/EPA
EPA/635/R-13/107
Preliminary Materials
www. ep a. go v/ir is
Preliminary Materials for the Integrated Risk Information System (IRIS)
Toxicological Review of tert-Butyl Alcohol (tert-Butanol)
[CASRN 75-65-0]
July 2013
NOTICE
This document is comprised of preliminary materials, consisting of a literature search strategy,
evidence tables, and exposure-response arrays. This information is distributed solely for the
purpose of pre-dissemination review under applicable information quality guidelines. It has not
been formally disseminated by EPA. It does not represent and should not be construed to represent
any Agency determination or policy. It is being circulated for review of its technical accuracy and
science policy implications.
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
DISCLAIMER
This document is comprised of preliminary materials for review purposes only. This
information is distributed solely for the purpose of pre-dissemination review under applicable
information quality guidelines. It has not been formally disseminated by EPA. It does not represent
and should not be construed to represent any Agency determination or policy. Mention of trade
names or commercial products does not constitute endorsement or recommendation for use.
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
CONTENTS
PREFACE v
1. DRAFT LITERATURE SEARCH STRATEGY 1-1
1.1. Literature Search and Screening Strategy for tert-Butanol 1-1
1.2. List of References Based on Search Strategy for tert-Butanol 1-5
1.2.1. Primary Sources of Health Effects Data 1-5
1.2.2. Not Primary Source of Health Effects Data, but Kept as Additional Resources 1-13
1.2.3. Kept for Possible Further Review 1-17
2. PRELIMINARY EVIDENCE TABLES AND EXPOSURE-RESPONSE ARRAYS 2-1
2.1. Data Extraction: Preparation of Preliminary Evidence Tables and Exposure-Response
Arrays 2-1
2.2. Kidney Effects 2-3
2.3.Thyroid Effects 2-13
2.4. Reproductive, Developmental, and Neurodevelopmental Effects 2-16
2.5. Central Nervous System (CNS) Effects 2-25
2.6. Other Systemic Effects (Body Weight, Liver, and Urinary Bladder) 2-28
2.7.GenotoxicEffects 2-37
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
TABLES
Table 1-1. Database search strategy for te/t-butanol 1-3
Table 1-2. Summary of additional search strategies for te/t-butanol 1-4
Table 2-1. Evidence pertaining to kidney effects in animals following oral exposure to te/t-
butanol 2-3
Table 2-2. Evidence pertaining to kidney effects in animals following inhalation exposure to tert-
butanol 2-9
Table 2-3. Evidence pertaining to thyroid effects in animals following oral exposure to tert-
butanol 2-13
Table 2-4. Evidence pertaining to reproductive effects in animals following exposure to tert-
butanol 2-16
Table 2-5. Evidence pertaining to developmental effects in animals following exposure to tert-
butanol 2-18
Table 2-6. Evidence pertaining to neurodevelopmental effects in animals following exposure to
te/t-butanol 2-21
Table 2-7. Evidence pertaining to CNS effects in animals following exposure to te/t-butanol 2-25
Table 2-8. Evidence pertaining to effects on body weight in animals following oral exposure to
te/t-butanol 2-28
Table 2-9. Evidence pertaining to liver effects in animals following oral exposure to te/t-butanol 2-30
Table 2-10. Evidence pertaining to liver effects in animals following inhalation exposure to te/t-
butanol 2-33
Table 2-11. Evidence pertaining to urinary bladder effects in animals following oral exposure to
te/t-butanol 2-34
Table 2-12. Evidence pertaining to genotoxic effects of te/t-butanol in vitro and in vivo studies 2-37
FIGURES
Figure 1-1. Literature search approach for te/t-butanol 1-2
Figure 2-1. Exposure response array of kidney effects in rats and mice following oral exposure
to te/t-butanol 2-11
Figure 2-2. Exposure-response array of kidney effects in rats and mice following subchronic
inhalation exposure to te/t-butanol 2-12
Figure 2-3. Exposure-response array of thyroid follicular cell effects in rats and mice following
chronic oral exposure to te/t-butanol 2-15
Figure 2-4. Exposure-response array of reproductive, developmental and neurodevelopmental
effects following oral exposure to te/t-butanol 2-23
Figure 2-5. Exposure-response array of reproductive and developmental effects following
inhalation exposure to te/t-butanol 2-24
Figure 2-6. Exposure-response array of body weight, liver effects, and urinary bladder effects
following oral exposure to te/t-butanol 2-36
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1
2 PREFACE
3 This document presents the draft literature search strategy, preliminary evidence tables,
4 and preliminary exposure-response arrays for tert-butyl alcohol (henceforth referred to as tert-
5 butanol) prepared under the auspices of EPA's Integrated Risk Information System (IRIS) Program.
6 This material is being released for public viewing and comment prior to a public meeting, providing
7 an opportunity for the IRIS Program to engage in early discussions with stakeholders and the public
8 on data that may be used to identify adverse health effects and characterize exposure-response
9 relationships.
10 The draft literature search strategy, preliminary evidence tables, and preliminary exposure-
11 response arrays are responsive to the National Research Council (NRC) 2011 report Review of the
12 Environmental Protection Agency's Draft IRIS Assessment of Formaldehyde. The literature search
13 strategy, which describes the processes for identifying scientific literature, screening studies for
14 consideration, and selecting studies for inclusion in evidence tables, is responsive to NRC
15 recommendations regarding systematic review of the scientific literature. In addition, NRC
16 recommendations for standardized presentation of key study data are addressed in the preliminary
17 evidence tables and preliminary exposure-response arrays.
18 EPA welcomes all comments on the draft literature search strategy, preliminary evidence
19 tables, and preliminary exposure-response arrays, such as remarks on the following:
20 • the clarity and transparency of the materials;
21 • the approach for identifying pertinent studies;
22 • the selection of studies for data extraction to preliminary evidence tables and exposure-
23 response arrays;
24 • any methodological considerations that could affect the interpretation of or confidence
25 in study results; and
26 • any additional studies published or nearing publication that may provide data for the
27 evaluation of human health hazard or exposure-response relationships.
28 The preliminary evidence tables and exposure-response arrays should be regarded solely as
29 representing the data on each endpoint that have been identified as a result of the draft literature
30 search strategy. They do not reflect any conclusions as to hazard identification or dose-response
31 assessment After obtaining public input and conducting additional study evaluation and data
32 integration, EPA will revise these materials to support the hazard identification and dose-response
33 assessment in a draft Toxicological Review.
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1. DRAFT LITERATURE SEARCH STRATEGY
1 1.1. Literature Search and Screening Strategy for tert-Butanol
2 The overall literature search approach is shown graphically in Figure 1-1. The initial
3 chemical-specific search was conducted in four online scientific databases in December, 2012, and
4 January, 2013, using the keywords and limits described in Table 1-1. After electronically
5 eliminating duplicates from the citations retrieved through these databases, 2,907 unique citations
6 were identified. An additional seven citations were obtained using additional search strategies
7 described in Table 1-2.
8 The resulting 2,410 citations were screened using the title, abstract, and/or full text for
9 pertinence to examining the health effects of tert-butanol exposure. A total of 2,226 references
10 were identified as not being pertinent and were excluded from further consideration (see Figure 1-
11 1 for the exclusion categories). A total of 106 references were identified as primary sources of
12 health effects data and were considered for data extraction to evidence tables and exposure-
13 response arrays (see Section 1.2.1). A total of 60 references were considered pertinent, but not as
14 primary sources of health effects data (e.g., ADME studies), and kept as additional resources for
15 development of the Toxicological Review (see Section 1.2.2). A total of 18 references did not
16 provide enough material to evaluate pertinence (e.g., foreign language), and were reserved for
17 further possible review (see Section 1.2.3).
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
Database Searches
(see Table 1 for keywords and limits)
Pubmed
n = 1,512
Web of Science
n = 462
Toxline
(incl. TSCATS)
n = 931
TSCATS 2
n = 2
(After duplicates removed electronically by HERO)
n = 2,907
Additional Search Strategies
(see Table 2-1 for methods and results)
n = 7
1
Combined Dataset
(After all duplicates removed)
n = 2,410
Manual Screening For Pertinence
(Title/Abstract/Full Text)
Excluded (not pertinent)
80 Biodegradation/environmental fate
75 Chemical analysis/fuel chemistry
1,143 Other chemical/ non-tert-butanol
86 Method of detection/exposure and
biological monitoring
624 Methodology/solvent
62 Not relevant exposure paradigms (e.g.,
dermal, eye irritation, etc.)
39 Not relevant species/matrixfe.g.,
amphibians, fish, etc.)
40 Abstract only/comment
25 Book chapter/section
15 General review papers
22 Society abstracts
14 QSAR
1 Unpublished data subsequently published
<-
Kept for Possible Further Review
18 Foreign language
Not Primary Source of Health Effects
Data, but Kept As Additional
Resource
17 Reviews, editorials
8 Health effects assessments by others
29 Toxicokinetic studies (not including PBTK)
6 PBTK modelingstudies
Primary Sources of Health Effects
Data
4 Human health effects studies
(includingone case report)
37 Animaltoxicologystudies
22 Genotoxicitystudies
43 Otherstudies involving direct
ad ministration of chemical, including
mechanisticstudies
1
2
Figure 1-1. Literature search approach for tert-butanol.
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
Table 1-1. Database search strategy for tert-butanol
Database
(Search Date)
Keywords
Limits
PubMed
(12/20/2012)
t-butanol OR 75-65-0[rn] OR "t-
butyl hydroxide" OR "2-methyl-2-
propanol" OR "trimethyl carbinol"
OR "t-butyl alcohol" OR tert-
butanol OR "tert-butyl alcohol"
OR tert-butyl alcoholfmesh]
None
Web of Science
(12/20/2012)
Topic = (t-butanol OR 75-65-0 OR
"t-butyl hydroxide" OR "2-methyl-
2-propanol" OR "trimethyl
carbinol" OR "t-butyl alcohol" OR
"tert-butanol" OR "tert-butyl
alcohol")
Refined by: Research Areas = (cell biology OR
respiratory system OR microscopy OR
biochemistry molecular biology OR
gastroenterology hepatology OR public
environmental occupational health OR oncology
OR physiology OR cardiovascular system
cardiology or toxicology OR life sciences
biomedicine other topics OR hematology OR
pathology OR neurosciences neurology OR
developmental biology)
Toxline
(includes
TSCATS)
(1/11/2013)
t-butanol OR 75-65-0 [rn] OR t-
butyl hydroxide OR 2-methyl-2-
propanol OR trimethyl carbinol OR
t-butyl alcohol OR tert-butanol OR
tert-butyl alcohol OR tert-butyl
alcohol
Not PubMed
TSCATS2
(1/4/2013)
75-65-0
None
2
3
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
Table 1-2. Summary of additional search strategies for tert-butanol
Approach used
Manual search
of citations
from reviews
Manual search
of citations
from reviews
conducted by
other
international
and federal
agencies
Source(s)
Review article: McGregor, D.
(2010). Tertiary-butanol: A
toxicological review. Crit Rev
Toxicol 40(8): 697-727.
Review article: Chen, M. (2005).
Amended final report of the safety
assessment of t-butyl alcohol as
used in cosmetics." Int J Toxicol
24(2): 1-20.
IPCS (International Programme on
Chemical Safety) (1987a).
Butanols: Four isomers: 1-butanol,
2-butanol, tert-butanol, isobutanol
[WHO EHC]. Geneva, Switzerland:
World Health Organization.
OSHA (Occupational Safety &
Health Administration). (1992).
Occupational safety and health
guideline for tert-butyl alcohol.
Cincinnati, OH: National Institute
for Occupational Safety and
Health.
Date
performed
1/2013
1/2013
1/2013
1/2013
Number of additional citations
identified
5 citations
2 citations
None
None
2
3
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-Butanol
1 1.2. List of References Based on Search Strategy for tert-Butanol
2 Citations for excluded references are not listed here, but can be found on the Health and
3 Environmental Research Online (HERO) Web site [http://hero.epa.gov/tert-Butanol].
4 1.2.1. Primary Sources of Health Effects Data
5 Data from citations in bold are displayed in Section 2. See Section 2.1 for a description of
6 the process of selecting these studies for evidence tables and exposure-response arrays.
7 Human health effects studies
8 1) Edwards, EK, Jr; Edwards, EK. (1982.). Allergic reaction to tertiary butyl alcohol in a
9 sunscreen. Cutis 29: 476-478.
10 2) Johanson, G; Nihlen, A; Lof, A. (1995). Toxicokinetics and acute effects of MTBE and ETBE in
11 male volunteers. Toxicol Lett 82/83: 713-718.
12 3) Laire, G; Viaene, MK; Veulemans, H; Masschelein, R; Nemery, B. (1997). Nocturnal oxygen
13 desaturation, as assessed by home oximetry, in long-term solvent-exposed workers. Am J
14 IndMed 32: 656-664.
15 4) Prah, JD; Goldstein, GM; Devlin, R; Otto, D; Ashley, D; House, D; Cohen, KL; Gerrity, T. (1994).
16 Sensory, symptomatic, inflammatory, and ocular responses to and the metabolism of methyl
17 tertiary butyl ether in a controlled human exposure experiment Inhal Toxicol 6: 521-538.
18 Animal toxicology studies
19 1) Acharya, S; Mehta, K; Rodrigues, S; Pereira, J; Krishnan, S; Rao, CV. (1995).
20 Administration of subtoxic doses of t-butyl alcohol and trichloroacetic acid to male
21 Wistar rats to study the interactive toxicity. Toxicol Lett 80: 97-104.
22 2) Acharya, S; Mehta, K; Rodriguez, S; Pereira, J; Krishnan, S; Rao, CV. (1997). A
23 histopathological study of liver and kidney in male Wistar rats treated with subtoxic
24 doses of t-butyl alcohol and trichloroacetic acid. Exp Toxicol Pathol 49: 369-373.
25 3) ARCO (ARCO Chemical Company). (1992). Initial submission: letter submitting preliminary
26 results from subchronic toxicity studies of tertiary butyl alcohol in rats and mice dated
27 10/14/92 and attachments. (88930000018). Newton Square, PA: Arco Chemical Company.
28 4) Atrens, D; van der Reest, A; Balleine, B; Menendez, J; Siviy, S. (1989). Effects of ethanol and
29 tertiary butanol on blood glucose levels and body temperature of rats. Alcohol 6: 183-187.
30 5) Belknap, JK; Deutsch, CK. (1982). Differential neurosensitivity to three alcohols and
31 phenobarbital in C57BL/6J and DBA/2J mice. Behav Genet 12: 309-317.
32 6) Bellin, SI; Edmonds, HL, Jr. (1976). The use of tert-butanol in alcohol dependence studies.
33 Proc West Pharmacol Soc 19: 351-354.
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1 7) Billitti, JE; Faulkner, BC; Wilson, BW. (20051. Absence of acute testicular toxicity of
2 methyl-tert butyl ether and breakdown products in mice. Bull Environ Contam
3 Toxicol 75: 228-235.
4 8) Cirvello, JD; Radovsky, A; Heath, JE; Farnell, DR; III, LC. [1995]. Toxicity and carcinogenicity
5 of t-butyl alcohol in rats and mice following chronic exposure in drinking water. Toxicol Ind
6 Health 11: 151-165.
7 9) Daniel, MA; Evans, MA. (1982). Quantitative comparison of maternal ethanol and
8 maternal tertiary butanol diet on postnatal development. J Pharmacol Exp Ther 222:
9 294-300.
10 10) Dow Chemical Co (Dow Chemical Company). [1992]. Letter submitting multiple studies on
11 multiple chemicals required for docket opts-82036 with attachments (sanitized).
12 11) Dow Chemical Co (Dow Chemical Company). [1994]. Animal toxicity experiments with ethyl
13 alcohol, tertiary butyl alcohol, and stoddard's solvent with cover letter dated 03/28/94.
14 (sanitized). (8694000270S). Midland, MI.
15 12) Eastman Kodak Company. [1963]. Toxicity report (summary) of t-butyl alcohol with cover
16 letter dated 02/15/94. Rochester, New York: Eastman Kodak Company.
17 13) Faulkner, TP; Wiechart, JD; Hartman, DM; Hussain, AS. (1989). The effects of prenatal
18 tertiary butanol administration in CBA/J and C57BL/6J mice. Life Sci 45:1989-1995.
19 14) Feller, DJ; Crabbe, JC. (1991). Effect of alcohols and other hypnotics in mice selected for
20 differential sensitivity to hypothermic actions of ethanol. J Pharmacol Exp Ther 256: 947-
21 953.
22 15) Grant, KA; Samson, HH. (1981). Development of physical dependence on t-butanol in
23 rats: An examination using schedule-induced drinking. Pharmacol Biochem Behav
24 14:633-637.
25 16) Grant, KA; Samson, HH. (1982). Ethanol and tertiary butanol induced microcephaly in
26 the neonatal rat: Comparison of brain growth parameters. Neurobehav Toxicol
27 Teratol 4: 315-321.
28 17) GSRI (Gulf South Research Institute). (1979a). Repeated dose test of t-butanol (c55367) in
29 B6C3F1 mice and Fischer 344 rats with cover letter dated 031594. (86940000173). Orleans
30 Parrish, LA.
31 18) GSRI (Gulf South Research Institute). (1979b). Subchronic test of t-butanol (c55367) in
32 B6C3F1 mice and Fischer 344 rats in drinking water with cover letter dated 031594.
33 (86940000172). Orleans Parish, LA.
34 19)Hard, GC; Bruner, RH; Cohen, SM; Pletcher, JM; Regan, KS. (20111. Renal
35 histopathology in toxicity and carcinogenicity studies with tert-butyl alcohol
36 administered in drinking water to F344 rats: A pathology working group review and
37 re-evaluation. Regul Toxicol Pharmacol 59: 430-436.
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1 20) Lindamood, C; Farnell, D; Giles, H; Prejean, J; Collins, J; Takahashi, K; Maronpot, R. [1992].
2 Subchronic toxicity studies of t-butyl alcohol in rats and mice. Fundam Appl Toxicol 19: 91-
3 100.
4 21) Lyondell Chemical Co. (Lyondell Chemical Company). [2003]. An oral gavage reproductive
5 and developmental toxicity screening in rats. (Document Control Number: 88030000222).
6 22)Lyondell Chemical Co. (Lyondell Chemical Company). (2004). Reproductive and
7 developmental toxicity screening test in rats by oral gavage. (Document Control
8 Number: 89-040000106).
9 23)Mccomb, J; Goldstein, D. (1979a). Additive physical dependence: evidence for a
10 common mechanism in alcohol dependence. J Pharmacol Exp Ther 210: 87-90.
11 24)Mccomb, J; Goldstein, D. (1979b). Quantitative comparison of physical dependence on
12 tertiary butanol and ethanol in mice: Correlation with lipid solubility. J Pharmacol
13 Exp Ther 208:113-117.
14 25) Nelson, BK. [1986]. Developmental neurotoxicology of in utero exposure to industrial
15 solvents in experimental animals. Neurotoxicology 7: 441-447.
16 26) Nelson, BK; Brightwell, WS; Khan, A; Burg, JR; Goad, PT. (1989). Lack of selective
17 developmental toxicity of three butanol isomers administered by inhalation to rats.
18 Fundam Appl Toxicol 12: 469-479.
19 27)Nelson, BK; Brightwell, WS; Khan, A; Shaw, PB; Krieg, EF, Jr; Massari, VJ. (1991).
20 Behavioral teratology investigation of tertiary-butanol administered by inhalation to
21 rats. Pharmacopsychoecologia 4:1-7.
22 28) Nelson, BK; Brightwell, WS; Krieg, EF, Jr. [1990]. Developmental toxicology of industrial
23 alcohols: A summary of 13 alcohols administered by inhalation to rats. Toxicol Ind Health 6:
24 373-387.
25 29) NTP (National Toxicology Program). (1995). Toxicology and carcinogenesis studies of
26 t-butyl alcohol (CAS no 75-65-0) in F344/N rats and B6C3F1 mice (drinking water
27 studies) (pp. 1-305). Research Triangle Park, NC.
28 30)NTP (National Toxicology Program). (1997). NTP technical report on toxicity studies
29 of t-butyl alcohol (CAS no 75-65-0) administered by inhalation to F344/N rats and
30 B6C3F1 mice. Research Triangle Park, NC.
31 31) Palmer, AA; Mckinnon, CS; Bergstrom, HC; Phillips, TJ. [2002]. Locomotor activity responses
32 to ethanol, other alcohols, and GABA-A acting compounds in forward- and reverse-selected
33 FAST and SLOW mouse lines. Behav Neurosci 116: 958-967.
34 32) Siviy, SM; Atrens, DM; Jirasek, M; Holmes, LJ. [1987]. Effects of ethanol and tertiary-butanol
35 on energy expenditure and substrate utilization in the rat. Alcohol 4: 437-442.
36 33)Snell, D. (1980). Impairment of avoidance behavior following short-term ingestion of
37 ethanol, tertiary-butanol, or pentobarbital in mice. Psychopharmacology 69: 53-57.
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1 34)Takahashi, K; Lindamood, C; Maronpot, R. (1993). Retrospective study of possible
2 alpha-2 mu-globulin nephropathy and associated cell proliferation in male Fischer
3 344 rats dosed with t-butyl alcohol. Environ Health Perspect 101: 281-285.
4 35)Thurman, RG; Winn, K; Urquhart, B. (1980). Rat brain cyclic AMP levels and
5 withdrawal behavior following treatment with t-butanol. Adv Exp Med Biol 126: 271-
6 281.
7 36) Williams, TM; Borghoff, SJ. (2001). Characterization of tert-butyl alcohol binding to
8 "alpha"2u-globulin in F-344 rats. Toxicol Sci 62: 228-235.
9 37) Wood, J; Laverty, R. (1979). Physical dependence following prolonged ethanol or t-
10 butanol administration to rats. Pharmacol Biochem Behav 10:113-119.
11 Gen otoxicity studies
12 1) Abbondandolo, A; Bonatti, S; Corsi, C; Corti, G; Fiorio, R; Leporini, C; Mazzaccaro, A; Nieri, R;
13 Barale, R; Loprieno, N. [1980]. The use of organic solvents in mutagenicity testing. DNA
14 Repair 79: 141-150.
15 2) ARCO (ARCO Chemical Company). (1994a). Evaluation of test article t-butyl alcohol
16 99.9% (MRI #635) and arconol (MRI #636) for mutagenic potential employing the
17 15178Y TK+/- mutagenesis assay w/cover letter dated 03/24/94. (TSCATS/451796).
18 3) ARCO (ARCO Chemical Company). (1994b). In vitro evaluation of t-butyl alcohol
19 99.9% to produce sister chromatid exchanges in Chinese hamster ovary cells with
20 cover letter dated 03/24/1994. (8EHQ86940000254). Newton Square, PA.
21 4) ARCO (ARCO Chemical Company). (1994c). In vitro evaluation of t-butyl alcohol - arconol
22 batch a209411 to produce sister chromatid exchanges in Chinese hamster ovary cells with
23 cover letter dated 03/24/1994. (8EHQ86940000261). Newton Square, PA.
24 5) ARCO (ARCO Chemical Company). (1994d). Microtox analysis of various alcohols with cover
25 letter dated 05/05/94. (TSCATS/451912).
26 6) ARCO (ARCO Chemical Company). (1994e). Salmonella/mammalian-microsome
27 preincubation mutagenicity assay with t-butyl alcohol with cover letter dated
28 03/24/1994. (8EHQ86940000253). Newton Square, PA.
29 7) Barilyak, IR; Kozachuk, SY. (1988). Investigation of the cytogenetic effect of a number of
30 monohydric alcohols on rat bone marrow cells. Cytol Genet 22(2): 51-54.
31 8) Brooks, TM; Meyer, AL; Hutson, DH. (1988). The genetic toxicology of some hydrocarbon
32 and oxygenated solvents. Mutagenesis 3: 227-232.
33 9) Clark, JB. (1953). The mutagenic action of various chemicals on micrococcus aureus. Proc
34 OklaAcad Sci 34:114-118.
35 10) Dickey, FH; Cleland, GH; Lotz, C. (1949). The role of organic peroxides in the induction
36 of mutations. PNAS 35: 581-586.
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review oftert-Butanol
1 11) Henry, B; Grant, SG; Klopman, G; Rosenkranz, HS. [1998]. Induction of forward mutations at
2 the thymidine kinase locus of mouse lymphoma cells: Evidence for electrophilic and non-
3 electrophilic mechanisms. MutatRes 397: 313-335.
4 12) Jimenez, J; Longo, E; Benitez, T. (1988). Induction of petite yeast mutants by
5 membrane-active agents. Appl Environ Microbiol 54: 3126-3132.
6 13)McGregor, D; Cruzan, G; Callander, R; May, K; Banton, M. (2005). The mutagenicity
7 testing of tertiary-butyl alcohol, tertiary-butyl acetate and methyl tertiary-butyl
8 ether in Salmonella typhimurium. Mutat Res 565:181-189.
9 14) McGregor, DB; Brown, A; Cattanach, P; Edwards, I; Mcbride, D; Caspary, WJ. (1988).
10 Responses of the L5178Y tk+/tk- mouse lymphoma cell forward mutation assay II: 18
11 coded chemicals. Environ Mol Mutagen 11: 91-118.
12 15) Microbiological Associates. [1994]. Salmonella/ Mammalian-microsome Plate Incorporation
13 Mutagenicity Assay (Ames Test) of T-butanol with Cover Letter dated 03219.
14 (TSCATS/442300).
15 16)Sgambato, A; lavicoli, I; De Paola, B; Bianchino, G; Boninsegna, A; Bergamaschi, A;
16 Pietroiusti, A; Cittadini, A. (2009). Differential toxic effects of methyl tertiary butyl
17 ether and tert-butanol on rat fibroblasts in vitro. Toxicol Ind Health 25:141-151.
18 17)Tang, G; Wang, J; Zhuang, Z. (1997). [Cytotoxicity and genotoxicity of methyl tert-
19 butyl ether and its metabolite to human leukemia cells]. Zhonghua Yufang Yixue
20 Zazhi 31: 334-337.
21 18) Williams-Hill, D; Spears, CP; Prakash, S; Olah, GA; Shamma, T; Moin, T; Kim, LY; Hill,
22 CK. (1999). Mutagenicity studies of methyl-tert-butylether using the Ames tester
23 strain TA102. Mutat Res 446:15-21.
24 19)Yamaguchi, T. [1980]. Activation with catalase of mutagenicity of hydroperoxides of some
25 fatty acids and hydrocarbons. Agric Biol Chem 44: 1989-1991.
26 20)Yuan, Y; Wang, HF; Sun, HF; Du, HF; Xu, LH; Liu, YF; Ding, XF; Fu, DP; Liu, KX. (2007).
27 Adduction of DNA with MTBE and TEA in mice studied by accelerator mass
28 Spectrometry. Environ Toxicol 22: 630-635.
29 21) Zeiger, E; Anderson, B; Haworth, S; Lawlor, T; Mortelmans, K. [1992]. Salmonella
30 mutagenicity tests: V Results from the testing of 311 chemicals. Environ Mol Mutagen 19: 2-
31 141.
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This document is a draft for review purposes only and does not constitute Agency policy.
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This document is a draft for review purposes only and does not constitute Agency policy.
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This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1 1.2.2. Not Primary Source of Health Effects Data, but Kept as Additional Resources
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This document is a draft for review purposes only and does not constitute Agency policy.
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28 Toxicokinetic studies (excluding physiologically-based toxicokinetic [PBTK] modeling studies)
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30 methyl-tert-butyl ether in rats and humans. Toxicol Sci 51: 1-8.
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34 metabolites in humans after oral exposure. Toxicol Sci 61: 62-67.
This document is a draft for review purposes only and does not constitute Agency policy.
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1 4) ARCO (ARCO Chemical Company). [1983]. Toxicologist's report on metabolism and
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13 ether (MTBE] following exposure of Wistar Rats for 13 weeks or one year via drinking
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16 13C-labeled methyl tert-butyl ether, ethyl tert-butyl ether, and tert-butyl alcohol in rats:
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20 and tert-butyl alcohol in male and female fischer 344 rats after single and repeated
21 inhalation [nose-only] exposure to mtbe (final report]. [TSCATS/412947].
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23 alcohols by human liver alcohol dehydrogenase: effect of ethanol and pharmacokinetic
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30 beverages, in rats. Trav Soc Pharm Montpellier 25: 51-62.
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34 methyl tert-butyl ether and other gasoline ethers by human liver microsomes and
35 heterologously expressed human cytochromes P450: Identification of CYP2A6 as a major
36 catalyst. Toxicol Appl Pharmacol 160: 43-48.
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1 17) Hong, JY; Yang, CS; Lee, M; Wang, YY; Huang, WQ; Tan, Y; Patten, CJ; Bondoc, FY. [19971.
2 Role of cytochromes P450 in the metabolism of methyl tert-butyl ether in human livers.
3 Arch Toxicol 71: 266-269.
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6 53:129-136.
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8 tertiary-butyl ether (MTBE) following short-term controlled exposures. J Expo Sci Environ
9 Epidemiol 11: 67-78.
10 20) Miller, MJ; Ferdinandi, ES; Klan, M; Andrews, LS; Douglas, JF; Kneiss, JJ. (1997).
11 Pharmacokinetics and disposition of methyl t-butyl ether in Fischer-344 rats. J Appl Toxicol
12 17:S3-S12.
13 21) Nihlen, A; Lof, A; Johanson, G. [1995). Liquid/air partition coefficients of methyl and ethyl t-
14 butyl ethers, t-amyl methyl ether, and t-butyl alcohol. J Expo Anal Environ Epidemiol 5: 573-
15 582.
16 22) Nihlen, A; Lof, A; Johanson, G. (1998a). Controlled ethyl tert-butyl ether (ETBE) exposure of
17 male volunteers: I Toxicokinetics. Toxicol Sci 46: 1-10.
18 23) Nihlen, A; Lof, A; Johanson, G. [1998b). Experimental exposure to methyl tertiary-butyl
19 ether: I Toxicokinetics in humans. Toxicol Appl Pharmacol 148: 274-280.
20 24) Nihlen, A; Lof, G; Johanson, G. [1997). Liquid/air partition coefficients of methyl and ethyl t-
21 butyl ethers, t-amyl methyl ether, and t-butyl-alcohol. J Clean Technol, Environ Toxicol,
22 OccupMed 6: 205-213.
23 25) Nihlen, A; Sumner, SCJ; Lof, A; Johanson, G. [1999). 13C2-labeled methyl tert-butyl ether:
24 toxicokinetics and characterization of urinary metabolites in humans. Chem Res Toxicol 12:
25 822-830.
26 26) Poet, TS; Valentine, JL; Borghoff, SJ. [1997). Pharmacokinetics of tertiary butyl alcohol in
27 male and female Fischer 344 rats. Toxicol Lett 92: 179-186.
28 27) Prah, J; Ashley, D; Blount, B; Case, M; Leavens, T; Pleil, J; Cardinal!, F. [2004). Dermal, oral,
29 and inhalation pharmacokinetics of methyl tertiary butyl ether (MTBE) in human
30 volunteers. Toxicol Sci 77: 195-205.
31 28) Turini, A; Amato, G; Longo, V; Gervasi, PG. (1998). Oxidation of methyl- and ethyl-tertiary-
32 butyl ethers in rat liver microsomes: role of the cytochrome P450 isoforms. Arch Toxicol 72:
33 207-214.
34 29) Vainiotalo, S; Riihimaki, V; Pekari, K; Teravainen, E; Aitio, A. (2007). Toxicokinetics of
35 methyl tert-butyl ether (MTBE) and tert-amyl methyl ether (TAME) in humans, and
36 implications to their biological monitoring. J Occup Environ Hyg 4: 739-750.
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1 PBTK modeling studies
2 1] Borghoff, S; Murphy, J; Medinsky, M. [1996]. Development of physiologically based
3 pharmacokinetic model for methyl tertiary-butyl ether and tertiary-butanol in male Fisher-
4 344 rats. Fundam Appl Toxicol 30: 264-275.
5 2) Borghoff, S; Parkinson, H; Leavens, T. [2010]. Physiologically based pharmacokinetic rat
6 model for methyl tertiary-butyl ether; comparison of selected dose metrics following
7 various MTBE exposure scenarios used for toxicity and carcinogenicity evaluation.
8 Toxicology 275: 79-91.
9 3] Kim, D; Andersen, ME; Pleil, JD; Nylander-French, LA; Prah, JD. [2007]. Refined PBPK model
10 of aggregate exposure to methyl tertiary-butyl ether. Toxicol Lett 169: 222-235.
11 4] Leavens, T; Borghoff, S. [2009]. Physiologically based pharmacokinetic model of methyl
12 tertiary butyl ether and tertiary butyl alcohol dosimetry in male rats based on binding to
13 alpha2u-globulin. Toxicol Sci 109: 321-335.
14 5] Nihlen, A; Johanson, G. [1999]. Physiologically based toxicokinetic modeling of inhaled ethyl
15 tertiary-butyl ether in humans. Toxicol Sci 51: 184-194.
16 6] Rao, HV; Ginsberg, GL. [1997]. A physiologically-based pharmacokinetic model assessment
17 of methyl t-butyl ether in groundwater for a bathing and showering determination. Risk
18 Anal 17: 583-598.
19 1.2.3. Kept for Possible Further Review
20 Foreign language
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22 433.
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29 Protoplasma 54: 455-475.
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32 are in german.
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34 butylacetat Arbete och Halsa 13: 1-45.
35 7] Brusewitz, S; Wennberg, A. [1984]. Criteria document for setting exposure limits for butanol
36 and butyl acetate. Arbete och Halsa 171.
This document is a draft for review purposes only and does not constitute Agency policy.
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1 8) Consejo Interamericano de Seguridad. [1996]. tert-Butyl alcohol.
2 9) Conso, F; Mignaee, C. [1984]. Monohydric alcohols other than ethyl alcohol. Encyclop/edie
3 M/edico Chirurgicale Intoxications 101.
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5 number of substances that may pollute the workplace air. (pp. 16-18]. Denmark.
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7 hydroxyl radicals with several phenyl-ureas and acetamides. Environ Technol 17: 707-716.
8 12] DFG (Deutsche Forschungsgemeinschaft). [1995]. 2-Amino-2-methyl-l-propanol. In MAK
9 value documentations. Weinheim, Germany: Wiley-VCH.
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15 certain organophosphorus compounds. Biokhimiya 34: 813-815.
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17 aliphatic alcohols. Arch Exp Pathol Phar 135:118-130.
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19 dehydrogenase (class III ADH] of mouse liver and its role in alcohol metabolism]. Nippon
20 Ika Daigaku Zasshi 59: 136-144.
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1
2. PRELIMINARY EVIDENCE TABLES AND
EXPOSURE-RESPONSE ARRAYS
2 2.1. Data Extraction: Preparation of Preliminary Evidence Tables and
3 Exposure-Response Arrays
4 The 106 references identified as primary sources of health effects data were considered for
5 data extraction to evidence tables and exposure-response arrays. References were first collated
6 with respect to exposure route, exposure duration, and type of endpoint, to identify those most
7 pertinent for evaluating the human health effects from chronic oral or inhalation exposure to tert-
8 butanol. As a result, data from 73 studies with one or more of the following characteristics were
9 not extracted into evidence tables or exposure-response arrays:
10 • The study involved dermal exposure;
11 • The study only involved acute or short-term exposures (less than 90 days/13 weeks), and it
12 was not conducted in the context of immune, neurological, developmental, or reproductive
13 toxicity;
14 • The data in the study only included endpoints related to possible mechanisms of toxicity;
15 • The study's endpoints did not exhibit responses in any of the 106 available references.
16 Data from the 33 remaining references were prepared in preliminary evidence tables. No
17 studies were excluded based on study quality considerations, so as to allow for public input on
18 methodological considerations that could affect the interpretation of or confidence in each study's
19 results. With regard to noncancer effects, health effect endpoints that were consistently affected in
20 chronic or subchronic studies were included in the evidence tables. All data demonstrating
21 carcinogenic effects were included. Supporting data that provide mechanistic information for each
22 selected endpoint were also included. For each included endpoint, all studies reporting data on that
23 endpoint are included regardless of the reported level or statistical significance of the response.
24 The tables are arranged in the order from the health effect with the most data to health effect with
25 the least data, with carcinogenic effects grouped with non-carcinogenic effects in the same tissue or
26 system. For each endpoint, the studies are presented beginning with subchronic studies followed
27 by chronic exposures. The evidence table for all reported genotoxicity endpoints follows. The
28 information in the preliminary evidence tables is displayed graphically in preliminary exposure
29 response arrays. In these preliminary arrays, the doses are labeled based only on statistical
30 significance as determined by the study's authors, without consideration of biological significance.
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1 As a consequence, endpoints for which the study's authors did not report results of statistical
2 significance tests were not included in these preliminary arrays.
3
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1 2.2. Kidney Effects
2
3
Table 2-1. Evidence pertaining to kidney effects in animals following oral
exposure to tert-butanol
Reference and study design
Results
Kidney weight (percent change as compared to
Lyondell Chemical Company (2004)
Sprague-Dawley rat;
12/sex/treatment
Gavage 0, 64, 160, 400, or
1,000 mg/kg-d
At least 9 weeks beginning 4 weeks
prior to mating through mating (up
to 2 weeks), gestation, and
lactation.
NTP (1995)
F344/N rat; 10/sex/treatment
Drinking water 0, 2.5, 5, 10, 20,
40 mg/mL
M: 0, 230, 490, 840, 1,520,
3,610a mg/kg-d
F: 0, 290, 590, 850, 1,560,
3,620a mg/kg-d
13 weeks
Males
Dose
( mg/kg-d 1
0
64
160
400
1,000
Females
Dose
(mg/kg-d)
0
64
160
400
1,000
Males
Dose
(mg/kg-d)
0
230
490
840
1,520
3,610
control)
Left absolute Left relative Right absolute
Weight Weight Weight
000
+6 +8 +6
+9 +14* +6
+12* +14* +14*
+18* +28* +20*
Left absolute Left relative Right absolute
Weight Weight Weight
000
-1 -2 +2
00+1
+3 +2 +4
+4 0 +7
Females
Absolute Relative Dose Absolute
Weight Weight (mg/kg-d) Weight
0000
+12* +19* 290 +19*
+17* +26* 590 +16*
+16* +32* 850 +29*
+26* +54* 1,560 +39*
All dead All dead 3,620 +36*
Right relative
Weight
0
+8
+11*
+17*
+31*
Right relative
Weight
0
0
0
+2
+2
Relative
Weight
0
+17*
+15*
+28*
+40*
+81*
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
Table 2-1. Evidence pertaining to kidney effects in animals following oral
exposure to tert-butanol (continued)
Reference and study design
NTP (1995)
BSCSFj mouse; 10/sex/treatment
Drinking water (0, 2.5, 5, 10, 20,
40 mg/mL)
M: 0, 350, 640, 1,590, 3,940,
8,210a mg/kg-d
F: 0, 500, 820, 1,660, 6,430,
11,620 a mg/kg-d
13 weeks
NTP (1995)
F344/N rat; 60/sex/treatment
(10/sex/treatment evaluated at 15
months)
Drinking water (0, 1.25, 2.5, 5, or 10
mg/mL)
M: 0, 90, 200, or 420a mg/kg-d
F: 0, 180, 330, or 650a mg/kg-d
2 years
Results
Males Females
Dose Absolute Relative Dose Absolute
(mg/kg-d) weight weight (mg/kg-d) weight
00000
350 +1 +1 500 0
640 +3 +2 820 -3
1,590 +2 +8 1,660 +1
3,940 +6 +22* 6,430 +6
8,210 0 +48* 11,620 +12*
Males Females
Dose Absolute Relative Dose Absolute
(mg/kg-d) weight weight (mg/kg-d) weight
00000
90 +4 +8 180 +8*
200 +11 +15* 330 +18*
420 +7 +20* 650 +22*
Only animals sacrificed at 15 months were evaluated for organ weights.
Relative
weight
0
-3
-1
0
+15*
+35*
Relative
weight
0
+14*
+21*
+42*
Histopathology
Acharya et al. (1997; 1995)
Wistar rat; 5-6 males/treatment
Drinking water (0 or 0.5%), 0 or 575
mg/kg-d
10 weeks
Lyondell Chemical Company (2004)
Sprague-Dawley rat;
12/sex/treatment
Gavage 0, 64, 160, 400, or 1,000
mg/kg-d
At least 9 weeks beginning 4 weeks
prior to mating through mating (up
to 2 weeks), gestation, and
lactation.
T" tubular degeneration, degeneration of the basement membrane of the
Bowman's
capsule, diffused glomeruli, and glomerular vacuolation (no incidences reported)
N|/ kidney glutathione (~40%)*
There were no changes in kidney histopathology observed.
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
Table 2-1. Evidence pertaining to kidney effects in animals following oral
exposure to tert-butanol (continued)
Reference and study design
NTP (1995)
F344/N rat; 10/sex/treatment
Drinking water (0, 2.5, 5, 10, 20, or
40 mg/mL)
M: 0, 230, 490, 840, 1,520, 3,610a
mg/kg-d
F: 0, 290, 590, 850, 1,560, 3,620a
mg/kg-d
13 weeks
NTP (1995)
B6C3Fj mouse; 10/sex/treatment
Drinking water (0, 2.5, 5, 10, 20, or
40 mg/mL)
M: 0, 350, 640, 1,590, 3,940,
8,210a mg/kg-d
F: 0, 500, 820, 1,660, 6,430,
ll,620a mg/kg-d
13 weeks
Results
Incidence (severity):
Males
Dose
(mg/kg-d)
0
230
490
840
1,520
3,610
There were
Females
Dose
Mineralization Nephropathv (mg/kg-d)
0/10
0/10
2/10 (1.5)
8/10*(1.4)
4/10*(1.0)
4/10*(1.0)
no changes in
7/10(1.0) 0
10/10(1.6*) 290
10/10 (2.6*) 590
10/10 (2.7*) 850
10/10(2.6*) 1,560
7/10(1.1) 3,620
kidney histopathology observed
Mineralization
10/10(1.7)
10/10 (2.0)
10/10 (2.0)
10/10 (2.0)
10/10 (2.0)
6/10 (1.2)
Nephropathv
2/10(1.0)
3/10(1.0)
5/10(1.0)
7/10* (1.0)
8/10* (1.0)
7/10* (1.0)
(histopathology data for the
13-week study were not provided)
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
Table 2-1. Evidence pertaining to kidney effects in animals following oral
exposure to tert-butanol (continued)
Reference and study design
NTP (1995)
F344/N rat; 60/sex/treatment
(10/sex/treatment evaluated at 15
months)
Drinking water (0, 1.25, 2.5, 5, 10
mg/mL)
M: 0, 90, 200, 420a mg/kg-d
F: 0, 180, 330, 650a mg/kg-d
2 years
Incidence (severity):
Males
Dose
(mg/kg-d)
n
u
90
200
420
Dose
(mg/kg-d)
0
90
200
420
Females
Dose (mg/kg-d)
0
180
330
650
Dose
(mg/kg-d)
0
180
330
650
Mineralization
(interim)
1 /m M n^
j./ j.u \ •j-.^-'j
2/10(1.0)
5/10(1.8)
9/10* (2.3)
Renal tubule
hyperplasia
(extended
evaluation)
12/50(2.3)
16/50 (2.3)
14/50 (2.2)
23/50* (2.8)
Mineralization11
Interim
10/10 (2.8)
10/10 (2.9)
10/10 (2.9)
10/10 (2.8)
Renal tubule
hyperplasia
0/50
0/50
0/50
1/50(1.0)
Results
Mineralization
(terminal)
TC/cn M n^
£\JJ J**J \1..**J 1
28/50(1.1)
35/50(1.3)
48/50* (2.2)
Transitional
epithelium
hyperplasia
25/50(1.7)
32/50(1.7)
36/50* (2.0)
40/50* (2.1)
Mineralization11
Terminal
49/50 (2.6)
50/50 (2.6)
50/50 (2.7)
50/50 (2.9)
Transitional
epithelium
hyperplasia
0/50
0/50
3/50 (1.0)
17/50*(1.4)
Linear mineralization
(terminal)
n/^n
u/ ju
5/50* (1.0)
24/50* (1.2)
46/50* (1.7)
Nephropathy
severity
3.0
3.1
3.1
3.3*
Inflammation
(suppurative)
incidence
2/50
3/50
13/50*
17/50*
Nephropathy
severity
1.6
1.9*
2.3*
2.9*
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
Table 2-1. Evidence pertaining to kidney effects in animals following oral
exposure to tert-butanol (continued)
Reference and study design
NTP (1995)
BSCSFj mouse; 60/sex/treatment
Drinking water (0, 5, 10, or 20
mg/mL)
M: 0, 540, 1,040, or 2,070a mg/kg-d
F: 0, 510, 1,020, or 2,110 mg/kg-d
2 years
Results
No changes in kidney
related histopathology observed.0
Tumors
NTP (1995)
F344/N rat; 60/sex/treatment
(10/sex/treatment evaluated at 15
months)
Drinking water (0, 1.25, 2.5, 5, or 10
mg/mL)
M: 0, 90, 200, or420a mg/kg-d
F: 0, 180, 330, or 650a mg/kg-d
2 years
Hard etal. (2011);
reanalysis of the slides in the NTP
(1995) study (see above)
NTP (1995)
B6C3F! mouse; 60/sex/treatment
Drinking water (0, 5, 10, or 20
mg/mL)
M: 0, 540, 1,040, or 2,070a mg/kg-d
F: 0, 510, 1,020, or 2,110 mg/kg-d
2 years
Male
Dose
(mg/kg-d)
0
90
200
420
Renal tubule
adenoma
7/50
7/50
10/50
10/50
Renal tubule
adenoma (multiple)
1/50
4/50
9/50*
3/50
Results do not include the animals sacrificed at 15 months. Females did
kidney tumors.
Male
Dose
(mg/kg-d)
0
90
200
420
Renal tubule
adenoma
3/50
9/50
9/50
9/50
Renal tubular
adenoma (multiple)
1/50
3/50
9/50
3/50
Renal tubule
adenoma or
carcinoma
8/50
13/50
19/50*
13/50
not develop
Renal tubule
adenoma or
carcinoma
4/50
13/50*
18/50*
12/50*
No changes in kidney-related tumors
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
Table 2-1. Evidence pertaining to kidney effects in animals following oral
exposure to tert-butanol (continued)
Reference and study design
Results
Additional studies potentially relevant for informing the mode of action
Williams and Borghoff (2001)
F344 rats; 4/sex
Single gavage dose: 500 mg/kg
Takahashietal. (1993)
F344 rats (M); 10/treatment
Drinking water (0, 0.25, 0.5, 1, 2 ,4%
w/v)
0,230,490, 840, 1,520 or 3,610a
mg/kg-d
13 weeks
NTP (1995)
F344/N rat; 10/sex/treatment
Drinking water (0, 2.5, 5, 10, 20, or
40 mg/mL)
M: 0, 230, 490, 840, 1,520, 3,610a
mg/kg-d
F: 0, 290, 590, 850, 1,560, 3,620a
mg/kg-d
13 weeks
Hard etal. (2011)
Reanalysis of the slides in the NTP
(1995) study (see above)
Males: T" binding of tert-butanol to a2u-globulin compared to females*
Females: no change in binding observed
T" in hyaline droplet accumulation (number and size) with T" severity for nephropathy
(no incidence data)
Male
Dose Hyaline droplet Hyaline crystals Nephropathy
(mg/kg-d) severity score severity score severity score
0 1 0.5 1
230 1.5 2*
490 2* 3*
840 2* 3*
1,520 2* 3*
3,610 >0.25* >0.25*
Accumulation of hyaline droplets:
Male
Dose Hyaline
(mg/kg-d) droplet accumulation
0 0/10
230 +e
490 ++
840 ++
1,520 ++
3,610 0/10
2*
3*
3*
3*
1
No information provided on females. No results from statistical tests reported.
Males: Confirmed accumulation of hyaline droplets increased with
in 13 week study above. No incidence data available.
Females: not evaluated
increasing dose-levels
1 a The high-dose group had an increase in mortality.
2 Linear mineralization not observed in female rats.
3 c Organs were not weighed in mice during the 2-year study.
4 Standard & extended evaluation combined.
5 e + or ++ indicated an increased accumulation relative to controls, as reported by the authors; no additional incidence data and
6 no results from statistical tests available.
7 * Statistically significant p < 0.05 as determined by the study authors.
8 Percentage change compared to control = (treated value - control value) 4- control value x 100.
9 Conversions from drinking water concentrations to mg/kg-d performed by study authors.
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1
2
Table 2-2. Evidence pertaining to kidney effects in animals following
inhalation exposure to tert-butanol
Reference and study design
Results
Kidney weight (percent change compared to control)
NTP (1997)
F344/N rat; 10/sex/treatment
Analytical concentration: 0, 134, 272, 542,
1,080, or 2,101 ppm (0, 406, 824, 1,643, 3,273
or 6,368 mg/m3 ) 6 hr/d, 5 d/wk
13 weeks
NTP (1997)
B6C3Fj mouse; 10/sex/treatment
Analytical concentration: 0, 134, 272, 542,
1,080, or 2,101 ppm (0, 406, 824, 1,643, 3,273
or 6,368 mg/m3) 6 hr/d, 5 d/wk
13 weeks
Dose
(mg/m3)
0
406
824
1,643
3,273
6,368
Dose
(mg/m3)
406
824
1,643
3,273
6,368
Males
Absolute Relative
weight weight
0 0
+1 +1
-2 -1
+3 +2
+11* +8*
+9.8* +9*
Males
Absolute Relative
weight weight
Of\
u
-6 -4
-1 +3
+4 +3
-10 -3
+3 +6
Females
Absolute
weight
0
-4
0
+4
+2
+4
Females
Absolute
weight
+1
+5
+1
0
+3
Relative
weight
0
-1
+1
+4
+2
+9*
Relative
weight
-3
+9
-2
+7
+15*
Histopathology
NTP (1997)
F344/N rat; 10/sex/treatment
Analytical concentration: 0, 134, 272, 542,
1,080, or 2,101 ppm (0, 406, 824, 1,643, 3,273
or 6,368 mg/m3 ) 6 hr/d, 5 d/wk
13 weeks
Male
Dose
(mg/m3)
0
406
824
1,643
3,273
6,368
Average severity
of chronic
nephropathv
1.0
1.4
1.4
1.6
1.9
2.0
Severity categories: 1= minimal, 2= mild. No
reported
results from statistical tests
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
Table 2-2. Evidence pertaining to kidney effects in animals following
inhalation exposure to tert-butanol (continued)
Reference and study design
NTP (1997)
B6C3Fj mouse; 10/sex/treatment
Analytical concentration: 0, 134, 272, 542,
1,080, or 2,101 ppm (0, 406, 824, 1,643, 3,273
or 6,368 mg/m3) 6 hr/d, 5 d/wk
13 weeks
Results
There were no kidney effects observed.
Additional studies potentially relevant for informing the mode of action
Borghoff et al. (2001)
F344 rat; 5/sex/treatment
Analytical concentration^, 250, 450, 1,750 ppm
(0,771, 1,387 or 5,395mg/m3) 6hr/d
10 days
Males: positive trend for accumulation of protein droplets (p < 0.05),
significant increase in accumulation of a2u-globulin at 5,394 mg/m3 as
compared to controls (no incidence data provided)
Females: No positive staining for a2u-globulin was observed in exposed
female rats.
1
2
3
4
5
* Statistically significant p < 0.05 as determined by study authors.
Conversion from ppm to mg/m3 is 1 ppm = 3.031 mg/m3.
Percentage change compared to control = (treated value - control value) 4- control value x 100.
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
I
2
3
4
5
6
^ 10,000 ;
•d
** i nnn -
01
o
Q
inn
10 -
• = exposures at which the endpoint was reported statistically significant by study authors
D = exposures at which the endpoint was reported not statistically significant by study authors
x = exposures at which all animals were dead and unable to be examined for the endpoint
1
X I
• 1
i :
i i
: • i
i i
1 • 1
1 1 I
1 [
1 [
1 [
1
1 I
! E
i ^
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1 [
1 ,
i
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l i
i i
i [
i i
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J
i[
ii
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ill i]
ittt1
II]
i m i
f f f f f f T
Eiililiii
'^•••nann
QQQ £ -5 N
i -H u a ^
» "Si § .2 *
i i 1 1 ^
i 3 3 3'pi PiPiPiPiPiPiPiPiPipiPiPiPi
II II [1 II
II II [1 II
i i i [i
o o o o
Pi Pi Pi Pi
2 2 fe fe
JgfefeC^g^g^cS c^.cS.-P-C-Co-- O '53 J3 J3 •§)•§)
„ . „ JJ1 JJ-I . y OOOOS.S'C S S'-'-'-f3 CS'-P nl 1 M M • R • R
|| » »'111il >i 1 s i ||1 111 i i
rg l I'l 1 » a i 1 1 >> g i l 11 |. » 1 i g
> !> „ „ 1 S 3.^ XS i> X J2 'Z3 ^ r-l !-H 2 !-H .£ 3^'-P3
lllfl|l{l!lliilliili!J|3ij!
^ Q X '^ & u ^ s & s §
"
3 ^S
1 |
i
2 ij^
Pi 1 S K
:1 1
a |— '
a £
H M
CTTTJ
r^wwn
1\TT
n
r
^
-tt --H O o3
-S S J 13
£33*
REPRO-
niir^TivF
T
T T I
i i--i--J
• iL
m Q Q Q Q
ra n n « «
Pi Pi Pi 3 3
2 5 rT 0 0
SS^ss
I | S 2 *
1 1 1 1 i
1 'S § I §
S S s -| '§
S-H s_ o H c3
ii! s
§ 1 § § i
S § -^ g o
"P T3 c^ 2 fi
S S ^ -a "S
niii
- - -s S •§
u " pi 13 "=3
^ § 1
Pi w
Sources: (A) Acharya et al. (1997; 1995); (B) Hard et al. (2011)*; (C) Lyondell (2004); (D) NTP (1995)
*:reanalysisof NTP (1995)
Figure 2-1. Exposure response array of kidney effects in rats and mice
following oral exposure to tert-butanol.
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
10,000
1
1
[
[
[
1 1
1 1
1 I
1 I
1 [
1 I
1 [
1 I
1 I
1 [
] 1
] [
1 [
] [
] [
1 [
1 [
1 [
1 [
1 [
1 I
1 [
1 I
1 I
1 [
• = exposures at which the endpoint was reported statistically significant by study authors
D = exposures at which the endpoint was reported not statistically significant by study authors
] 1
] [
1 [
] [
] [
1
1
1
1
1
C
'5 1,000
2
0)
u
o
U
100
00
'5
.
oo
'5
o
00
'5
00
'5
I
I
1
2
3
4
5
Source: NTP (1997)
Figure 2-2. Exposure-response array of kidney effects in rats and mice
following subchronic inhalation exposure to tert-butanol.
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1 2.3. Thyroid Effects
2
3
Table 2-3. Evidence pertaining to thyroid effects in animals following oral
exposure to tert-butanol
Reference and study design
Follicular cell hyperplasia
NTP (1995)
F344/N rat; 60/sex/treatment
(10/sex/treatment evaluated at 15
months)
Drinking water (0, 1.25, 2.5, 5, or 10
mg/mL)
M: 0, 90, 200, or420a mg/kg-d
F: 0, 180, 330, or 650a mg/kg-d
2 years
NTP (1995)
B6C3Fj mouse; 60/sex/treatment
Drinking water (0, 5, 10, or 20 mg/mL)
M: 0, 540, 1,040, or 2,070a mg/kg-d
F: 0, 510, 1,020, or 2,110 mg/kg-d
2 years
Tumors
NTP (1995)
F344/N rat; 60/sex/treatment
(10/sex/treatment evaluated at 15
months)
Drinking water (0, 1.25, 2.5, 5, or 10
mg/mL)
M: 0, 90, 200, or420a mg/kg-d
F: 0, 180, 330, or 650a mg/kg-d
2 years
Incidence15
Males
Dose
(mg/kg-d)
0
90
200
420
Incidence (severity)
Males
Dose
(mg/kg-d)
0
540
1,040
2,070
Incidence
Dose (mg/kg-d)
Male
0
90
200
420
Female
0
180
330
6,500
Follicular eel
hyperplasia
3/50
0/49
0/50
0/50
Follicular eel
hyperplasia
5/60 (1.2)
18/59* (1.6)
15/59* (1.4)
18/57* (2.1)
Follicular cell
adenoma
2/50
0/49
0/50
0/50
1/50
0/50
1/50
0/50
Results
Females
Dose
(mg/kg-d)
0
180
330
650
Females
Dose
(mg/kg-d)
0
510
1,020
2,110
Follicular cell
carcinoma
2/50
0/49
0/50
0/50
1/50
0/50
1/50
0/50
Follicular cell
hyperplasia
0/50
0/50
0/50
0/50
Follicular cell
hyperplasia
19/58 (1.8)
28/60 (1.9)
33/59* (1.7)
47/59* (2.2)
This document is a draft for review purposes only and does not constitute Agency policy,
2-13 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
Table 2-3. Evidence pertaining to thyroid effects in animals following oral
exposure to tert-butanol (continued)
Reference and study design
NTP (1995)
B6C3FJ mouse; 60/sex/treatment
Drinking water (0, 5, 10, or 20 mg/mL)
M: 0, 540, 1,040, or 2,070a mg/kg-d
F: 0, 510, 1,020, or 2,110 mg/kg-d
2 years
Incidence
Dose
(mg/kg-d)
Male
0
540
1,040
2,070
Female
0
510
1,020
2,110
Follicular cell
adenoma
1/60
0/59
4/59
1/57
2/58
3/60
2/59
9/59*
Results
Mortality-
adjusted rate
(%)
3.6
0.0
10.1
5.9
5.6
8.6
4.9
19.6
Follicular cell
carcinoma or
adenoma
1/60
0/59
4/59
2/57
2/58
3/60
2/59
9/59*
Mortality-
adjusted rate
(%)
3.6
0.0
10.1
8.7
5.6
8.6
4.9
19.6
1
2
3
4
5
6
7
8
There was a significant decrease in survival in the high-dose group.
Results do not include the animals sacrificed at 15 months.
* Statistically significant p < 0.05 as determined by the study authors.
Conversions from drinking water concentrations to mg/kg-d performed by study authors.
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
10,000
1
2
3
4
5
1,000
SB
100
10
• = exposures at which the endpoint was reported statistically significant by study authors
D = exposures at which the endpoint was reported not statistically significant by study authors
• II
II ||
• II
u u
o o
^3 [T i
.2 •$
1 i
u ^
ffi
n II
I ] [|
Tin
n
1 1
ti 1
4
ta 3 » »
g UH O O
="" •? ^ Lu
'S S3 2 ^
-1 & i i
1 1 § 1
M1 K -S -3
< <
a
1 1
11
" I
4
s s
2 fe
§ s
I I
1 <
Source: NTP (1995)
NONCANCER
CANCER
Figure 2-3. Exposure-response array of thyroid follicular cell effects in rats
and mice following chronic oral exposure to tert-butanol.
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1 2.4. Reproductive, Developmental, and Neurodevelopmental Effects
2
3
Table 2-4. Evidence pertaining to reproductive effects in animals following
exposure to tert-butanol
Reference and study design
Results
Oral
Billittietal. (2005)
CD-I male mice; number unclear
Gavage, 0, 400,1,000, 2,000 mg/kg
Single dose
no effect on testosterone levels in feces or serum (data not provided)
no effect on body weight (statistical tests not reported)
T" testes weights (averaged weights in the 1,000 and 2,000 mg/kg groups
+14% higher relative to controls; p < 0.05)
higher percentage (+7%; p < 0.05) of sloughing in the seminiferous
epithelium in the control animals
Lyondell Chemical Company (2004)
Sprague-Dawley rat; 12/sex/treatment
Gavage 0, 64,160, 400, or 1,000 mg/kg-d
PO Males and Females: At least 9 weeks
beginning 4 weeks prior to mating through
mating (up to 2 weeks), gestation, and lactation.
PO reproductive effects
M: No effects weights of male reproductive organs or sperm observed
Dose
(mg/kg-d) 0 64 160 400 1000
Pregnancy index
91.7% 91.7% 100% 100% 91.7%
Live pups/litter response relative to control
0 -9 -11 -7 -33*
NTP (1995)
F344/N rat; 10/sex/treatment
Drinking water (0, 2.5, 5,10, 20, or 40 mg/mL)
M: 0, 230, 490, 840, 1,520, 3,610a mg/kg-d
F: 0, 290, 590, 850, 1,560, 3,620a mg/kg-d
13 weeks
No significant effect on weights of male reproductive organs or sperm
observed
No significant effect on female estrous cycle (0, -2, -4, 0, +8 % change
relative to control)
NTP (1995)
B6C3Fj mouse; 10/sex/treatment
Drinking water (0, 2.5, 5,10, 20, or 40 mg/mL)
M: 0, 350, 640, 1,590, 3,940, 8,210a mg/kg-d
F: 0, 500, 820, 1,660, 6,430, ll,620a mg/kg-d
13 weeks
No significant effect on weights of male reproductive organs or sperm
observed
T" length of estrous cycle
Response relative to control: 0, +5, +5, +5, +6, +28*%
4
5
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
Table 2-4. Evidence pertaining to reproductive effects in animals following
exposure to tert-butanol (continued)
Reference and study design
Results
Inhalation
NTP (1997)
F344/N rat; 10/sex/treatment
Analytical concentration: 0,134, 272, 542,
1,080, or 2,101 ppm (0, 406, 824,1,643, 3,273
or 6,368 mg/m3) 6 hr/d, 5 d/wk
13 weeks
No significant effect on weights of male reproductive organs or sperm
observed
No significant effect on female estrous cycle (0, -4, +2, +4 % change relative
to control)
Evaluations were only performed for concentrations >542 ppm
1
2
3
4
5
6
NTP (1997)
B6C3Fj mouse; 10/sex/treatment
Analytical concentration: 0,134, 272, 542,
1,080, or 2,101 ppm (0, 406, 824,1,643, 3,273
or 6,368 mg/m3) 6 hr/d, 5 d/wk
13 weeks
No significant effect on weights of male reproductive organs or sperm
observed
No significant effect on female estrous cycle (0, -3, -9, -5 % change relative
to control)
Evaluations were only performed for concentrations >542 ppm
* Statistically significant p < 0.05 as determined by the study authors.
Conversions from drinking water concentrations to mg/kg-d performed by study authors.
Conversion from ppm to mg/m3 is 1 ppm = 3.031 mg/m3.
Percentage change compared to control = (treated value - control value) 4- control value x 100.
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1
2
Table 2-5. Evidence pertaining to developmental effects in animals following
exposure to tert-butanol
Reference and study design
Results
Oral
Daniel and Evans (1982)
Swiss Webster (Cox) mouse; 15 pregnant
dams/treatment
Liquid diet (0, 0.5, 0.75, 1.0%, w/v)
0 (isocaloric amounts of maltose/dextrin),
3,324, 4,879, 6,677 mg/kg-d
GD 6-20
Faulkner etal. (1989)
CBA/J mouse; 7 pregnant females in control,
12 pregnant females in treated
Gavage (10.5 mmoles/kg twice a day);
0 (tap water), 1,556 mg/kg-d
GD 6-18
No statistical analysis was conducted on any of these data
Maternal
Percent change compared to control:
Number of litters
Dose Body weight on Body weight (% pregnant
(mg/kg-d) GD 20 gain dams)
000 11(77%)
3,324 +2 -3 12(80%)
4,879 -5 -19 8(53%)
6,677 -10 -20 7(47%)
Fetal
Percent change compared to control:
Dose Number of Fetal body weight
(mg/kg-d) neonates/litter on PND 2
000
3,324 -1 -7
4,879 -29 -19
6,677 -49 -38
Number of stillborn also increased with dose (3, 6, 14, and 20, respectively),
but appropriate denominators not reported so statistical significance of this
change could not be calculated. The high dose also caused a delay in eye
opening and a lag in weight gain during PND 2-10 (information was only
provided in text or figures)
Maternal results not reported.
Fetal
Percent change compared to
control: Incidence:
Dose Live Fetal Sternal Skull
(mg/kg-d) fetuses/litter weight variations variations
000 4/28 1/28
1,556 -41* -4 7/30 3/30
Sternal variations: misaligned or unossified sternebrae
Skull variations: moderate reduction in ossification of supraoccipital bone
Number of total resorptions (10 resorptions/66 implants in controls, 37/94
implants in treated) and resorptions per litter resorptions per litter (+118%)
increased (p < 0.05)
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
Table 2-5. Evidence pertaining to developmental effects in animals following
exposure to tert-butanol (continued)
Reference and study design
Results
Faulkner etal. (1989)
C57BL/6J mouse; 5 pregnant females in
controls, 9 pregnant females treated
Gavage (10.5 mmoles/kg twice a day)
0 (tap water), 1,556 mg/kg-d
GD 6-18
Maternal results not reported.
Fetal
Percent change compared to
control: Incidence:
Dose
(mg/kg-d)
0
1,556
Live
fetuses/litter
0
-58%*
Fetal
weight
0
-4
Sternal
variations Skull variations
5/21
9/16
1/21
7/16
Sternal variations: misaligned or unossified sternebrae
Skull variations: moderate reduction in ossification of supraoccipital bone
Number of total resorptions (4 resorptions/44 implants in controls, 38/68
implants in treated) and resorptions per litter resorptions per litter (+428%)
increased (p < 0.05)
Lyondell Chemical Company (2004)
Sprague-Dawley rat; 12/sex/treatment
Gavage 0, 64,160, 400, or 1,000 mg/kg-d
PO Males and Females: At least 9 weeks
beginning 4 weeks prior to mating through
mating (up to 2 weeks), gestation, and
lactation.
Fl Males and Females: 7 weeks
(throughout gestation and lactation; 1 male
and 1 female from each litter was treated
themselves from PND 21-28)
Response relative to control
Dose
64
(mg/kg-d) 0
Maternal effects
Body weight gain GD 0-20
0
Body weight gain PND 1-21
0
Fl Reproductive effects
0
Viability index
96.4% 98.7%
Lactation index
100% 100%
Sex ratio (% males)
54.4 52.3
-3
+3
64
160
-4
-10
160
98.2%
100%
400
50.9
Pup weight/litter PND 1 response relative to control
0 +6 +4
Pup weight PND 28 response relative to control
M: 0 +2 0
F: 0 0 -4
+3
400
99.4%
99.2%
53.4
+7
0
-2
1000
-16*
+100*
1000
74.1%*
98.8%
52.1
-10
-12*
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
Table 2-5. Evidence pertaining to developmental effects in animals following
exposure to tert-butanol (continued)
Reference and study design
Results
Inhalation
Nelson etal. (1989)
Sprague-Dawley rat; 15 pregnant
dams/treatment
Whole body inhalation
Analytical concentration: 0, 2,200, 3,510,
5,030 ppm (0, 6,669, 10,640, 15,248
mg/m3), 7 hr/d
r;n 1 1 Q
Maternal: Unsteady gait (no statistical tests reported), dose-dependent \|/ in
body weight gain (results presented in figure only), dose-dependent \|/ in food
consumption ranging from 7-36% depending on dose and time
Fetal
Percent change compared to control:
Number of
Dose live Resorptions
(mg/m3) fetuses/litter per litter
000
6,669 0 +9
10,640 +15 -18
15,248 +8 0
Percent change compared to
control: Incidence:
Skeletal Skeletal
Dose Fetal weight Fetal weight variation variation
(mg/m3) (males) (females) by litter by fetus
000 10/15 18/96
6,669 -9* -9* 14/17 35/104
10,640 -12* -13* 14/14 53/103*
15,248 -32* -31* 12/12 76/83*
Skeletal variation by litter refers to the number of variations observed in the
number of litters examined. Skeletal variation by fetus refers to the number of
variations observed in the total number of fetuses examined. Fetuses are not
categorized by litter.
1
2
3
4
5
6
* Statistically significant p < 0.05 as determined by study authors.
Conversions from diet concentrations to mg/kg-d performed by study authors.
Conversion from ppm to mg/m3 is 1 ppm = 3.031 mg/m3.
Percentage change compared to control = (treated value - control value) 4- control value x 100.
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1
2
Table 2-6. Evidence pertaining to neurodevelopmental effects in animals
following exposure to tert-butanol
Reference and study design
Results
Oral
Daniel and Evans (1982)
Liquid diet (0, 0.5, 0.75, or 1.0%, w/v); GD6-20;
Swiss Webster (Cox) mouse; 15 pregnant
dams/treatment; after birth half the pups were
nursed with their treated dams and the other
half were fostered by untreated dams who
recently gave birth
0 (isocaloric amounts of maltose/dextrin),
3,324, 4,879, or 6,677 mg/kg-d
Results were presented in figures only with no comparison to control or in
tables with only comparison between pups fostered with their maternal
dams and those fostered with untreated dams with no indication of dose.
Results indicate
• a dose-dependent increase in the time it took for the righting reflex
with more time needed in animals maintained with maternal dams
• a dose-dependent decrease in open field behavior with less activity
with pups maintained with maternal dams
• a dose-dependent decrease in rotorod performance with the pups
from maternal dams having lower performances
• a dose-dependent decrease in the amount of time the pups were
able to avoid a cliff with animals maintained with their maternal
dams having less avoidance time
Grant and Samson (1982)
Surgical cannulation; male and female Long-
Evans rat fetus; 8 control and 12 treated
PND 4-7 (a period of brain growth) with
consecutive daily doses of 1,440, 2,160, 600,
and 2,690 mg/kg-d tert-butanol on PND 4, 5, 6,
and 7, respectively (average daily dose of 1,723
mg/kg-d)
\|/ Absolute and relative brain weights
Response relative to control (only relative data provided, but no changes
were noted in body weight): 0, -16%*
Brain biochemical parameters included: \|/ DNA levels in the hindbrain
(-16%*) and \|/ protein levels in the forebrain (-15%*).
Inhalation
Nelson etal. (1991)
Whole body inhalation; Sprague-Dawley rat; 15
pregnant dams/treatment
Analytical concentration: 0, 6,000, or 12,000
mg/m3; 7 hr/d GD 1-19
Data were not presented specifically by dose nor were any tables or figures
of the data provided
Maternal toxicity was noted by decreased food consumption and body
weight gains
Results in offspring
• increase in rotorod performance in high-dose group (16 versus 26
revolutions/min for controls and 3,500 mg/m3 animals, respectively)
• decreased time held on wire in the performance ascent test in the
low-dose group (16 sec versus 10 sec for controls and 1,750 mg/m3
animals, respectively)
There were some differences in neurochemical measurements in the brain
between control and treated offspring, but they were not related to dose
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
Table 2-6. Evidence pertaining to neurodevelopmental effects in animals
following exposure to tert-butanol (continued)
Reference and study design
Results
Nelson etal. (1991)
Whole body inhalation; adult male Sprague-
Dawley rats (18/treatment) mated to untreated
females
Analytical concentration: 0, 6,000, or 12,000
mg/m3; 7 hr/d for 6 wk
Data were not presented specifically by dose nor were any tables or figures
of the data provided
Results (generally only specified as paternally treated versus controls) in
offspring indicate
• increase in rotorod performance (16 versus 20 revolutions/min for
controls and 3,500 mg/m3 animals, respectively)
• decreased time in open field (less time to reach the outer circle of
the field, 210 sec versus 115 seconds for controls and 3,500 mg/m
animals, respectively)
There were some differences in neurochemical measurements in the brain
between control and treated offspring, but they were not related to dose
1
2
3
4
5
6
* Statistically significant p < 0.05 as determined by study authors.
Conversions from diet concentrations to mg/kg-d performed by study authors.
Percentage change compared to control = (treated value - control value) 4- control value x 100.
This document is a draft for review purposes only and does not constitute Agency policy,
2-22 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
100,000
10,000
1,000
100
10
2
3
4
5
6
7
• = exposures at which the endpoint was reported statistically significant by study authors
D
= exposures at which the endpoint was reported not statistically significant by study authors
1
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T1F VFT ,OP1V
Fetal
iFNTAT,
Sources: (A) Billitti et al. (2005); (B) Faulkner et al. (1989); (C) Grant and Samson (1982); (D) Lyondell Chemical
Company (2004); (E) NTP (1995)
Figure 2-4. Exposure-response array of reproductive, developmental and
neurodevelopmental effects following oral exposure to tert-butanol.
This document is a draft for review purposes only and does not constitute Agency policy,
2-23 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
-1 10,000 :
M)
e
Concentrati
— "o
D O
D O
• = exposures at which the endpoint was reported statistically significant by study authors
D = exposures at which the endpoint was reported not statistically significant by study authors
I I
n n n m • •
[i u n u
4 4 i i
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1
2
3
00
o
g
"«
W
g
8.
00
o
REPRODUCTIVE
(Parental)
Sources: (A) NTP (1997); (B) Nelson et al. (1989); (C) Nelson et al. (1991)
DEVELOPMENTAL
(Fetal)
g
£
4
5
6
Figure 2-5. Exposure-response array of reproductive and developmental
effects following inhalation exposure to tert-butanol.
This document is a draft for review purposes only and does not constitute Agency policy,
2-24 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1 2.5. Central Nervous System (CNS) Effects
2
3
Table 2-7. Evidence pertaining to CNS effects in animals following exposure to
tert-butanol
Reference and study design
Results
Oral
Grant and Samson (1981)
Male Long-Evans rat; 4-6/treatment;
daily intakes were estimated to be 700 to
2,800 mg/kg depending on the treatment
and time
Drinking water
Scheduled-induced condition (maintained
at 80% body weight):
Treatment 1: 0.5% for 5 days, then 1% for
60 days
Treatment 2:Drinking water stepwise
increase with 0.25%, 0.50%, 1.0%, 2.0%,
and 2.5% for 5 days each and 3.0%, and
3.5% for 10 days each, then 3.0% for 40
days
Treatment 3: 1.0% for 5 days, 2.0% for 5
days, then 1.0% for 5 days and 3.0% for
90 days
Home cage condition:
Treatment 1: 80% body weight
administered 0.5% 5 days, then 1.0% for
90 days
Treatment 2: free access to food, 1.0% for
5 days, 2.0% for 10 days, and 3.0% for 90
days
Treatment 3: 80% body weight on water
After treatment, all animals were given
water to replace t-butanol
5 of 15 animals treated with 3% t-butanol had to be removed from the
experiment based on self-withdrawal and/or self-mutilation (2 died),
trend of increased t-butanol intake and decreased food intake prior to
removal. Symptoms were not observed with 1% t-butanol or with
control.
1 of 4 animals receiving 3.5% t-butanol self-mutilated, ceased drinking,
and was removed from the experiment.
60 days of 3% t-butanol was related to moderate seizure activity
(withdrawal scores of 9, 5, and 6).
90 days of 3% t-butanol had withdrawal scores of 12, 6, and 7
At least one animal from every group had a withdrawal score of 0, and
only animals exposed to 3% t-butanol had withdrawal scores of 6 or
higher. Significantly higher withdrawal scores were observed in animals
receiving greater amounts of t-butanol (Fischer's exact p<0.002).
Schedule-induced conditioning resulted in greater withdrawal
symptoms over the home cage conditions.
Withdrawal symptoms were considered less than those observed with
ethanol.
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
Table 2-7. Evidence pertaining to CNS effects in animals following exposure
to tert-butanol (continued)
Reference and study design
Results
Wood and Laverty (1979)
Male Wistar rat; 12 rats/20-day
treatment and 24 rats on time-course
withdrawal sequence (4 rats withdrawn
on days 4, 6, 8,10,12, and 14)
Liquid diet; 44-54 mmol/kg (mean 47
mmol/kg); daily consumption was
variable with spontaneous periods of
abstinence in a few rats; blood alcohol
levels 2-25 mmol/L
4-20 days
Signs of intoxication in the 20-day study included docility and slight
ataxia while on the diet.
One rat out of 12 in the 20-day study spontaneously withdrew from the
diet on Day 10, and had signs of irritability, hyperactivity, and muscular
rigidity.
Following removal of t-butanol after 20 days, animals initially appeared
intoxicated. Head bobbing and paw shaking were observed 3-4 hours
after withdrawal. Muscular rigidity, tail signs, abnormal gait, tremor,
and irritability were apparent 5-6 hours after withdrawal.
4/12 treated rats had spontaneous forelimb convulsions
5/12 treated rats had audiogenic convulsions; resulted in 3 deaths.
In the surviving 8/12 rats, irritability, hyperreactivity, and muscular
rigidity were considerable at 24 hours post-withdrawaland in some
animals lasted for up to 72 hours.
In the time-course group, withdrawal symptoms were seen with as little
as 4 days of t-butanol intake. Severity rating increased with increasing
days on the diet.
Snelland Harris (1980)
Male DBA/2J mouse; 20 mice/treatment
1.25% t-butanol via liquid diet
3,390 mg/kg-day (average)
7 days
Shock avoidance behavior was impaired after cessation of treatment.
Latencies for experimental group was significantly (p < 0.05) longer than
the controls.
One day after withdrawal, the number of trials where animals avoided
shock was significantly (p < 0.05) greater in the control group (control:
35/150; t-butanol: 6/150).
Even 2 days after withdrawal, treated animals showed a significant (p <
0.01) deficit in avoidance response measured by both latency and
number of avoidances (control: 51/100; t-butanol: 35/100).
At time of withdrawal, there was no difference in body temperature and
withdrawal scores were low (0.20 ± 0.13, not significantly different from
the control).
Body temperature
3 hours after withdrawal
8 hours after withdrawal
Withdrawal scores
3 hours after withdrawal
8 hours after withdrawal
Control
37.6 ±0.1
37.4 ±0.1
Control
0
0
t-butanol
34.9 ± 0.4*
35.7 ±0.3*
t-butanol
0.30 ±0.21
0.30 ±0.15
This document is a draft for review purposes only and does not constitute Agency policy,
2-26 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
Table 2-7. Evidence pertaining to CNS effects in animals following exposure
to tert-butanol (continued)
Reference and study design
Results
Thurman etal. (1980)
Female Sprague-Dawley rat; 12-
14/treatment
Gavage; 5.7% in saline every 8 hours for
up to 6 days
14 symptoms of withdrawal were scored according to severity on a 1-3 point
scale (every 2 hours beginning 6-8 hours after last treatment.
• Treatment caused a steady increase in withdrawal score (results
presented in a figure)
Inhalation
McComb and Goldstein (1979a)
Male Swiss-Webster mouse; 14
mice/treatment
Two 3-day cycles separated by 24 hours
of no treatment (withdrawal reaction
observed for 24 hours following each
exposure period); mice were maintained
on either a low (range 3.5-6.4 mM) or
high (range 6.5-10.0 mM) blood alcohol
level
Withdrawal reaction consisted of signs of CNS hyperexcitability, including
tremors, spontaneous convulsions, and convulsions elicited by handling
Withdrawal peak height
Low blood alcohol High blood alcohol
3 days of exposure (n=ll) 0.79 ±0.12 1.43 ±0.07
6 days of exposure (n=13) 1.49 ±0.08 1.63 ±0.10
McComb and Goldstein (1979b)
Male Swiss-Webster mouse; 24
mice/treatment
Mice received an initial i.p. priming dose
of 6.8 or 10.1 mmol/kg t-butanol; t-
butanol vapor concentration was
maintained between 50 and 80 |amol/ms
for 24 hours then were steadily increased
to maintain a constant blood alcohol level
Withdrawal was measured after 1, 3, 6 or
9 days
Withdrawal reaction consisted of signs of CNS hyperexcitability,
including tremors, spontaneous convulsions, and convulsions elicited by
handling.
Intensity of withdrawal symptoms was related to blood levels and
duration of exposure (results provided in figure only).
o At mean blood levels of 5mM t-butanol (range 2.4-6.6 mM),
severity of withdrawal reaction rose steadily through day 9.
o At mean blood levels of 8.5 mM (range 6.8-10.7 mM) and
above, a ceiling of withdrawal levels occurred at a height of
approximately 1.5.
Peak withdrawal reactions occurred 3-5 hours after removal of t-
butanol and was 4-5 times greater than with ethanol.
1
2
1 Statistically significant p < 0.05 as determined by study authors.
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1 2.6. Other Systemic Effects (Body Weight, Liver, and Urinary Bladder)
2
3
Table 2-8. Evidence pertaining to effects on body weight in animals following
oral exposure to tert-butanol
Reference and study design
Acharyaetal. (1995)
Wistar rat; 5-6 males/treatment
Drinking water (0 or 0.5%), 0 or 575 mg/kg-d
10 weeks
Lyondell Chemical Company (2004)
Sprague-Dawley rat; 12/sex/treatment
Gavage 0, 64, 160, 400, or 1,000 mg/kg-d
At least 9 weeks beginning 4 weeks prior to
mating through mating (up to 2 weeks),
gestation, and lactation.
NTP (1995)
F344/N rat; 10/sex/treatment
Drinking water (0, 2.5, 5, 10, 20, or 40 mg/mL)
M: 0, 230, 490, 840, 1,520, 3,610a mg/kg-d
F: 0, 290, 590, 850, 1,560, 3,620a mg/kg-d
13 weeks
NTP (1995)
B6C3FJ mouse; 10/sex/treatment
Drinking water (0, 2.5, 5, 10, 20, or 40 mg/mL)
M: 0, 350, 640, 1,590, 3,940, 8,210a mg/kg-d
F: 0, 500, 820, 1,660, 6,430, ll,620a mg/kg-d
13 weeks
Results
Body weight in treated animals lower than controls by ~7% (p< 0.05); (results
only provided in a figure)
Percent change compared to control:
Males Females
Dose Dose
(mg/kg-d) Body weight (mg/kg-d)
000
64 -2 64
160 -4 160
400 +2 400
1,000 -7 1,000
Percent change compared to control:
Males Females
Dose Dose
(mg/kg-d) Body weight (mg/kg-d)
000
230 -4 290
490 -5* 590
840 -12* 850
1,520 -17* 1,560
3,610 All dead 3,620
Body weight
0
0
-2
+1
+4
Body weight
0
+2
+1
+1
-2
-21*
Percent change compared to control:
Males Females
Dose Dose
(mg/kg-d) Body weight (mg/kg-d) Body weight
0000
350 -1 500 +3
640 +1 820 -1
1,590 -4 1,660 +4
3,940 -14* 6,430 -6
8,210 -24* 11,620 -15*
High-dose females had a significantly lower initial weight, but also had a
significantly lower body weight gain indicating that there was some effect of
treatment
This document is a draft for review purposes only and does not constitute Agency policy,
2-28 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
Table 2-8. Evidence pertaining to effects on body weight in animals following
oral exposure to tert-butanol (continued)
Reference and study design
NTP (1995)
F344/N rat; 60/sex/treatment
(10/sex/treatment evaluated at 15 months)
Drinking water (0, 1.25, 2.5, 5, 10 mg/mL)
M: 0, 90, 200, 420a mg/kg-d
F: 0, 180, 330, 650a mg/kg-d
2 years
NTP (1995)
BSCSFj mouse; 60/sex/treatment
Drinking water (0, 5, 10, 20 mg/mL);
M: 0, 540, 1,040, 2,070a mg/kg-d
F: 0, 510, 1,020, 2,110 mg/kg-d
2 years
Results
Percent change compared to control:
Males
Dose
Females
Dose
(mg/kg-d) Body weight (mg/kg-d) Body weight
0000
90 -15 180 -2
200 -18 330 -5
420 -24 650 -21
Only animals that survived at the end of 2 years were evaluated for body
weight. Note: statistical significance not determined by study authors.
Percent change compared to control:
Males
Dose
Females
Dose
(mg/kg-d) Body weight (mg/kg-d) Body weight
0000
540 +1 510 -2
1,040 -2 1,020 -3
2,070 -1 2,110 -12
Only animals that survived at the end of 2 years were evaluated for body
weight. Note: statistical significance not determined by study authors.
2
3
4
5
6
7
aThere was a significant decrease in survival in the high-dose group.
* Statistically significant p < 0.05 as determined by study authors.
Conversions from drinking water concentrations to mg/kg-d performed by study authors.
Percentage change compared to control = (treated value - control value) 4- control value x 100.
This document is a draft for review purposes only and does not constitute Agency policy,
2-29 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1
2
Table 2-9. Evidence pertaining to liver effects in animals following oral
exposure to tert-butanol
Reference and study design
Results
Liver weight
Acharyaetal. (1995)
Wistar rat; 5-6 males/treatment
Drinking water (0 or 0.5%), 0 or 575 mg/kg-d
10 weeks
Lyondell Chemical Company (2004)
Sprague-Dawley rat; 12/sex/treatment
Gavage 0, 64, 160, 400, or 1,000 mg/kg-d
At least 9 weeks beginning 4 weeks prior to
mating through mating (up to 2 weeks),
gestation, and lactation.
NTP (1995)
F344/N rat; 10/sex/treatment
Drinking water (0, 2.5, 5, 10, 20, or 40 mg/mL)
M: 0, 230, 490, 840, 1,520, 3,610a mg/kg-d
F: 0, 290, 590, 850, 1,560, 3,620a mg/kg-d
13 weeks
NTP (1995)
B6C3Fj mouse; 10/sex/treatment
Drinking water (0, 2.5, 5, 10, 20, or 40 mg/mL)
M: 0, 350, 640, 1,590, 3,940, 8,210a mg/kg-d
F: 0, 500, 820, 1,660, 6,430, ll,620a mg/kg-d
13 weeks
No significant treatment-related effects (results were
figure)
only providec
in a
Percent change compared to control:
Males
Dose
(mg/kg-d)
0
64
160
400
1,000
Absolute Relative
weight weight
0 0
-1 0
-3 +1
-2 -1
+8 +16*
Females
Dose
(mg/kg-d)
0
64
160
400
1,000
Absolute
weight
0
-4
-7
+2
+8
Relative
weight
0
-4
-5
+1
+3
Percent change compared to control:
Males
Dose
(mg/kg-d)
0
230
490
840
1,520
3,610
Absolute Relative
weight weight
0 0
-2 +4
+1 +8*
+5 +20*
+8 +31*
All dead All dead
Females
Dose
(mg/kg-d)
0
290
590
850
1,560
3,620
Absolute
weight
0
+11*
+10*
+12*
+15*
+9*
Relative
weight
0
+9*
+9*
+11*
+16*
+41*
Percent change compared to control:
Males
Dose
(mg/kg-d)
0
350
640
1,590
3,940
8,210
Absolute Relative
weight weight
0 0
+2 +3
-1 -2
-1 +5
0 +14*
-16 +22*
Females
Dose
(mg/kg-d)
0
500
820
1,660
6,430
11,620
Absolute
weight
0
-1
-5
-8
-2
-6
Relative
weight
0
-4
-3
_9*
+6
+13*
This document is a draft for review purposes only and does not constitute Agency policy,
2-30 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
Table 2-9. Evidence pertaining to liver effects in animals following oral
exposure to tert-butanol (continued)
Reference and study design
NTP (1995)
F344/N rat; 60/sex/treatment
(10/sex/treatment evaluated at 15 months)
Drinking water (0, 1.25, 2.5, 5 or 10 mg/mL)
M: 0, 90, 200, or420a mg/kg-d
F: 0, 180, 330, or 650a mg/kg-d
2 years
Results
Percent change compared to control:
Males Females
Dose Absolute Relative Dose Absolute Relative
(mg/kg-d) weight weight (mg/kg-d) weight weight
00 0000
90 +2 +7 180 -14* -8
200 +8 +11 330 -3 -1
420 +1 +14* 650 -6 +9*
Only animals sacrificed at 15 months were evaluated for organ weights.
Histopathology
Acharvaetal. (1997: 1995)
Wistar rat; 5-6 males/treatment
Drinking water (0, 0.5%), 0, 575 mg/kg-d
10 weeks
Lyondell Chemical Company (2004)
Sprague-Dawley rat; 12/sex/treatment
Gavage 0, 64, 160, 400, or 1,000 mg/kg-d
At least 9 weeks beginning 4 weeks prior to
mating through mating (up to 2 weeks),
gestation, and lactation.
NTP (1995)
F344/N rat; 10/sex/treatment
Drinking water (0, 2.5, 5, 10, 20, or 40 mg/mL)
M: 0, 230, 490, 840, 1,520, 3,610a mg/kg-d
F: 0, 290, 590, 850, 1,560, 3,620a mg/kg-d
13 weeks
NTP (1995)
B6C3Fj mouse; 10/sex/treatment
Drinking water (0, 2.5, 5, 10, 20, 40 mg/mL)
M: 0, 350, 640, 1,590, 3,940, 8,210a mg/kg-d
F: 0, 500, 820, 1,660, 6,430, ll,620a mg/kg-d
13 weeks
/T> liver glycogen (~ 7 fold)*
^incidence of centrilobular necrosis, vacuolation of hepatocytes, loss of
hepatocyte architecture, peripheral proliferation, and lymphocyte
infiltration (incidences and results of statistical tests not reported)
No treatment-related effects observed.
No treatment-related effects observed (histopathology data for the
study were not provided)
No treatment-related effects observed (histopathology data for the
study were not provided)
13-week
13-week
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
Table 2-9. Evidence pertaining to liver effects in animals following oral
exposure to tert-butanol (continued)
Reference and study design
NTP (1995)
F344/N rat; 60/sex/treatment
(10/sex/treatment evaluated at 15 months)
Drinking water (0, 1.25, 2.5, 5, 10 mg/mL)
M: 0, 90, 200, or 420a mg/kg-d
F: 0, 180, 330, or 650a mg/kg-d
2 years
NTP (1995)
BSCSFj mouse; 60/sex/treatment
Drinking water (0, 5, 10, 20 mg/mL)
M: 0, 540, 1,040, or 2,070a mg/kg-d
F: 0, 510, 1,020, or 2,110 mg/kg-d
2 years
Results
No treatment-related
effects observed.
Males Females
Dose Incidence of fatty Dose
(mg/kg-d)
0
540
1,040
2,070
change (mg/kg-d)
12/59 0
5/60 510
8/59 1,020
29/59* 2,110
Incidence of fatty
change
11/60
8/60
8/60
6/60
1
2
3
4
5
The high-dose group had an increase in mortality.
* Statistically significant p < 0.05 as determined by study authors.
Conversions from drinking water concentrations to mg/kg-d performed by study authors.
Percentage change compared to control = (treated value - control value) 4- control value x 100.
This document is a draft for review purposes only and does not constitute Agency policy,
2-32 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1
2
Table 2-10. Evidence pertaining to liver effects in animals following
inhalation exposure to tert-butanol
Reference and study design
Liver Weight
NTP (1997)
F344/N rat; 10/sex/treatment
Analytical concentration: 0, 135, 270, 540,
1,080, or 2,101 ppm (0, 406, 824, 1,643, 3,273
or 6,368 mg/m3) 6 hr/d, 5 d/wk
13 weeks
NTP (1997)
B6C3F1 mouse; 10/sex/treatment
Analytical concentration: 0, 134, 272, 542,
1,080, or 2,101 ppm (0, 406, 824, 1,643, 3,273
or 6,368 mg/m3) 6 hr/d, 5 d/wk
13 weeks
Percent change
Dose
2
( mg/m )
0
406
824
1,643
3,273
6,368
Percent change
Dose
(mg/m )
0
406
824
1,643
3,273
6,368
compared to
Males
Absolute
wsisht
0
-8
-2
+1
+10
+5
compared to
Males
Absolute
weight
0
-1
+4
+7
-8
+5
Results
control:
Relative
wsisht
0
-8
-1
-1
+7
+5
control:
Relative
weight
0
0
+9
+5
-2
+7
Females
Absolute
wsisht
0
0
0
+3
+9
+4
Females
Absolute
weight
0
+1
+1
+5
+2
+8
Relative
wsisht
0
+3
0
+2
+9*
+8*
Relative
weight
0
-4
+5
+1
+9*
+21*
3
4
5
6
7
8
* Statistically significant p < 0.05 as determined by the study authors.
Conversion from ppm to mg/m3 is 1 ppm = 3.031 mg/m3.
Percentage change compared to control = (treated value - control value) 4- control value x 100.
This document is a draft for review purposes only and does not constitute Agency policy,
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-------
Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1
2
Table 2-11. Evidence pertaining to urinary bladder effects in animals
following oral exposure to tert-butanol
Reference and study design
Results
Histopathology
NTP (1995)
F344/N rat; 10/sex/treatment
Drinking water (0, 2.5, 5, 10, 20, 40
mg/mL)
M: 0, 230, 490, 840, 1,520, 3,610a
mg/kg-d
F: 0, 290, 590, 850, 1,560, 3,620a
mg/kg-d
13 weeks
NTP (1995)
B6C3Fj mouse; 10/sex/treatment
Drinking water (0, 2.5, 5, 10, 20, 40
mg/mL)
M: 0, 350, 640, 1,590, 3,940,
8,210a mg/kg-d
F: 0, 500, 820, 1,660, 6,430,
ll,620a mg/kg-d
13 weeks
NTP (1995)
F344/N rat; 60/sex/treatment
(10/sex/treatment evaluated at 15
months)
Drinking water (0, 1.25, 2.5, 5, or 10
mg/mL)
M: 0, 90, 200, 420a mg/kg-d
F: 0, 180, 330, 650a mg/kg-d
2 years
Incidence (severity):
Males
Females
Transitional
epithelial
Transitional
epithelial
Dose (mg/kg-d) hyperplasia Dose (mg/kg-d) hyperplasia
0
230
490
840
1,520
3,610
Severity: 1 =
0/10 0
not evaluated 290
not evaluated 590
0/10 850
1/10 (3.0) 1,560
7/10* (2.9) 3,620
minimal, 2 = mild, 3 = moderate, 4 = marked
0/10
not evaluated
not evaluated
not evaluated
0/10
3/10 (2.0)
Incidence (severity):
Males
Dose
(mg/kg-d)
0
350
640
1,590
3,940
8,210
Severity: 1 =
Females
Transitional
epithelial Inflam- Dose
hyperplasia mation (mg/kg-d)
0/10 0/10 0
not evaluated 500
not evaluated 820
0/10 0/10 1,660
6/10* (1.3) 6/10* (1.3) 6,430
10/10* (2.0) 10/10* (2.3) 11,620
minimal, 2 = mild, 3 = moderate, 4 = marked
Transitional
epithelial Inflam-
hyperplasia mation
0/10 0/10
0/1 0/1
not evaluated
not evaluated
0/10 0/10
3/9 (2.0) 6/9* (1.2)
No treatment-related effects observed
This document is a draft for review purposes only and does not constitute Agency policy,
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-------
Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
Table 2-11. Evidence pertaining to urinary bladder effects in animals
following oral exposure to tert-butanol (continued)
Reference and study design
NTP (1995)
B6C3F! mouse; 60/sex/treatment
Drinking water (0, 5, 10, or 20 mg/mL)
M: 0, 540, 1,040, 2,070a mg/kg-d
F: 0, 510, 1,020, 2,110 mg/kg-d
2 years
Results
Incidence
(severity):
Males
Transitional
Dose epithelial
(mg/kg-d) hyperplasia
0
540
1,040
2,070
Severity: 1
1/59 (2.0)
3/59 (1.7)
1/58 (1.0)
17/59* (1.8)
Inflam-
mation
0/59
3/59 (1.7)
1/58 (1.0)
37/59* (2.0)
= minimal, 2 = mild, 3 = moderate
Females
Dose
(mg/kg-d)
0
510
1,020
2,110
, 4 = marked
Transitional
epithelial
hyperplasia
0/59
0/60
0/59
3/57(1.0)
Inflam-
mation
0/59
0/60
0/59
4/57* (2.0)
1
2
3
4
The high-dose group had an increase in mortality.
* Statistically significant p < 0.05 as determined by study authors.
Conversions from drinking water concentrations to mg/kg-d performed by study authors.
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1
2
3
4
5
l\J\J, \J\J\J
10,000
,— v
A
•d
• = exposures at which the endpoint was reported statistically significant by study authors
D = exposures at which the endpoint was reported not statistically significant by study authors
x = exposures at which all animals were dead and unable to be examined for the endpoint
1
|
v • 1
j? '1 i <
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-------
Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
1 2.7. Genotoxic Effects
2
3
Table 2-12. Evidence pertaining to genotoxic effects of tert-butanol in vitro
and in vivo studies
Species/
cell line
Test system
(strain/species)
Exposure
(dose/
concentration)
Results
Metabolic activation
-S9
+S9
Reference
In vitro
Bacterial systems
Salmonella
typhimurium
E.coli
Neurospora crassa
Saccharomyces
cerevisiae
Reverse mutation
(TA98, TA100,
TA1535, TA1537,
TA1538)
Reverse mutation
(TA102)
Reverse mutation
(TA98, TA100, TA102,
TA1535, TA1537)
Reverse mutation
(WP2 uvrA/PKMlOl)
Reverse mutation, ad-
3A locus (allele 38701)
Mitochondrial
mutation (K5-5A,
MMY1, D517-4B and
DS8)
10 mg/plate
2.9-10,000 u.g/plate
1-4 mg/plate
5-5,000 |Jg/plate
5-5,000 |Jg/plate
1.75mol/L
4.0% (vol/vol)
-
ND
-
-
+a
-
+
-
-
ND
Zeiger et al. (1987)
ARCO (1994e)
Williams-Hill et al. (1999)
McGregor et al. (2005)
McGregor et al. (2005)
Dickey et al. (1949)
Jimenez etal. (1988)
Mammalian cells - rodent
Mouse lymphoma
cells L5178YTK+/~
Chinese hamster
ovary
Rat fibroblasts
Gene mutation
Sister-chromatid
exchange
Chromosomal
aberrations
DNA damage (comet
assay)
625-5,000 mg/mL
2.4-32 ul/mL
1.25-5 mg/mL
0.31-20 ul/mL
(-S9);
0. 625-20 ul/mL
(+S9)
1.25-5 mg/mL
0.44 mmol/L (IC50)
-
-
-
b
-
+C
-
-
-
-
ND
McGregor et al. (1988)
ARCO (1994a)
NTP (1995)
ARCO (1994b)
NTP (1995)
Sgambato et al. (2009)
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review oftert-ButanoI
Species/
cell line
Test system
(strain/species)
Exposure
(dose/
concentration)
Results
Metabolic activation
-S9
+S9
Reference
Mammalian cells - human
Human HL-60
leukemia cells
DNA damage (comet
assay)
1-30 mmol/L
+
ND
Tang et al. (1997)
In vivo
Mammalian - rodent
Male Kunming
mouse liver, kidney
and lung cells
BSCSFi mouse
peripheral blood
cells
DNAadducts
Micronucleus
formation
0. 1-1,000 ng/kgb.w.
2.5-40 mg/mL
drinking water
+
NA
NA
Yuan et al. (2007)
NTP (1995)
1
2
3
4
5
6
ND = not determined; NA = not applicable
aEffect is predicted to be due to mitochondrial membrane composition.
Results were stated to be statistically increased in the 20 |ag/mL with and without activation and the 10 Mg/mL with activation,
but results did not meet positive criteria for the assay.
CDNA damage was completely reversed with increase in time of exposure.
This document is a draft for review purposes only and does not constitute Agency policy,
2-38 DRAFT—DO NOT CITE OR QUOTE
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