In mice,
death resulted within 2-18 hours. Other signs of toxldty were depression
In both rats and mice, coma within 10-15 minutes In rats and excitability
for 3-4 days In rats.
Gruber (1923) reported that pure benzyl alcohol In volumes of 2.5-10.8
mi administered by stomach tube to dogs weighing 12.5-27 kg caused*
catharsis and emesls, usually within minutes of dosing. In other studies,
1.0-5.0 mi of pure benzyl alcohol administered IntraperUoneally to dogs
and rabbits and Intramuscularly to rabbits caused a marked Increase In urine
flow {Gruber, 1924).
Benzyl alcohol elicited an antlarrhythmlc effect 1n dogs within 30-60
seconds after an Intravenous Injection of 0.1-0.4 ml/kg of a 4% solution
(Elchbaum and Yasaka, 1976). A similar response 1n rats occurred after an
injection of 0.2-0.6 ml/kg of 1-2% benzyl alcohol. In cats, subcutaneous
administration of 50-100 ml/kg of lactated Ringer's solution containing
1.5% benzyl alcohol as a preservative (doses of benzyl alcohol were 392 and
660 mg/kg) resulted In toxic signs Including ataxla, hyperesthesla, fasdcu-
latlons of head and ear muscles, slight but Increasingly severe depression,
coma, respiratory failure, convulsions and death (Culllson et al., 1983).
0269d -31- 11/01/89
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Lower doses produced a slower advancement of signs and longer progression,
but death resulted In all cases. Cats apparently have a pronounced sensi-
tivity to drugs containing benzene rings, particularly phenol. This Is due,
In part, to a relative deficiency In their ability to detoxify xenoblotlcs
by glucuronlc acid conjugation because of a lack of UDP-glucuronyltransfer-
ase activity with respect to some substrates (Wllcke, 1984).
3ones (1967) reported an acute dermal LD5Q of <5.0 ml/kg In guinea
pigs. Cats were particularly sensitive to dermal application of benzyl
alcohol, with an average survival time of 22 hours (two animals) after one
20 ma application of 100% benzyl alcohol to their shaved backs (Graham and
Kulzenga, 1945). Signs of toxlclty Included excessive salivation and
twitching at the site of application. Later, animals exhibited generalized
tremor, muscular 1ncoord1nat1on, hind limb paralysis and violent convul-'
slons, sometimes leading to prostration, and then respiratory failure and
death. The cats' body weights decreased by 200-400 g, but probably from
Inability to eat and drink.
Grant (1974) reported that "severe strlate keratopathy developed,
progressing to chronic edema of the cornea, with vesicles, bullae and dirty
plgtnented appearance of the endothellum" following Intraocular use of a
benzyl alcohol-preserved saline solution during cataract surgery 1n humans.
In a comparative study of the Irrltancy of synthetic perfumes to the
skin of animals and humans, Motoyoshl et al. (1979) found that benzyl
alcohol (>97% pure) had little or no Irritation response In guinea pigs or
miniature swine, but was moderately Irritating to rabbits when applied at
100% concentration; In humans, benzyl alcohol was mildly Irritating when
applied to the skin In a 32% solution In acetone. In these tests, no
correlation was found between the animal and human tests for the synthetic
perfumes.
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HypersensHWIty reactions In humans have been reported after the
parenteral administration of Injectable drugs or diluents containing benzyl
alcohol as a bacteMostatlc agent. Grant et al. (1982) noted that a
55-year-old man showed symptoms Including sudden onset of fatigue, nausea
and diffuse angloedema following an Intramuscular Injection of vitamin B,?
that contained benzyl alcohol as a preservative. A skin test consisting of
Intracutaneous Injections of vitamin B12, with and without benzyl alcohol
(0.9%) as a preservative, and saline with benzyl alcohol revealed a positive
wheal-and-flare response only to the solutions containing benzyl alcohol.
Signs of an allergic dermatitis (erythema, palpable edema and raised
borders) were seen In a 46-year-old woman treated with sodium tetradecyl
sulfate, formulated with 1% benzyl alcohol (Shmunes, 1984). A patch test of
5% benzyl alcohol In petrolatum showed a moderately severe response at 48'
hours, while a patch test of the Injectable treatment solution containing IX
benzyl alcohol was negative. In another case, a 49-year-old male patient
developed a hypersensH1v1ty reaction characterized by fever and a maculo-
papular rash on the chest and arms after receiving three different Injec-
tions for antlneoplastlc chemotherapy, all preserved with benzyl alcohol
(Wilson et al., 1986). The sensitivity was also confirmed with skin testing.
Contact allergies have also been reported following use of benzyl
alcohol-containing topical solutions or creams. A 36-year-old woman and a
43-year-old man developed contact dermatitis at the site of application of a
perfume and an aftershave lotion, respectively, both of which contained
benzyl alcohol (Fisher, 1975). Both patients responded positively to patch
tests with 1% benzyl alcohol In petrolatum, but negatively to scratch,
Intradermal and subcutaneous Injections of 1% benzyl alcohol In saline.
0269d -33- 11/01/89
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Allergic reactions were also reported In a 44-year-old white woman using a
sunscreen (Edwards, 1981), a 46-year-old woman being treated with a topical
cortlcosterold (Lazzarlnl, 1982) and a 41-year-old Japanese woman prescribed
a cream for tinea pedls {Shojl, 1983). In all cases, the solutions
contained benzyl alcohol, and all patients had a positive reaction to a
patch test with benzyl alcohol In petrolatum. In a study of allergic
reactions to a number of perfume Ingredients, 4 of 242 patients reacted
positively to a benzyl alcohol skin test (Van Joost et al., 1985).
Several reports describe toxldty In preterm neonates exposed Intra-
vascularly to solutions that contained benzyl alcohol as a preservative.
Brown et al. (1982) gave details of 10 of 16 low birth weight Infants
(<1250 g) who died following exposure to bacterlostatlc normal saline
containing benzyl alcohol so that the amount of benzyl alcohol received was*
minimally 130 mg/kg/day, the average was 191 mg/kg/day and the maximum was
405 mg/kg/day. The symptoms of toxldty, seen between day 2 and 4 of admin-
istration, were slowly progressive bradycardla, often with gasping respira-
tion (resulting In the name "gasping syndrome"), seizures, unresponslveness
and extremely depressed EEGs, characteristic of progressive metabolic
acldosls. Gershanlk et al. (1982) reported that 10 low birth weight or
premature Infants developed "gasping syndrome" following hospltallzatlon and
exposure to benzyl alcohol through administration of bacterlostatlc saline.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding carclnogenldty from Inhala-
tion exposure to benzyf alcohol were not located In the available literature
cited In Appendix A.
6.2.2. Oral. In 2-year toxicology and carclnogenesls studies using
F344/N rats and B6C3F1 mice (see Section 6.1.2.2.), animals were gavaged 5
0269d
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days/week with technical-grade benzyl alcohol (99% pure) suspended In corn
oil to achieve concentrations of 0, 200 and 400 mg/kg for rats and 0, 100
and 200 mg/kg for mice (NTP, 1988). There was an Increased Incidence of
epithelial hyperplasla In the forestomachs of the high dose male rats
(control, 0/48; low dose, 0/19; high dose, 4/50), and 1/19 low-dose and 1/50
high-dose male rats had squamous cell paplllomas In the same tissue. A
negative trend was seen 1n the Incidence of adenomas and adenomas or
carcinomas (combined) of the anterior pituitary gland of female rats;
vehicle controls had a higher Incidence than the high-dose group.
There was a slightly Increased Incidence of adenomas of the adrenal
cortex 1n high-dose male mice (control, 0/48; low dose, 0/44; high dose,
3/48; p=0.044 In life table and Incidental tumor tests); despite the
occurrence of this tumor being somewhat uncommon historically In corn'
oll-gavaged controls, the number that occurred was within the historical
range, and therefore not attributed to the compound treatment. There was a
negative trend of adenomas of the Harderlan gland In male mice, but the
Incidences In the dosed groups were not significantly different from the
vehicle controls.
6.2.3. Other Relevant Information. Pertinent data regarding the carclno-
genldty from other routes of exposure to benzyl alcohol were not located In
the available literature cited 1n Appendix A.
6.3. MUTAGENICITY
Benzyl alcohol has been tested for mutagenlclty and clastogenlclty In a
number of assay systems. In a short-term mutagenlclty test used by the NTP,
benzyl alcohol (99.8% pure) was assayed at a minimum of five dose levels In
a prelncubatlon modification of the Salmonella/mammalian mlcrosome assay
(Hortelmans et al., 1986). It did not produce reverse mutations 1n
0269d -35- 11/01/89
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Salmonella typhlmurlum strains TA1535, TA1537, TA97, TA98 and TA100 1n the
presence or absence of Aroclor !254-1nduced rat and hamster metabolic
activating systems. Similar results were reported for benzyl alcohol (3
oinol/plate) by Florin et al. (1980) after testing constituents of tobacco
smoke for mutagenlclty in four strains of S. typhlmurlum with and without
S-9 from Aroclor-lnduced rats. Rogan et al. (1986) also reported that
benzyl alcohol was not mutagenlc 1n two strains of S. typhlmurlum (TA98 and
TA100), but the presence or absence of an activation system was not noted.
Ishldate et al. (1984) also found benzyl alcohol to be negative at a maximum
dose of 10 mg/plate In reverse mutation assays using £. typhlmurlum strains
7A92, TA1535, TA100, TA1537, TA94 and TA98, with and without S-9 activation.
Benzyl alcohol was not mutagenlc In E_. coll WP2 uvrA. It exhibited
antlmutagenlc activity 1n a test In £. col1 WP2 uvrA (trp~) pretreated*
with furylfuramlde (AF-2) without a cytotoxlc effect In the bacteria (1035
jig/m8. reduced the number of AF-2-1nduced trp~ revertants to 50%), but
did not suppress the mutagenlc activity of N-methyl-N'-nltrd-N-nltrosoguanl-
dine. However, In a rec assay using Bacillus subtil Is M45 (rec~ ) and H17
(rec*), benzyl alcohol was found to cause DNA damage to the organisms
(Kuroda et al., 1984; Yoo, 1986). In an experiment designed to determine
the practicality of using P3478 (pol A") E,. coll. a repair-deficient
mutant, 1n predicting the carcinogenic potential of compounds, benzyl
alcohol gave a negative response at 10-50 pi and had reduced toxlclty when
tested with metabolic activation at 10 »i (Muck et al., 1976).
In a mlcronucleus test conducted In six 8-week-old male ddY mice, benzyl
alcohol was administered In a single Intraperltoneal Injection (Hayashl et
al., 1988). From each mouse, 1000 PCEs were scored at low and high power,
and the number of MNPCEs was noted. The ratio of PCEs to total erythrocytes
02690
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was also determined. Concurrent negative and positive controls, as well as
historical control data from the testing laboratory, were evaluated to
determine a true spontaneous level of frequencies of HNPCEs. Benzyl alcohol
was negative 1n the hi vitro chromosomal aberration test, meaning that the
total Incidence of cells with aberrations (Including gaps) was <4.9%.
Ishldate et al. (1988) also reported negative results when benzyl alcohol
was tested 1n mammalian cell culture at 1000 yg/mi (9.2 mM) for 48 hours.
Haters et al. (1982) found that benzyl alcohol did not Induce DNA
damage, nor did It Inhibit growth of human alveolar cells, A549, when added
to the medium at <0.5 mM concentration.
The evidence for mutagenlclty of benzyl alcohol was equivocal 1n the
L5178Y tk\\/tk~ mouse lymphoma cell forward mutation assay (McGregor et
al., 1988).
6.4. DEVELOPMENTAL TOXICITY
The only Information available on teratogenldty of benzyl alcohol Is
from a study In chick embryos Injected with 0.01-0.02 mil of undiluted
benzyl alcohol either before Incubation or within the first 7 days of Incu-
bation (Duralswaml, 1953). There were a number of embryonic abnormalities,
but because many of the treated embryos did not survive to day 11 of
Incubation, and an anatomic and physiologic maternal-fetal relationship 1s
lacking, this test was judged unsuitable for determining teratogenlc risk to
humans.
6.5. OTHER REPRODUCTIVE EFFECTS
Benzyl alcohol was tested In mice for possible embryotoxlc, fetotoxlc
and neonatal toxic responses In a study that screened compounds for
potential reproductive hazard (Hazelden, 1983; Hardln et al., 1987). Fifty
SPF, pregnant female CD-I mice, 42-60 days old at the start of the study,
0269d -37- 11/01/89
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were gavaged with benzyl alcohol mixed 1n distilled water at 750 mg/kg bw,
the MTD In this strain of mice. Fifty mice given only vehicle were used as
controls. Mice were treated from gestation days 7-14, the period of maximum
organogenesls. Mice were observed once dally for clinical signs and twice
dally for mortality. Mice that died were not necropsled. Body weights of
the dams were recorded Initially, on gestation days 7 (which determined the
dally dosage) and 18, and on day 3 postpartum. Pups/litter and total Utter
weights were recorded within 12 hours of parturition (day 1 postpartum) and
again 48 hours later. Three Indices of reproductive performance determined
for the compound and the concurrent vehicle control Included: reporductlve
Index = number of animals pregnant/number mated; gestation Index = number of
pregnancies resulting In live pups/number of pregnancies; viability Index =
number of pups alive on day 3 post par turn/number alive on day 1 postpartum,'
Reproductive and gestation Indices and mean gestation lengths were not
significantly different In treated and control mice. Mean day 18 maternal
body weight was significantly less In treated mice than In controls for both
unadjusted data (p<0.05) and data adjusted for day 1 postpartum litter size
(p<0.001). Day 3 post par turn maternal weight was less (p<0.05), and maternal
body weight gain over the treatment period (gestation days 7-18) was less
using both unadjusted (p<0.05) and adjusted data (p<0.001) when comparing
treated animals with the vehicle controls. Differences from controls
recorded In Utter weight data Included lower mean Utter mean pup weight on
day 1 postpartum (p<0.01); lower mean litter mean pup weight on day 3
postpartum (p<0.001); lower mean litter weight change days 1-3 postpartum
(p<0.05); and lower mean Utter mean pup weight change days 1-3 postpartum
(p<0.001). Signs of maternal toxlclty Included Increased dam mortality,
cyanosis, dyspnea, hypothermia, behavioral pathologies and pHoerectlon.
0269d
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In a preliminary, short-term, jm vWo developmental toxldty test In
mice, benzyl alcohol was given a score of Intermediate priority classifica-
tion or "no decision" when rated according to maternal toxldty relative to
five Indices of potential developmental toxldty, I.e., the proportion of
pregnant survivors that produced a Utter of at least one live born pup,
average Utter size and pup weight at birth, and average pup survival and
weight gain to 3 days of age (York et al., 1988). No other Information was
given.
6.6. SUMMARY
No Information was located regarding subchronlc or chronic exposure to
benzyl alcohol by Inhalation. Systemic effects from a 16-day gavage study
using male and female F344/N rats and B6C3F1 mice at doses of 0, 125, 250,
500, 1000 and 2000 mg/kg given 5 days/week Included Increased mortality and-
lethargy In both species at doses >1000 mg/kg, mean body weights 18% lower
than controls In male rats receiving 1000 mg/kg, unusual bleeding In male
rats and mice at >1000 mg/kg and rough hair coats In male rats at the 500
and 1000 mg/kg, In female rats at 250 and 500 mg/kg, In male mice at >500
mg/kg and In female mice at >1000 mg/kg (NTP, 1988). No hlstopathologlcal
effects attributable to treatment were noted In either sex of either
species. Effects on rats and mice from 91-day treatment at doses of 0, 50,
100, 200, 400 and 800 mg/kg given 5 days/week were similar to the shorter-
term experiment. There was Increased mortality at the highest dosage In
male rats and female mice (and possibly female rats); other deaths were
attributed to the gavage procedure. Signs of neurotoxlclty followed dosing
at 800 mg/kg 1n rats and mice, but this was considered an acute effect.
Mean body weights of the highest dosage rats of both sexes and the female
mice receiving >400 mg/kg were slightly lower than those of controls. Male
0269d -39- 11/01/89
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rats at the 800 mg/kg level exhibited hlstopathologlcal effects of the
hippocampus, thymus, kidney and skeletal muscle, as well as unusual
bleeding; female rats at this dose also showed necrosis of the hippocampus.
No hlstopathologlcal effects attributable to treatment were seen In the mice.
Chronic oral studies consisted of 103-week gavage studies In rats and
mice (NTP, 1988} and a developmental toxlclty and reproduction study 1n mice
by Hazelden (1983). In the NTP (1988) study, rats and mice of both sexes
were given doses of 0, 200 and 400 mg/kg and 0, 100 and 200 mg/kg, respec-
tively, administered 5 days/week for 2 years. Survival of the female rats
at both dose levels was significantly lower than that of vehicle controls.
However, many of the deaths were gavage-related and not compoundTrelated.
High-dose male rats had a higher Incidence of epithelial hyperplasla of the
forestomach, and a squamous cell papllloma was seen In one male rat In the*
high- and low-dose groups. In female mice, survival 1n the high-dose group
was significantly higher than 1n controls after the 74th week. Survival did
not differ among other groups of either sex. Although mice were treated
with lower doses of benzyl alcohol, they were still the less sensitive
species, since there were no toxlcologlcally significant effects even at the
200 mg/kg dose, which produced systemic effects In the rats.
In acute studies, rats died within 14 days after exposure to 1000 ppm
(4422 mg/m3) of benzyl alcohol for 8 hours (Smyth et a!., 1951). Single
oral-dose LD5Qs 1n animals range from -1000-2000 mg/kg (Jenner et al.,
1964; Graham and Kulzenga, 1945). The average survival time of cats was 22
hours from one 20 mi application of 100% benzyl alcohol to their shaved
backs (Graham and Kulzenga, 1945). Cats have a pronounced sensitivity to
drugs containing benzene rings Is due, In part, to a relative deficiency In
their ability to detoxify xenoblotlcs by glucuronlc add conjugation
(Wllcke, 1984). An acute dermal ID of <5.0 ml/kg was reported for
0269d
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guinea pigs {Jones, 1967). Benzyl alcohol reportedly causes severe eye
problems following Us use 1n ocular surgery (Grant, 1974), dermal Irrita-
tion 1n rabbits and humans (Motoyoshl, 1979), hypersensltlvlty reactions
(Grant et al., 1982; Shmunes, 1984; Wilson et al., 1986) and contact
allergies In humans (Fisher, 1975; Edwards, 1981; Lazzarlnl, 1982; Shojl,
1983; Van Joost et al., 1985).
A higher Incidence of preterm Infant mortality resulted from Intravascu-
lar and Intramuscular administration of drugs containing benzyl alcohol as a
preservative, so that dosages averaged 191 mg/kg/day (Brown et al., 1982).
No Information was found regarding carclnogenlclty from Inhalation
exposure to benzyl alcohol. A 2-year gavage study using rats and mice with
doses of 0, 200 and 400 mg/kg, and 0, 100 and 200 mg/kg, respectively, was
negative for carclnogenlclty under the conditions of the study (NTP, 1988).
Benzyl alcohol was negative 1n reverse mutation assays with S. typhl-
murlum. with and without metabolic activating systems (Hortelmans et al.,
1986; Florin et al., 1980; Rogan et al., 1986; Ishldate et al., 1984) and In
tests with E_. coll WP2 uvrA, but It caused DNA damage 1n a rec assay with B_.
subtmis (Kuroda et al., 1984; Yoo, 1986). It was negative In a micro-
nucleus test 1n ddY mice (Hayashl et al., 1988) and In mammalian cell
culture (Ishldate et al., 1988). Benzyl alcohol did not Induce DNA damage
In human alveolar cells (Waters et al., 1982). In the mouse L5178Y/tk*"/-
lympnoma forward mutation assay, results were equivocal (McGregor et al.,
1988).
In a reproductive and developmental toxlclty study, gavaged doses of 750
mg/kg/day given to pregnant mice on gestation days 7-14 resulted 1n lower
mean Utter and pup weights, and signs of maternal toxlclty Including lower
mean body weights and Increased mortality (Hazelden, 1983; Hardln et al.,
1987).
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUNAN
The Flavor and Extract Manufacturers Association reported that benzyl
alcohol was granted GRAS (generally recognized as safe) status (FEMA, 1965),
and the FDA has approved Us use In food (Opdyke, 1974).
Because of reports of fatalities In newborns weighing <2.5 g that had
been exposed to benzyl alcohol through bacterlostatlc solutions used for
flushing Intravenous catheters, the FDA recommended 1n a letter to pediatri-
cians, hospital pharmacists and hospital administrators, that "solutions
used to flush intravascular catheters or for diluting or reconstituting
medications In newborns not contain benzyl alcohol or any other preserva-
tive" (Anonymous, 1982).
7.2. AQUATIC
Guidelines and standards for the protection of aquatic life from
exposure to benzyl alcohol were not located In the available literature
cited In Appendix A.
0269d
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the carclnogenldty of
benzyl alcohol to animals or humans from Inhalation exposure were not
located In the available literature cited In Appendix A.
8.1.2. Oral. Benzyl alcohol was negative for carclnogenldty In 103-week
gavage studies In rats at dosage levels of 200 and 400 mg/kg administered 5
days/week (143 and 286 mg/kg/day) and In mice at dosage levels of 100 and
200 mg/kg (71 and 143 mg/kg/day} (NTP, 1988).
8.1.3. Other Routes. Pertinent data regarding the carclnogenldty of
benzyl alcohol to animals or humans from other routes of exposure were not
located In the available literature cited In Appendix A.
8.1.4. Weight of Evidence. No data were located regarding the carclno-*
genldty of benzyl alcohol to humans. In a well designed and well conducted
study, there was no evidence of carcinogenic activity from benzyl alcohol
administered orally by gavage 5 days/week for 103 weeks to male or female
F344/N rats at doses of 200 and 400 mg/kg, or to male or female B6C3F1 mice
at doses of 100 and 200 mg/kg (NTP, 1988), Applying guidelines for carcino-
genic risk assessment adopted by the U.S. EPA (1986b), benzyl alcohol Is
assigned to Group E, evidence of noncarclnogenlclty for humans.
8.1.5. Quantitative Risk Estimates.
8.1.5.1. INHALATION A complete lack of data precludes estimation
of carcinogenic potency of benzyl alcohol from Inhalation exposure.
8.1.5.2. ORAL The only carclnogenldty data located regarding
benzyl alcohol were the negative gavage studies In rats and mice by NTP
(1988). Quantitative estimation of carcinogenic potency cannot be performed
for oral exposure to benzyl alcohol.
0269d -43- 11/01/89
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8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME (SUBCHRONIC) Pertinent data regarding
the subchronlc Inhalation toxlclty of benzyl alcohol were not located 1n the
available literature cited In Appendix A; therefore, derivation of an RfD
for subchronlc Inhalation exposure Is not possible.
8.2.1.2. CHRONIC Pertinent data regarding the chronic Inhalation
toxlclty of benzyl alcohol were not located In the available literature
cited 1n Appendix A; therefore, derivation of an RfD for chronic Inhalation
exposure Is not possible.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME (SUBCHRONIC) -- Subchronlc gavage studies
on mice and rats were conducted for 16 days at dosages of 0, 125, 250, 500,*
1000 and 2000 mg/kg given 5 days/week (converted doses: 0, 89, 179, 357, 714
and 1429 mg/kg/day) and 91 days at dosages of 0, 50, 100, 200, 400 and 800
mg/kg given 5 days/week (converted doses: 0, 36, 71, 1435, 286 and 571
mg/kg/day} (NTP, 1988). From the 16-day study. Increased mortality was
reported In rats and mice at doses of >1000 mg/kg (Recs. #13, 16). Other
signs of toxlclty at >1000 mg/kg In male rats Included decreased body
weights, lethargy, hemorrhaglng under the skin and blood In the urinary and
GI tracts (Rec. #13). At dosages of >500 mg/kg (LOAEL) 1n male rats (Rec.
#14) and >250 mg/kg (LOAEL) 1n female rats (Rec. #17), rough hair coats were
observed. No effects were seen 1n males at doses <250 or In females at
doses <125 rag/kg (NOAELs) (Recs. #15, 18). Systemic effects 1n mice
Included Increased mortality at dosages >1000 mg/kg (Rec. #19), and lethargy
and rough hair coats In males at dose levels >500 mg/kg (LOAEL) (Rec. #20)
and 1n females at dose levels >1000 mg/kg (Rec. #22). The highest dosages
0269d
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11/01/89
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were associated wHh blood In the urinary bladder In both sexes. No effects
were seen In male mice at doses <250 mg/kg or In female mice at doses <5QO
mg/kg (NOAELs) (Recs. #21, 23).
In the 91-day study, adverse effects In the brain (hippocampus), thymus,
kidney and skeletal muscle 1n male rats were reported at 800 mg/kg (Rec. #3)
but not at lower doses. Female rats exhibited the same effect on the
hippocampus at the same dose level (Rec. #4). Eight of 10 male rats In the
800 mg/kg dose group died, with four deaths judged to be accidental; there
were two deaths In the female rats at this dosage level, with one death
attributed to the gavage procedure. Rats of both sexes exhibited signs of
neurotoxklty following dosing wHh >800 mg/kg. At this dose level, some
decrease 1n final mean body weights was seen In both sexes, as well as
hlstopathologlcal effects In males, Including necrosis In the hippocampus,'
skeletal muscle necrosis, thymlc atrophy and kidney nephrosls. At the 400
mg/kg dose level (LOAEL), female rats had final mean body weights 9% lower
than those of controls (Rec. #5). Effects In mice Included Increased
mortality 1n females at the highest dosage and some decrease In final mean
body weights of females given >400 mg/kg (Rec. #9). At the highest dosage,
mice of both sexes exhibited signs of neurotoxlclty following dosing.
In the 91-day study, a NOAEL of 143 mg/kg/day (200 mg/kg administered 5
days/week) (Rec. #2) was Identified for female rats, which were the more
sensitive sex. Applying an uncertainty factor of 100 (10 for Interspedes
extrapolation multiplied by 10 to protect unusually sensitive Individuals)
results In an RfD for subchronlc oral exposure of 1.43 mg/kg/day, which Is
rounded to 1 mg/kg/day.
Confidence In the key study Is high, with effects occurring In a
dose-related manner. Therefore, confidence In the subchronlc RfD 1s high.
0269d -45- 11/01/89
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8.2.2.2. CHRONIC Chronic gavage studies were conducted for 103
weeks on rats and mice at dosage levels of 0, 200 and 400 mg/kg and 0, 100
and 200 mg/kg, respectively, administered 5 days/week {NTP, 1988).
Converted dosages calculated by multiplying by 5 (number of doses/week) and
dividing by 7 (days/week) are: for rats, 0, 143 and 286 mg/kg/day and for
mice, 0, 71 and 143 mg/kg/day. A dosage of 400 mg/kg (LOAEL) was associated
with an Increased Incidence of hyperplasla of the epithelium of the fore-
stomach In male rats (Rec. #11), with no effects observed In males at the
lower dose of 200 mg/kg {Rec. #12). Both the 200 (Rec. #1) and 400 mg/kg
doses were associated with Increased mortality In female rats, but the
ultimate cause of death remains In doubt. Deaths of many female rats In
both dosage groups (low dose, 17; high dose, 13), but of only one In the
control group, were attributed to accidental causes, I.e., the gavage'
procedure. NTP (1988), however, concluded that administration of benzyl
alcohol reduced the survival of dosed female rats. There Is no firm
evidence that the mortality was or was not associated with the chemical or
with a combined effect of the chemical and the method of administration.
Therefore, the LOAEL of 286 mg/kg/day for male rats was Identified as the
appropriate dose from which an RfO can be derived (Rec. #11). Applying an
uncertainty factor of 10 to extrapolate from rats to humans, 10 to protect
unusually sensitive Individuals and 10 to extrapolate from a LOAEL to a
NOAEL results 1n a chronic oral RfD of 0.286 mg/kg/day, which Is rounded to
0.3 mg/kg/day.
0269d
11/01/89
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The toxlclty of benzyl alcohol was discussed In Chapter 6 and dose-
response data are summarized In Table 9-1. The data available for deriving
CSs are from chronic and subchronlc gavage studies (NTP, 1988) and a repro-
ductive toxlclty study by Hazelden (1983). In the chronic oral studies,
groups of 50 male and 50 female F344/N rats and B6C3F1 mice were gavaged
with benzyl alcohol at dosages of 0, 200 and 400 mg/kg, and 0, 100 and 200
mg/kg, respectively, 5 days/week for 103 weeks. In the 91-day studies,
groups of 10 F344/N rats and 86C3F1 mice of each sex were gavaged with
benzyl alcohol at dosages of 0, 50, 100, 200, 400 and 800 mg/kg 5 days/week.
Survival decreased In female rats at chronic exposures of >200 mg/kg for 2
years and In male rats exposed to 800 mg/kg for 91 days. Although Increased4
mortality was observed In the male and female rats at the higher dose It was
not specifically attributed to the chemical and may have been due to the
gavage administration procedure. High-dose male rats had a higher Incidence
of epithelial hyperplasla of the forestomach compared with the controls.
Other effects observed In male rats given 800 mg/kg for 91 days were
necrosis of the dentate gyrus of the hippocampus, skeletal muscle necrosis,
thymlc congestion, hemorrhage, and atrophy and nephrosls of the kidney.
Necrosis of the dentate gyrus of the hippocampus was also observed In female
rats at this dosage level. A dosage of 400 mg/kg 1n rats and 800 mg/kg In
mice, given S days/week for 91 days, was associated with decreased mean body
weights. No signs of toxlclty were observed In the mice at the dosage
levels eliciting toxic effects In the rat, Indicating that rats may be the
more sensitive species.
0269d -47- 11/01/89
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0269d
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In the study by Hazelden (1983), a dosage of 750 mg/kg/day administered
by gavage to pregnant CD-I mice for gestation days 7-14 was associated with
decreased mean litter and pup weights, maternal toxlclty and mortality.
Although mortality was observed In these mice, the deaths were a result of
acute exposure to a high dose In this strain.
Table 9-1 summarizes the toxlclty data of benzyl alcohol. Table 9-2
presents the CSs and RQs derived associated with each effect presented In
Table 9-1. The guidelines for calculation of a chronic toxlclty RQ (U.S.
EPA, 1984) recommend the use of chronic data, If adequate. Hence the RQ of
1000 associated with Increased hyperplasla of the epithelium of the fore-
stomach In male rats Is most appropriately chosen to represent the chronic
toxlclty of benzyl alcohol (Table 9-3).
9.2. BASED ON CARCINOGENICITY
As reviewed In Chapter 6, cardnogenlclty data for benzyl alcohol are
limited to gavage studies In rats and mice conducted for the NTP (1988). In
this study there was an Increase In tumors of the adrenal cortex In male
mice (3/48 high dose vs. 0/48 control; p=0.044 In life table and Incidental
tumor tests). Although 3/48 was considered by NTP to be within the range of
historical controls, these results should be considered equivocal evidence
of carcinogenic activity rather than negative. It 1s suggested, therefore,
based on U.S. EPA (1986) guidelines that benzyl alchol could be assigned to
Group 0. Since potency factors cannot be derived for this chemical, a
hazard ranking based on carclnogenclty 1s not possible for this compound.
0269d -49- 11/01/89
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0269d
-50-
11/01/89
-------
TABLE 9-3
Benzyl Alcohol
(CAS No. 100-51-6)
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral, gavage
Species/sex: rat/male
Dose*: 3605 mg/day
Duration: 103 weeks
Effect: Increased hyperplasla of the epithelium of the fore-
stomach compared with controls
RVd: 1
RVe: 6
CS: 6
RQ: 1000
Reference: NTP, 1988
*Equ1valent human dose
0269d -51- 11/01/89
-------
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0269d -65- 11/01/89
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Swann, R.L., D.A. Laskowskl, P.3. McCall, K. Vander Kuy and H.J. Dlshburger.
1983. A rapid method for the estimation of the environmental parameters
octanol/water partition coefficient, soil sorptlon constant, water to air
ratio and water solubility. Res. Rev. 85: 17-28.
Takeoka, 6.R., R.A. Flath, M. Guntert and W. Jennings. 1988. Nectarine
volatlles: Vacuum steam distillation versus headspace sampling. J. Agrlc.
Food Chem. 36: 553-560.
Treon, J.F. and M.3. Stasik. 1983. Alcohols. In: Encyclopedia of Occupa-
tional Health and Safety, 3rd rev. ed., L. Parmegg1an1, Ed. U.S. EPA,
Washington, DC. 1: 109-112.
«
TSCAPP. 1989. Computer print-out of non-confidential production data from
TSCA Inventory OPTS, CID, U.S. EPA, Washington, DC. Online 3/28/89.
Urano, K. and Z. Kato. 1986. Evaluation of blodegradatlon ranks of
priority organic compounds. J. Haz. Hat. 13: 147-159.
U.S. EPA. 1980. Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45: 79347-79357.
U.S. EPA. 1984. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxlclty Data. Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Emergency and Remedial Response, Wash-
ington, DC.
0269d
-66-
11/01/89
-------
U.S. EPA. 1986a. Methodology for Evaluating Reportable Quantity Adjust-
ments Pursuant to CERCLA Section 102, Prepared by the Carcinogen Assessment
Group, Office of Health and Environmental Assessment for the Office of
Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1986b. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51: 33992-34003.
U.S. EPA. 1987. Graphical Exposure Modeling System (GEMS). Fate of
Atmospheric Pollutants (FAP),. Office of Toxic Substances, Washington, DC.
U.S. EPA/OWRS (Office of Water Regulations and Standards). 1986. Guide-
lines for Deriving Numerical National Water Quality Criteria for the*
Protection of Aquatic Organisms and Their Uses. U.S. EPA, Washington, DC.
p. 22-58, 98. NTIS PB85-227049/XAB.
USITC (U.S. International Trade Commission). 1987. Synthetic Organic
Chemicals United States Production and Sales, 1986. Publ. No. 2009,
Washington, DC. p. 214, 239, 240.
USITC (U.S. International Trade Commission). 1988. Synthetic Organic
Chemicals United States Production and Sales, 1987. Publ. No. 2118,
Washington, OC. p. 15-37.
Valshnav, D.D. 1986. Chemical structure-blodegradatlon Inhibition and fish
acute toxlclty relationships for narcotic Industrial chemicals. Toxlcol.
Assess. 1(2): 227-240.
0269d -67- 11/01/89
-------
Van Joost, T., E. Stolz and J.C.S. van der Hoek. 1985. Simultaneous
allergy to perfume Ingredients. Contact Dermatitis. 12: 115-116.
Haters, R., R. MUzayans, J. Meredith, G. Mallalah, N. Danford and a. Parry.
1982. Correlations In mammalian cells between types of ONA damage rates of
DNA repair and the biological consequences. Prog. Mutat. Res. 4: 247-259.
Weast, R.C., M.J. Astle and W.H. Beyer. 1988. CRC Handbook of Chemistry
and Physics, 69th ed. CRC Press, Inc., Boca Raton, FL. p. C-146.
Wllcke, J.R. 1984. Idlosyncracles of drug metabolism 1n cats. Effects on
pharmacotherapeutks In feline practice. Vet. Clln. North. Am. 14:
1345-1354.
Wilson, J.P., D.A. Sollmando Jr. and M.S. Edwards. 1966. Parenteral benzyl
alcohol Induced hypersensltlvlty reaction. Drug Intell. Clln. Pharm. 20:
689-691.
Wilson, C.L., 0.0. Franklin and B.E. Otto. 1987. Fruit volatlles Inhibi-
tory to MonlUnla fructlcola and Botrytls clneren. Plant DIs. 71(4):
316-319.
Wood, E.M. 1954. The toxldty of 3400 chemicals to fish. Fish Toxlclty
Report No. 1. U.S. Fish and Wildlife Service, Department of the Interior,
Leetown, WV. (Cited 1n Llpnlck et. al., 1985}
0269d
-68-
11/01/89
-------
Yoo, Y.S. 1986. Mutagenlc and antlmutagenlc activities of flavoring agents
In foodstuffs. J. Osaka City Med. Center. 34: 267-88.
York, R.6., P.L. Barnwell, H. Plerrera, R.L. Schuler and B.O. Hardln. 1988.
Evaluation of twelve chemicals In a preliminary developmental toxlclty test.
37: 503-504.
0269d -69- 11/01/89
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APPENDIX A
LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
CHEMUNE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
SCISEARCH
Federal Research In Progress
These searches were conducted In April, 1989, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts}.
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1987. TLVs: Threshold Limit Values for Chemical Substances 1n the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 28. John Wiley and
Sons, NY. p. 2879-3816.
0269d
-70-
11/01/89
-------
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John WHey and
Sons, NY. p. 3817-5112.
Grayson, M. and D. Eckroth, Ed. 1978-1984. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, WHO, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA 600/6-84-010. NTIS PB84-243906. SRI International, Menlo
Park, CA.
NTP (National Toxicology Program). 1987. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report In the Special Review
Program. Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call In Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Pub!.
1892, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndholz, H., Ed. 1983. The Merck Index, 10th ed. Merck and Co..
Inc., Rahway, NJ.
Worthing, C.R. and S.6. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
0269d -71- 11/01/89
-------
In addition, approximately 30 compendia of aquatic toxldty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute ToxIcHy
of Chemicals to Fish and Aquatic Invertebrates. Summaries, of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior. Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water
Prepared for the Resources Agency of
Quality Control Board. Publ. No. 3-A.
Quality Criteria, 2nd ed.
California, State Water
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0269d
-72-
11/01/89
-------
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APPENDIX C
DOSE/DURATION RESPONSE GRAPHS FOR EXPOSURE TO BENZYL ALCOHOL
C.I. DISCUSSION
Dose/duration-response graphs for Inhalation and oral exposure to benzyl
alcohol generated by the method of Crockett et al. (1985) using the computer
software by Durkin and Heylan (1988) are presented 1n Figures C-l through
C-4. Data used to generate these graphs are presented In Section C.2. In
the generation of these figures, all responses are classified as adverse
(FEL, AEL or LOAEL) or nonadverse (NOEL or NOAEL) for plotting. For Inhala-
tion exposure the ordlnate expresses concentration 1n either of two ways.
In Figure C-l, the experimental concentration expressed as mg/m3 was
multiplied by the time parameters of the exposure protocol (e.g., hours/day
and days/week) and Is presented as expanded experimental concentration*
[expanded exp cone (mg/m3)]. In Figure C-2, the expanded experimental
concentration was multiplied by the cube root of the ratio of the animal:
human body weight to adjust for species differences In basal metabolic rate
(Mantel and Schnelderman, 1975) to estimate an equivalent human or scaled
«»
concentration [scaled cone (mg/m3)]. For oral exposure, the ordlnate
expresses dosage as human equivalent dose. The animal dosage In mg/kg/day
1s multiplied by the cube root of the ratio of the an1mal:human body weight
to adjust for species differences In basal metabolic rate (Mantel and
Schnelderman, 1975). The result 1s then multiplied by 70 kg, the reference
human body weight, to express the human equivalent dose as mg/day for a 70
kg human.
The boundary for adverse effects (solid line) 1s drawn by Identifying
the lowest adverse effect dose or concentration at the shortest duration of
exposure at which an adverse effect occurred. From this point, an Infinite
0269d
-74-
11/01/89
-------
e
u
z
ieee
e.eeei
fInhalation Exposure)
.061
HUNAN E4U1U DURATION Cfraction lif*sput>
ENVELOP METHOD
Key: F . FEL
SoUd Line - Adverse Effects Boundary
FIGURE C-l
Dose/Duration Response Graph for Inhalation Exposure to
Benzyl Alcohol, Expanded Concentration
0269d
-75-
11/01/89
-------
1000
n
I
lee
Benzyl alcoKol
0.0001
BENZALC.DDP
ENVELOP METHOD
0.001
Key: F . FEL
Solid Line « Adverse Effects Boundary
FIGURE C-2
Dose/Duration Response Graph for Inhalation Exposure to
Benzyl Alcohol, Scaled Concentration
0269d
-76-
-------
leeeee
leeee -
H
g
3
9
hi
9
1800 -
100
e.eeai
BEWZflLC.DDP
aI Exposure)
alcohol
I IMI| 1I 1 I I I III
e.eei e.ei e.i
HUNAN EQUIV DURATION (fraction lif*ci»an>
EMUELOP METHOD
Key: N . NOEL
L - LOEL
F « FEL
Solid Line - Adverse Effects Boundary
Dashed Line - No Adverse Effects Boundary
FIGURE C-3
Dose/Duration Response Graph for Oral Exposure to
Benzyl Alcohol. Envelope Method
0269d
-77-
11/01/89
-------
180688
J
I
H
2
9
18888 r
1888 -
188
8.8881
(fir*! Exposure)
8.881 8.81 8.1
HUNAN EQUIU DURATION (fraction lifespan)
CENSORED DATA METHOD
Key: N . NOEL
L - LOEL
F « FEL
Solid Line Adverse Effects Boundary
Dashed Line » No Adverse Effects Boundary
FIGURE C-4
Dose/Duration Response Graph for Oral Exposure to
Benzyl Alcohol, Censored Date Method
0269d
ll/01/89
-------
line Is extended upward, parallel to the dose axis. The starting point 1s
then connected to the lowest adverse effect dose or concentration at the
next longer duration of exposure that has an adverse effect dose or concen-
tration equal to or lower than the previous one. This process Is continued
to the lowest adverse effect dose or concentration. From this point, a line
1s extended to the right, parallel to the duration axis. The region of
adverse effects lies above the adverse effects boundary.
Using the envelope method, the boundary for no adverse effects (dashed
line) Is drawn by Identifying the highest no adverse effects dose or concen-
tration. From this point, a line parallel to the duration axis Is extended
to the dose or concentration axis. The starting point Is then connected to
the next lower or equal no adverse effect dose or concentration at a longer
duration of exposure. When this process can no longer be continued, a line'
1s dropped parallel to the dose or concentration axis to the duration axis.
The no adverse effects region lies below the no adverse effects boundary.
At either ends of the graph between the adverse effects and no adverse
effects boundaries are regions of ambiguity. The area (1f any) resulting
from Intersection of the adverse effects and no adverse effects boundaries
Is defined as the region of contradiction.
In the censored data method, all no adverse effect points located In the
region of contradiction are dropped from consideration and the no adverse
effect boundary Is redrawn so that It does not Intersect the adverse effects
boundary and no region of contradiction Is generated. This method results
In the most conservative definition of the no adverse effects region.
As seen from Figures C-l and C-2, only one data point was available for
Inhalation exposure. Figure C-3 presents the dose-duration response graph
generated by the envelope method. The adverse effects boundary Is defined
0269d -79- 11/01/89
-------
by five points, corresponding to an LD5Q In rabbits of 1040 tng/kg (Graham
and Kulzenga, 1945) (Rec. #27), a mouse LD5_ of 1580 mg/kg (Jenner et a!.,
1964) (Rec. #26), maternal mortality and body weight decrease In mice
gavaged with 750 mg/kg during days 7-14 of gestation, decreased Utter and
pup weights (Hazelden, 1983) (Rec. #7), rough hair coat 1n female rats given
250 mg/kg 5 days/week for 16 days (NTP, 1988) (Rec. #17) and Increased
mortality In female rats gavaged with 200 mg/kg 5 days/week for 103 weeks
(NTP, 1988) (Rec. #1). The no effects boundary Is defined by two points one
representing no effects observed 1n male rats at dose levels <400 mg/kg
given 5 days a week for 91 days (NTP, 1988) (Rec. #6), and the other repre-
senting the 2-year study by NTP (1988) where no effects were seen In male
mice at the 100 mg/kg dosage given 5 days a week (Rec. #10). The region of
contradiction contains some LOAELs, NOAELs and NOELs.
When the graph Is redrawn to eliminate the region of contradiction (see
Figure C-4), the no adverse effects boundary Is defined by the points repre-
senting the dose levels of 200 mg/kg 5 days/week for 91 days (Rec. #2) and
200 mg/kg, 5 days/week for 2 years (Rec. #12), both given to male rats for 2
years and producing no observed effects (NTP, 1988).
C.2. DATA USED TO GENERATE DOSE/DURATION-RESPONSE GRAPHS
C.2.1. Inhalation Exposure.
Chemical Name: Benzyl Alcohol
CAS Number: 100-51-6
Document Title: Health and Environmental Effects Document for Benzyl
Alcohol
Document Number: Pending
Document Date: Pending
Document Type: HEED
0269d
-BO-
l/01/89
-------
RECORD #1
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
NR
PEL
Inhalation
Dose: 4422.000
Duration Exposure: 0.3 days
Duration Observation: 14.0 days
Number Exposed: 6
Number Responses: 3
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 10
Acute Inhalation toxlclty reported; no other endpolnts,
Maximum Inhalation of saturated vapor 2 hours without death.
Smyth et al.. 1951
C.2.2. Oral Exposure.
Chemical Name:
CAS Number:
Document Title:
Document Number:
Document Date:
Document Type:
Benzyl alcohol
100-51-6
Health and Environmental Effects Document for Benzyl
Alcohol
Pending
Pending
HEED
RECORD #1
Comment:
Citation:
Species:
Sex:
Effect:
Rats
Female
LOAEL
Route:
Dose: 143.000
Duration Exposure: 103.0 weeks
Duration Observation: 103.0 weeks
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Gavage
50
33
DEATH
BODY
10
Doses given: 0, 200, 400 mg/kg/day x 5 days/week = 0, 143,
286 mg/kg/day. Nonaccldental deaths: control, 13; low, 16;
high, 20/50. Accidental deaths 1, 17, 13/50. LOAEL basis
for chronic RfD.
NTP, 1988
0269d
-81-
11/01/89
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RECORD #2:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Female
NOAEL
Gavage
Dose: 143.000
Duration Exposure: 91.0 days
Duration Observation: 91.0 days
Number Exposed: 0
Number Responses: 9
Type of Effect: WGTDC
Site of Effect: BODY
Severity Effect: 4
Dosages: 0, 50, 100, 200, 400, 800 mg/kg 5 days/week = 0, 36,
71, 143, 286, 571 mg/kg/day. NOAEL 1s basis for subchronlc
RfD.
NTP, 1988
RECORD #3:
Species:
Sex:
Effect:
Route:
Rats
Male
PEL
Gavage
Dose:
Duration
Duration
Exposure:
Observation:
571.000
91.0 days
91.0 days
Comment:
Citation:
Number Exposed: 10 10 9 10
Number Responses: 4598
Type of Effect: DEATH NECRO NECRO ATROP
SHe of Effect: BODY MSKEL BRAIN THYHS
Severity Effect: 10 8 8 8
Four additional deaths attributed to gavage procedure.
of the hlstopathologlc effects occurred at lower doses.
NTP, 1988
9
6
FUNP
KIDNY
8
None
RECORD #4:
Species:
Sex:
Effect:
Route:
Rats
Female
AEL
Gavage
Dose:
Duration
Duration
Exposure:
Observation:
571.000
91.0 days
91.0 days
Comment:
Citation:
Number Exposed: 7
Number Responses: 7
Type of Effect: NECRO
Site of Effect: BRAIN
Severity Effect: 8
Other effects: final mean body weights 5% lower than controls;
staggering and lethargy following dosing. See Rec. #2 for
dosing schedule.
NTP, 1988
0269d
-82-
11/01/89
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RECORD #5: Species: Rats
Sex: Female
Effect: LOAEL
Number Exposed: 9
Number Responses: 9
Type of Effect: HGTOC
Site of Effect: BODY
Severity Effect: 4
Dose: 286.000
Duration Exposure: 91.0 days
Duration Observation: 91.0 days
Comment: See Rec. #2.
Citation: NTP, 1988
RECORD #6: Species: Rats
Sex: Male
Effect: NOAEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
Dose: 286.000
10
0
DEATH
BODY
10
Duration Exposure: 91
Duration Observation: 91
9 10 9
000
NECRO ATROP FUNP
BRAIN THYMS KIDNY
888
.0 days
.0 days
10
0
NECRO
MSKEL
8
Comment: No hlstopathologlc effects at doses <571 mg/kg/day. One male
died In 200 mg/kg dose group (143 mg/kg/day) after dosing.
Citation: NTP. 1988
RECORD #7:
Species: Mice
Sex: Female
Effect: AEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
19
50
DEATH
BODY
10
Dose:
Duration Exposure:
Duration Observation;
21 21
21 21
WGTDC RE PRO
BODY FETUS
4 9
750.000
8.0 days
21.0 days
Comment: Maternal toxlclty on treatment days 7-14: hunched, tremors,
subdued, prostrate, dyspnoea, swollen and cyanotlc abdomen,
plloerectlon, cyanosis. Increased maternal toxlclty: 19/50
vs. 0/50 controls.
Citation: Hazelden, 1983
0269d
-83-
11/01/89
-------
RECORD #8:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Mice
Female
LOAEL
Gavage
Dose: 571.000
Duration Exposure: 91.0 days
Duration Observation: 91.0 days
Number Exposed: B
Number Responses: 8
Type of Effect: WGTDC
SHe of Effect: BODY
Severity Effect: 4
Dosages: 0, 50, 100, 200, 400, 800 mg/kg x 5 days/week = 0,
36, 71, 143, 286, 571 mg/kg/day. Final mean body weight 854
lower than controls. Signs of neurotoxlclty after dosing.
NTP, 1988
RECORD #9:
Species:
Sex:
Effect:
Route:
Mice
Female
NOAEL
Gavage
Dose:
Duration
Duration
Exposure:
Observation:
286.000
91.0 days
91.0 days
Comment:
Citation:
Number Exposed: 9
Number Responses: 0
Type of Effect: WGTDC
SHe of Effect: BODY
Severity Effect: 4
Final mean body weight 5X lower than controls.
related hlstopathologlcal effects were observed.
NTP, 1988
No compound-
RECORD #10:
Species:
Sex:
Effect:
Route:
Mice
Female
NOEL
Gavage
Dose:
Duration
Duration
Exposure:
Observation:
71.000
103.0 weeks
103.0 weeks
Comment:
Citation:
Number Exposed: 50
Number Responses: 0
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 10
Doses were 100 and 200 mg/kg, 5 days/week,
NTP, 1988
0269d
-84-
11/01/89
-------
RECORD #11
Comment;
Citation:
Species:
Sex:
Effect:
Route:
Rats
Hale
LOAEL
Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Hyperplasla of the
200 and 400 mg/kg,
NTP, 1988
Dose:
Duration Exposure:
Duration Observation:
286.000
103.0 weeks
103.0 weeks
50
4
HYPRP
COLON
3
epithelium of
5 days/week.
the forestomach. Doses were
RECORD #12:
Species:
Sex:
Effect:
Route:
Rats
Male
NOAEL
Gavage
Dose:
Duration
Duration
Exposure:
Observation:
143.000
103.0 weeks
103.0 weeks
Number Exposed: 50
Number Responses: 0
Type Of Effect: HYPRP
SHe of Effect: COLON
Severity Effect: 3
Comment:
Citation:
RECORD #13:
See Rec. #11.
NTP, 1988
Species: Rats
Sex: Male
Effect: FEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
5
2
DEATH
BODY
10
Dose:
Duration
Duration
5
NR
8EHAV
BODY
7
Exposure:
Observation:
5
NR
WGTDC
BODY
4
5
NR
HEMOR
CARDV
5
714.000
16.0 days
16.0 days
5
NR
IRRIT
COLON
5
Comment: Doses were 125, 250, 500, 1000, 2000 mg/kg, 5 days/week,
Effects were seen at >1000 mg/kg.
Citation: NTP, 1988
0269d
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RECORD #14:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Male
LOAEL
Gavage
Dose: 357.000
Duration Exposure: 16.0 days
Duration Observation: 16.0 days
Number Exposed: 5
Number Responses: MR
Type of Effect: FUNS
Site of Effect: SKIN
Severity Effect: 2
Comment:
Citation:
RECORD #15:
Rough hair coat the only effect observed at 500 mg/kg.
NTP, 1988
Species:
Sex:
Effect:
Route:
Rats
Male
NOAEL
Gavage
Dose:
Duration Exposure:
Duration Observation:
179.000
16.0 days
16.0 days
Number Exposed: 5
Number Responses: 0
Type of Effect: FUNS
Site of Effect: SKIN
Severity Effect: 2
Comment:
Citation:
RECORD #16:
See Rec. #13.
NTP, 1988
Species:
Sex:
Effect:
Route:
Rats
Female
FEL
Gavage
Dose:
Duration Exposure:
Duration Observation:
714.000
16.0 days
16.0 days
Number Exposed: 5
Number Responses: 3
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 10
See Rec.-#13.
NTP, 1988
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RECORD #17
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Female
LOAEL
Gavage
Dose: 179.000
Duration Exposure: 16.0 days
Duration Observation: 16.0 days
Number Exposed: 5
Number Responses: NR
Type of Effect: FUNS
Site of Effect: SKIN
Severity Effect: 2
Comment:
Citation:
RECORD #18:
Rough hair
NTP, 1988
Species:
Sex:
Effect:
Route:
coat was
Rats
Female
NOAEL
Gavage
the only effect noted. See Rec
Dose:
Duration Exposure:
Duration Observation:
. #13.
89.000
16.0 days
16.0 days
Number Exposed: 5
Number Responses: 0
Type of Effect: FUNS
Site of Effect: SKIN
Severity Effect: 2
Comment:
Citation:
RECORD #19:
See Rec. #13.
NTP, 1988
Species:
Sex:
Effect:
Route:
Mice
Hale
AEL
Gavage
Dose:
Duration Exposure:
Duration Observation:
7H.OOO
16.0 days
16.0 days
Number Exposed: 5
Number Responses: 1
Type of Effect: DEATH
SHe of Effect: BODY
Severity Effect: 10
All mice at the next higher dose level (1429 mg/kg) died.
None of the control mice died.
NTP, 1988
0269d
-87-
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RECORD #20:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Mice
Male
LOAEL
Gavage
Number Exposed: 5
Number Responses: NR
Type of Effect: BEHAV
Site of Effect: BODY
Severity Effect: 7
Dose:
Duration Exposure:
Duration Observation;
5
NR
FUNS
SKIN
2
357.000
16.0 days
16.0 days
Dosages: 0, 125, 250, 500, 1000, 2000 mg/kg x 5 days/week =
0, 89, 179t 357, 714, 1429 mg/kg/day. No compound-related
hlstopathologlcal effects seen.
NTP, 1988
RECORD #21:
Comment:
Citation:
RECORD #22:
Species: Mice
Sex: Male
Effect: NOAEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
See Rec. #20.
NTP, 1988
Species: Mice
Sex: Female
Effect: FEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
5
0
BEHAV
BODY
7
5
2
DEATH
BODY
10
Dose:
Duration
Duration
5
0
FUNS
SKIN
2
Dose:
Duration
Duration
5
NR
BEHAV
BODY
7
Exposure:
Observation:
Exposure:
Observation:
.
5 5
NR NR
IRRIT FUNS
OTHER SKIN
5 2
178.000
16.0 days
16.0 days
714.000
16.0 days
16.0 days
Comment: All animals died in 2000 mg/kg groups of both sexes.
Lethargy and rough hair coats were seen; also blood In the
urinary bladder. See Rec. #20.
Citation: NTP, 1988
0269d
11/01/89
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RECORD #23:
Comment:
Citation:
RECORD #24:
Species: Mice
Sex: Female
Effect: NOAEL
Route: Gavage
Number Exposed: 5
Number Responses: 0
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 10
See Rec. #20.
NTP, 1988
Species: Rats
Sex: Both
Effect: PEL
Route: Gavage
Dose:
Duration
Duration
5
0
BEHAV
BODY
7
Dose:
Duration
Duration
Exposure:
Observation:
5
0
IRRIT
OTHER
5
5
0
FUNS
SKIN
2
Exposure:
Observation:
357.000
16.0 days
16.0 days
1230.000
1.0 days
14.0 days
Comment:
Citation:
Number Exposed: 10
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 10
Depression and then coma within 10-15 minutes,
3-4 days.
Jenner et al., 1964
Excitable for
RECORD #25:
Species:
Sex:
Effect:
Route:
Rats
NR
FEL
Gavage
Dose:
Duration
Duration
Exposure:
Observation:
2080.000
1.0 days
1.0 days
Comment:
Citation:
Number Exposed: 20
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 10
Graham and Kulzenga, 1945
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RECORD #26:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Mice
NR
PEL
Gavage
Dose: 1580.000
Duration Exposure: 1.0 days
Duration Observation: 14.0 days
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
SHe of Effect: BODY
Severity Effect: 10
Depression; death occurred within 2-18 hours.
Jenner et al., 1964
RECORD #27:
Species:
Sex:
Effect:
Route:
Rabbits
NR
PEL
Gavage
Oose:
Duration
Duration
Exposure:
Observation:
1040.000
1.0 days
1.0 days
Comment:
Citation:
Number Exposed: 9
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 10
Graham and Kulzenga, 1945
NR = Not reported
0269d
-90-
11/01/89
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