U.S. Environmental Protection Agency
Hazard Characterization Document
September, 2009
SCREENING-LEVEL HAZARD CHARACTERIZATION
Cyclohexyl Derivatives Category
4-ferf-Butylcyclohexanol (CASRN 98-52-2)
4-ferf-Butyl cyclohexyl acetate (CASRN 32210-23-4)
The High Production Volume (HPV) Challenge Program1 was conceived as a voluntary
initiative aimed at developing and making publicly available screening-level health and
environmental effects information on chemicals manufactured in or imported into the United
States in quantities greater than one million pounds per year. In the Challenge Program,
producers and importers of HPV chemicals voluntarily sponsored chemicals; sponsorship
entailed the identification and initial assessment of the adequacy of existing toxicity
data/information, conducting new testing if adequate data did not exist, and making both new
and existing data and information available to the public. Each complete data submission
contains data on 18 internationally agreed to "SIDS" (Screening Information Data Set1'2)
endpoints that are screening-level indicators of potential hazards (toxicity) for humans or the
environment.
The Environmental Protection Agency's Office of Pollution Prevention and Toxics (OPPT) is
evaluating the data submitted in the HPV Challenge Program on approximately 1400 sponsored
chemicals by developing hazard characterizations (HCs). These HCs consist of an evaluation of
the quality and completeness of the data set provided in the Challenge Program submissions.
They are not intended to be definitive statements regarding the possibility of unreasonable risk of
injury to health or the environment.
The evaluation is performed according to established EPA guidance2'3 and is based primarily on
hazard data provided by sponsors; however, in preparing the hazard characterization, EPA
considered its own comments and public comments on the original submission as well as the
sponsor's responses to comments and revisions made to the submission. In order to determine
whether any new hazard information was developed since the time of the HPV submission, a
search of the following databases was made from one year prior to the date of the HPV
Challenge submission to the present: (ChemID to locate available data sources including
Medline/PubMed, Toxline, HSDB, IRIS, NTP, AT SDR, IARC, EXTOXNET, EPA SRS, etc.),
STN/CAS online databases (Registry file for locators, ChemAbs for toxicology data, RTECS,
Merck, etc.) and Science Direct. OPPT's focus on these specific sources is based on their being
of high quality, highly relevant to hazard characterization, and publicly available.
OPPT does not develop HCs for those HPV chemicals which have already been assessed
internationally through the HPV program of the Organization for Economic Cooperation and
Development (OECD) and for which Screening Initial Data Set (SIDS) Initial Assessment
Reports (SIAR) and SIDS Initial Assessment Profiles (SIAP) are available. These documents are
presented in an international forum that involves review and endorsement by governmental
1 U.S. EPA. High Production Volume (HPV) Challenge Program; http://www.epa.gov/chemrtk/index.htm.
2 U.S. EPA. HPV Challenge Program - Information Sources; http://www.epa.gov/chemrtk/pubs/general/guidocs.htm.
3 U.S. EPA. Risk Assessment Guidelines; http://cfpub.epa.gov/ncea/raf/rafguid.cfm.
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authorities around the world. OPPT is an active participant in these meetings and accepts these
documents as reliable screening-level hazard assessments.
These hazard characterizations are technical documents intended to inform subsequent decisions
and actions by OPPT. Accordingly, the documents are not written with the goal of informing the
general public. However, they do provide a vehicle for public access to a concise assessment of
the raw technical data on HPV chemicals and provide information previously not readily
available to the public.
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Chemical Abstract Service
Registry Number
(CASRN)
98-52-2
32210-23-4
Chemical Abstract Index
Name
Cyclohexanol, 4-(l,l-dimethylethyl)-
Cyclohexanol, 4-(l,l-dimethylethyl)-, acetate
Structural Formula
CH3
h3c
OH
CH3
CASRN 98-52-2
o.
>
ch3
ch3
h3c
o
ch3
CASRN 32210-23-4
Summary
Category member CASRN 98-52-2 is a solid at ambient temperature with moderate water
solubility and moderate vapor pressure. Category member CASRN 32210-23-4 is a liquid with
moderate water solubility and moderate vapor pressure. CASRN 98-52-2 is expected to have
high mobility in soil and CASRN 32210-23-4 is expected to have moderate mobility in soil.
Volatilization is considered moderate for both compounds based on their Henry's Law constants.
The rate of hydrolysis is considered negligible for both compounds. The rate of atmospheric
photo-oxidation is considered moderate. CASRNs 98-52-2 and 32210-23-4 are expected to have
low persistence (PI) and low bioaccumulation potential (Bl).
Acute oral toxicity of rats and acute dermal toxicity of rabbits to the category members is low.
CASRN 32210-23-4 was irritating to rabbit skin and eyes. Repeated oral exposure of rats to
CASRN 98-52-2 for 28 days showed clinical signs indicative of neurotoxicity and decreased
body weights at 300 mg/kg-bw/day (highest dose) and increased relative epididymis weight at all
doses; statistically significant at the high dose. The LOAEL and NOAEL values were 300 and
150 mg/kg-bw/day. Reproductive toxicity data were not provided. Although no effects were
seen on the other reproductive organs in the 28-day repeated-dose toxicity study of CASRN 98-
52-2, the significance of effects on epididymides is unclear. Therefore, EPA recommended that
the submitter conduct a combined reproductive/developmental toxicity screening test
(OECD TG 421) on CASRN 98-52-2 to address these endpoints. The submitted prenatal
developmental toxicity study established a NOAEL of 640 mg/kg-bw/day based on no maternal
or developmental toxicity at the highest dose tested. The category members did not induce gene
mutations or chromosomal aberrations in vitro.
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The 96-hour LC50 of CASRN 98-52-2 and 32210-23-4 for fish was 8.1 and 8.6 mg/L,
respectively. The 48-hour EC50 of CASRN 98-52-2 and 32210-23-4 for aquatic invertebrates
was 46 and 23 mg/L, respectively. The 96-hour ErCso of CASRN 98-52-2 and 32210-23-4 for
aquatic plants was 45 and 22 mg/L, respectively and EbC50 for CASRN 32210-23-4 is 17 mg/L.
The reproductive toxicity endpoint remains as data gaps under the HPV Challenge Program.
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The sponsor, the Cyclohexyl Derivatives Consortium of the Flavor and Fragrance High
Production Volume Consortia, submitted a Test Plan and Robust Summaries to EPA for the
Cyclohexyl Derivatives category on August 19, 2003. EPA posted the submission on the
ChemRTK HPV Challenge website on August 28, 2003
(http://www.epa.gov/chemrtk/pubs/summaries/cvclodrv/cl4686tc.htm). EPA comments on the
original submission were posted on the website on January 7, 2004. Public comments were also
received and posted to the website. The sponsor submitted updated/revised documents on
November 27, 2006, which were posted to the ChemRTK website on January 30, 2007. The
Cyclohexyl Derivatives category consists of the following compounds:
Sponsored Chemicals
4-fert-Butylcyclohexanol CASRN 98-52-2
4-/£/7-Butyl cyclohexyl acetate CASRN 32210-23-4
Category Justification
For human health, the grouping of the two substances (4-fe/V-butylcyclohexanol and its ester, 4-
/f/7-butyl cyclohexyl acetate) in the category is based on structural similarity and common
metabolic pathways in mammalian species. The ester, 4-/£/7-butyl cyclohexyl acetate, undergoes
rapid enzymatic hydrolysis to the alcohol, 4-fert-butylcyclohexanol, which is then eliminated as
the glucuronic acid conjugate. For the purposes of ecotoxicity testing, the category approach
was not used because these chemicals are in different chemical classes. For example, 4-tert-
butylcyclohexanol is considered in neutral-organics class and 4-te/V-buty 1 cyclohexy 1 acetate is in
the ester class. Therefore, a read-across approach was not used for ecotoxicity endpoints.
1. Chemical Identity
1.1 Identification and Purity
The following description is taken from the final Test Plan (2007):
This category consists of 2 substances, 4-/e/V-b uty 1 cy c 1 oh e x an o 1 and its corresponding acetate ester,
4-/c77-butylcyclohexyl acetate. 4-/c77-Butylcyclohexanol and its corresponding acetate ester, 4-tert-
butylcyclohexyl acetate are used primarily in soap perfumes. Both substances exist in cis and trans
forms, trans-4-tert- B uty 1 cy cl oh exy 1 acetate exhibits a strong woody aroma while cis-4-
leributy 1 cyc 1 ohexy 1 acetate is a more intense woody aroma with a flowery note. The ester has far
greater use as a fragrance than does the corresponding alcohol. The alcohol serves as a synthetic
precursor of the acetate. Wide variation in the ratio of the cis and trans isomers does not
significantly alter the physical properties. A mixture of cis and trans alcohol is prepared by
hydrogenation of 4-/c77-butylphenol. The acetate is obtained by acetylation of the cis and trans
mixture of the alcohol.
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1.2 Physical-Chemical Properties
The physical-chemical properties of the cyclohexyl derivatives category are summarized in
Table 1. CASRN 98-52-2 is a solid at ambient temperature with moderate water solubility and
moderate vapor pressure. CASRN 32210-23-4 is a liquid with moderate water solubility and
moderate vapor pressure.
Table 1. Physical-Chemical Properties of the Cyclohexyl Derivatives1
Property
Cyclohexanol, 4-(l,l-
dimethylethyl)-
Cyclohexanol, 4-(l,l-dimethylethyl)-,
acetate
CASRN
98-52-2
32210-23-4
Molecular Weight
156.27
198.31
Physical State
Solid at ambient temperature
Liquid
Melting Point
56.6-58.6°C (94 % cis isomer);
56-58°C;
55-70°C;
82.5-83°C (90 % trans isomer)
-50°C
Boiling Point
224-228°C;
223°C
241°C;
260°C
Vapor Pressure
<0.075 mm Hg at 20°C
0.03-0.05 mm Hg at 20°C
Water Solubility
<100 mg/L at 20°C
90 mg/L at 20°C
Dissociation
Constant (pKa)
Not applicable
Not applicable
Henry's Law
Constant
1.4xl0"4 atm-m3/mole
(estimated)2
2.2><10"5 atm-m3/mole (estimated)2
Log Kow
3.23
4.80
'The Flavor and Fragrance High Production Volume Consortia. December 28, 2006. Revised Robust Summary and
Test Plan for Alkyl-substituted Cyclohexanol Derivatives at
http://www.epa.gov/chemrtk/pubs/summaries/cvclodrv/cl4686tc.htm.
2U.S. EPA. 2008. Estimation Programs Interface Suite™ for Microsoft® Windows, v 3.20. United States
Environmental Protection Agency, Washington, DC, USA at
http://www.epa.gov/opptintr/exposure/pubs/episuite.htm.
Measured data in bold text
2 General Information on Exposure
2.1 Production Volume and Use Pattern
No IUR data available for CASRN 98-52-2. CASRN 32210-23-4 had an aggregated production
volume in the United States of 1 million to 10 million pounds during calendar year 2005. This
aggregated value does not include the production volume of CASRN 98-52-2, which did not
have IUR submissions. Non-confidential information in the IUR4 indicated that the industrial
processing and uses of CASRN 32210-23-4 include processing as odor agents. In addition, non-
4 USEPA, 2006. Inventory Update Reporting Database.
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confidential information in the IUR indicated that commercial and consumer products containing
the chemical include paper products and soaps and detergents, among other uses. The HPV
submission for the cyclohexyl derivatives category states that these chemicals are used primarily
in soap perfumes.5
2.2 Environmental Exposure and Fate
No quantitative information is available on environmental releases.
The environmental fate properties are provided in Table 2. CASRN 98-52-2 is expected to have
high mobility in soil and CASRN 32210-23-4 is expected to have moderate mobility in soil.
Both compounds were readily biodegradable using a CO2 evolution test similar to the modified
Sturm procedure (OECD 301D). Using the Manometric respirometric test (OECD 301F),
CASRN 32210-23-4 was not readily biodegradable, but achieved 54% degradation after 28 days.
Volatilization is considered moderate based on the Henry's Law constants of these compounds.
The rate of hydrolysis is considered negligible for both substances. CASRN 98-52-2 and
CASRN 32210-23-4 are expected to have low persistence (PI) and low bioaccumulation
potential (Bl).
5 The Cyclohexyl Derivatives Consortium and The Flavor and Fragrance High Production Volume Consortia, 2006.
Revised Test Plan for Alkyl-substituted Cyclohexanol Derivatives. Accessed: 01/16/09.
http://www.epa.gov/chemrtk/pubs/summaries/cvclodrv/cl4686rt.pdf
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Table 2. Environmental Fate Characteristics of the Cyclohexyl Derivatives1
Property
Cycloexanol, 4-(l,l-
dimethylethyl)-
Cyclohexanol, 4-(l,l-dimethylethyl)-,
acetate
CASRN
98-52-2
32210-23-4
Photodegradati on
Half-life
6.4 hours (estimated)
8.8 hours (estimated)
Hydrolysis
Half-life
Stable
266 days at pH 8 (estimated);
7.2 years at pH 7 (estimated)
Biodegradation
90% in 19 days (readily
biodegradable)
68-75% in 28 days (readily
biodegradable);
54% in 28 days (not readily
biodegradable);
24% in 28 days (not inherently
biodegradable)
B i oconcentrati on
BCF = 61 (estimated)2
BCF = 991 (estimated)2
Log Koc
1.8 (estimated)2
2.7 (estimated)2
Fugacity
(Level III Model)
Air = 1.87%
Water = 38.1%
Soil = 59.5%
Sediment = 0.588%
Air = 1.36%
Water = 18.1%
Soil = 66%
Sediment = 14.6%
Persistence3
PI (low)
PI (low)
B i oaccumul ati on3
B1 (low)
B1 (low)
'The Flavor and Fragrance High Production Volume Consortia. December 28, 2006. Revised Robust Summary and
Test Plan for Alkyl-substituted Cyclohexanol Derivatives.
http://www.epa.gov/chemrtk/pubs/summaries/cvclodrv/cl4686tc.htm.
2U.S. EPA. 2008. Estimation Programs Interface Suite™ for Microsoft® Windows, v 3.20. United States
Environmental Protection Agency, Washington, DC, USA. http://www.epa.gov/opptintr/exposure/pubs/episuite.htm.
3Federal Register. 1999. Category for Persistent, Bioaccumulative, and Toxic New Chemical Substances. Federal
Register 64, Number 213 (November 4, 1999) pp. 60194-60204.
Measured data in bold text
3 Human Health Hazard
A summary of health effects data submitted for SIDS endpoints is provided in table 3. The table
also indicates where data for tested category members are read across (RA) to untested members
of the category.
Acute Oral Toxicity
4-tert-Butylcyclohexanol (CASRN 98-52-2)
Rats (10/sex/dose, strain not reported) were administered 4-/£/7-butyl cyclohexanol via gavage
(dose(s) not stated).
LD50 = 4200 mg/kg-bw
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4-tert-Butylcyclohexyl acetate (CASRN 32210-23-4)
(1) Rats (5/sex/dose, strain not reported) were administered 4-fert-butylcyclohexyl acetate via
gavage at 500 or 5000 mg/kg-bw. Mortality was 3/10 rats at 500 mg/kg-bw and 8/10 rats at
5000 mg/kg-bw.
LD50 = > 500 and < 5000 mg/kg-bw
(2) Rats (number/sex/dose and strain not reported) were administered 4-fert-butylcyclohexyl
acetate as a 2-30% emulsion (in Traganth, dose(s) not stated) via gavage.
LD50 = 4800 mg/kg-bw
(3) Rats (10/dose, sex and strain not reported) were administered 4-fert-butylcyclohexyl acetate
via gavage at 5000 mg/kg-bw. No information on mortality was reported.
LD50 = 5000 mg/kg-bw
Acute Dermal Toxicity
4-tert-Butylcyclohexanol (CASRN 98-52-2)
Rabbits (6, sex and strain not reported) were administered 4-fert-butylcyclohexanol dermally at
5000 mg/kg-bw. No additional information was provided.
LD50 > 5000 mg/kg-bw
4-tert-Butylcyclohexyl acetate (CASRN 32210-23-4)
Rabbits (4, sex and strain not reported) were administered 4-fert-butylcyclohexyl acetate
dermally at 5000 mg/kg-bw. One rabbit died.
LD50 > 5000 mg/kg-bw
Repeated-Dose Toxicity
4-tert-Butylcyclohexanol (CASRN 98-52-2)
Wistar rats (30/sex/dose) were administered 4-fert-butylcyclohexanol via gavage (in corn oil) at
0, 50, 150 or 300 mg/kg-bw/day for 28 days with a 14 day post-dosing recovery period. Clinical
signs indicative of neurotoxicity were observed predominantly at the highest dose (ataxia,
padding movements, defense against touching, aggressiveness, hunchback/squatting position,
walking on tiptoes and slight convulsions) after 2, 3 and 4 weeks of treatment. However,
evaluation of the functional observation battery (FOB) showed no treatment-related
abnormalities. During the recovery period, some high-dose males showed a statistically
significant (p-value is not provided) increase in landing-foot-splay and rearing and a decrease in
grip strength. However, these differences did not show a consistent pattern in individual
animals. An increase in motor activity was observed in high-dose females. Slight decreases in
body weights and body weight changes were observed in high-dose males (statistically
significant only for males in the recovery group during week 4 of the treatment). At the end of
the treatment period, high-dose males showed a statistically significant increase in relative
adrenal weight. At the end of the recovery period, males at all doses showed increased relative
epididymis weight that was statistically significant at the highest dose. Histopathological
examination revealed no effects on any male or female sex organs or tissues, including the
epididymis. There was an increase in the number of high-dose males with eosinophilic hyaline
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droplets in the epithelial cell cytoplasm of the proximal tubules which is consistent with alpha
2|i-globulin nephropathy.
LOAEL = 300 mg/kg-bw/day (based on decreased body weights and organ weight changes)
NOAEL = 150 mg/kg-bw/day
Reproductive Toxicity (CASRN 98-52-2)
No adequate reproductive toxicity data were provided. At the end of the recovery period,
evaluation of male reproductive organs from the 28-day repeated-dose toxicity study showed
increased relative epididymis weight that was statistically significant at the highest dose. This
change was not observed at the end of the treatment period. Histopathological evaluation of
testes, epididymides, seminal vesicles, prostate, ovaries, uterus, mammary gland and vagina from
this study showed no effects. Because the significance of effects on epididymides is unclear,
EPA recommended that the submitter conduct a combined reproductive/developmental toxicity
screening test (OECD TG 421) on CASRN 98-52-2 to address these endpoints. However, the
submitter provided a prenatal developmental toxicity study that addresses the developmental
toxicity endpoint only (described below). The reproductive toxicity endpoint remains as data
gaps under the HPV Challenge Program.
Developmental Toxicity
4-tert-Butylcyclohexyl acetate (CASRN 32210-23-4)
In a modified developmental toxicity screening test (OCED TG 421), pregnant Crl:CD(SD) rats
were administered 4-fert-butylcyclohexyl acetate (a mixture of 71% trans and 28% cis) in corn
oil via gavage at 0, 40, 160 or 640 mg/kg-bw/day during gestation days 7 - 20. Rats were
Caesarean-sectioned on day 21 of gestation and examined for number and distribution of corpora
lutea, implantation sites and placenta. Live and dead fetuses and early and late resorptions were
recorded. Fetuses were examined for sex ratio, gross external alterations and skeletal and soft
tissue alterations. There were no effects on maternal body weights, weight gain, food
consumption or organ weights. Pup viability, body weights, external observations and
microscopic examination showed no significant alterations that could be related to the
administration of the test substance.
NOAEL (maternal/developmental toxicity) = 640 mg/kg-bw/day (based on no effects at the
highest dose tested)
Genetic Toxicity — Gene mutation
In vitro
4-tert-Butylcyclohexanol (CASRN 98-52-2)
Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 were exposed to
4-fert-butylcyclohexanol at 10 to 5000 |ig/plate in the presence and absence of metabolic
activation. Positive and negative controls were used but their response was not provided.
Cytotoxicity was observed at and above 250 |ig/plate.
4-terf-Butylcyclohexanol was not mutagenic in this assay.
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4-tert-Butylcyclohexyl acetate (CASRN 32210-23-4)
Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 were exposed to
4-fert-butylcyclohexyl acetate at 8 to 5000 |ig/plate in a bacterial reverse mutation assay in the
presence and absence of metabolic activation. Positive and negative controls were used but their
response was not provided. Cytotoxicity was observed at and above 200 |ig/plate.
4-terf-Butylcyclohexyl acetate was not mutagenic in this assay.
Genetic Toxicity — Chromosomal Aberrations
In vitro
4-tert-Butylcyclohexanol (CAS No. 98-52-2)
Chinese Hamster V79 lung cells were exposed to 4-fert-butylcyclohexanol at 50, 250 and 500
|ig/mL (test 1) and 20, 100 and 200 |ag/m L (test 2) with metabolic activation or at 10, 60 or 100
|ig/mL (tests 1 and 2) without metabolic activation. The cells were harvested and scored after 18
and 28 hours. A statistically significant increase in aberrations was observed at the highest
concentration with metabolic activation at the 28 hour sampling time. However, the incidence of
aberration was within the normal range of the test system and related to the low control incidence
of the experiment (0%). Since no dose-related increase in chromosomal aberrations could be
detected in repeat experiments, this result was not considered biologically significant. Positive
and negative controls were used; however, their response was not reported. Cytotoxicity was
observed at and above 60 jag/mL without metabolic activation and at and above 200 jag/m L with
metabolic activation.
4-terf-butylcyclohexanol did not induce chromosome aberrations in this assay.
Additional Information
Skin Irritation
4-tert-Butylcyclohexyl acetate (CASRN 32210-23-4)
(1) Rabbits (species, sex and number not specified) were administered 4-tert-butylcyclohexyl
acetate dermally to the ears and backs. Observations of the backs included slight erythema after
1 and 5 min, severe erythema and slight edema at 15 min, and severe erythema and edema at
20 hours. On day 8, slight redness and severe scaling were observed. Observations of the ears
included severe erythema and edema with blistering after 20 hours. Severe necrosis was
recorded on day 8. (Bhatia, S.P., et al, Food and Chemical Toxicology 46 (2008) S36-S41)
¥-terf-Butylcyclohexyl acetate was irritating to rabbit skin.
(2) New Zealand white rabbits (number, sex not reported) were administered 0.5 mL neat 4-tert-
clcyclohexyl acetate dermally for 4 hours under semi-occlusive conditions. The test sites were
assessed for irritation immediately after treatment and then 24, 48 and 72 hours later. Slight to
moderate irritation reactions were observed. (Bhatia, S.P., et al, Food and Chemical Toxicology
46 (2008) S36-S41)
¥-terf-Butylcyclohexyl acetate was irritating to rabbit skin.
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(3) New Zealand albino rabbits were administered 0.5 mL neat 4-fert-clcyclohexyl acetate
dermally onto clipped, intact dorsal skin for 4 hours under semi-occlusive conditions. The
treated sites were assessed for reactions at 1, 24, 48, 72 and 168 hours after patch removal.
Irritation was observed at 1, 24, 48, 72 and 168 hours. 4-te/V-butylcyclohexyl acetate was not
considered to be an irritant, as its mean erythema and edema score was 1.8 and 1.0, respectively.
(Bhatia, S.P., et al, Food and Chemical Toxicology 46 (2008) S36-S41)
¥-terf-Butylcyclohexyl acetate was not irritating to rabbit skin.
(4) Using the same method and test concentration as above (3), another 4-hour semi-occlusive
patch test was conducted on three New Zealand rabbits. Irritation was observed at 1, 24, 48, 72
and 168 hours. 4-fert-Butylcyclohexyl acetate was considered to be an irritant, as its mean
erythema and edema score was 2 and 1.3, respectively. (Bhatia, S.P., et al, Food and Chemical
Toxicology 46 (2008) S36-S41)
¥-terf-Butylcyclohexyl acetate was irritating to rabbit skin.
Eye Irritaiton
4-tert-Butylcyclohexyl acetate (CASRN 32210-23-4)
(1) Albino rabbits (3/dose, sex not specified) were instilled 0.1 mL aliquot of 0.625% solution
(vehicle not reported) into the right eye of each rabbit with no further treatment while the left eye
served as control. Scores were recorded according to the Draize scale. Slight to moderate
conjunctival irritation with chemosis and discharge were observed in all three rabbits (mean
score for redness 1.9 and for chemosis 1). All eyes cleared by day 4. (Bhatia, S.P., et al, Food
and Chemical Toxicology 46 (2008) S36-S41)
¥-terf-Butylcyclohexyl acetate was irritating to rabbit eyes.
(2) Rabbits (number, sex, strain not specified) were instilled 0.05 mL neat 4-fert-butylcyclohexyl
acetate to the surface of one eye while the untreated eye served as the control. The test material
produced slight redness at 1 and 24 hours after application. All reactions cleared by day 8.
(Bhatia, S.P., et al, Food and Chemical Toxicology 46 (2008) S36-S41)
¥-terf-Butylcyclohexyl acetate was irritating to rabbit eyes.
Conclusion: Acute oral toxicity of rats and acute dermal toxicity of rabbits to the category
members is low. CASRN 32210-23-4 was irritating to rabbit skin and eyes. Repeated oral
exposure of rats to CASRN 98-52-2 for 28 days showed clinical signs indicative of neurotoxicity
and decreased body weights at 300 mg/kg-bw/day (highest dose) and increased relative
epididymis weight at all doses; statistically significant at the high dose. The LOAEL and
NOAEL values were 300 and 150 mg/kg-bw/day. Reproductive toxicity data were not provided.
Although no effects were seen on the other reproductive organs in the 28-day repeated-dose
toxicity study of CASRN 98-52-2, the significance of effects on epididymides is unclear.
Therefore, EPA recommended that the submitter conduct a combined
reproductive/developmental toxicity screening test (OECD TG 421) on CASRN 98-52-2 to
address these endpoints. The submitted prenatal developmental toxicity study established a
NOAEL of 640 mg/kg-bw/day based on no maternal or developmental toxicity at the highest
dose tested. The reproductive toxicity endpoint remains as data gaps under the HPV Challenge
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Program. The category members did not induce gene mutations or chromosomal aberrations in
vitro.
Table 3: Summary of Health Effects
Endpoints
4-fert-butylcyclohexanol
(CAS No. 98-52-2)
4-ferf-butylcyclohexyl
acetate
(CAS No. 32210-23-4)
Structure
ch3
H3C ( ) 0
ch3
Acute Oral Toxicity
LD5o (mg/kg-bw)
4200
5000
4800
> 500 < 5000
Acute Dermal Toxicity
LD5o (mg/kg-bw)
>5000
>5000
Repeated-Dose Toxicity
NOAEL/LOAEL
Oral (mg/kg-bw/day)
(28-day)
NOAEL = 150
LOAEL = 300
No Data
NOAEL = 150
LOAEL = 300
(RA)
Reproductive Toxicity
No data
No effects on reproductive
organs in the repeated-dose
toxicity study
No data
No effects on reproductive
organs in the repeated-dose
toxicity study
(RA)
Developmental Toxicity
NOAEL/LOAEL
Oral (mg/kg-bw/day)
Maternal/Developmental Toxicity
No Data
NOAEL = 640 (hdt)
(RA)
NOAEL = 640 (hdt)
Genetic Toxicity -Gene Mutation
In vitro
Negative
Negative
Genetic Toxicity -Chromosomal
Aberrations
In vitro
Negative
No Data
Negative
(RA)
Additional Information
Skin Irritation
Eye Irritation
—
Irritating
Irritating
Measured data in bold text; (RA) = Read Across; hdt = highest dose tested
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U.S. Environmental Protection Agency
Hazard Characterization Document
September, 2009
4 Hazards to the Environment
A summary of aquatic toxicity data submitted for SIDS endpoints is provided in Table 4. The
table also indicates where data for tested category members are read across (RA) to untested
members of the category.
Acute Toxicity to Fish
4-tert-Butylcyclohexanol (CASRN 98-52-2)
Golden ide {Leuciscus idus) were exposed to 4-fert-butylcyclohexanol at nominal concentrations
of 0, 13, 16 and 20 mg/L under static conditions for 48 hours. Mortality was 0, 20 and 100% at
13, 16 and 20 mg/L, respectively. ECOSAR 1.0 estimated value of 8.085 mg/L for a 96-hour
LC50 corroborated with the 48-hour experimental value.
48-h LCso = 17 mg/L
96-h LCso = 8.1 mg/L (ECOSAR 1.0)
4-tert-Butylcyclohexyl acetate (CASRN 32210-23-4)
(1) Golden ide (Leuciscus idus) were exposed to 4-/c/7-butylcyclohexyl acetate at nominal
concentrations of 0, 10, 13, 16 and 20 mg/L under static conditions for 48 hours. Marlowet EF
was used as a solubilizer. Mortality was 0, 10, 80 and 100% at 10, 13, 16 and 20 mg/L.
48-h LCso = 14 mg/L
(2) Juvenile carp (Cyprinus carpio) were exposed to 4-fert-butylcyclohexyl acetate at nominal
concentrations ranging from 4 to 34 mg/L under semi-static conditions for 96 hours.
96-h LCso = 8.6 mg/L
Acute Toxicity to Aquatic Invertebrates
4-tert-Butylcyclohexanol (CASRN 98-52-2)
Water fleas {Daphnia magna) were exposed to 4-/£/7-butylcyclohexanol at nominal
concentrations (not stated) under static conditions for 48 hours.
48-h EC50 = 46 mg/L
4-tert-Butylcyclohexyl acetate (CASRN 32210-23-4)
(1) Water fleas (Daphnia magna) were exposed to 4-fert-butylcyclohexyl acetate at nominal
concentrations of 2.8 to 28.4 mg/L (measured concentrations, 2.4 to 28.4 mg/L) under static
conditions for 48 hours.
48-h EC50 = 23.4 mg/L
(2) Water fleas (Daphnia magna) were exposed to 4-fert-butylcyclohexyl acetate at measured
concentrations of 2.6 to 22 mg/L under static conditions for 24 hours. ECOSAR 1.0 estimated a
48-hour EC50 of 0.446 mg/L for Daphnia.
24-h EC50 = 7 mg/L
48-h EC50 = 0.446 mg/L (ECOSAR 1.0)
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U.S. Environmental Protection Agency
Hazard Characterization Document
September, 2009
Toxicity to Aquatic Plants
4-tert-Butylcyclohexanol (CASRN 98-52-2)
Freshwater algae (Scenedesmus subspicatus) were exposed to 4-fert-butylcyclohexanol at
nominal concentrations of 4.4 to 148 mg/L (measured concentrations: 4.6 to 110 mg/L) for 72
hours.
72-h EC50 (growth rate) = 45 mg/L
4-tert-Butylcyclohexyl acetate (CASRN 32210-23-4)
Freshwater algae {Scenedesmus subspicatus) were exposed to 4-fert-butylcyclohexyl acetate at
nominal concentrations of 0.76 to 27.3 mg/L (measured concentrations, 0.76 to 27.3 mg/L) for
72 hours.
72-h EC50 (biomass) = 17 mg/L
72-h EC50 (growth rate) = 22 mg/L
Conclusion: The 96-hour LC50 of CASRN 98-52-2 and 32210-23-4 for fish was 8.1 and 8.6
mg/L, respectively. The 48-hour EC50 of CASRN 98-52-2 and 32210-23-4 for aquatic
invertebrates was 46 and 23 mg/L, respectively. The 96-hour ErCso of CASRN 98-52-2 and
32210-23-4 for aquatic plants was 45 and 22 mg/L, respectively and EbC50 for
CASRN 32210-23-4 is 17 mg/L.
Table 4: Summary of Environmental Effects -Aquatic Toxicity Data
Endpoints
Cyclohexanol, 4-
(1,1 -dimethylethyl)-
(CASRN 98-52-2)
Cyclohexanol, 4-( 1,1-
dimethylethyl)-, acetate
(CASRN 32210-23-4)
Fish 96-h LCS0 (mg/L)
8.1(e)
8.6
Aquatic Invertebrates 48-h EC50
(mg/L)
46
23.4
Aquatic Plants 72-h EC50 (mg/L)
(growth rate)
(Biomass)
45
22
17
Measured data in bold; (e) = estimated data (i.e. derived from modeling)
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