United States
Environmental Protection
1=1 m m Agency
EPA/690/R-12/034F
Final
11-19-2012
Provisional Peer-Reviewed Toxicity Values for
Triacetin
(CASRN 102-76-1)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Jason C. Lambert, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
ICF International
9300 Lee Highway
Fairfax, VA 22031
PRIMARY INTERNAL REVIEWERS
Ghazi Dannan, PhD
National Center for Environmental Assessment, Washington, DC
Zheng (Jenny) Li, PhD, DABT
National Center for Environmental Assessment, Washington, DC
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300).
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CONTENTS
COMMONLY USED ABBREVIATIONS	iii
BACKGROUND	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVS	 1
INTRODUCTION	2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER)	4
HUMAN STUDIES	4
Oral Exposures	4
Sub chronic-Duration Studies	4
Chronic-Duration Studies	9
Developmental Studies	9
Reproduction Studies	9
Carcinogenicity Studies	9
Inhalation Exposures	9
ANIMAL STUDIES	9
Oral Exposures	9
Short-term Studies	10
Sub chronic-Duration Studies	10
Chronic-Duration Studies	14
Developmental Studies	14
Reproductive/Developmental Studies	14
Carcinogenicity Studies	15
Inhalation Exposures	15
Short-term Studies	15
Sub chronic-Duration Studies	15
Chronic-Duration Studies	16
Developmental Studies	16
Reproduction Studies	16
Carcinogenicity Studies	16
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)	16
Genotoxicity	16
DERIVATION 01 PROVISIONAL VALUES	 19
DERIVATION 01 ORAL REFERENCE DOSE	20
Derivation of Subchronic and Chronic Provisional RfD (p-RfD)	20
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS	20
Derivation of Subchronic and Chronic Provisional RfC (p-RfC)	20
CANCER WOE DESCRIPTOR	20
MODE OI ACTION DISCI SSION	21
Mutagenic Mode-of-Action	21
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES	21
Derivation of provisional Oral Slope Factor (p-OSF)	21
Derivation of Provisional Inhalation Unit Risk (p-IUR)	21
APPENDIX A. PROVISIONAL SCREENING VALUES	22
APPENDIX B. DATA TABLES	26
APPENDIX C. BMD OUTPUTS	27
APPENDIX D. REFERENCES	28
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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMCL
benchmark concentration lower bound 95% confidence interval
BMD
benchmark dose
BMDL
benchmark dose lower bound 95% confidence interval
HEC
human equivalent concentration
HED
human equivalent dose
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
POD
point of departure
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
RfC
reference concentration (inhalation)
RfD
reference dose (oral)
UF
uncertainty factor
UFa
animal-to-human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete-to-complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
TRIACETIN (CASRN 102-76-1)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database flittp://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (www.epa.eov/iris). the respective PPRTVs are removed
from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
QUESTIONS REGARDING PPRTVS
Questions regarding the contents and appropriate use of this PPRTV assessment should
be directed to the EPA Office of Research and Development's National Center for
Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300).
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INTRODUCTION
Triacetin, also known as glyceryl triacetate (CAS No. 102-76-1), is a colorless, oily
liquid with a slightly fatty odor and a mild, sweet taste that is bitter at concentrations above
0.05% (see Figure 1). Occupational exposure to triacetin can occur through dermal contact and
inhalation at production sites during operations such as cleaning, sampling, analysis, and drum
filling. Triacetin has the following uses in consumer products: a solvent for celluloid and
photographic films; a plasticizer for cigarette filters; a fungicide in cosmetics; a fixative in
perfumery; and a general purpose food additive. A table of physicochemical properties is
provided below (see Table 1).
Figure 1. Triacetin Structure
Table 1. Physicochemical Properties of Triacetin (CASRN 102-76-l)a
Property (unit)
Value
Boiling point (°C)
258-259
Melting point (°C)
3
Density (g/cm )
1.1562
Vapor pressure (mm Hg at 25°C)
0.00248
pH (unitless)
7
Solubility in water (g/100 mL at 25°C)
5.8-7.0
Relative vapor density (air =1)
7.52
Molecular weight (g/mol)
218.21
aACGIH (2011), ChemlDPlus (2011), OECD (2002).
No Reference Dose (RfD), Reference Concentration (RfC), or cancer assessment for
triacetin is included on the U.S. EPA IRIS database (U.S. EPA, 2010a) or on the Drinking Water
Standards and Health Advisories List (U.S. EPA, 2009). No RfD or RfC values are reported in
the HEAST (U.S. EPA, 2010b). The Chemical Assessments and Related Activities (CARA) list
does not include a Health and Environmental Effects Profile (HEEP) for triacetin (U.S. EPA,
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1994). The toxicity of triacetin has not been reviewed by the ATSDR (2011), and the World
Health Organization does not list an Environmental Health monograph for triacetin (WHO,
2011). CalEPA (2008, 2009) has not derived toxicity values for exposure to triacetin. No
occupational exposure limits for triacetin have been derived or recommended by the American
Conference of Governmental Industrial Hygienists (ACGIH, 2011), the National Institute of
Occupational Safety and Health (NIOSH, 2010), or the Occupational Safety and Health
Administration (OSHA, 2011).
The HEAST (U.S. EPA, 2010b) does not report a cancer weight-of-evidence (WOE)
classification or an oral slope factor (OSF) for triacetin. The International Agency for Research
on Cancer (IARC, 2011) has not reviewed the carcinogenic potential of triacetin. Triacetin is not
included in the 12th Report on Carcinogens (NTP, 2011). CalEPA (2008) has not derived a
quantitative estimate of carcinogenic potential for triacetin.
Triacetin has been reviewed by several committees worldwide and is considered safe
under specified exposure scenarios (Ellis and Rodford, 1996). An estimate of the cumulative
oral intake in the United Kingdom suggests that an adult might ingest 7.8 mg triacetin/day, and
the daily intake was calculated to be 0.111 mg/kg-day (OECD, 2002). The Database of Select
Committee on GRAS Substances (SCOGS) Reviews Report No. 30, Glycerin and Glycerides
(U.S. FDA, 1975) states that triacetin has been found to be without toxic effects in long-term
feeding tests in rats at levels that were several orders of magnitude greater than those to which
consumers are exposed. Triacetin was exempted from the requirement of a tolerance when used
as a solvent or cosolvent in accordance with good agricultural practice as inert (or occasionally
active) ingredients in pesticide formulations applied to animals [40 CFR 180.930], The United
States Food and Drug Administration (U.S. FDA) concluded that triacetin is generally
recognized as safe (GRAS) when used: as a food additive [21 CFR 184.1901]; in food or food
packaging [21 CFR 181.27]; as a general purpose food additive in animal drugs, feeds, and
related products [21 CFR 582.1901]; or in certain over the counter drug products
[21 CFR 310.545], The Cosmetic Ingredients Review Expert Panel concluded that triacetin is
safe as used in cosmetic formulations (Fiume, 2003). The Joint FAO/WHO Expert Committee
on Food Additive (JECFA) considered it unnecessary to assign an acceptable daily intake (ADI),
as triacetin is metabolized in the same manner as other dietary triglycerides. In various
assessments of triacetin, the JECFA concluded that, based on the available data and anticipated
daily intake, triacetin did not represent a hazard to health (JECFA, 1975, 2002). In a separate
evaluation, the European Union's Scientific Committee for Food endorsed the JECFA position
for triacetin (Commission for the European Communities: Scientific Committee for Food, 1992).
Literature searches were conducted on sources published from 1900 through
December 2011 for studies relevant to the derivation of provisional toxicity values for triacetin
(CASRN 102-76-1). Searches were conducted using U.S. EPA's Health and Environmental
Research Online (HERO) database of scientific literature. HERO searches the following
databases: AGRICOLA; American Chemical Society; BioOne; Cochrane Library; DOE: Energy
Information Administration, Information Bridge, and Energy Citations Database; EBSCO:
Academic Search Complete; GeoRef Preview; GPO: Government Printing Office;
Informaworld; IngentaConnect; J-STAGE: Japan Science & Technology; JSTOR: Mathematics
& Statistics and Life Sciences; NSCEP/NEPIS (EPA publications available through the National
Service Center for Environmental Publications [NSCEP] and National Environmental
Publications Internet Site [NEPIS] database); PubMed: MEDLINE and CANCERLIT databases;
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SAGE; Science Direct; Scirus; Scitopia; SpringerLink; TOXNET (Toxicology Data Network):
ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP,
GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS, ITER, LactMed, Multi-Database Search,
NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI; and TSCATS; Virtual Health Library; Web
of Science (searches Current Content database among others); WHO; and Worldwide Science.
The following databases outside of HERO were searched for health-related values: ACGIH,
ATSDR, CalEPA, U.S. EPA IRIS, U.S. EPA HEAST, U.S. EPA HEEP, U.S. EPA OW,
U.S. EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS.
REVIEW OF POTENTIALLY RELEVANT DATA
(CANCER AND NONCANCER)
Table 2 provides an overview of the relevant database for triacetin and includes all
potentially relevant repeated-dose subchronic- and chronic-duration studies. Principal studies
are identified. The phrase "statistical significance" used throughout the document, indicates a
p-value of <0.05.
HUMAN STUDIES
Oral Exposures
The effects of oral exposure of humans to triacetin have been evaluated in two separate
subchronic case studies (Madhavarao et al., 2009; Segel et al., 2011).
Subchronic-Duration Studies
Madhavarao et al. (2009)
In a peer-reviewed study, Madhavarao et al. (2009) administered triacetin in infant
formula to a 13-month-old girl and an 8-month-old boy for 6 and 4.5 months, respectively. The
initial dose was 25 mg/kg twice daily (50 mg/kg-day) for the first week, followed by a doubling
each subsequent week up to a maximum dose of 250 mg/kg twice daily (500 mg/kg-day). These
infants were previously diagnosed with Canavan disease, a fatal dysmyelinating genetic disorder
characterized by mutations in the enzyme aspartoacylase, resulting in a greatly reduced or absent
capacity to hydrolyze the brain metabolite A'-acetylaspartate to acetate and aspartate. Triacetin
was selected for use as a dietary supplement as it is known to be an acetate precursor. The stated
aim of this study was to determine the tolerability of low-dose oral triacetin administration in
infants having Canavan disease. This study received Institutional Review Board approval and
obtained parental consent. The following outcome criteria were evaluated prior to initiation of
treatment and reviewed at 4 months of treatment: neurological status, brain magnetic resonance
imaging and magnetic resonance spectroscopy, urine A-acetylaspartate levels, and
ophthalmoscopic examination. Treatment-related effects were screened clinically and by blood
work-up of complete blood count, kidney function, electrolytes, liver function, and venous blood
gas measurements.
The study authors did not identify a NOAEL or LOAEL; however, they stated that oral
administration of triacetin caused no detectable toxicity, and that the infant patients showed no
deterioration in their clinical status (Madhavarao et al., 2009). The NOAEL is 500 mg/kg-day; a
LOAEL was not determined under the conditions tested.
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Table 2. Summary of Potentially Relevant Data for Triacetin
Category
Number of
Male/Female,
Strain, Species,
Study Type, Study
Duration
Dosimetry"
Critical Effects
NOAEL"
BMDL/
BMCLa
LOAEL'
Reference
(Comments)
Notesb
Human
1. Oral (mg/kg-d)
Acute0
ND
Short-termd
ND
Subchronic1
1/1 infant patients,
feeding, 6 mo.
exposure (girl) or
4.5 mo. exposure
(boy); case study
25 mg/kg twice daily
(50 mg/kg-d), doubling
weekly to 250 mg/kg
twice daily (500 mg/kg-d)
(Adjusted)
No effects
500
NDr
NDr
Madhavarao et al. (2009)
PR
Subchronic1
1/1 infant patients,
feeding, 6 mo.
exposure (boy) or
4.5 mo. exposure
(girl); case study
500 mg/kg four times
daily (2,000 mg/kg-d),
doubling every 3 d to
4,500 mg/kg-d
No effects
(discomfort reported
in both children by
parents at
5,000 mg/kg-d;
maximum dose
titrated back to
4,500 mg/kg-d)
4,500
NDr
NDr
Segel et al. (2011)
PR
Chronicf
ND
2. Inhalation (mg/m3)
Acute0
ND
Short-termd
ND
Subchronic0
ND
Chronicf
ND
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Table 2. Summary of Potentially Relevant Data for Triacetin
Category
Number of
Male/Female,
Strain, Species,
Study Type, Study
Duration
Dosimetry"
Critical Effects
NOAEL"
BMDL/
BMCLa
LOAEL'
Reference
(Comments)
Notesb
Animal
1. Oral (mg/kg-d)
Short-termd
0/8, S-D rat, feeding,
18 d
13,869; 25,670; 25,843
(Adjusted)
No adverse effects
25,843
NDr
NDr
Shapira et al. (1969)
(Concentration of triacetin
was not the only variable;
multiple other dietary factors
included in exposure source
confounds interpretation;
protein levels impacted
body-weight gain)
PR
Subchronic0
0/8, S-D rat, feeding,
30 d
16,367 (Adjusted)
No adverse effects
16,367
NDr
NDr
Lynch et al. (1994) (Limited
scope of endpoints examined
for toxicity; multiple other
dietary factors included in
exposure source confounds
interpretation)
PR
Subchronic0
0/8, S-D rat, feeding,
30 d
16,367 (Adjusted)
No adverse effects
16,367
NDr
NDr
Lynch and Bailey (1995)
(Limited scope of endpoints
examined for toxicity;
multiple other dietary factors
included in exposure source
confounds interpretation)
PR
Subchronice
12/12 S-D rat,
gavage, 41-48 d
from 14 d prior to
mating to
Postpartum Day
(PPD) 3
0, 40, 200, or
1,000 (Adjusted)
No adverse effects
1,000
NDr
NDr
MHW (1998) (This was a
combined OECD repeated
dose and
reproductive/developmental
toxicity screening test
[OECD TG 422])
NPR
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Table 2. Summary of Potentially Relevant Data for Triacetin
Category
Number of
Male/Female,
Strain, Species,
Study Type, Study
Duration
Dosimetry"
Critical Effects
NOAEL"
BMDL/
BMCLa
LOAEL'
Reference
(Comments)
Notesb
Subchronic1
0/8, S-D rat, feeding,
12-13 wk
17,228; 25,843 (Adjusted)
Decreased body
weight, increased
liver weight (The
toxicological
significance of these
findings could not be
ascertained)
ND
NDr
NDr
Shapira et al. (1975)
(Concentration of triacetin
was not the only variable; the
toxicological significance of
these findings could not be
ascertained)
PR
Subchronic1
Unreported number
and sex, rat, feeding
and drinking,
approximately
110-120d
4,200 during Postnatal
Days (PNDs) 7-14, 5,800
during PNDs 15-22/23,
7099 in food and 7,504 in
water, totaling 14,603 for
the remaining treatment
period (Adjusted)
No adverse effects
14,603
(feed and
water doses
combined)
NDr
NDr
Madhavarao et al. (2009)
(Deficiencies in reporting of
study details limits
interpretation of results)
PR
Chronic
ND
Reproductive/
Developmental
12/12 S-D rat,
gavage, 41-48 d
from 2 wk prior to
mating to PPD 3
0, 40,200, or 1,000
(Adjusted)
No adverse effects in
dams or offspring
F0: 1,000
Fl: 1,000
NDr
NDr
MHW (1998) (Systemic
toxicity including
reproductive parameters
examined in dams; health
status of offspring also
examined)
NPR; PS
Carcinogenicity
ND
2. Inhalation (mg/m3)
Short-termd
ND
Subchronice
3/3 rat, (strain
unreported)
whole-body vapor
inhalation, 6 h/d,
5 d/wk, 103 d
397 for 90 d; 2 additional
wk at 117 followed by
13,181 (saturated vapor)
No adverse effects
397
NDr
NDr
Fassett (1955) as
summarized in OECD (2002)
NPR;
original
document
could not
be
obtained
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Table 2. Summary of Potentially Relevant Data for Triacetin
Category
Number of
Male/Female,
Strain, Species,
Study Type, Study
Duration
Dosimetry"
Critical Effects
NOAEL3
BMDL/
BMCLa
LOAEL3
Reference
(Comments)
Notesb
Subchronic1
3 rat (sex and strain
unreported), 6 h/d,
5 d/wk, 64 d
398; 13,181
No adverse effects
13,181
NDr
NDr
Unichema Chemie B.V.
(1994) as summarized by
Fiume (2003)
NPR;
original
document
could not
be
obtained
Subchronic1
Unreported number
and sex, rat, heated
vapor, 6 h/d, 5 d/wk,
13 wk
398
No adverse effects
398
NDr
NDr
Fassett (1963) as
summarized by Ellis and
Rodford (1996)
PR;
original
document
could not
be
obtained
Chronicf
ND
Developmental
ND
Reproductive
ND
Carcinogenicity
ND
dosimetry: NOAEL, BMDL/BMCL, and LOAEL values are converted to an adjusted daily dose (ADD in mg/kg-d) for oral noncancer effects and a human equivalent
concentration (HEC in mg/m3) for inhalation noncancer effects. All long-term exposure values (4 wk and longer) are converted from a discontinuous to a continuous
(weekly) exposure. Values from animal developmental studies are not adjusted to a continuous exposure.
HECexresp = (ppm x MW ^ 24.45) x (hours per day exposed ^ 24) x (days per week exposed ^ 7) x blood gas partition coefficient.
bNotes: IRIS = Utilized by IRIS, date of last update; PS = principal study, PR = peer reviewed, NPR = not peer reviewed.
0 Acute = Exposure for 24 hr or less (U.S. EPA, 2002).
dShort-term = Repeated exposure for >24 hr <30 d (U.S. EPA, 2002).
eSubchronic = Repeated exposure for >30 d up to approximately 10% of the lifespan in humans (based on 70-yr typical human lifespan; >30-90 days in typically used
laboratory animal species) (U.S. EPA, 2002).
fChronic = Repeated exposure for >10% lifespan (U.S. EPA, 2002).
DU = data unsuitable, NA = not applicable, NV = not available, ND = no data, NDr = not determinable, NI = not identified, NP = not provided, NR = not reported,
NR/Dr = not reported but determined from data, NS = not selected, S-D = Sprague-Dawley.
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Segeletal. (2011)
Similar to the Madhavarao et al. (2009) study above, Segel et al. (2011) administered
triacetin in infant formula to a 12-month-old boy and an 8-month-old girl for 6 and 4.5 months,
respectively. Both of the infants were previously diagnosed with Canavan disease, and as such,
triacetin was being evaluated for efficacy as a dietary supplement (as explained under
Madhavarao et al. [2009] above). The stated aim of this study was to determine the tolerability
and efficacy of high-dose triacetin administration in infants with Canavan disease. The initial
dose was 500 mg/kg four times daily (2,000 mg/kg-day) for the first 3 days, followed by a
doubling of dose every 3 days up to a maximum dose of 4,500 mg/kg-day (the target maximum
dose was 5,000 mg/kg-day, but the parents reported 'discomfort' in each child at this specific
dose). The children were evaluated prior to treatment and at 4.5 months after the initiation of
treatment for the following outcomes: neurological status, brain magnetic resonance imaging and
magnetic resonance spectroscopy, urine /V-acetylaspartate levels, and ophthalmoscopic
examination. Treatment-related effects were screened clinically and by blood work-up of
complete blood count, kidney function, electrolytes, liver function, and venous blood gas
measurements.
The study authors did not identify a NOAEL or LOAEL; although the study authors did
state that administration of triacetin caused no detectable toxicity in either patient at a daily dose
of 4,500 mg/kg-day; at the highest dose attempted (5,000 mg/kg-day), the study authors alluded
to a potential problem with gastric acidity (Segel et al., 2011). The NOAEL is 4,500 mg/kg-day
for lack of effects in human infants; a LOAEL was not determined under the conditions tested.
Chronic-Duration Studies
No studies were identified.
Developmental Studies
No studies were identified.
Reproduction Studies
No studies were identified.
Carcinogenicity Studies
No studies were identified.
Inhalation Exposures
No studies were identified.
ANIMAL STUDIES
Oral Exposures
The effects of oral exposure of animals to triacetin have been evaluated in one short-term
(Shapira et al., 1969) and five subchronic studies (MHW, 1998; Madhavarao et al., 2009;
Lynch et al., 1994; Lynch and Bailey, 1995; Shapira et al., 1975). Additionally, the MHW study
(1998) also evaluated reproductive toxicity.
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Short-term Studies
Shapiraetal. (1969)
In a peer-reviewed study, Shapira et al. (1969) developed a system capable of serving a
regenerative food supply. A mixture of triacetin, glycerol, and Hydrogenomonas eutropha
(bacteria, rich in protein) was used as a food supplement and a major portion of the diet. Groups
of eight male weanling Sprague-Dawley rats were fed one of 12 different diets for 18 days,
containing low, medium, or high protein contents (12, 24, and 48% protein, respectively), along
with variable carbohydrate sources, including triacetin. The different protein and carbohydrate
contents of the 12 diets are shown in Table B-l.
The adjusted doses for triacetin are calculated to be 13,869, 25,670, and
25,843 mg/kg-day for the diets containing triacetin at 16.1, 29.8, and 30% (by weight),
respectively. In addition to the dietary components shown above, all diets contained 5%
USP XIV salt mixture (plus 16.5 mg ZnSCVlOO g diet), 5% safflower oil, 2% a-cellulose,
1% vitamins, 1% agar, and a total of 2 parts water to each part dry weight. After formulation,
the diets were stored at 4°C and fed fresh daily. The animals were caged as pairs and weighed
daily. No mortality or clinical signs of toxicity were mentioned; however, the study authors did
not report any evaluations other than body weights. It is not apparent from the report that
statistical analyses were performed on the body-weight data. This study was performed as part
of research into regenerative food systems performed at the Ames Research Center for NASA.
The study authors reported that growth was not adversely affected over 18 days when
29.8% triacetin (by weight in the diet; equivalent to 25,670 mg/kg-day) was included with
29.8% glycerol and 27% protein from H. eutropha (minimally affected when protein was casein;
see Table B-l). The authors stated that these data show that over 90% of the calories of the diet
of growing rats can be composed of a mixture of H. eutropha, glycerol, and triacetin without a
detrimental effect on the growth of the animal. However, these results also demonstrate that
adequate nutritional needs must be met with regards to protein levels. When fed similar amounts
of triacetin (29.8-30%), animals fail to achieve the expected body-weight gain when fed the low
protein diet, but not when fed the medium protein diet. The study authors did not define a
NOAEL or LOAEL; however, the highest dose of 25,843 mg/kg-day showed no adverse effects;
therefore, the NOAEL is 25,843 mg/kg-day. A LOAEL for triacetin is not available under the
conditions tested. The study authors reported only limited information to assess the toxicity of
this compound in this 18-day study, and the dietary exposure to rats included multiple
supplements in addition to triacetin; therefore, this study is not considered suitable for derivation
of a subchronic p-RfD.
The report by Shapira et al. (1969) also included general findings related to triacetin from
a "number of three month feeding studies." However, because detailed methodology and data
from these studies were not presented, these generalized findings are unsupported and are not
included in this report.
Subchronic-Duration Studies
Lynch et al. (1994)
In a peer-reviewed study, Lynch et al. (1994), administered to eight Sprague-Dawley
male rats one of three diets for 30 days: control diet, diet with 30% of the energy as corn oil, or
diet with 30% of the energy as mainly short chain triglycerides (95% triacetin and 5% corn oil).
All diets contained 20.6% protein (by percentage of calories), and 1.0%, 3.5%, and 5.0% weight
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percent vitamins, minerals, and fiber, respectively. The triacetin-diet contained 19.0% triacetin
by weight, which is equivalent to an adjusted dose of 16,367 mg/kg-day.
Rats were housed individually in plastic metabolism cages (Lynch et al., 1994). Food
intake was measured daily, and body weights were determined at Day 0 and every 5 days
thereafter. Animals were euthanized after 30 days, and blood was collected. Nonfasting plasma
glucose, triglycerides, total ketone bodies, free fatty acids, lactate, and pyruvate were measured.
Jejunal and colon segments were excised and weighed. Intestinal mucosal cells were analyzed
for DNA, RNA, and protein content. The protein-DNA ratio for each group was calculated as an
index of cell size. Other jejunal and colon segments were fixed in neutral buffered formalin,
processed routinely, and analyzed by light microscopy to determine villus height in the jejunum
and crypt depth in the colon. Carcasses were eviscerated, frozen, and homogenized with an
equivalent weight of water. Aliquots were removed and lyophilized for determination of percent
moisture. All data were analyzed by analysis of variance (ANOVA) to determine significant
statistical differences among groups caused by diet. When a significant difference was observed,
Duncan's Multiple Range Test was used to further analyze the differences. This study did not
include relevant evaluation of hematology, clinical chemistry, urinalysis, organ weights, or gross
or microscopic pathology.
Lynch et al. (1994) stated that there were no adverse, treatment-related effects observed
on mortality, clinical signs, body weights, food consumption, lactate, ketone body, glucose
concentrations, mean villus height, intestinal crypt depth, and carcass composition. Compared to
the control group, plasma free fatty acids were decreased (p < 0.05) by 44%, and plasma
triglycerides were increased (p < 0.05) by 22%. DNA content was increased (p < 0.05) by
approximately 68% in the colon mucosa. RNA content was decreased (p < 0.05) by
approximately 33% in the jejunum. The protein:DNA ratio was decreased (p < 0.05) by 38% in
the jejunum. The study authors reported no NOAEL or LOAEL; however, the only dose of
triacetin tested, 16,367 mg/kg-day, showed no toxic effects; therefore, the NOAEL is
16,367 mg/kg-day. A LOAEL is not available under the conditions tested. The study authors
reported only limited information to assess the toxicity of this compound in this study; therefore,
this study is not suitable for derivation of a subchronic p-RfD.
Lynch and Bailey (1995)
In a peer-reviewed study by Lynch and Bailey (1995), eight Sprague-Dawley male rats
were administered one of three diets for 30 days, with one of the diets containing 19% triacetin
by weight (adjusted dose of 16,367 mg/kg-day). The study methodology was the same as
described previously in Lynch et al. (1994). In the present study, the adipose cell size and
number (as measured by a Coulter counter) for epididymal, perirenal, and inguinal fat depots
were reported.
Lynch and Bailey (1995) reported that mean adipose cell size in the triacetin-treated
group was less than the control for the epididymal, inguinal, and perirenal fat depots, but cell
number was unaffected. A moisture-free sample was used to determine percent lipid with a
modified Soxhlet method. Percent protein was determined with the Kjeldahl method, and the
percent ash was determined by combustion. The study authors reported no NOAEL or LOAEL;
however, the only dose tested, 16,367 mg/kg-day, showed no toxic effects. Therefore, the
NOAEL is 16,367 mg/kg-day, and a LOAEL is not available under the conditions tested. The
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study authors reported only the limited results detailed above to assess the toxicity of this
compound in this study; therefore, this study is not suitable for derivation of a subchronic p-RfD.
Ministry of Health and Welfare, Japan (MHW, 1998)
This study (MHW, 1998) was performed by the Kashima Laboratory of the Mitsubishi
Chemical Safety Institute in accordance with the OECD combined repeated dose and
reproductive/developmental toxicity screening test guideline (OECD TG 422). Twelve
Sprague-Dawley [Cij:CD (SD) IGS] rats/sex (males: 317-375 g; females: 203-240 g; 9 weeks
old) were administered triacetin (>98.2% purity) in 3% aqueous gum arabic by gavage once
daily at doses of 0, 40, 200, or 1,000 mg/kg-day. Males were dosed for 44 days beginning
2 weeks prior to mating; females were dosed for 41-48 days from 14 days before mating to
Postpartum Day (PPD) 3.
In the adults, mortality/morbidity and clinical signs of toxicity were recorded once a day
(MHW, 1998). Body weights were measured on Days 0, 3, 7, and 14 of premating in both sexes.
Body weights were also measured on Days 21, 28, 35, and 42, and at termination in the males,
and on Gestation Days (GD) 0, 7, 14, and 20, PPDs 0 and 4, and at termination in the females.
Food consumption (g/rat/day) was recorded for: Days 0-3, 3-7, and 7-14 in both sexes;
Days 21-28, 28-35, and 35-42 in the males; and GDs 0-7, 7-14, 14-20, and PPD 0-4 in the
females. The following hematological and clinical chemistry parameters were determined in
blood collected from males at termination: erythrocytes, hemoglobin, hematocrit, mean
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin
concentration, reticulocyte ratio, thrombocytes, leukocyte differential counts, aspartate
aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, alanine phosphatase,
total bilirubin, urea nitrogen, glucose, total cholesterol, triglyceride, total protein, albumin,
albumin:globulin ratio, calcium, inorganic phosphorus, sodium, potassium, and chloride.
Urinalysis was not performed. It was stated that absolute and relative organ weights were
recorded for brain, pituitary, thyroid, heart, liver, kidney, spleen, adrenal gland, thymus, testes,
and epididymis; however, data were only presented for thymus, liver, spleen, kidney, adrenal,
testes, and epididymis. At necropsy, the following tissues were collected from the controls and
1,000-mg/kg-day group: brain, spinal cord, pituitary, eye, thyroid (with parathyroid), thymus,
heart, trachea, lung, liver, kidney, adrenal gland, spleen, stomach, small intestine, large intestine,
pancreas, urinary bladder, bone marrow, sciatic nerve, lymph node, testes, epididymis, prostate,
seminal vesicle, ovary, uterus, vagina, mammary gland, and any organ that might be expected to
have histopathological changes. The following tissues were examined and reported in the
histological findings: heart, thymus, spleen, esophagus, stomach, duodenum, liver, kidney, testes,
epididymis, ovary, adrenal, brain, and skin. Reproductive data, including reproductive
performance indices, delivery data, and litter size, and pup viability indices, pup body weights,
and pup body-weight gains were presented. It was stated that the data were analyzed with the
Kruskal-Wallis test for noncontinuous data, Dunnett's test, or Scheffe's test for continuous data,
and the Chi-square test for quantal data. It was also stated that the study complied with Good
Laboratory Practice (GLP) standards.
One 1,000-mg/kg-day male was found dead on Day 32 (MHW, 1998). This animal was
observed grossly to have hemorrhage of the thymus and congestion of the lung, liver, and
kidney; microscopic examination revealed slight diffuse hemorrhage of the thymus. In the
absence of any evidence of systemic toxicity in any other animal at any dose level, this death is
considered incidental to treatment. In the animals that survived to scheduled necropsy, triacetin
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had no effects on clinical signs of toxicity, body weights, body-weight gains, food consumption,
organ weights, or gross or histological pathology findings. Statistically significant decreases
were observed in percent of band neutrophils and creatinine in the 40- and 1,000-mg/kg-day
males; statistically significant increases in inorganic phosphorus were also noted in the
200-mg/kg-day males. These changes were stated to be within physiological ranges and/or were
not dose-dependent. Reproductive and offspring results are discussed under the
Reproductive/Developmental Studies section below. In the absence of any reliable finding of
toxicity in treated adult rats, the NOAEL was determined to be 1,000 mg/kg-day; a LOAEL was
not determined under the conditions tested.
Shapiraetal. (1975)
In a peer-reviewed study, Shapira et al. (1975) fed groups of eight male Sprague-Dawley
rats diets for 13 weeks containing various carbohydrates in order to investigate the feasibility of
replacing starch with alternative carbohydrate sources. The study tested six types of diets: Diet 1
(control, 60% starch), Diet 2 (30% glycerol and 30% propylene glycol), Diet 3 (30% glycerol
and 30% triacetin), Diet 4 (30% propylene glycol and 30% triacetin), Diet 5 (40% glycerol and
20%) propylene glycol), and Diet 6 (40% glycerol and 20% triacetin). For the diets that included
triacetin, the daily adjusted doses of triacetin were 17,228 and 25,843 mg/kg-day for 20 and
30%) triacetin diets, respectively. Each diet also contained 27% casein and 5% safflower oil.
Identical amounts of cellulose, salts, and vitamins were present in all diets. Rats were kept in
pairs in stainless steel cages. For periods of 3-4 and 12-13 weeks, food consumption, body-
weight gain, water intake, and liver weight were reported. It is not apparent from the report that
statistical analyses were performed.
In this study (Shapira et al., 1975), body weights were decreased by 20% after
12-13 weeks on Diets 3 and 6 (triacetin with glycerol), but body weights were comparable for
the control diet and Diet 4 (triacetin with propylene glycol). Water intake varied, and it is not
possible to make conclusions without additional test groups where the concentrations of triacetin
are varied (while other components remained the same). Body-weight gains as growth percent
for periods of 3-4 and 12-13 weeks decreased 29-52% in all triacetin groups compared to the
control group. However, due to the other variables in the dietary exposure media (e.g., casein,
glycerol, or propylene glycol), it is difficult to attribute changes in body weight to triacetin alone.
Alternatively, it is possible that feeding with 30% triacetin may have negatively impacted
nutrition over the 13-week period. Regardless, this effect is not considered to be a clear
indication of systemic toxicity for triacetin. Relative liver weights were increased by 41-67%).
The study authors reported no NOAEL or LOAEL, and the data gaps are such that it is not
possible to determine a NOAEL or LOAEL for this study. Insufficient toxicological parameters
were examined in this study, and the impact of dietary protein was not sufficiently evaluated;
therefore, this study is not considered suitable for derivation of a subchronic p-RfD.
Madhavarao et al. (2009)
In a peer-reviewed study by Madhavarao et al. (2009), wild-type and tremor rat pups
(6-12 males or females per group) received triacetin orally twice daily, initially at a dose of
4.2 g/kg during Postnatal Days (PND)s 7-14, then at 5.8 g/kg during PNDs 15-23, and
thereafter in both food (7.5%) and water (5%) for a total treatment period of 110-120 days. The
calculated doses in food and water are 7,099 mg/kg-day and 7,504 mg/kg-day, respectively,
yielding a total oral dose of 14,603 mg/kg-day after PND 23. The tremor rat model of
aspartoacylase deficiency is a natural mutant strain that has the entire aspartoacylase gene
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deleted. This rat model mimics Canavan disease in humans (described earlier in the Human
Studies section [Madhavarao et al., 2009]); thus, this study was conducted to support the efficacy
of oral triacetin supplementation for aspartate deficiency. These rats were bred at the Center of
Laboratory Animal Medicine at the Uniformed Services University of the Health Sciences,
Bethesda, MD, where the studies were conducted. The study authors did not clearly present the
number or sex of rats treated. A subset of rats was treated for approximately 110 days, and food
intake and body weights were measured on a regular basis throughout the study (schedule not
reported). Another subset of rats was treated for approximately 120 days, euthanized, and
histopathology and biochemical analyses (29 different blood serum analytes such as lipids,
proteins, electrolytes [e.g., Na, Mg]) were conducted. A limited set of tissues were fixed in
10% neutral-buffered formalin. Brain, spinal cord, lung, heart, liver, kidney, stomach, small and
large intestine, and spleen were processed routinely, and slides from 2-4 rats per group were
examined microscopically. When the data satisfied the assumptions of normality and equal
variance, one-way ANOVA was performed followed by the Holm-Sidak post hoc test. When the
data failed the assumptions of normality or equal variance or both, Kruskal-Wallis ANOVA of
the ranks was applied, and differences in ranks were compared by Dunn's method.
No significant differences in the mean blood chemistry values occurred between treated
and untreated groups, and no lesions indicating toxicity were detectable in any of the tissues
examined microscopically (Madhavarao et al., 2009). Although triacetin-treated rats displayed
slightly decreased food consumption and decreased body weights, the differences in weights
between the treated and untreated groups were not statistically significant (data not presented).
The study authors reported no NOAEL or LOAEL; the treated rats showed no adverse effects.
Therefore, the NOAEL is 14,603 mg/kg-day, and a LOAEL is not available under the conditions
tested. The study authors stated that these data support the use of triacetin supplementation for
effective treatment of infants diagnosed with aspartoacylase deficiency. However, the following
information was not provided: (a) whether the study complied with GLP standards; (b) the purity
of the test compound; and (c) rat husbandry conditions. Hematology, urinalysis, organ weights,
and necropsy were not performed or were not reported. Histology was limited to 10 tissues, and
samples from only 2-4 rats were examined in each group. Due to these data omissions, this
study is not considered suitable for derivation of a subchronic p-RfD.
Chronic-Duration Studies
No studies were identified.
Developmental Studies
Please refer to offspring data provided in MHW (1998) below.
Reproductive/Developmental Studies
The study prepared for the Ministry of Health and Welfare, Japan (MHW, 1998) is
selected as the principal study and deemed adequate for the derivation of screening level
subchronic and chronic p-RfDs. In a combined repeated dose and reproductive toxicity
screening study, 12 Sprague-Dawley [Cij:CD (SD) IGS] rats/sex were administered triacetin by
gavage once daily at doses of 0, 40, 200, or 1,000 mg/kg-day. Males were dosed for 44 days
beginning 2 weeks prior to mating; females were dosed for 41-48 days from 14 days before
mating to PPD 3. The methodology of this study (MHW, 1998) was previously described under
Subchronic Studies above. The results of the offspring and reproductive parameters are reported
here.
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No treatment-related effects were observed on copulation, fertility, implantation, number
of corpora lutea, gestation length, or delivery in exposed dams (MHW, 1998). No
treatment-related effects were noted for the limited number of developmental parameters
examined such as viability, offspring born alive, and offspring alive at PND 4. In addition,
offspring body weights for triacetin-treated groups were similar to controls at PNDs 0 and 4.
Although the study authors reported no NOAEL or LOAEL for reproductive effects, the highest
dose of 1,000 mg/kg-day showed no adverse reproductive effects. Furthermore, triacetin
exposure before, during, and immediately after pregnancy did not result in overt toxicity in
offspring. Therefore, the NOAEL for this study is 1,000 mg/kg-day for both offspring
(developmental) and reproductive parameters. A LOAEL is not determined under the conditions
tested.
Carcinogenicity Studies
No studies were identified.
Inhalation Exposures
The effects of inhalation exposure of animals to triacetin have been evaluated in
3 subchronic studies in rats: Fassett (1955); Unichema Chemie B.V. (1994); and Fassett (1963).
The original citations for these studies cannot be obtained; the information from each study is
obtained from the indicated summary articles.
Short-term Studies
No studies were identified.
Subchronic-Duration Studies
Fassett (1955), as summarized in OECD (2002)
Information for the non-peer-reviewed study by Fassett (1955) is reported in the OECD
Screening Information Dataset (2002) robust summaries; the original citation cannot be obtained.
In this study, three rats/sex (strain not reported) were exposed to triacetin vapor by whole-body
vapor inhalation exposure for 6 hours/day, 5 days/week, at a concentration of 249 ppm (HEC is
397 mg/m ) for 90 days. A concurrent control group was not exposed. It was stated that
inhalation was further extended for another week at 73.72 ppm (HEC is 117 mg/m3), followed by
a week at 8,271 ppm (saturated vapor; HEC is 13,181 mg/m ). Treating the animals at
73.72 ppm for an additional week after no observed effect from 13 weeks of treatment at
249 ppm is without apparent reason; therefore, the summary article may be mistaken. Body
weights were recorded prior to the first exposure, every 2-9 days during testing, and prior to
termination. Limited hematology (red and white blood cell counts and hemoglobin) and
urinalysis (albumin and sugar) parameters were measured. Liver and kidneys were weighed, and
microscopic findings for trachea, bronchi, lung, kidney, liver, and bladder were reported.
No symptoms of toxicity were noted during the exposure period (Fassett [1955], as
summarized in OECD [2002]). Average daily weight gain was 2.2 g/rat and was considered
normal. Hematological evaluation and urinalysis showed no abnormalities in any of the animals.
No histopathological changes were observed at the time of necropsy. The study author reported
an estimated NOAEL of 249 ppm (HEC is 397 mg/m3) for the 90-day study. A LOAEL was not
observed under the conditions tested. OECD (2002) stated that, although this inhalation study
was considered to be useful, it did not fully comply with the current testing protocol. Due to the
limited toxicity data, this study is not considered suitable for derivation of a subchronic p-RfC.
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Unichema Chemie B. V. (1994), as summarized by Fiume (2003)
Information for the non-peer-reviewed study by Unichema Chemie B.V. (1994) was
reported by Fiume (2003); the original citation could not be obtained. Three rats (sex and strain
not reported) were exposed to 250 ppm (HEC is 398 mg/m3) by inhalation for 6 hours per day,
5	days per week, for 64 days. Three rats were also exposed to 8,271 ppm (HEC is
13,181 mg/m3) for 6 hours per day for 64 days. No adverse effect was observed. The study
"3
author reported a NOAEL of 13,181 mg/m ; a LOAEL was not determined under the conditions
tested. Due to the extremely limited toxicity data, this study is not considered suitable for
derivation of a subchronic p-RfC.
Fassett (1963), as summarized by Ellis andRodford (1996)
Information for the peer-reviewed study by Fassett (1963) was reported in a glycerol
triacetate safety evaluation by Ellis and Rodford (1996); the original citation could not be
obtained. Inhalation concentrations of triacetin averaging 250 ppm (HEC is 398 mg/m ) for
6	hours per day, 5 days per week, for 13 weeks produced no symptoms or histopathology in rats
(sex and strain not reported). No changes were reportedly seen in liver and kidney weights,
blood counts, or urine analysis. This concentration is considered the NOAEL; a LOAEL is not
determined under the conditions tested. Due to the extremely limited toxicity data, this study is
not considered suitable for derivation of a subchronic p-RfC.
Chronic-Duration Studies
No studies were identified.
Developmental Studies
No studies were identified.
Reproduction Studies
No studies were identified.
Carcinogenicity Studies
No studies were identified.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Other studies that are not appropriate for selection of a point of departure (POD) for
triacetin and the determination of p-RfD, p-RfC, p-OSF, or p-IUR values may, however, provide
supportive data supplementing a WOE approach to hazard identification and dose-response
assessment. These studies may include, but are not limited to, information regarding toxic
mode-of-action/mechanistic details, metabolism/toxicokinetics, or potential adverse health
outcomes following shorter-term (e.g., <30-days) exposure durations. Although some
acute/short-term duration studies exist for triacetin, the experimental designs involved the
intravenous route of exposure, which is not necessarily relevant for informing hazard or dose
response via the oral or inhalation routes and, thus, are not included.
Genotoxicity
Four genotoxicity studies are available indicating that triacetin has no mutagenic
potential (Litton Bionetics, Inc. [1976a,b], Unichema Chemie B.V. [1994], and Efremova
[1962]) and are presented in Table 3 and summarized briefly below.
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Litton Bionetics, Inc. (1976a) evaluated the mutagenic potential of triacetin in an Ames
plate and suspension test using Salmonella typhimurium (strains TA1535, TA1537, and TA1538)
with and without metabolic activation. Test concentrations were 0.000325%, 0.00065%, and
0.0013%) (w/v). Doses were selected based on the results of a preliminary toxicity test. The
activation systems included S9 prepared from the liver of male ICR mouse, S-D rat, or Rhesus
monkey. A negative control (solvent) and appropriate positive controls were used and gave
expected results. Triacetin was not mutagenic with or without metabolic activation.
Table 3. Summary of Triacetin Genotoxicity Studies
Endpoint
Test System
Dose
Concentration"
Resultsb
Comments
References
Without
Activation
With
Activation
Genotoxicity studies in prokaryotic organisms
Reverse
mutation
Salmonella
typhimurium TA1535,
TA1537, and TA1538
in the Ames plate test
or suspension test with
or without S9
0, 0.000325,
0.00065, and
0.0013%


Negative and
positive controls
gave the
expected results
Litton
Bionetics,
Inc. (1976a)
Reverse
mutation
S. typhimurium
TA1535, TA1537,
TA98, and TA100 in
the Ames plate test
with or without S9
o,
50-5,000 (ig/plate


The source
document could
not be obtained.
This
information is
from a review
Unichema
Chemie B.V.
(1994), as
summarized
by Fiume
(2003)
Gene
conversion
Saccharomyces
cerevisiae strain D4 in
a suspension test with
or without S9
0, 1.25, 2.5, and
5%


Negative and
positive controls
gave the
expected results
Litton
Bionetics,
Inc. (1976b)
Genotoxicity studies in nonmammalian eukaryotic organisms
Mutation
Drosophila
melanogaster
0.2-0.3 mg


The source
document could
not be obtained.
This
information is
from a review
Efremova
(1962), as
summarized
in Fiume
(2003)
aLowest effective dose for positive results, or, highest dose tested for negative results.
b- = negative, NA = not applicable, ND = no data.
No evidence of mutagenic potential was obtained in an Ames test using S. typhimurium
(strains TA1535, TA1537, TA98, and TA100) with and without metabolic activation at
concentrations up to 5,000 [j,g/plate (Unichema Chemie B.V., 1994). The source document could
not be obtained; this information was provided in the Final Report on the Safety Assessment of
Triacetin (Fiume, 2003).
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Litton Bionetics, Inc. (1976b) evaluated the mutagenic potential of triacetin in a
suspension test using Saccharomyces cerevisiae strain D4 with and without metabolic activation.
Test concentrations were 1.25%, 2.5%, and 5.0% (w/v). Doses were selected based on the
results of a preliminary toxicity test. The activation systems included S9 prepared from the liver
of male ICR mouse, S-D rat, or Rhesus monkey. Appropriate negative and positive controls
were used and gave expected results. Triacetin did not result in gene conversions in the
suspension test with or without metabolic activation.
Efremova (1962) treated adult Drosophila melanogaster with a dose of 0.2-0.3 mg
triacetin in an in vivo assay and found triacetin not to be mutagenic. The source document could
not be obtained; this information was provided in the Final Report on the Safety Assessment of
Triacetin (Fiume, 2003).
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DERIVATION OF PROVISIONAL VALUES
Table 4 presents a summary of noncancer reference values. Table 5 presents a summary of cancer values. No cancer values could be
derived. IRIS data are indicated in the table, if available.
Table 4. Summary of Noncancer Reference Values for Triacetin
Toxicity Type
(Units)
Species/
Sex
Critical Effect
Reference
Value
POD Method
PODhed
UFc
Principal Study
Screening Subchronic
p-RfD (mg/kg-day)
Rat/M/F
No effects observed
8 x 101
NOAEL
240
3
MHW (1998)
Screening Chronic
p-RfD (mg/kg-day)
Rat/M/F
No effects observed
8 x 101
NOAEL
240
3
MHW (1998)
Subchronic p-RfC
(mg/m3)
NDr
Chronic p-RfC
(mg/m3)
NDr
NDr = not determinable.
Table 5. Summary of Cancer Values for Triacetin
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF
NDr
p-IUR
NDr
NDr = not determinable.
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DERIVATION OF ORAL REFERENCE DOSE
Derivation of Subchronic and Chronic Provisional RfD (p-RfD)
Studies identified for the oral route of exposure provided no evidence of triacetin toxicity
(i.e., highest doses evaluated were all NOAELs). This was due, in part, to the prevalence of
factors that confounded interpretation of hazard (resulting in a lack of hazard) and dose-response
(e.g., dietary supplements in the exposure medium that might have conferred cytoprotective
properties on target tissues). The combined subchronic/developmental/reproductive study
performed for the Ministry of Health and Welfare, Japan (MHW, 1998) was the only study
identified that did not suffer from confounding study design conditions, and it is deemed the
principal study for the derivation of subchronic and chronic p-RfDs. However, because it cannot
be conclusively determined that this study is peer reviewed, and the attendant uncertainty of a
hazard database comprised only of NOAELs, screening subchronic and chronic p-RfDs are
derived in Appendix A.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
Derivation of Subchronic and Chronic Provisional RfC (p-RfC)
Three subchronic inhalation studies were located; however, the original documents for
these studies could not be obtained. The available data suggest that a saturated triacetin vapor
atmosphere of up to 13,181 mg/m3 can be tolerated without adverse effect for at least 64 days
(Unichema Chemie B.V. [1994], as summarized by Fiume [2003]). However, the available
summaries for these studies presented only limited experimental details and toxicity data. Due to
these limitations, it is not possible to derive subchronic or chronic p-RfCs from these studies.
CANCER WOE DESCRIPTOR
Table 6 identifies the cancer WOE descriptor for triacetin. No data could be located
regarding the carcinogenicity of triacetin. Therefore according to EPA's Guidelines for
Carcinogen Risk Assessment (U.S. EPA, 2005), there is inadequate information to assess the
human carcinogenic potential of triacetin.
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Table 6. Cancer WOE Descriptor for Triacetin
Possible WOE Descriptor
Designation
Route of Entry
(oral, inhalation,
or both)
Comments
"Carcinogenic to Humans "
NS
NA
NA
"Likely to be Carcinogenic
to Humans "
NS
NA
NA
"Suggestive Evidence of
Carcinogenic Potential"
NS
NA
NA
"Inadequate Information to
Assess Carcinogenic
Potential"
Selected
Both
No carcinogenicity studies were
identified.
"Not Likely to be
Carcinogenic to Humans "
NS
NA
NA
NA = not applicable; NS = not selected.
MODE OF ACTION DISCUSSION
The Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005) define mode-of-action
".. .as a sequence of key events and processes starting, with the interaction of an agent with a
cell, proceeding through operational and anatomical changes, and resulting in cancer formation"
(p. 1-10). Examples of possible modes of carcinogenic action for any given chemical include
"...mutagenicity, mitogenesis, inhibition of death, cytotoxicity with reparative cell proliferation,
and immune suppression" (p. 1-10). No carcinogenicity studies in human or animals were
located (see the "Cancer WOE Descriptor" above).
Mutagenic Mode-of-Action
Triacetin was not mutagenic in Salmonella typhimurium TA98, TA100, TA1535,
TA1537, or TA1538 in the Ames plate assay or suspension test, with or without metabolic
activation. Triacetin did not result in gene conversion of Saccharomyces cerevisiae strain D4 in
a suspension test, with or without metabolic activation. Triacetin did not result in mutation in
Drosophila melanogaster, a eukaryotic organism. There are no available studies to evaluate
mutagenic action, and there is no evidence of carcinogenic potential in humans or animals.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Derivation of provisional Oral Slope Factor (p-OSF)
No human or animal studies examining the carcinogenicity of triacetin following oral
exposure were identified. Therefore, it is not possible to derive a p-OSF.
Derivation of Provisional Inhalation Unit Risk (p-IUR)
No human or animal studies examining the carcinogenicity of triacetin following
inhalation exposure were identified. Therefore, it is not possible to derive a p-IUR.
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APPENDIX A. PROVISIONAL SCREENING VALUES
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
subchronic or chronic p-RfDs for triacetin. However, information is available for this chemical
which, although insufficient to support derivation of a provisional toxicity value, under current
guidelines, may be of limited use to risk assessors. In such cases, the Superfund Health Risk
Technical Support Center summarizes available information in an Appendix and develops a
"screening value." Appendices receive the same level of internal and external scientific peer
review as the PPRTV documents to ensure their appropriateness within the limitations detailed in
the document. Users of screening toxicity values in an appendix to a PPRTV assessment should
understand that there is considerably more uncertainty associated with the derivation of an
appendix screening toxicity value than for a value presented in the body of the assessment.
Questions or concerns about the appropriate use of screening values should be directed to the
Superfund Health Risk Technical Support Center.
DERIVATION OF SCREENING LEVEL ORAL REFERENCE DOSES
Derivation of a Screening Level Subchronic Provisional RfD (Screening Subchronic p-RfD)
The two available human studies (Madhavarao et al. [2009] and Segel et al. [2011]) were
carefully evaluated in the selection of a principal study and POD. While NOAELs based on a
lack of effect in human infants were identified in both of these studies, limitations in study
design, questionable exposure compliance during the reported treatment period, and the
preexistent disease condition of the infants raises concern over the reliability of the NOAELs.
Specifically, only two infants were examined in both the Madhavarao et al. (2009) and
Segel et al. (2011) studies. The study authors noted difficulties in maintaining the infants on
treatment due to concerns raised by the parents; thus, the difference in exposure period between
the male and female infants in each study. In addition, Segel et al. (2011) reported that one of
the patients left the country (Israel) two weeks after commencing treatment; follow-up was
purportedly monitored by a primary care physician, unrelated to the study, and in the new
country of residence (not specified). Lastly, the infants were previously diagnosed with Canavan
disease, which results in a significant decrement in acetate levels. Considering that triacetin is an
acetate precursor, it is plausible that the triacetin exposures were in part augmenting the
deficiency rather than inducing a potential toxicity. Neither human study was considered further
for principal study or POD identification.
The study prepared for the Ministry of Health and Welfare, Japan (MHW, 1998) is
selected as the principal study and is deemed adequate for the derivation of screening level
subchronic and chronic p-RfDs. The MHW (1998) combined subchronic/developmental and
reproductive study in rats provides the most complete evaluation of the toxicity of triacetin and
identified a NOAEL of 1,000 mg/kg-day for lack of toxicity in either maternal F0 dams or F1
offspring. There are additional subchronic feeding studies (Shapira et al. [1969], Lynch et al.
[1994], and Madhavarao et al. [2009]), suggesting that much higher levels of triacetin may be
tolerated by rats without adverse effects. For example, the study by Shapira et al. (1969)
indicates that triacetin can be tolerated in the diet up to levels that hinder nutrition (e.g.,
25,843 mg/kg-day), and the studies by Madhavarao et al. (2009) and Lynch et al. (1994) indicate
that rats can tolerate diets containing up to 14,603-16,367 mg/kg-day of triacetin without harm.
However, it should be noted that all of these oral repeat-dose studies, except for the MHW
(1998) study, employed exposures that included a host of additional dietary supplements (e.g.,
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minerals, vitamins, protein, and carbohydrates) that might influence tissue kinetics and dynamics
in response to triacetin. Indeed, acute oral exposure to triacetin alone in rats revealed lethal dose
(LD50) values ranging from >2,000-12,800 mg/kg (OECD, 2002). Mice appear to be slightly
more sensitive, particularly females, to acute oral triacetin exposure with LD50s ranging from
1,100-9,300 mg/kg (OECD, 2002). In addition, many of the repeat-dose studies were severely
lacking in the number of toxicological parameters examined, including the studies by
Lynch et al. (1994), Lynch and Bailey (1995), Shapira et al. (1969), and Shapira et al. (1975);
thus, some caution is warranted in the interpretation of the higher NOAELs identified in these
studies compared to MHW (1998).
The principal study (MHW, 1998) was performed by the Kashima Laboratory of the
Mitsubishi Chemical Safety Institute in accordance with the OECD combined repeated dose and
reproductive/developmental toxicity screening test guideline (OECD TG 422). Because it could
not be conclusively determined that this study was peer reviewed and the fact that no effects
were observed, screening values are derived below. An adequate number of animals were dosed
for a subchronic duration at levels up to 1,000 mg/kg-day and included exposure to progeny
during a potentially susceptible lifestage. The parental F0 animals were dosed for 41-48 days
from 14 days before mating to PPD3; thus, F1 offspring were exposed throughout gestation and
potentially indirectly until PND 4. In the absence of any finding of toxicity in offspring, the
NOAEL is considered to be 1,000 mg/kg-day for F1 rats and is selected as the POD to derive
both screening subchronic and chronic p-RfDs.
EPA guidance recommends expressing gestational exposures as a daily average during
the period of exposure and not to extrapolate to lifetime exposure (U.S. EPA, 1991), so no
duration adjustment was needed for each dose in the principal study. However, the POD was
extrapolated to a corresponding human equivalent dose using the EPA's guidance document
entitled, "Recommended Use of Body Weight3 4 as the Default Method in Derivation of the Oral
Reference Dose" (U.S. EPA, 2011). The Agency endorses a hierarchy of approaches for
deriving human equivalent oral exposures (i.e., HEDs) from data in laboratory animals, with the
preferred approach being physiologically based toxicokinetic modeling. Other approaches can
include using chemical-specific information, in the absence of a complete physiologically-based
toxicokinetic model. In lieu of either chemical-specific kinetic models or data to inform the
derivation of human equivalent oral exposures, EPA endorses body weight scaling to the
3/4 power (i.e., BW3 4) as a default approach to extrapolate toxicologically equivalent doses of
orally administered agents from adult laboratory animals to adult humans for the purpose of
deriving an oral RfD. No physiologically-based toxicokinetic modeling information exists for
triacetin. Therefore, consistent with EPA guidance (U.S. EPA, 2011), the POD is converted to a
HED employing a standardized dosimetric adjustment factor (DAF) derived as follows:
DAF = (BWa1/4 - BWh1/4)
where
DAF	=	dosimetric adjustment factor
BWa	=	animal body weight
BWh	=	human body weight
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Using a BWa of 0.25 kg for rats and a BWh of 70 kg for humans (U.S. EPA, 1988), the resulting
DAF is 0.24. Applying this DAF to the NOAEL identified from the MHW (1998) study yields a
NOAELhed as follows:
NOAELhed = 1,000 mg/kg-day x DAF
= 1,000 mg/kg-day x 0.24
= 240 mg/kg-day
The screening subchronic p-RfD for triacetin is derived as follows:
Screening Subchronic p-RfD = NOAELhed UFc
= 240 mg/kg-day ^ 3
= 8 x 10 mg/kg-day
Table A-l summarizes the uncertainty factors (UFs) for the screening subchronic p-RfD for
triacetin.
Table A-l. UFs for Screening Subchronic p-RfD of Triacetin
UF
Value
Justification
ufa
1
A UFa of 1 is applied for interspecies extrapolation to account for potential toxicokinetic and
toxicodynamic differences between rats and humans. Although several limitations in the
Segel et al. (2011) human study (e.g., preexistent disease condition, confounded exposures)
significantly decreases confidence in making inferences regarding potential differences in the
toxicokinetics or toxicodynamics of triacetin between rats and humans, the NOAEL of
4,500 mg/kg-day identified in human infants (Madhavarao et al., 2009) is considerably greater
than the NOAEL of 1,000 mg/kg-day identified in neonatal rats (MHW, 1998). Therefore, a
UFa of 1 is applied.
ufd
3
A UFd of 3 is selected even though there are no acceptable two-generation reproduction studies,
or peer-reviewed developmental studies. However, the MHW (1998) study reported no
reproductive or developmental toxicity associated with triacetin exposure. Additionally, the
Cosmetic Ingredient Review Expert Panel concluded that triacetin does not present a risk of
reproductive or developmental toxicity because it is metabolized to glycerol and acetic acid,
which are not reproductive or developmental toxicants (Fiume, 2003). Although triacetin
appears to be relatively inert in animals and humans during a potentially sensitive lifestage,
acute oral exposure studies using triacetin alone have identified LD50s as low as 2,000 mg/kg in
rats. Considering the rat developmental POD of 1,000 mg/kg-day, there is some uncertainty in
where a LOAEL for a significant biological effect from a triacetin-only repeat-dose (e.g.,
subchronic or chronic) study may occur along the dose-response continuum between the POD
(NOAEL) of 1,000 mg/kg-day and LD50 of approximately 2,000 mg/kg. Therefore, a UFD of 3
is applied.
UFh
1
A UFh of 1 is applied for intra-species differences to account for potentially susceptible
individuals in human populations. Segel et al. (2011) demonstrated that infants, a sensitive
human population, can tolerate daily doses of up to 4,500 mg/kg-d.
ufl
1
A UFl of 1 is applied for using a POD based on a NOAEL.
UFS
1
A UFS of 1 is applied because the exposure occurred during a developmental lifestage.
UFC
3

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Derivation of a Screening Chronic Provisional RfD (Screening Chronic p-RfD)
No chronic toxicity study was located. Therefore, MHW (1998) was also used to derive
the screening chronic p-RfD. While the principal study, POD, and resultant screening chronic
p-RfD are the same as the screening subchronic p-RfD above, the derivation below is shown for
completeness.
Screening Chronic p-RfD = NOAELhed UFc
= 240 mg/kg-day ^ 3
= 8 x 10 mg/kg-day
Table A-2 summarizes the UFs for the screening chronic p-RfD for triacetin.
Table A-2. UFs for Screening Chronic p-RfD of Triacetin
UF
Value
Justification
ufa
1
A UFa of 1 is applied for interspecies extrapolation to account for potential toxicokinetic and
toxicodynamic differences between rats and humans. Although several limitations in the
Segel et al. (2011) human study (e.g., preexistent disease condition, confounded exposures)
significantly decreases confidence in making inferences regarding potential differences in the
toxicokinetics or toxicodynamics of triacetin between rats and humans, the NOAEL of
4,500 mg/kg-day identified in human infants (Madhavarao et al., 2009) is considerably greater
than the NOAEL of 1,000 mg/kg-day identified in neonatal rats (MHW, 1998). Therefore, a
UFa of 1 is applied.
ufd
3
A UFd of 3 is selected even though there are no acceptable two-generation reproduction studies,
or peer-reviewed developmental studies. However, the MHW (1998) study reported no
reproductive or developmental toxicity associated with triacetin exposure. Additionally, the
Cosmetic Ingredient Review Expert Panel concluded that triacetin does not present a risk of
reproductive or developmental toxicity because it is metabolized to glycerol and acetic acid,
which are not reproductive or developmental toxicants (Fiume, 2003). Although triacetin
appears to be relatively inert in animals and humans during a potentially sensitive lifestage,
acute oral exposure studies using triacetin alone have identified LD50s as low as 2,000 mg/kg in
rats. Considering the rat developmental POD of 1,000 mg/kg-day, there is some uncertainty in a
LOAEL for a significant biological effect from a triacetin-only repeat-dose (e.g., subchronic or
chronic) study may occur along the dose-response continuum between the POD (NOAEL) of
1,000 mg/kg-day and LD50 of approximately 2,000 mg/kg. Therefore, a UFD of 3 is applied.
UFh
1
A UFh of 1 is applied for intraspecies differences to account for potentially susceptible
individuals in human populations. Segel et al. (2011) demonstrated that infants, a sensitive
human population, can tolerate daily doses of up to 4,500 mg/kg-d.
ufl
1
A UFl of 1 is applied for using a POD based on a NOAEL.
UFS
1
A UFS of 1 is applied because the exposure occurred during a developmental lifestage.
UFC
3

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APPENDIX B. DATA TABLES
Table B-l. Initial and Terminal Body Weights of Weanling Male S-D Rats Fed Diets
Containing Various Levels of Triacetin for 18 Days"
Target
Protein
Dietary Components by % Weight
Animal weight (g) ±
SEM
Protein Source
Carbohydrate Source
Content
Casein
H. Eutropha
Glycerol
Triacetinb
Starch
Original
Day 18
12%
13.7
0
0
0
73.3
79.1 ±2.9
152.8 ±4.5

13.7
0
30
30
13.3
78.0 ±3.4
117.4 ± 4.3

0
13.4
0
0
73.6
77.0 ± 5.0
148.6 ±6.3

0
13.4
30
30
13.6
77.0 ±3.9
129.4 ±6.3
24%
27.4
0
0
0
59.6
76.3 ±2.9
186.9 ±4.9

27.4
0
29.8
29.8
0
84.1 ±2.6
166.8 ±6.9

0
26.8
0
0
60.2
76.5 ±4.2
182.9 ±3.1

0
26.8
29.8
29.8
0.2
74.9 ±4.0
178.8 ±3.4
48%
54.8
0
0
0
32.2
79.3 ± 1.7
181.0 ± 3.3

54.8
0
16.1
16.1
0
78.6 ±4.1
178.1 ± 5.1

0
53.6
0
0
33.4
78.4 ±3.2
204.3 ± 13.1

0
53.6
16.7
16.1
0
83.3 ±3.1
191.5 ±8.3
aSource: Shapiraetal. (1969).
bThe three dietary levels of triacetin (16.1, 29.8, and 30%) are equivalent to adjusted doses of 13,869, 25,670, and
25,843 mg/kg-day, respectively.
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APPENDIX C. BMD OUTPUTS
No BMD modeling was conducted for this assessment.
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