Safety Assessment of
Monoalkylglycol Dialkyl Acid Esters
as Used in Cosmetics

Status:Release Date:
Panel Meeting Date:

Final Report
November 16, 2017
September 11-12, 2017

The 2017 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito,
M.D.; Ronald A. Hill, Ph.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; James G. Marks, Jr., M.D.; Ronald C. Shank,
Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Executive Director is Bart Heldreth, Ph.D. This
report was prepared by Lillian C. Becker, Scientific Analyst/Writer.

© Cosmetic Ingredient Review

1620 L Street, NW, Suite 1200  Washington, DC 20036-4702  ph 202.331.0651  fax 202.331.0088  cirinfo@cir-safety.org

ABSTRACTThe Cosmetic Ingredient Review (CIR) Expert Panel (Panel) reviewed the safety of 28 monoalkylglycol dialkyl acid esters as usedin cosmetics. The most common cosmetic function reported for this group of ingredients is as a skin conditioning agent; otherreported functions film former, hair conditioning agent, opacifying agent, plasticizer, slip modifier, solvent, surface modifier, andviscosity increasing agent. The Panel reviewed the relevant data for these ingredients and concluded that these monoalkylglycol
dialkyl acid esters are safe in cosmetics in the present practices of use and concentration described in this safety assessment.
INTRODUCTION
This is a safety assessment of 28 monoalkylglycol dialkyl acid esters as used in cosmetics (Table 1). The ingredients inthis report are structurally related to each other as alkyl esters of monoalkyl diols (i.e. not polyalkyldiols such as polyethylene
glycols (PEGs)) that vary by type of diol and lengths of the fatty acid residues. The ingredients in this report include:
Butylene Glycol Dicaprylate/Dicaprate
Butylene Glycol Diisononanoate
Diethylpentanediol Dineopentanoate
Dioctadecanyl Didecyltetradecanoate
Dioctadecanyl Ditetradecyloctadecanoate
Glycol Dibehenate
Glycol Diethylhexanoate
Glycol Dilaurate
Glycol Dioleate
Glycol Dipalmate/Palm Kernelate/Olivate/Macadamiate
Glycol Dipalmate/Rapeseedate/Soyate
Glycol Dipivalate
Glycol Distearate
Glycol Ditallowate

Hexanediol Distearate
Neopentyl Glycol Dicaprate
Neopentyl Glycol Dicaprylate/Dicaprate
Neopentyl Glycol Dicaprylate/Dipelargonate/Dicaprate
Neopentyl Glycol Diethylhexanoate
Neopentyl Glycol Diheptanoate
Neopentyl Glycol Diisononanoate
Neopentyl Glycol Diisostearate
Neopentyl Glycol Dilaurate
Propanediol Dicaprylate
Propanediol Dicaprylate/Caprate
Propanediol Diisostearate
Propanediol Dipelargonate
Trimethyl Pentanyl Diisobutyrate

According to the web-based International Cosmetic Ingredient Dictionary and Handbook (wINCI Dictionary), the mostcommon cosmetic function reported for this group of ingredients is as a skin conditioning agent; other the reported functions ofthese ingredients include film former, hair conditioning agent, opacifying agent, plasticizer, slip modifier, solvent, surface
modifier, and viscosity increasing agent – nonaqueous (Table 1).1
Some of these ingredients have been previously assessed for safety by the Panel. Glycol Distearate has been previously
reviewed by the Panel and was found to be safe as used; the conclusion was reaffirmed in 2001 (Table 2).2,3 Neopentyl Glycol
Dicaprylate/Dipelargonate/Dicaprate and Neopentyl Glycol Diisononanoate have also been reviewed by the Panel and were foundto be safe as used in 2011.4
The Panel has reviewed related ingredients, moieties, and component parts of these ingredients (Table 2). These CIR
safety assessments have been utilized herein, in part, to inform the safety of the monoalkylglycol dialkyl acid esters. Please see theoriginal reports for further details (http://www.cir-safety.org/ingredients).
Data on the molecular weight and log P are useful in determining if these ingredients may penetrate the skin and areprovided in the chemical and physical properties table (Table 3). If it is possible that monoalkylglycol dialkyl acid esters penetrate
the skin and/or toxicity data are lacking, data on the hydrolysis products of these ingredients are also useful in determining safety.
Data on neopentanoic acid, a hydrolysis product of Diethylpentanediol Dineopentanoate, are provided in Table 4. There were nodata for the other hydrolysis product of Diethylpentanediol Dineopentanoate, i.e., 2,4-diethyl-1,5-pentanediol. However, data on
1,5-Pentanediol and Isopentyldiol, which may be used as surrogates for 2,4-diethyl-1,5-pentanediol due to their similar chemical
structures, are available from the CIR report on alkane diols. These data are also summarized in Table 4.
This safety assessment includes relevant published and unpublished data that are available for each endpoint that isevaluated. Published data are identified by conducting an exhaustive search of the world’s literature. A listing of the searchengines and websites that are used and the sources that are typically explored, as well as the endpoints that CIR typically evaluates,
is provided on the CIR website (http://www.cir-safety.org/supplementaldoc/preliminary-search-engines-and-websites;
http://www.cir-safety.org/supplementaldoc/cir-report-format-outline). Unpublished data are provided by the cosmetics industry, as
well as by other interested parties.
Pertinent data were discovered in the European Chemicals Agency (ECHA) database for Glycol Distearate, Neopentyl
Glycol Dicaprylate/Dicaprate, Neopentyl Glycol Diethylhexanoate, Neopentyl Glycol Diheptanoate, and Trimethyl Pentanyl
Diisobutyrate.5-9 Data were also discovered in this database for neopentanoic acid, a hydrolysis product of Diethylpentanediol
Dineopentanoate.10 The ECHA website provides summaries of information submitted by industry. ECHA is cited in thisassessment to identify the source of the data obtained from these summaries.
Summaries from the original reports on Glycol Distearate, Neopentyl Glycol Dicaprylate/Dipelargonate/Dicaprate, andNeopentyl Glycol Diisononanoate are included in the appropriate sections in italics.3,4 Please see the original reports for further

details (http://www.cir-safety.org/ingredients).
CHEMISTRY
Definition and Structure
The ingredients in this report are structurally related to each other as alkyl diesters of monoalkane diols. These
ingredients vary by the type of diol and the size of the carboxylic acid residues (Figure 1). For example, Neopentyl Glycol
Dicaprate is a diol (neopentyl glycol) esterified at both hydroxyl groups with a carboxylic acid (capric acid) (Figure 2).

Figure 1. Monoalkylglycol Dialkyl Acid Esters in which “ORO” is the residue of a diol and “R’C(O)” and “R”C(O)” are theresidues of a fatty acids.

Figure 2. Neopentyl Glycol Dicaprate, wherein “ORO” from Figure 1 is the residue of neopentyl glycol, and both R’C(O)” and“R”C(O)” are the residues of capric acid.

Physical and Chemical Properties
Physical and chemical properties for the monoalkylglycol dialkyl acid esters in this safety assessment are presented inTable 3.
Some of the monoalkylglycol dialkyl acid esters (e.g., Neopentyl Glycol Diethylhexanoate and Propanediol Dicaprylate)are clear or yellow liquids that are insoluble in water. 8,11-13 However, longer-chain diesters, such as Glycol Distearate, can bewhite to cream-colored waxy solids.3 Estimated and experimental log P values range from 4.91 (for Trimethyl Pentanyl
Diisobutyrate) to 46.27 (for Dioctadecanyl Ditetradecyloctadecanoate), supporting the statements that these ingredients are quite
lipophilic and thus poorly water-soluble.4-6,8,9,14,15 The physical properties of these ingredients may vary within specified limits
according to the proportions of mono- and di-esters, and other components (e.g., variations in how many of the glycol residues in
Glycol Distearate are mono- or di-substituted with stearic acid). Depending on the intended use, these variations can be set during
manufacturing to achieve the desired physical characteristics.
Diethylpentanediol Dineopentanoate is reported to be stable at 25°C under storage conditions.16
The average residual ash on ignition reported by one vendor for Neopentyl Glycol Dicaprate is 0.05%.17
Trimethyl Pentanyl Diisobutyrate is stable at pH 4.0 and 7.0.18 The half-life in water at pH 9 is 178 days.
UV Absorption
Data provided by a manufacturer indicated that Neopentyl Glycol Diisononanoate did not significantly absorb light in the
250 to 400 nm range.4 The structures of these ingredients lack chromophores that would result in UV absorption above 210 nm.
Method of Manufacture
In general, alkyl esters can be produced via the esterification of carboxylic acids with the corresponding glycols (with orwithout a metal catalyst).19 These carboxylic acids and glycols are often derived from plant or animal sources (e.g., Glycol
Dipalmate/Rapeseedate/Soyate and Glycol Ditallowate). Acids from these sources are often mixtures; accordingly, the resulting
esters are also mixtures (e.g., Glycol Dipalmate/Palm Kernelate/Olivate/ Macadamiate and Glycol Dipalmate/Rapeseedate/
Soyate).

Impurities/Constituents
Ethylene glycol and/or ethylene oxide are used as starting material for the synthesis of Glycol Stearate. These starting
materials are expected to also be used as starting materials for Glycol Distearate, a related ingredient. Because the former isknown to be contaminated with traces of 1,4-dioxane, it is possible that such traces could also appear in the final synthesizedmaterial.20 A safety data sheet on a product mixture containing Glycol Distearate recited that 1,4-dioxane was not detected.21
A batch of Neopentyl Glycol Diheptanoate was reported to be > 99% pure; the impurities were not named.6
One batch of Trimethyl Pentanyl Diisobutyrate was reported to be > 99% pure, and another batch was reported to be
98.95% pure.7 The impurities were not named. Another source also reported that Trimethyl Pentanyl Diisobutyrate was > 99%
pure and the major impurity was 2,2,4-trimethyl-1,3-pentanediol monoisobutyrate.18
A product data sheet for a product mixture containing Glycol Distearate (88% to 95%), ethylene glycol monostearate (5%to 15%), and ethylene glycol (< 4%), reported that this product contained < 0.0000001% toluene.21,22 According to this productdata sheet, this product mixture contains < 0.001% of the following: cadmium, mercury, antimony, arsenic, chromium, cobalt,
nickel, lead, or silver. It was also reported to not contain ethylene oxide or propylene oxide.
USE
Cosmetic
The safety of the cosmetic ingredients included in this assessment is evaluated based on data received from the U.S. Foodand Drug Administration (FDA) and the cosmetic industry on the expected use of these ingredients in cosmetics. Use frequencies
of individual ingredients in cosmetics are collected from manufacturers and reported by cosmetic product category in FDA’s
Voluntary Cosmetic Registration Program (VCRP) database. Use concentration data are submitted by the cosmetics industry in
response to surveys conducted by the Council, of maximum reported use concentration by product category.
According to VCRP survey data received in 2017, Glycol Distearate was reported to be used in 1663 formulations, mostly
in hair products (1041 formulations); this is an increase from 28 uses in 2001.2,4,23 Trimethyl Pentanyl Diisobutyrate andNeopentyl Glycol Diheptanoate are used in 399 (all nail products) and 415 (mostly in skin care products) formulations,
respectively. The rest of the ingredients with reported uses were used in 102 or fewer formulations. As for the other ingredientsthat were previously reviewed by CIR, Neopentyl Glycol Dicaprylate/Dipelargonate/Dicaprate and Neopentyl Glycol
Diisononanoate had no uses reported to the VCRP in 2001 or 2017 (Table 5, Table 6, and Table 7).
The results of the concentration of use survey conducted by the Council in 2016 indicate Neopentyl Glycol
Diethylhexanoate had the highest reported maximum concentration of use; it is used at up to 57% (face and neck products andbody and hand products).24 Neopentyl Glycol Dicaprate had the next highest reported maximum concentration of use in a leave-on
formulation; it is used at up to 40% (in lipsticks).
In 2001, Glycol Distearate was reported to be used at up to 9% in rinse-off products (non-coloring hair products) and at
up to 6% in leave-on products (body and hand products); in 2016, the maximum concentrations of use for rinse-off and leave-on
formulations were reported to have increased to 10% (non-coloring hair products) and 13.1% (products used around the eye),respectively.2,4,24 In 2009, Neopentyl Glycol Diisononanoate was reported to be used at up to 1% in rinse-off products (skincleansing products); in 2016, the maximum concentrations of use have increased to 1.3% in leave-on products (body and handproducts) and 5% in rinse-off products (skin cleansing products). There were no reported maximum concentrations of use for
Neopentyl Glycol Dicaprylate/Dipelargonate/ Dicaprate in 2009 or 2016.
In some cases, no uses were reported in the VCRP, but concentration of use data were reported in the industry survey.
For example, Glycol Diethylhexanoate had no reported uses in the VCRP, but a maximum use concentration in a foundation (5%)
was provided in the industry survey. Therefore, it should be presumed there is at least one use in every category for which aconcentration is reported.
The ingredients not in use according to 2017 VCRP data and the Council survey are listed in Table 7.
Several of the monoalkylglycol dialkyl acid esters are reported to be used in products applied near the eye (e.g.,
Neopentyl Glycol Dicaprate is used at the highest reported concentration at up to 50% in eye makeup removers). Several of these
ingredients are reported to be used in products (lipsticks) that may be ingested and come in contact with mucus membranes (e.g.,
Neopentyl Glycol Dicaprate is used at the highest reported concentration at up to 40%). According to VCRP data, Glycol
Distearate, Neopentyl Glycol Dicaprylate/Dicaprate and Neopentyl Glycol Diheptanoate are reported to be used in baby products;
industry only reported a concentration of use for Neopentyl Glycol Diheptanoate (up to 2.2% in the category of baby lotions, oils
and creams).
Additionally, some of the monoalkylglycol dialkyl acid esters are used in cosmetic sprays and could possibly be inhaled.
For example, Neopentyl Glycol Diheptanoate was reported to be used in a pump hair spray at up to 19.5%. In practice, 95% to
99% of the droplets/particles released from cosmetic sprays have aerodynamic equivalent diameters > 10 µm, with propellant
sprays yielding a greater fraction of droplets/particles below 10 µm compared with pump sprays.25-29 Therefore, most
droplets/particles incidentally inhaled from cosmetic sprays would be deposited in the nasopharyngeal and bronchial regions andwould not be respirable (i.e., they would not enter the lungs) to any appreciable amount. 25,27 Neopentyl Glycol Dicaprate isreported to be used in spray deodorants at up to 4%. There is some evidence indicating that deodorant spray products can release
substantially larger fractions of particulates having aerodynamic equivalent diameters in the range considered to be respirable. 25
However, the information is not sufficient to determine whether significantly greater lung exposures result from the use ofdeodorant sprays, compared to other cosmetic sprays. Neopentyl Glycol Dicaprate was reported to be used in face powders at up
to 16.8%. Conservative estimates of inhalation exposures to respirable particles during the use of loose-powder cosmetic products
are 400- to 1000-fold less than protective regulatory guidance limits for inert airborne respirable particles in the workplace.30
None of the monoalkylglycol dialkyl acid esters recited in this report are restricted from use in any way under the rules
governing cosmetic products in the European Union.31
Non-Cosmetic
Trimethyl Pentanyl Diisobutyrate is a secondary plasticizer, used in combination with other plasticizers, and is used in
products like weather stripping, furniture, wall paper, vinyl flooring, sporting goods, traffic cones, vinyl gloves, inks, water-based
paints, and toys.32
Relevant regulations in the Code of Federal Regulations that indicate how Trimethyl Pentanyl Diisobutyrate, Glycol
Distearate, and Glycol Ditallowate may be used in foods or food packaging are provided in Table 8.
The Australian National Industrial Chemicals Notification and Assessment Scheme (NICNAS) rates Trimethyl Pentanyl
Diisobutyrate as Tier 1.33 Chemicals identified based on the Tier I assessment do not pose an unreasonable risk to workers, publichealth, and/or the environment.
TOXICOKINETICS STUDIES
Absorption, Distribution, Metabolism, and Excretion (ADME)
AnimalORAL EXPOSURE
Trimethyl Pentanyl Diisobutyrate
In an oral metabolic fate and disposition study of radio-labeled 3-[14C]-Trimethyl Pentanyl Diisobutyrate, the test
substance was administered in corn oil to male Sprague-Dawley rats (n = 3) by gavage at a dosage of approximately 250 mg/kg.7,34
An additional set of rats was administered approximately 186.7 mg/kg of radio-labeled 2,2,4-trimethyl-1,3-pentanediol (3-[14C]TMPD), a potential metabolite of Trimethyl Pentanyl Diisobutyrate. The rats were killed and examined on days 8, 15, and 22
post-dosing. Trimethyl Pentanyl Diisobutyrate was rapidly absorbed and excreted, with renal excretion accounting for 47% to
72% of the dose within 5 to 10 days of dosing; the greatest portion of the urinary radioactivity was eliminated in the first 72 h.
Radioactivity in the feces accounted for 14% to 31% of the dose; fecal elimination was virtually complete by 7 days after dosing.
Measurements of radioactivity in expired CO2 did not differ from controls. Excretions accounted for 95% to 99% of theadministered dose. About half of the urinary radioactivity was identified as 3-[14C]-TMPD or its metabolites. Less than 1% of theadministered radioactivity was retained in the tissues and carcass. In the rats administered 3-[14C]-TMPD, urinary excretionaccounted for 94% of the dose with 93% being excreted within the first 48 h. Expired air contained no detectable [14C]-CO2 in
excess of background, accounting for less than 0.01% of the dose. The feces accounted for 2.4% of the dose, with most of the
fecal radioactivity being excreted within 48 h of dosing. Four major urinary metabolites were identified for Trimethyl Pentanyl
Diisobutyrate: 75% of the dose was present as an O-glucuronide of 3-[14C]-TMPD, approximately 1.5% was excreted unchanged,
approximately 7% was present as 2,2,4-trimethyl-3-hydroxyvaleric acid and its glucuronides, and < 4% was present as a further
breakdown product, 2-methylmalonic acid.
In a similar oral metabolic fate and disposition study of radio-labeled Trimethyl Pentanyl Diisobutyrate (236, 250, 283,
350, or 895 mg/kg; as diisobutyrate ester of 3-[14C]-2,2,4-trimethyl-1,3-pentanediol), the test substance was administered toSprague-Dawley rats (n = 5/group) by gavage.34 Urine, feces, and cage washes were collected every 24 h. Air samples wereanalyzed for [14C]. One rat was killed and necropsied on Day 8 after administration, two on Day 14, and one on Day 22.
Trimethyl Pentanyl Diisobutyrate was rapidly absorbed and excreted, with renal excretion accounting for 47% to 72% of the dose
within 5 to 10 days of dosing; the greatest portion of the urinary radioactivity was eliminated in the first 72 h. Radioactivity in thefeces accounted for 14% to 31% of the dose; fecal elimination was virtually complete by 7 days after dosing with the majority
isolated after 48 h. No radio-labeled CO2 was detected. Total excretion was 95% to 99% of the dose. The majority of therecovered Trimethyl Pentanyl Diisobutyrate was in the form of metabolites. The amount of residual radioactivity in the tissues
was similar to controls.
Rats (strain and n not specified) were orally administered unlabeled Trimethyl Pentanyl Diisobutyrate (475 mg/kg) andfecal samples were collected and extracted with acetone after 24 h (method of administration not specified). 35 Analysis of theextract showed that 8% to 36% of the dose remained as Trimethyl Pentanyl Diisobutyrate, 18% to 27% was the monoester, andtrace amounts of TMPD were detected. In urine, Trimethyl Pentanyl Diisobutyrate, TMPD, the monoester of TMPD, andconjugates of TMPD and 2,2,4-trimethyl-3-hydroxyvaleric acid were detected. Concentrations were not quantified.
Rats (strain and n not specified) were orally administered unlabeled Trimethyl Pentanyl Diisobutyrate (196 or 208
mg/kg).35 At 48 h after dosing, the major urinary metabolite was the O-glucuronide of TMPD (72% to 73% of the dose). Other
compounds detected in the urine were the sulfate (6.4% to 6.5%) and free forms of TMPD (1% to 1.7%), and free 2,2,4-trimethyl3-hydroxyvaleric acid (3%) and its glucuronide (4.3% to 4.4%).

TOXICOLOGICAL STUDIES
Acute Dose Toxicity
DermalNeopentyl Glycol Diisononanoate
The acute dermal toxicity of undiluted [Neopentyl Glycol Diisononanoate] was evaluated using 10 SD CD strain rats (5males and 5 females).4 A dose of 2000 mg/kg body was applied…. None of the animals died and there were no signs of systemic
toxicity or dermal irritation. Necropsy findings were not indicative of any abnormalities and an LD50 of > 2000 mg/kg wasreported.
Acute dermal toxicity studies are summarized in Table 9.
The dermal LD50 of Trimethyl Pentanyl Diisobutyrate was reported to be > 20 mL/kg in guinea pigs and > 2000 mg/kg in
rabbits.7,18,34 Clinical signs were: instances of diarrhea, few feces, and soiling of the anogenital area. Glycol Distearate was nottoxic to rabbits at 100%.5
Oral
Neopentyl Glycol Diisononanoate
The acute oral toxicity of undiluted [Neopentyl Glycol Diisononanoate] was evaluated using groups of 4 SD CD rats.4
One group was dosed orally with 300 mg/kg and the remaining 2 groups were dosed with 2000 mg/kg. None of the animals died,and there were no signs of systemic toxicity in any of the 3 groups. Necropsy did not reveal any abnormal findings and an LD50 of> 2000 mg/kg body weight was reported.
Glycol Distearate
Glycol Distearate [has] been tested in [four] studies for acute oral toxicity in rats….3 During the various studies, dosesof 13 or more g/kg body weight [13,000 mg/kg] in corn oil produced effects which included diarrhea, wet oily coats, and nasal
hemorrhage; the symptoms appeared within four days following administration, but disappeared within the next six days. No
animals were dosed with high levels of corn oil alone. One study on Glycol Distearate reported that at the 14-day gross autopsy[necropsy], the stomach contained residues which appeared to be the test material.
Acute oral toxicity studies are summarized in Table 9.
The oral LD50 of Trimethyl Pentanyl Diisobutyrate was reported to be > 2000 mg/kg in rats.7,18,34 Clinical signs included
moderate weakness and some vasodilatation. No clinical abnormalities were observed in mice administered up to 6400 mg/kg bygavage.7,18,34 The oral LD50 of Diethylpentanediol Dineopentanoate was estimated to be ≥ 2500 mg/kg in rats.16,36 The oral LD50
of Glycol Distearate for mice was reported to be > 5000 mg/kg.5,37 The oral LD50 of Neopentyl Glycol Dicaprate was reported to
be > 2000 mg/kg in rats.17 The oral LD50 of Neopentyl Glycol Diethylhexanoate was reported to be > 2000 mg/kg in rats and >1880 mg/kg in mice.9 No mortalities or clinical signs of toxicity were observed when rats were orally administered a single doseof Neopentyl Glycol Diheptanoate (2000 mg/kg).8
Inhalation
Acute inhalation toxicity studies are summarized in Table 9.
In rats, the lowest lethal concentration (LClo) of Trimethyl Pentanyl Diisobutyrate was reported to be > 0.12 mg/L in one
4-h inhalation toxicity test and 5.30 mg/L in another. 7,18,34 The acute inhalation LC50 of Neopentyl Glycol Diheptanoate wasreported to be > 5.22 mg/L in rats exposed to the test substance for 4 h; clinical signs included hunched posture, increased
respiratory rate, and piloerection. 6,8
Short-Term Toxicity Studies
DermalGlycol Distearate
Two formulations [containing Glycol Distearate] were tested for 28 days.3 The concentration of Glycol Distearate
ranged from 0.05% to 0.5%. Following complete gross and microscopic examination, including hematology, there was noevidence of systemic toxic effects.
A separate but similar 28-day study reported on two formulations containing Glycol Distearate at a concentration in therange of 0.05-0.4%. … The report noted no “gross necropsy or microscopic alterations” in the tissue related to the test.
A shampoo containing 1-3% Glycol Distearate was applied at concentrations of 0.05% and 0.3% to 10 animals [rabbits](five male and five female) at each concentration. After four weeks, there were no systemic effects or deaths resulting from theapplication of the test compound….

Oral
Trimethyl Pentanyl Diisobutyrate
In a preliminary combined repeated dose/reproductive and developmental toxicity study, male and female SpragueDawley rats (n not specified) were exposed by gavage to Trimethyl Pentanyl Diisobutyrate (0, 500, 750, or 1000 mg/kg/day; 0.5
mL/100g body weight) for 2 weeks.7,34 There were increases in the liver weights of both sexes in the 500, 750, and 1000
mg/kg/day groups and in the kidney and adrenal gland weights of both sexes in the 750 and 1000 mg/kg/day groups.
In three feeding experiments conducted concurrently, Trimethyl Pentanyl Diisobutyrate (0.0, 0.1% and 1.0%) was
administered to albino Holtzman rats (n = 10/sex/group) for 51 to 99 days.7 Experiment 1: three groups were given diets
containing Trimethyl Pentanyl Diisobutyrate (0, 0.1% and 1.0%) together with 5.0% corn oil for 51 days; these rats were killed
and necropsied without further treatment. Experiment 2: three groups were given diets containing Trimethyl Pentanyl
Diisobutyrate (0, 0.1% and 1.0%) for 99 days [See Subchronic Toxicity Studies.]. Experiment 3: four groups, with the first twoof the groups fed diets containing Trimethyl Pentanyl Diisobutyrate (0.1% and 1.0%) for 52 days, followed by a 47-day recovery
period; the next two groups were given the control diet for 52 days, followed by 47 days in which the rats were fed diets
containing Trimethyl Pentanyl Diisobutyrate (0.1% and 1.0%). The control group from Experiment 2 was used as a control groupfor Experiment 3.
There were no test-substance related mortalities, and all rats exhibited normal appearance and behavior throughout the
study. Feed consumption and utilization were not affected. In Experiment 1, the minimal reduction (< 10%) in body weight gainin the groups administered Trimethyl Pentanyl Diisobutyrate at 1.0% was not statistically significantly different compared with
controls. Liver weights, relative to body weight, were slightly increased in rats consuming all of the 1.0% Trimethyl Pentanyl
Diisobutyrate diets, but much of the increase was attributed to the slightly lower body weights of the treated rats. Relative kidneyweights were increased only for rats on the 52-day feeding regimen, and the increase was considered to have no toxicologicalsignificance. No biologically significant differences were observed among groups in hematology or clinical chemistry
determinations. No morphologic evidence of toxicity was observed in any of the rats at necropsy or on microscopic examinationof tissues from multiple organ systems. The authors considered 1.0% Trimethyl Pentanyl Diisobutyrate administered in the diet tobe the no-observed-adverse-effect-level (NOAEL) in both male and female rats under all conditions in this study.
In the livers of the male and female rats fed 1.0% Trimethyl Pentanyl Diisobutyrate in the diet for 51 days, there was anincrease in p-nitroanisole demethylase, uridine phosphorylase (UDP)-aminophenol, and UDP-bilirubin glucuronyl transferase
activities, while glucose-6-phosphatase activity remained at control levels. When both sexes were treated with 1.0% Trimethyl
Pentanyl Diisobutyrate in the diet for 52 days and then returned to the control diet for 47 days, p-nitroanisole demethylase andbilirubin glucuronyl transferase activities returned to control levels. It was concluded that the repeated exposure to high doses of
Trimethyl Pentanyl Diisobutyrate caused reversible adaptive changes in the livers of male and female rats. Increases in enzymatic
activity observed at high oral doses were reversed and returned to control levels when Trimethyl Pentanyl Diisobutyrate wasremoved from the diet.7
In a combined repeated dose and reproductive/developmental toxicity study, Trimethyl Pentanyl Diisobutyrate (0, 30, 150
and 750 mg/kg/day in corn oil) was administered to Sprague-Dawley rats (n = 12/sex) by gavage for 44 (males) or 40 to 53(females) consecutive days.7,18,34 The control group received corn oil. [See the Developmental and Reproductive Toxicity section
for results related to reproduction.] All rats survived and there were no treatment-related clinical signs. Slight decreases in bodyweight gain were observed in the 750 mg/kg/day males, but no changes in feed consumption were identified. Slight increases in
feed consumption were observed in females, but the relationship to the test substance was not clear. Hematology and serum
clinical chemistry parameters, evaluated in the males, showed no hematological effects. Serum clinical chemistry changes(including increased serum protein, creatinine, and bilirubin) in the 150 and 750 mg/kg/day males suggested an effect on the liverand kidneys. Other serum chemistry changes in males of one or more groups included increased albumin, calcium, and inorganic
phosphorus, and decreased serum glutamic oxaloacetic transaminase (SGOT), glutamic pyruvic transaminase (SGPT), chloride,
and gamma-glutamyl transpeptidase. These latter findings were not considered to be suggestive of a toxic effect on any particularorgan system. Organ weight differences that were considered to be related to the test substance included increased relative liver
weights in 150 and 750 mg/kg/day males, increased absolute liver weights in 750 mg/kg/day males, increased absolute and relative
kidney weights in 150 and 750 mg/kg/day males, and increased absolute and relative liver weights in 750 mg/kg/day females.
Histopathological examination revealed necrosis of the proximal tubules, dilatation of distal tubules, and fibrosis in the kidneys
and centrilobular swelling of hepatocytes in the livers of males in the 750 mg/kg/day group. Basophilic tubules and hyaline
dilatation were present in kidneys of males from all dose groups, were enhanced in a dose-dependent manner in the 150 and 750
mg/kg/day groups, and were considered related to the test substance. The NOAEL for repeat oral administration of Trimethyl
Pentanyl Diisobutyrate under the conditions of this study was reported to be 30 mg/kg/day for males and 150 mg/kg/day forfemales.
Subchronic Toxicity Studies
DermalGlycol Distearate
Two formulations [containing Glycol Distearate] were tested [on rats] for 91 days.3 The concentration of Glycol
Distearate applied to the animals ranged from 0.05% to 0.5%. No evidence of treatment-induced systemic effects was observed.

Oral
Trimethyl Pentanyl Diisobutyrate
In a feeding study, CD[Crl:CD(SD)] rats (n = 20/sex) were exposed to Trimethyl Pentanyl Diisobutyrate (0, 30, 150 or
750 mg/kg/day) in feed for 90 days.7,34 The rats were then killed and necropsied. There were no test substance-related mortalities,
clinical signs, or neurobehavioral abnormalities. In the high-dose male group, kidney weights were increased along with anincreased presence of hyaline droplets and an increased incidence of chronic progressive nephropathy. Other observed effects thatwere not considered to be adverse included: hyaline droplets in all groups of treated males, minimal decreases in body weight
gain, and clinical chemistries indicative of a possible effect on the liver in both high-dose males and females (these were not foundto be correlated with microscopic examination). In male rats, the lowest-observed-effect-level (LOEL) was reported to be 750
mg/kg/day, and the NOAEL was reported to be 150 mg/kg/day. The NOAEL in female rats was reported to be 750 mg/kg/day.
In three feeding experiments conducted concurrently (described above in Short-Term Toxicity Studies, Oral), Trimethyl
Pentanyl Diisobutyrate (0.0, 0.1% and 1.0%) was administered to albino Holtzman rats (n = 10/sex/group) for up to 99 days.7 In
the subchronic portion of the experiment, three groups were administered diets containing Trimethyl Pentanyl Diisobutyrate (0,0.1% and 1.0%) for 99 days.
There were no test substance-related mortalities, and all rats exhibited normal appearance and behavior throughout the
study. Feed consumption and utilization were not affected. The reduction (< 10%) in growth in the groups administered
Trimethyl Pentanyl Diisobutyrate at 1.0% was not statistically significant. Liver weights, relative to body weights, were slightly
increased in animals consuming the 1.0% diet immediately before the end of the experiment, but much of the increase wasattributed to the rats’ slightly lower body weights. No biologically-significant differences were observed among groups inhematology or clinical chemistry determinations. No morphologic evidence of toxicity was observed in any of the rats at necropsy
or on microscopic examination of tissues from multiple organ systems. Analysis of the livers showed that when Trimethyl
Pentanyl Diisobutyrate (0.1% and 1%) was fed to both sexes for 99 days, p-nitroanisole demethylase activity increased for both
sexes at the high dose, while bilirubin glucuronyl transferase activity was elevated only in high-dose females. The authors
considered 1.0% Trimethyl Pentanyl Diisobutyrate administered in the diet to be the NOAEL in both male and female rats under
all conditions in this study.7
In a feeding study, albino Holtzman rats (n = 10/sex) were given Trimethyl Pentanyl Diisobutyrate (0.1% and 1.0% infeed) for 102 days.7,34 The average estimated dosage rates over 100 days for the low-dose group was 75.5 and 83.5 mg/kg/day formales and females, respectively, and 772 and 858.5 mg/kg/day for the high-dose group, respectively. The rats were killed andnecropsied on day 103. There were no test-substance related mortalities; one female rat was euthanized on Day 55 because ofweight loss and signs of a respiratory infection. Rats in all groups demonstrated normal growth, and there were no differences in
feed consumption or utilization. The rats also exhibited normal appearance and behavior throughout the study. No differenceswere observed among groups in hematology results. Slightly increased liver weights were observed in the 1.0% group of males
relative to the control group, but differences were considered likely to be adaptive by the authors and not representative of a toxic
effect. Kidney weights were decreased relative to controls in both the 0.1% and 1.0% groups of females, but the effect was
attributed to unusually high kidney weights in the control group. No morphologic evidence of toxicity was found in any of theanimals during gross necropsy or upon microscopic examination of a number of tissues from multiple organ systems. The authors
considered 1.0% in the diet to be a NOAEL in both male and female rats.
In a feeding study, Beagle dogs (n = 4/sex) were administered Trimethyl Pentanyl Diisobutyrate (0, 0.1%, 0.35%, or 1.0%
in feed) for 90 days.7,34 All dogs survived, neurological reflexes were unimpaired, and no abnormal clinical signs or behavioral
abnormalities were observed at any time. Weight gain and feed consumption were unaffected by treatment, and there were noabnormalities noted in a series of hematology, clinical chemistry, or urinalysis parameters measured during and at the end of thestudy. Slight alterations noted in some organ weights were within normal limits and were not considered toxicologicallyimportant. Gross and microscopic pathology findings were unremarkable. The NOAEL for both male and female dogs wasreported to be 1.0%.
DEVELOPMENTAL AND REPRODUCTIVE TOXICITY (DART) STUDIES
Oral Exposure
Trimethyl Pentanyl Diisobutyrate
In a reproductive/developmental toxicity study, conducted in accordance with Organization for Economic Co-operation
Guidelines (OECD GL) 421 (Reproduction/Developmental Toxicity Screening Test), Trimethyl Pentanyl Diisobutyrate (0, 1.5,
4.5, or 15.0 mg/g feed) was administered to Sprague-Dawley (Crl:CD(SD)IGS BR) rats (n = 12/sex) ad libitum in the diet.7,34 The
female rats were treated over 4 phases of the study for a total of 40 to 51 days: premating (14 days), mating (1 to 8 days),gestation (21 to 23 days), and early lactation (4 to 5 days). All male rats were treated from the beginning of the premating period
to the final treatment of the female rats for a total of 51 days. Females that delivered a litter, and their offspring, were killed ondays 4 or 5 postpartum. Females that had evidence of mating but did not deliver were killed on gestation day (GD) 23. The final
calculated dosage rate was approximately 0, 91, 276 and 905 mg/kg/day for male rats and 0, 120, 359 and 1135 mg/kg/day forfemale rats, respectively.
For the females in the high-dose group, there was a decrease in total number of implants, number of live pups on postnatal

day 4, and litter weights on postnatal days 0 and 4. There were no adverse effects on reproductive performance, fertility index,
fecundity index, precoital interval, gestation duration, percent pup survival, pre- and post-implantation loss, live and dead pups on
postnatal day 0, percentage of male and female pups, mean pup body weight and pup body weight change, or reproductive organ
weights in the adults. Reductions in body weight and feed consumption values in the high-dose group adults were transient andwere not considered toxicologically significant. For the males, there were minimal reductions in sperm counts observed in thetestes and/or epididymis of treated male rats, but there were no treatment-related gross or microscopic lesions in any groups and noadverse effect on reproductive performance. The NOAEL for developmental or reproductive toxicity was reported to be 4.5 mg/g
feed in the diet, which was equivalent to 276 mg/kg/day for males and 359 mg/kg/day for females.7,34
In a combined repeated dose and reproductive/developmental toxicity study, Trimethyl Pentanyl Diisobutyrate (0, 30, 150
and 750 mg/kg/day in corn oil) was administered to Sprague-Dawley rats (n = 12/sex) by oral gavage for 44 (males) or 40 to 53(females) days beginning prior to mating.7,18,34 [See the Subchronic Toxicity Studies section for results related to repeated dose
toxicity.] The control group received corn oil. All rats survived and there were no treatment-related clinical signs. One mating
pair in the mid- and high-dose groups failed to copulate. Slight increases in feed consumption were observed in females during the
gestation period only, but there was no clear relationship to the test substance. There were no gross or microscopic effects
observed on any reproductive organ in either sex. All pregnant rats delivered normally and there were no adverse effects on any
reproductive parameters observed. A decrease in estrous cycle length in the high-dose female group, compared to controls, wasattributed to a larger than normal number of rats in the high-dose group with shorter cycle lengths; there were no differences whendata for this study were compared to historical control data (mean estrous cycle 4.0 to 4.4 days for the previous 3 years). The
NOAEL for reproductive toxicity of Trimethyl Pentanyl Diisobutyrate under the conditions of this study was reported to be 750
mg/kg/day for male and female rats. There were no treatment-related effects observed in the external examination of pups born,mortalities were similar across the groups, and pup body weights increased until sacrifice on day 4 of lactation. Necropsy ofstillborn pups, dead pups, and pups surviving until day 4 of lactation did not demonstrate any treatment-related effects. The
NOAEL for embryo/fetal toxicity was reported to be 750 mg/kg/day.
In a study conducted in accordance with OECD TG 414 (Prenatal Developmental Toxicity Study), pregnant SpragueDawley Crl:CD(SD) rats (n = 25) were given Trimethyl Pentanyl Diisobutyrate (0, 0.15%, 0.45%, or 1.50%) in feed on GD 6
through 20.7 The dosage rates were calculated to be 0, 118, 343 and 1077 mg/kg/day, respectively. There were no mortalities
among the dams. One female in each test group was not gravid. Net body weight gain in the high-dose group was lower than thecontrol group. There were no macroscopic test substance-related observations reported. There were no adverse effects on thenumber of corpora lutea, implantation sites, viable fetuses or early/late resorptions observed. There were no dead fetuses in anygroup. The mean male, female, and combined fetal weights in the high-dose group were lower than those of the control group.
However, these weights were within the laboratory’s historical control data range for these study types. Because of lower bodyweight gains and/or body weight loss, the NOAEL for maternal toxicity was reported to be 343 mg/kg/day.
There were no test substance-related external and visceral malformations or developmental variations observed. Whenthe total malformations and developmental variations were evaluated on a proportional basis, no differences from the control groupwere noted. Test substance-related skeletal malformations (bent scapula) were noted in one fetus from the mid-dose group and in
4 fetuses (3 litters) from the low-dose group. There was a higher mean litter proportion of the skeletal developmental variation insternebra(e) nos. 5 and/or 6 (unossified) was observed in the high-dose group. The litter proportion of bent rib(s) was consideredby the authors to represent skeletal variations rather than malformations. Based on lower mean fetal body weights at 1.50% (1077
mg/kg/day), an exposure level of 0.45% (343 mg/kg/day) was reported to be the NOAEL for embryo/fetal development for
Trimethyl Pentanyl Diisobutyrate in the diet of rats.7
Glycol Distearate
In a study conducted in accordance with OECD TG 414 (Prenatal Developmental Toxicity Study) and EU Method B.31
(Prenatal Developmental Toxicity Study), Glycol Distearate (0, 100, 300, or 900 mg/kg/day; as a C16-18 mixture) was
administered by gavage to pregnant Sprague-Dawley CD rats (n = 24) on GD 6 through 15.5 The control group received 0.5%
sodium carboxymethylcellulose and 0.25% Cremophor® in distilled water. The dams were killed and necropsied on GD 20. The
pups were examined for litter size and weights, viability, sex ratio, and grossly visible abnormalities. The pups were also
examined for external, visceral, and skeletal abnormalities. There were no mortalities during the study period. No Glycol
Distearate-related symptoms were observed in the treatment groups when compared to the control group. Body weights, bodyweight gains, and corrected body weights were within expected ranges. There were no differences observed among the mean
reproduction data of the test groups compared to the control group. Necropsies revealed no macroscopic changes in the dams ofthe treatment groups. No test substance-related effects were observed in the treatment groups. Pre-implantation loss, postimplantation loss, mean number of resorptions, embryonic deaths, and total fetuses were not affected by treatment. No treatmentrelated fetal abnormalities were found at necropsy. The NOAEL for maternal toxicity was reported to be > 900 mg/kg/day. The
teratogenicity NOAEL was reported to be > 900 mg/kg/day.

GENOTOXICITY STUDIESIn Vitro
Neopentyl Glycol Diisononanoate
The Ames test was…used to evaluate the mutagenicity of [Neopentyl Glycol Diisononanoate] (in acetone; doses up to
5000 µg/plate) in the Salmonella typhimurium strains…[TA1535, TA1537, TA98, TA100, and TA102].4 Results were negativewith and without metabolic activation.
In vitro genotoxicity studies of monoalkylglycol dialkyl acid esters are summarized in Table 10.
Trimethyl Pentanyl Diisobutyrate was not mutagenic in mammalian cell mutation assays (up to 2000 µg/mL), Ames tests
using Salmonella typhimurium and Escherichia coli (up to 5000 µg/plate), and a mammalian chromosome aberration test (up to
1000 µg/mL).5,7,18,34 Diethylpentanediol Dineopentanoate was not mutagenic in an Ames test up to 5000 µg/plate.16,36 Glycol
Distearate was not mutagenic in Ames tests up to 5000 µg/plate.5,37 Neopentyl Glycol Dicaprate was not mutagenic at up to 5000
µg/plate in an Ames test.17 Neopentyl Glycol Diethylhexanoate was not mutagenic in a mammalian cell mutation assay (up to 600µg/mL), an Ames test (up to 5000 µg/plate), and mammalian chromosome aberration tests (up to 100 µg/mL).9 Propanediol
Dicaprylate/Caprate was not mutagenic in an Ames test at 0.005 mL/plate. 38
CARCINOGENICITY STUDIES
Carcinogenicity data were not found in the published literature and no unpublished data were provided.
OTHER RELEVANT STUDIES
Endocrine Activity
Trimethyl Pentanyl Diisobutyrate (0.001, 0.01, 0.1 or 1 mM) was tested for endocrine receptor agonist and antagonist
activity in multiple cell lines.39 The cells were exposed for 24 to 48 h (depending of the cell line). The cells tested were: atransfected estrogen receptor (ER) cell line (MCF7-ER) used to assess the potential for interactions with a human estrogen receptor(hER2); and cell lines, tailored for luciferase illumination with gene expression, containing the human peroxisome proliferatoractivated receptor (hPPARy), human thyroid ß receptor (hTR ß), human estrogen receptor (hER1), and mouse aryl hydrocarbon
receptor (mAhR). The results were positive for hER1 agonist activity with > 50% response (response exceeded 50% of the
maximal standard induction or response was clearly dose related). Positive results were also observed for hER2 agonist activity inthe transfected MCF7-ER cells, with a >10% response. The results were negative for mAhR, hPPARy, and hTR ß agonist activity
in the activated luciferase cell lines. All cell lines were negative for endocrine receptor antagonism.
IRRITATION AND SENSITIZATION STUDIES
Irritation
Glycol Distearate
Two formulations [containing Glycol Distearate] were tested for 28 days [in rabbits].3 The concentration of Glycol
Distearate ranged from 0.05% to 0.5%. According to the report, the skin irritation that was caused by the surfactant ranged fromslight to severe.
A separate but similar 28-day study reported on two formulations containing Glycol Distearate at a concentration in therange of 0.05-0.4%. Investigators associated both formulations with the development of primary irritation. The report noted no“gross necropsy or microscopic alterations” in the tissue related to the test.
A shampoo containing 1-3% Glycol Distearate was applied at concentrations of 0.05% and 0.3% to 10 animals [rabbits](five male and five female) at each concentration. Slight transient skin irritation was observed in one rabbit at the 0.05% level
and in most animals at the 0.3% level.
Draize type procedures were used to test…Glycol Distearate for primary irritation of albino rabbit skin; the ingredientswere found to be nonirritating to slightly irritating…. In addition, when … Glycol Distearate [was] tested for corrosivity
according to the procedures of the U.S. Department of Transportation, [it was] found to be noncorrosive to rabbit skin.
A shampoo formulation containing Glycol Distearate was tested in three separate experiments on groups containing six
rabbits each (three males and three females). A fourth experiment involved similar procedures, but had five male and five female
rabbits per group. The material was applied daily, five days per week to intact or abraded skin equivalent to 10% of the skin areaof the back; this remained on the animal for seven hours each day before washing. [The shampoo was practically non-irritating.]
Two formulations were tested for 91 days. The concentration of Glycol Distearate applied to the animals [rabbits]
ranged from 0.05% to 0.5%. The skin irritation that resulted was reported to be similar to that produced by other forms ofshampoo.
Neopentyl Glycol Diisononanoate
Predictive human [n = 52] skin irritation tests results for undiluted … [Neopentyl Glycol Diisononanoate] were
negative….4

Animal
Irritation assays are summarized in Table 11.
Trimethyl Pentanyl Diisobutyrate was not irritating to guinea pigs at 100% and was not, or was mildly, irritating to
rabbits at 100%.7,34 Diethylpentanediol Dineopentanoate (neat) was a non-irritant to rabbit skin.16,36 Glycol Distearate was not
irritating to rabbits and guinea pigs at up to 100%.5,37 Neopentyl Glycol Diethylhexanoate (concentration not specified, testedneat) was not irritating to the skin of rabbits.9 There were no signs of erythema or edema observed when Neopentyl Glycol
Diheptanoate was administered to rabbits at 100%.8
Human
NEOPENTYL GLYCOL DICAPRATE
In a human patch test (n = 21 females, 2 males), Neopentyl Glycol Dicaprate (neat) was administered using Finn
chambers for 30 to 60 min and 24-h.17 There were no signs of irritation in any subject at any time period.
DIETHYLPENTANEDIOL DINEOPENTANOATEIn a human patch test (n = 45), Diethylpentanediol Dineopentanoate (neat; 1 mg) was dermally administered in Finn
chambers, under occlusion, for 24 h.16,36 The test sites were examined at 1 and 24 h after removal. No reactions were observed inany of the subjects. The test substance was a non-irritant.
Sensitization
Glycol Distearate
Sensitization studies were conducted in guinea pigs on Glycol Stearate and Glycol Distearate.3 Each ingredient was
injected intradermally into the shaven back of each of two male, white guinea pigs. Following an initial 0.05 mL injection, 0.1 mL
injections were given three times a week for a total of ten injections. Two weeks later a challenge injection was given, andreadings were taken 24 hours later. Both ingredients were found to be nonsensitizing [at 0.1%].
A repeated insult patch test with 50% w/v Glycol Distearate in mineral oil was performed on 125 subjects ranging in age
from 19 to 76 years.3 Patches containing 0.25 g of [the] sample were applied for 24 h to the dorsal aspect of the upper arm ofeach individual. Patches were applied to the same site each Monday, Wednesday, and Friday of the three-week induction period.
Each site was scored for irritation a total of nine times. Challenge patches were applied to both arms of each subject 14 days
after the final insult patch; the sites were graded for sensitization reactions after 48 and 96 h. No visible skin changes
characteristic of irritation or sensitization were observed in any subject; all scores were zero.
Neopentyl Glycol Diisononanoate
A maximization test on [Neopentyl Glycol Diisononanoate] was performed ….4 Undiluted test material was applied
during the second induction and challenge phase. Initially, the skin was treated with SLS [sodium laurel sulfate] because topicalinduction with undiluted [Neopentyl Glycol Diisononanoate] did not induce skin irritation in a preliminary experiment. Neopentyl[Glycol Diisononanoate] was classified as a nonsensitizer.
AnimalAnimal sensitization studies are summarized in Table 12.
In two skin sensitization studies, Trimethyl Pentanyl Diisobutyrate at 1% was not sensitizing in guinea pigs.7,34 In aguinea pig maximization test, Diethylpentanediol Dineopentanoate was not sensitizing to albino guinea pigs when injected with
Diethylpentanediol Dineopentanoate at 25% (in paraffin oil with Freund's complete adjuvant), then applied topically at 100%; thechallenge was a topical application at 100%.16,36 Glycol Distearate (100%) was not sensitizing in a Buehler test in Pirbright guinea
pigs.5 In a sensitization assay conducted in accordance with OECD TG 406, Glycol Distearate (concentration not specified,assumed 100%) was not sensitizing to guinea pigs.37 In a test conducted in a manner similar to that described in OECD TG 406,
Neopentyl Glycol Diheptanoate was not sensitizing to Dunkin-Hartley guinea pigs.6,8 The induction phase was conducted using a
concentration of 100% Neopentyl Glycol Diheptanoate and the challenge at 30% in corn oil and 100%.
Human
Summaries of human repeated insult patch tests (HRIPTs) are summarized in Table 13.
Trimethyl Pentanyl Diisobutyrate and Neopentyl Glycol Diethylhexanoate were not sensitizers in multiple HRIPTs at up
to 100%.7,9,34,40,41 Propanediol Dicaprylate/Caprate and Propanediol Dipelargonate were not sensitizers in HRIPTs. 42,43
OCULAR IRRITATION STUDIES
Neopentyl Glycol Diisononanoate
A study evaluating the ocular irritation potential of [Neopentyl Glycol Diisononanoate] in rabbits was conducted…
[Neopentyl Glycol Diisononanoate] (0.1 mL) … was classified as a minimal ocular irritant.4

In Vitro
Neopentyl Glycol Dicaprate (25% in corn oil) was predicted to have practically no irritation potential in a hen’s egg testchorio-allantoic membrane (HET-CAM) assay.17 Propanediol Dicaprylate/Caprate (100%) was tested for potential ocular irritation
using the EpiOcular™ in vitro assay.44 Exposures were for 20 min and 1 and 4 h. The estimated Draize ocular irritation score was
0 and the test substance was classified as non-irritating.
AnimalOcular irritation studies using rabbits are summarized in Table 14.
Trimethyl Pentanyl Diisobutyrate, Glycol Distearate, Neopentyl Glycol Diethylhexanoate, and Neopentyl Glycol
Diheptanoate were not ocular irritants at 100% in rabbits.5,7-9,34 Diethylpentanediol Dineopentanoate (undiluted) was a minimal
ocular irritant in rabbits.16,36
CLINICAL STUDIESRetrospective and Multicenter Studies
Glycol Distearate
Occupational Exposure: Two manufacturers reported that they have been manufacturing Glycol Stearates and Glycol
Distearates for between 20 and 30 years.3 According to both, no employee reported that his or her health might have been
adversely affected by exposure to these compounds. This conclusion was based upon: (a) 30 employees who for 10 years had
potentially been exposed to Glycol Stearate for 1 % of their work time; (b) 70 employees who for 20 years had potentially been
exposed to Glycol Distearate for 20% of their work time; and (c) 50 employees who for 30 years had potentially been exposed to
Glycol Stearate for 5% of their work time. One manufacturer noted that its labor turnover was very low, so that some individuals
had been exposed to the ingredients for many of the years during which they had been produced there.
SUMMARY
This is a safety assessment of 28 monoalkylglycol dialkyl acid esters as used in cosmetics. The Panel has reviewed
related ingredients, moieties, and component parts of these ingredients that have been previously reviewed by CIR. The
ingredients in this report are structurally-related alkyl esters of monoalkyl diols that vary by type of diol and length of the
carboxylic acid residues.
The most common cosmetic function for this group of ingredients is as a skin conditioning agent. Other reported
functions of these ingredients include film former, hair conditioning agent, opacifying agent, plasticizer, slip modifier, solvent,surface modifier, and viscosity increasing agent – nonaqueous.
According to VCRP survey data received in 2017, Glycol Distearate was reported to be used in 1663 formulations, mostly
in hair products (1041 formulations); this is an increase from 28 uses in 2001. Trimethyl Pentanyl Diisobutyrate and Neopentyl
Glycol Diheptanoate are used in 399 (all nail products) and 415 (mostly in skin care products) formulations, respectively. The restof the ingredients with reported uses were used in 102 or fewer formulations. As for the other ingredients that were previously
reviewed by CIR, Neopentyl Glycol Dicaprylate/Dipelargonate/Dicaprate and Neopentyl Glycol Diisononanoate had no uses
reported to the VCRP in 2001 or 2017.
The results of the concentration of use survey conducted by the Council in 2016 indicate Neopentyl Glycol
Diethylhexanoate had the highest reported maximum concentration of use; it is used at up to 57% in the categories of face andneck products and body and hand products. Neopentyl Glycol Dicaprate had the next highest reported maximum concentration ofuse in leave-on formulations; it is used up to 40% in lipsticks. In 2001, Glycol Distearate was reported to be used at up to 9% in
rinse-off products and up to 6% in leave-on products; in 2016, the maximum concentrations of use were reported to have increased
to 10% in hair products and 13.1% in eye liners, respectively.
In rats, orally administered, radio-labeled Trimethyl Pentanyl Diisobutyrate was rapidly absorbed and excreted, with renal
excretion accounting for the majority of the recovered radioactivity. In urine, Trimethyl Pentanyl Diisobutyrate, 3-[14C]-TMPD,
and conjugates of TMPD and 2,2,4-trimethyl-3-hydroxyvaleric acid were detected. No radioactivity was detected in CO2.
The dermal LD50 of Trimethyl Pentanyl Diisobutyrate was reported to be > 20 mL/kg in guinea pigs and > 2000 mg/kg in
rabbits. Clinical signs were: diarrhea, few feces, and soiling of the anogenital area. Glycol Distearate was not toxic to rabbits at
100%.
The oral LD50 for Trimethyl Pentanyl Diisobutyrate was reported to be > 2000 mg/kg in rats. Clinical signs included
moderate weakness and some vasodilatation. No clinical abnormalities were observed in mice administered up to 6400 mg/kg bygavage. The oral LD50 of Diethylpentanediol Dineopentanoate was reported to be ≥ 2500 mg/kg in rats. The oral LD50 for Glycol
Distearate in rats was reported to be > 5000 mg/kg. At 13,000 mg/kg and above, diarrhea, wet oily coats, and nasal hemorrhage
were observed within 4 days after dosing, which resolved Day 10. The oral LD50 for mice was reported to be > 5000 mg/kg. In
another study in rats, there were no mortalities at up to 16,000 mg/kg; at 13,000 mg/kg and above, diarrhea, wet oily coats, andnasal hemorrhage were observed within 4 days after dosing, which resolved Day 10. The oral LD50 of Glycol Distearate wasreported to be > 5000 mg/kg in mice. The oral LD50 of Neopentyl Glycol Diethylhexanoate was reported to be > 2000 mg/kg inrats and > 1880 mg/kg in mice. No mortalities or clinical signs of toxicity were observed when rats were orally administered asingle dose of Neopentyl Glycol Diheptanoate (2000 mg/kg).
In rats, the LClo of Trimethyl Pentanyl Diisobutyrate was reported to be > 0.12 mg/L in one 4-h inhalation toxicity test
and 5.30 mg/L in another. The acute inhalation LC50 of Neopentyl Glycol Diheptanoate was reported to be > 5.22 mg/L in rats;
clinical signs included hunched posture, increased respiratory rate, and piloerection.
Rats orally exposed to Trimethyl Pentanyl Diisobutyrate for 2 weeks showed increases in the liver weights of both sexes
in the 500, 750, and 1000 mg/kg/day groups and in the kidney and adrenal gland weights of both sexes in the 750 and 1000
mg/kg/day groups. The NOAEL was reported to be 1.0% in both male and female rats administered Trimethyl Pentanyl
Diisobutyrate in feed for up to 99 days. The oral NOAEL for Trimethyl Pentanyl Diisobutyrate was reported to be 30 mg/kg/day
for males (44 days) and 150 mg/kg/day for females (40 to 53 days). All rats survived and there were no treatment-related clinicalsigns.
In male rats, the LOEL was reported to be 750 mg/kg/day and the NOAEL was reported to be 150 mg/kg/day for
Trimethyl Pentanyl Diisobutyrate administered in feed for 90 days; the NOAEL in female rats was reported to be 750
mg/kg/day. The NOAEL in both male and female rats was reported to be 1.0% in a feeding study of Trimethyl Pentanyl
Diisobutyrate administered for 102 days. There were no test-substance related mortalities and the rats also exhibited normal
appearance and behavior throughout the study. The NOAEL for both male and female beagles was reported to be 1.0% in afeeding study of Trimethyl Pentanyl Diisobutyrate administered for 90 days. All dogs survived, neurological reflexes were
unimpaired, and no abnormal clinical signs or behavioral abnormalities were observed at any time.
The NOAEL of Trimethyl Pentanyl Diisobutyrate for developmental or reproductive toxicity was reported to be 4.5 mg/g
feed (equivalent to 276 mg/kg/day for males and 359 mg/kg/day for females) in the diet of rats administered from 14 days prior tomating through early lactation. For the females in the high-dose group, there was a decrease in total number of implants, numberof live pups on postnatal day 4, and litter weight on postnatal days 0 and 4. There were no adverse effects on reproductive
performance, fertility index, fecundity index, precoital interval, gestation duration, percent pup survival, pre- and post-implantation
loss, live and dead pups on postnatal day 0; percentage of male and female pups, mean pup body weight and pup body weightchange, or reproductive organ weights in the adults. For the males, there were minimal reductions in sperm counts observed in thetestes and/or epididymides of treated male rats, but there were no treatment-related gross or microscopic lesions in any groups andno adverse effect on reproductive performance.
The NOEL for reproductive toxicity of Trimethyl Pentanyl Diisobutyrate in a combined repeated dose andreproductive/developmental toxicity study was reported to be 750 mg/kg/day for male and female rats. The NOEL for Trimethyl
Pentanyl Diisobutyrate administered throughout pregnancy for embryo/fetal toxicity was reported to be 750 mg/kg/day in rats. All
pregnant rats delivered normally and there were no adverse effects on any reproductive parameters observed. In another study,
due to lower body weight gains and/or body weight loss, the NOAEL for maternal toxicity was reported to be 4.5 mg/g/day
Trimethyl Pentanyl Diisobutyrate in feed (343 mg/kg/day). Based on lower mean fetal body weights at 1.50% (15 mg/g/day; 1077
mg/kg/day), an exposure level of 0.45% (4.5 mg/g/day; 343 mg/kg/day) was reported to be the NOAEL for embryo/fetal
development for Trimethyl Pentanyl Diisobutyrate in the diet of rats.
The NOAEL for the maternal toxicity of Glycol Distearate (as a C16-18 mixture) was reported to be ≥ 900 mg/kg and theteratogenicity NOAEL was reported to be ≥ 900 mg/kg when administered on GD 6 to 15. There were no mortalities during thestudy period. No Glycol Distearate-related symptoms were observed in the treatment groups when compared to the control group.
Trimethyl Pentanyl Diisobutyrate was not mutagenic in mammalian cell mutation assays (up to 2000 µg/mL), Ames tests(up to 5000 µg/plate), and a mammalian chromosome aberration tests (up to 1000 µg/mL). Diethylpentanediol Dineopentanoate
was not mutagenic in an Ames test up to 5000 µg/plate. Glycol Distearate was not mutagenic in Ames tests up to 5000 µg/plate.
Neopentyl Glycol Diethylhexanoate was not mutagenic in a mammalian cell mutation assay (up to 600 µg/mL), an Ames test (upto 5000 µg/plate), and mammalian chromosome aberration tests (up to 100 µg/mL). Neopentyl Glycol Dicaprate was not
mutagenic at up to 5000 µg/plate in an Ames test. Propanediol Dicaprylate/Caprate was not mutagenic in an Ames test at 0.005
mL/plate.
In tests for endocrine receptor agonist and antagonist activity of Trimethyl Pentanyl Diisobutyrate in multiple cell lines,
results were positive for hER1 agonist activity, with a > 50% response, and positive results were observed for hER2 agonist
activity in the transfected MCF7-ER cells, with a > 10% response. The results were negative for mAhR, hPPARy, and hTR ß
agonist activity in luciferase reporter cell lines. All cell lines were negative for endocrine receptor antagonism.
Trimethyl Pentanyl Diisobutyrate was not irritating to guinea pigs at 100% and was not or was mildly irritating to rabbits
at 100%. Diethylpentanediol Dineopentanoate (neat) was a non-irritant to rabbit skin. Glycol Distearate was not irritating to
rabbits and guinea pigs at 100%. Neopentyl Glycol Diethylhexanoate (tested neat) was not irritating to the skin of rabbits. There
were no signs of erythema or edema observed when Neopentyl Glycol Diheptanoate was administered to rabbits at 100%.
In a human patch test, Neopentyl Glycol Dicaprate (neat) was not irritating when administered for up to 24 h. In a humanpatch test, Diethylpentanediol Dineopentanoate (neat) was a dermal non-irritant.
In two skin sensitization studies in guinea pigs, Trimethyl Pentanyl Diisobutyrate was not considered to be a skinsensitizer at 1%. In a guinea pig maximization test, Diethylpentanediol Dineopentanoate was not sensitizing to albino guinea pigs
when injected with Diethylpentanediol Dineopentanoate at 25% (in paraffin oil with Freund's complete adjuvant), then applied
topically at 100%; the challenge was a topical application at 100%. There were no signs of sensitization in a Buehler test of
Glycol Distearate at 100% in guinea pigs. Neopentyl Glycol Diheptanoate at 100% was not sensitizing in guinea pigs whenchallenged at 30% and 100%. In a guinea pig maximization test, Diethylpentanediol Dineopentanoate was a non-sensitizer at
25%.
In three HRIPTs, Trimethyl Pentanyl Diisobutyrate was not sensitizing at 1.0%. In two HRIPTs, Neopentyl Glycol
Diethylhexanoate was not sensitizing at 100%. Propanediol Dicaprylate/Caprate and Propanediol Dipelargonate were notsensitizers in HRIPTs at up to 100%.
Neopentyl Glycol Dicaprate (25% in corn oil) was predicted to have practically no irritation potential in a HET-CAM
assay. Propanediol Dicaprylate/Caprate was not an ocular irritant in an in vitro assay. Trimethyl Pentanyl Diisobutyrate, Glycol
Distearate, Neopentyl Glycol Diethylhexanoate, and Neopentyl Glycol Diheptanoate were not ocular irritants at 100% in rabbits.
Diethylpentanediol Dineopentanoate was a minimal ocular irritant in rabbits.
DISCUSSION
The Panel examined the available data for these 28 monoalkylglycol dialkyl acid ester cosmetic ingredients. Data fromprevious reports on three of these ingredients (e.g., Glycol Distearate, Neopentyl Glycol Dicaprylate/Dipelargonate/Dicaprate, andNeopentyl Glycol Diisononanoate) and from reports on related ingredients, moieties, component parts, and potential hydrolysis
product surrogates of these ingredients, were also examined.
When assessing safety, the Panel noted that Glycol Distearate had a substantial amount of data over multiple end points
and was considered an appropriate representative molecule among these ingredients. The Panel was comfortable using thisingredient for read-across to inform on the safety of the other ingredients, given the molecular weights and log P values.
Additionally, the acute dermal toxicity of the smaller ingredients (i.e., Neopentyl Glycol Diisononanoate and Trimethyl Pentanyl
Diisobutyrate) demonstrated no concerns, and acute oral toxicity at relatively high doses presented little concern. Estimated andexperimental log P values, ranging from 4.91 to 46.27, supported the statements that these ingredients are not likely to penetrate
the skin to any significant amount. Safety was supported by the conclusions in previous safety assessments by CIR on related
ingredients and several of the component parts of many of these ingredients. The Panel was not concerned about the lack ofcarcinogenicity data due to these data profiles (including negative Ames assays) and the lack of structural alerts for any of these
ingredients. The Panel also noted that the reduction in sperm in the reproduction study on Trimethyl Pentanyl Diisobutyrate was
not a significant toxicological result with regards to cosmetic use.
For the ingredient Diethylpentanediol Dineopentanoate, the Panel used the available toxicity data on this ingredient (e.g.,acute oral, genotoxicity, irritation, and sensitization) in combination with toxicity data on one of its potential hydrolysis products,
neopentanoic acid. Since toxicity data on the other potential hydrolysis product, 2,4-diethyl-1,5-pentanediol, were not available,
the Panel used the data on Isopentyldiol and 1,5-Pentanediol, from the CIR report on alkane diols, as surrogates. The Panel was
satisfied that this combination of data were sufficient to come to a conclusion of safety on Diethylpentanediol Dineopentanoate atits current reported maximum concentration of use (1% in rinse-off formulations).
The available impurity data show that the concentrations of potentially problematic source materials for the manufactureof these monoalkylglycol dialkyl acid esters are low or below detection. The component parts of these ingredients are highly
reactive in the context of the synthetic process and are unlikely to survive hydrolysis in the finishing steps of manufacturing.
The Panel acknowledged that some of the monoalkylglycol dialkyl acid esters may be formed from plant-derived
constituents (e.g., Glycol Dipalmate/Palm Kernelate/Olivate/Macadamiate and Glycol Dipalmate/Rapeseedate/Soyate. The Panelthus expressed concern regarding pesticide residues and heavy metal that may be present in botanical ingredients. They stressedthat the cosmetics industry should continue to use the necessary procedures to sufficiently limit amounts of such impurities in an
ingredient before blending them into cosmetic formulations. The Panel also acknowledged that some of the monoalkylglycol
dialkyl acid esters may be formed from animal-derived constituents (e.g., Glycol Ditallowate). The Panel considered the risks
inherent in using animal-derived ingredients, namely the transmission of infectious agents. While tallow may be used in the
manufacture of at least one ingredient in this safety assessment and is clearly animal-derived, the Panel notes that tallow is highly
processed, and tallow derivatives even more so. The Panel agrees with determinations by the FDA that tallow derivatives are notrisk materials for transmission of infectious agents.
There are two ingredients that contain a 2-ethylhexanoic acid residue (i.e., Glycol Diethylhexanoate and Neopentyl
Glycol Diethylhexanoate). If absorbed and metabolized, the resulting metabolite, 2-ethylhexanoic acid, can be a liver andreproductive toxicant. The Panel considered the maximum concentrations at which these ingredients are expected to be used incosmetics. For example, Neopentyl Glycol Diethylhexanoate is reported to be used up to 57% in products with dermal contact andNeopentyl Glycol Diheptanoate is reported to be used in hairsprays that might be inhaled at up to 19.5%. The Panel suggested thatthe process of metabolic conversion results in a time course that allows clearance of 2-ethylhexanoic acid at rates such that levels
cannot attain toxicological significance. Also, the data present no reason to be concerned about toxicity from these ingredients ortheir metabolites at the levels used in cosmetics.
The Panel noted the possible presence of 1,4-dioxane and ethylene oxide impurities in ethylene glycol diester ingredients.
They stressed that the cosmetics industry should continue to use current good manufacturing practices (cGMPs) to limit these
impurities from the ingredients containing ethylene glycol or ethylene glycol esters before blending them into cosmetic
formulations.
The Panel recognizes that there are data gaps regarding use and concentration of some of these ingredients. However, theoverall information available on the types of products in which these ingredients are used, and at what concentrations are in final

formulations, indicates a pattern of use which the Panel considered in assessing safety.
The Panel discussed the issue of incidental inhalation exposure from cologne, toilet waters, perfumes, other fragrance
preparations, pump and aerosol hair sprays, spray body and hand products, and deodorants. These ingredients are reportedly used
at concentrations up to 19.5% in cosmetic products that may be sprayed (Neopentyl Glycol Diheptanoate in a pump hair spray) andup to 16.8% in loose powder products (Neopentyl Glycol Dicaprate in face powders) that may become airborne. Neopentyl Glycol
Dicaprate was reported to be used in spray deodorants at up to 4%. The limited data available from acute inhalation studies
suggest little potential for respiratory effects at relevant doses. The Panel believes that the sizes of a substantial majority of theparticles of these ingredients, as manufactured, are larger than the respirable range and/or aggregate and agglomerate to form muchlarger particles in formulation. Thus, the adverse effects reported using high doses of respirable particles in the inhalation studies
do not indicate risks posed by use in cosmetics. The Panel noted that droplets/particles from cosmetic products would not be
respirable to any appreciable amount. In addition, the Panel considered other data available to characterize the potential formonoalkylglycol dialkyl acid esters to cause systemic toxicity, irritation, sensitization, reproductive and developmental toxicity,and genotoxicity. Coupled with the small actual exposure in the breathing zone and the concentrations at which the ingredients areused, the available information indicates that incidental inhalation would not be a significant route of exposure that might lead to
local respiratory or systemic effects. A detailed discussion and summary of the Panel’s approach to evaluating incidental
inhalation exposures to ingredients in cosmetic products is available at http://www.cir-safety.org/cir-findings.
CONCLUSION
The Panel concluded that the following monoalkylglycol dialkyl acid ester ingredients are safe in cosmetics in the present
practices of use and concentration described in this safety assessment:

Butylene Glycol Dicaprylate/Dicaprate
Butylene Glycol Diisononanoate*
Diethylpentanediol Dineopentanoate
Dioctadecanyl Didecyltetradecanoate*
Dioctadecanyl Ditetradecyloctadecanoate*
Glycol Dibehenate*
Glycol Diethylhexanoate
Glycol Dilaurate
Glycol Dioleate*
Glycol Dipalmate/Palm Kernelate/Olivate/Macadamiate*
Glycol Dipalmate/Rapeseedate/Soyate*
Glycol Dipivalate*
Glycol Distearate
Glycol Ditallowate*

Hexanediol Distearate*
Neopentyl Glycol Dicaprate
Neopentyl Glycol Dicaprylate/Dicaprate
Neopentyl Glycol Dicaprylate/Dipelargonate/Dicaprate*
Neopentyl Glycol Diethylhexanoate
Neopentyl Glycol Diheptanoate
Neopentyl Glycol Diisononanoate
Neopentyl Glycol Diisostearate
Neopentyl Glycol Dilaurate*
Propanediol Dicaprylate
Propanediol Dicaprylate/Caprate
Propanediol Diisostearate*
Propanediol Dipelargonate*
Trimethyl Pentanyl Diisobutyrate* Not reported to be in current use. Were ingredients in this group not in current use to be used in the future, the expectationis that they would be used in product categories and at concentrations comparable to others in this group.

TABLES
Table 1. Definitions, idealized structures, and functions of the monoalkylglycol dialkyl acid esters in thissafety assessment.1,CIR Staff
Ingredient CAS No.
Trimethyl Pentanyl Diisobutyrate
6846-50-0

Definition & Structure
Trimethyl Pentanyl Diisobutyrate is the organic compound that conforms to
the formula:

Function(s)Plasticizer

Butylene Glycol
Dicaprylate/Dicaprate

Butylene Glycol Dicaprylate/Dicaprate is a mixture of the butylene glycol
diesters of caprylic and capric acids.

Skin-conditioning
agent - occlusive

Butylene Glycol Diisononanoate

Butylene Glycol Diisononanoate is the diester of butylene glycol andbranched chain nonanoic acids. It conforms generally to the formula:

Skin-conditioning
agent – emollient;skin-conditioning
agent – occlusive;viscosity
increasing agent nonaqueous

Diethylpentanediol
Dineopentanoate
762268-78-0[one example of an “iso]Diethylpentanediol Dineopentanoate is the organic compound that conforms
to the formula:Hair conditioning
agent; skinconditioning
agent miscellaneousTable 1. Definitions, idealized structures, and functions of the monoalkylglycol dialkyl acid esters in thissafety assessment.1,CIR Staff
Ingredient CAS No.
Dioctadecanyl
Didecyltetradecanoate

Definition & Structure
Dioctadecanyl Didecyltetradecanoate is the organic compound that
conforms to the formula:

Function(s)Skin-conditioning
agent – emollient;skin-conditioning
agent miscellaneous

Dioctadecanyl
Ditetradecyloctadecanoate

Dioctadecanyl Ditetradecyloctadecanoate is the organic compound that
conforms to the formula:

Skin-conditioning
agent – emollient;skin-conditioning
agent miscellaneous

Glycol Dibehenate
79416-55-0

Glycol Dibehenate is the diester of ethylene glycol and behenic acid. It
conforms generally to the formula:

Opacifying agent;skin-conditioning
agent – occlusive;viscosity
increasing agent nonaqueousTable 1. Definitions, idealized structures, and functions of the monoalkylglycol dialkyl acid esters in thissafety assessment.1,CIR Staff
Ingredient CAS No.
Glycol Diethylhexanoate

Definition & Structure
Glycol Diethylhexanoate is the diester of ethylene glycol and2-ethylhexanoic acid. It conforms to the formula:

Function(s)Skin-conditioning
agent – occlusive;viscosity
increasing agent– nonaqueous

Glycol Dilaurate
624-04-4

Glycol Dilaurate is the diester of ethylene glycol and lauric acid. It conforms
to the formula:

Skin-conditioning
agent viscosity
increasing agent– nonaqueous –occlusive

Glycol Dioleate

Glycol Dioleate is the diester of ethylene glycol and oleic acid. It conforms
to the formula:

Opacifying agent;skin-conditioning
agent – occlusive;viscosity
increasing agent nonaqueous

Glycol Dipalmate/Palm
Kernelate/Olivate/Macadamiate

Glycol Dipalmate/Palm Kernelate/Olivate/Macadamiate is the diester ofethylene glycol with a mixture of fatty acids derived from palm oil, palm
kernel oil, olive oil and macadamia nut oil.

Skin-conditioning
agent - emollient[wherein RC(O)- represents fatty acid residues derived from palm oil, palm kernel oil, olive oiland macadamia nut oil.]Table 1. Definitions, idealized structures, and functions of the monoalkylglycol dialkyl acid esters in thissafety assessment.1,CIR Staff
Ingredient CAS No.
GlycolDipalmate/Rapeseedate/Soyate

Glycol Dipivalate

Definition & Structure
Glycol Dipalmate/Rapeseedate/Soyate is the diester of ethylene glycol witha mixture of palm acid, rapeseed acid and soy acid.

Function(s)Skin-conditioning
agent - emollient[wherein RC(O)- represents fatty acid residues derived from palm acid, rapeseed acid and soy
acid.]
Glycol Dipivalate is the organic compound that conforms to the formula:
Skin-conditioning
agent – emollient

Glycol Distearate
627-83-8
91031-31-1

Glycol Distearate is the diester of ethylene glycol and stearic acid. It
conforms generally to the formula:

Opacifying agent;skin-conditioning
agent – occlusive;viscosity
increasing agent nonaqueous

Glycol Ditallowate

Glycol Ditallowate is the diester of ethylene glycol and Tallow Acid. It
conforms generally to the formula:

Opacifying agent;skin-conditioning
agent – occlusive

Hexanediol Distearate
26730-92-7

where RCO- represents the fatty acids derived from tallow.
Hexanediol Distearate is the diester of hexanediol and stearic acid. It
conforms generally to the formula:

Skin-conditioning
agent – occlusive;viscosity
increasing agent nonaqueousTable 1. Definitions, idealized structures, and functions of the monoalkylglycol dialkyl acid esters in thissafety assessment.1,CIR Staff
Ingredient CAS No.
Neopentyl Glycol Dicaprate
27841-06-1

Definition & Structure
Neopentyl Glycol Dicaprate is the diester of neopentyl glycol and decanoic
acid that conforms to the formula:

Function(s)Skin-conditioning
agent – emollient;viscosity
increasing agent nonaqueous

Neopentyl Glycol
Dicaprylate/Dicaprate
70693-32-2

Neopentyl Glycol Dicaprylate/Dicaprate is the diester of neopentyl glycol
and a blend of caprylic and capric acids.

Skin-conditioning
agent – emollient;viscosity
increasing agent nonaqueous

Neopentyl Glycol Dicaprylate/
Dipelargonate/Dicaprate[wherein RC(O)- represents fatty acid residues derived from caprylic and capric acids.]
Neopentyl Glycol Dicaprylate/Dipelargonate/Dicaprate is the diester of
Skin-conditioning
neopentyl glycol and a blend of caprylic, pelargonic and capric acids.
agent – emollient;viscosity
increasing agent nonaqueous

Neopentyl Glycol
Diethylhexanoate
28510-23-8[wherein RC(O)- represents fatty acid residues derived from caprylic, pelargoinc, and capric
acids.]
Neopentyl Glycol Diethylhexanoate is the diester of neopentyl glycol and
Skin-conditioning
2-ethylhexanoic acid. It conforms to the formula:
agent – emollient;viscosity
increasing agent nonaqueous

Neopentyl Glycol Diheptanoate
68855-18-5

Neopentyl Glycol Diheptanoate is the diester of neopentyl glycol andheptanoic acid. It conforms to the formula:

Skin-conditioning
agent – emollient;viscosity
increasing agent– nonaqueous

Neopentyl Glycol Diisononanoate
27841-07-2

Neopentyl Glycol Diisononanoate is the organic compound that conforms to
the formula:

Skin-conditioning
agent – emollientTable 1. Definitions, idealized structures, and functions of the monoalkylglycol dialkyl acid esters in thissafety assessment.1,CIR Staff
Ingredient CAS No.
Neopentyl Glycol Diisostearate
109884-54-0

Definition & Structure
Neopentyl Glycol Diisostearate is the diester of neopentyl glycol andisostearic acid. It conforms to the formula:

Neopentyl Glycol Dilaurate
10525-39-0[one example of an “iso”]
Neopentyl Glycol Dilaurate is the diester of neopentyl glycol and lauricacid. It conforms to the formula:

Function(s)Skin-conditioning
agent – occlusive;viscosity
increasing agent nonaqueous

Skin-conditioning
agent – emollient;viscosity
increasing agent– nonaqueous

Propanediol Dicaprylate
1020852-63-4
56519-71-2

Propanediol Dicaprylate is the organic compound that conforms to theformula:Skin-conditioning
agent – emollient;solvent

Propanediol Dicaprylate/Caprate
1072005-10-7

Propanediol Dicaprylate/Caprate is the organic compound that conforms
generally to the formula:

Skin-conditioning
agent – emollient

where RC(O)- represents a mixture of caprylic and capric acid residues.

Table 1. Definitions, idealized structures, and functions of the monoalkylglycol dialkyl acid esters in thissafety assessment.1,CIR Staff
Ingredient CAS No.
Propanediol Diisostearate

Propanediol Dipelargonate
28267-33-6

Definition & Structure
Propanediol Diisostearate is the organic compound that conforms generally
to the formula:

Function(s)Skin-conditioning
agent – emollient[one example of an “iso”]
Propanediol Dipelargonate is the organic compound that conforms to theformula:Skin-conditioning
agent – emollient

Table 2. Previous safety assessments by CIR of monoalkylglycol dialkyl acid esters and related ingredients,
moieties, and component parts.
Ingredient, Related Ingredients, or Component
Glycol Distearate; Glycol Stearate, Glycol Stearate SE
Neopentyl Glycol
Dicaprylate/Dipelargonate/Dicaprate, Neopentyl
Glycol Diisononanoate, Pelargonic Acid (nonanoicacid) and nonanoate esters
Butylene Glycol, Hexylene Glycol, Ethoxydiglycol,
Dipropylene Glycol
Alkane diols (1,5-Pentanediol and Isopentyldiol)

Propylene glycol esters
Oleic Acid, Lauric Acid, Palmitic Acid, Myristic Acid,and Stearic Acid
Plant-derived fatty acid oils (which primarily comprise
glyceryl triesters)
Alkyl esters (e.g., Isooctyl Caprylate/Caprate, Cetearyl
Isononanoate, and Cetearyl Behenate)
Tallow, Tallow Glyceride, Tallow Glycerides,
Hydrogenated Tallow Glyceride, and HydrogenatedTallow Glycerides
Alkyl ethylhexanoates

Conclusion (year)a

Reference

Safe as used (1982)
Safe as used (2011)

2,3

Safe as used (2006)

45,46

Safe in cosmetics in the present practices of use andconcentration; the data are insufficient to come to a conclusionof safety for 1,4-Butanediol (2017, tentative report)
Safe as cosmetic ingredients in the practices of use andconcentration described in this safety assessment (2014)
Safe in the present practices of use and concentration (2006)

47

4

48

45,49

Safe as used (2011)50

Safe in cosmetic formulations in the present practices of use
and concentration when formulated to be non-irritating (2013)
Safe in present practices of use (1990, 2006)

51

Safe in cosmetic formulations in the present practices of use
and concentrations when formulated to be nonirritating (2015).
2-Ethylhexanoic acid, a possible metabolite, had been shown to
be a liver and developmental toxicant in animal studies at highdoses; in developmental toxicity studies, it was postulated thatthe maternal liver toxicity began a cascade of effects that
included metallothionein (MT) induction, zinc accumulation in
the liver due to MT binding, and a resulting zinc deficiency in

52,53

54

Table 2. Previous safety assessments by CIR of monoalkylglycol dialkyl acid esters and related ingredients,
moieties, and component parts.
Conclusion (year)athe developing embryo; the zinc deficiency causes thedevelopmental toxicity; a reproductive/developmental toxicity
study was also performed with up to 1% dietary di-2-ethylhexyl
terephthalate (DEHT; a 2-ethylhexanoic acid precursor); no
reproductive or developmental effects were observed,
suggesting that the process of metabolic conversion of DEHT
to 2-ethylhexanol and subsequent hydrolysis to 2-ethylhexanoic
acid results in a time course of 2-ethylhexanoic acid appearance
such that allows clearance before sufficient levels can arise to
produce acute liver toxicity.
a
Please see the original reports for details (https://www.cir-safety.org/ingredients).
Ingredient, Related Ingredients, or Component

Table 3. Chemical and physical properties of monoalkylglycol dialkyl acid
esters in this safety assessment.
Property

Value

Reference

LiquidColorless/clear
Slight286.41
0.94
0.92
0.005
0.00090.01130.00066
0.089
-70
-10
281.5
280
0.012713.3
13.2
0.001-0.002
0.015
4.91 est.

7

Trimethyl Pentanyl Diisobutyrate
Physical Form
Color
Odor
Molecular Weight g/mol
Density
Viscosity kg/(s*m)
Vapor pressure mmHg @ 20oC

Melting Point oC
Boiling Point oC
Water Solubility g/L @ 27.5oC & pH 3.6-4/6@ 23.65oC & pH 4.09-4.83@ 23.65oC & pH 7.79-8.26@ 20.5oC@ 25oC
log P

Molecular Weight g/mollog P

Butylene Glycol Dicaprylate/Dicaprate
342.52 – 398.63
7.28 – 9.24 est.

7
7
18
7
7
7
32
7
18
35
32
18
18
18,32
7
7
7
32
18
14

15
15

Butylene Glycol Diisononanoate
Physical Form
Molecular Weight g/mol
Water Solubility
log P

Physical Form
Color
Odor
Molecular Weight g/mol
Boiling Point oC
Water Solubility
log P

Liquid370.57
Insoluble
8.12 est.
Diethylpentanediol Dineopentanoate
LiquidColorless to very paleyellow
Faint characteristic
328.49> 200
Insoluble
6.42 est.

55
55
55
14

16
16

16
56
16
16
14

ReferenceTable 3. Chemical and physical properties of monoalkylglycol dialkyl acid
esters in this safety assessment.
Property

Value

Physical Form
Molecular Weight g/mol
Water Solubility
log P

Dioctadecanyl Didecyltetradecanoate
Liquid1240.21
Insoluble
38.42 est.

Physical Form
Molecular Weight g/mol
Water Solubility
log P

Dioctadecanyl Ditetradecyloctadecanoate
Liquid1464.64
Insoluble
46.27 est.

Reference
57
57
57
14

58
58
58
14

Glycol Dibehenate
707.2020.05 est.

59

LiquidPale yellow
314.470.94 est.
0 est.
< -20
75
7.66 est.
9.62 est.

9

Molecular Weight g/mol
log P

14

Glycol Diethylhexanoate
Physical Form
Color
Molecular Weight g/mol
Density/Specific Gravity @ 20oC
Vapor Density mmHg
Melting Point oC
Boiling Point oC
log P

9
15
9
9
9
9
9
9

Glycol Dilaurate
426.67
10.23 est.

60

590.97
15.69 est.

61

230.303.13 est.

15

Solid
Waxy solid
White
White to cream
595.0
0.858
8.04
75
75.3
79
74.7
67-68
75 - 75.5241209
016.12 est.

5

Molecular Weight g/mol
log P

14

Glycol Dioleate
Molecular Weight g/mol
log P

14

Glycol Dipivalate
Molecular Weight g/mol
log P

14

Glycol Distearate
Physical Form
Color
Molecular Weight g/mol
Density/Specific Gravity @ 78oC g/cm3
Viscosity kg/(s*m)@ 80oC
Melting Point oC

Boiling Point oC @ 20 mmHg
@ 15 mmHg
Water Solubility g/L @ 25oC
log P

3
5
3
62
5

5
5
5,62
5
5
5
5
5
5
5

Hexanediol Distearate
Molecular Weight g/mol
log P

651.1118.08 est.

63
14

Table 3. Chemical and physical properties of monoalkylglycol dialkyl acid
esters in this safety assessment.
Property

Value

Reference

412.650.93 est.
9.62 est.

64

Neopentyl Glycol Dicaprate
Molecular Weight g/mol
Density @ 20oC
log P

Neopentyl Glycol Dicaprylate/Dicaprate
LiquidOily liquid
Color
Clear or yellowish
Molecular Weight g/mol
356.55 – 412.66
Density @ 25oC
0.890-0.920
Melting Point oC< 20o
Water Solubility g/L @ 20 C & pH 5.4-6.8
92.9
log P
7.66 – 9.62 est.
Physical Form

Neopentyl Glycol Dicaprylate/Dipelargonate/Dicaprate
Molecular Weight g/mol
356.60 - 412.66
log P
7.66 – 9.62 est.

Physical Form
Color

Neopentyl Glycol Diethylhexanoate
LiquidPale yellow
Clear
Slight, characteristic356.540.920< -20
Insoluble

Odor
Molecular Weight g/mol
Specific Gravity @ 25oC
Melting Point oC
Water Solubility
Other Solubility
Hydrophobic solvents (esters, mineral oil, mineralspirits, and aromatic hydrocarbons)
log P

6

6
65
65
15
65
6
6
14

15
14

8,11,12
8
11
11
12
11
8
11

Soluble11

7.51 est.

14

Neopentyl Glycol Diheptanoate
Physical Form
LiquidColorLight straw
Molecular Weight g/mol
328.5
Density/Specific Gravity @ 20oC
0.927
o
@ 20 C
0.92
Viscosity kg/(s*m) @ 25oC
1.29
@ 40oC0.58
o@ 100 C
0.193
Vapor pressure mmHg @ 20oC
0 est.
Melting Point oC-33o
Water Solubility g/L @ 20 C & pH 6.2 - 6.7< 0.05log P
6.68 est.

Molecular Weight g/mol
Melting Point oC
Boiling Point oC
log P

6

Neopentyl Glycol Diisosononanoate
384.59132.4 est.
565.02 est.
7.03 est.

6,8
6,8
8
8
8
8
8
8
8
8
8
8

4
4
4
4

Neopentyl Glycol Diisostearate
Molecular Weight g/mol
log P

637.0717.34 est.

66

468.750.911
532.6
11.59 est.

67

14

Neopentyl Glycol Dilaurate
Molecular Weight g/mol
Density
Boiling Point oC
log P

67
67
14

Table 3. Chemical and physical properties of monoalkylglycol dialkyl acid
esters in this safety assessment.
Property

Value

Reference

LiquidWhite
Neutral328.490.91-0.93< -5Insoluble
6.79 est.

13

Propanediol Dicaprylate
Physical Form
Color
Odor
Molecular Weight g/mol
Specific Gravity @ 25oC
Melting Point oC
Water Solubility
log P

Molecular Weight g/mol
Specific Gravity @ 25oC
log P

Propanediol Dicaprylate/Caprate
328.49 – 384.60
0.91 - 0.93
6.79 – 8.75 est.

13
13
15
13
13
13
14

15
68
14

Propanediol Diisostearate
Molecular Weight g/mol
log P

609.03
16.46 est.

15

LiquidClear
356.54Insoluble

69

Miscible
Insoluble
Miscible
Miscible
Miscible
Miscible
7.77 est.

69

14

Propanediol Dipelargonate
Physical Form
Color
Molecular Weight g/mol
Water Solubility
Other Solubility
Ethanol
Propylene Glycol
Isopropyl Myristate
Castor Oil
Mineral Oil
Isododecane
log P
est.=estimated

69
70
69

69
69
69
69
69
14

Table 4. Available toxicity studies for the hydrolysis product of Diethylpentanediol Dineopentanoate, neopentanoic
acid, and on 1,5 pentanediol and isopentyldiol.
Animal (n)Dose/
Concentration(s)Methods

Results

Reference

LD50 = 3160 mg/kg
Two rabbits died within 48 h of exposure in
the 3160 mg/kg group. Death waspreceded by marked depression, severe
dyspnea, prostration, excessive urination,and coma. Congestion of lungs, adrenals,
kidneys, blanched areas on liver andspleen, inflammation of the bladder mucosa
and gastrointestinal tract.
LD50 = between 2-4 mL
None of the rats died in the low-dosegroup. All of the males and 2 of 4 females
died in the high-dose group by day 2.

10Acute Dermal
Neopentanoic acid
New Zealand50, 200, 794, or 3160
White Rabbita
mg/kg(4/sex)Rat (4/sex)

2 or 4 mL, neat

Similar to OECD Guideline 402(Acute Dermal Toxicity). Test
substance was in contact for 24 hunder occlusion. The rabbits werethen observed for 14 days.

Test substance was in contact for 24 hunder occlusion. The rabbits werethen observed for 9 days.

10Table 4. Available toxicity studies for the hydrolysis product of Diethylpentanediol Dineopentanoate, neopentanoic
acid, and on 1,5 pentanediol and isopentyldiol.
Animal (n)1,5 Pentanediol
Male New
Zealand (albino)
Rabbit (4)Dose/
Concentration(s)20 mL/kg

Methods

Rabbit trunk was clipped free of hair;single application of test substance tohairless skin and covered withocclusive plastic film for 24 h, atwhich point plastic film was removed;
rabbits were observed for 14 days;
researchers noted that doses >20
ml/kg could not be “retained incontact with the skin”

Results

Reference

LD50 > 20 ml/kg was reported

71

LD50 = 2000 mg/kg
None of the rats died in the 3 low-dosegroups. 2 died on day 2 in the1450 mg/kg
group, all 5 died by day 2 in the 5000
mg/kg group, and all 5 died within 24 h in
the 10,000 mg/kg group.
Clinical signs:
1450 mg/kg-slight to marked depression,
dyspnea and ataxia at 24 h, death within 48
h post-dose. Survivors showed depression,
severe dyspnea, depressed reflexes,
sprawling, incoordination, and abnormal
gait.
5000 and 10000 mg/kg-depression,
dyspnea, ataxia, and sprawling of limbs
within one hour post-dose. Marked
depression, severe dyspnea and prostration
preceded death in all animals within 1 to 48
h.
Gross pathology:
5000 and 10000 mg/kg - congestion oflungs, liver, kidneys, and adrenals; pyloric
portion of the stomach grossly
hemorrhagic.
LD50 = between 1 and 2 mL/kg
No rats died in the 0.5 mL/kg group; 1female died on day 4 in the 1.0 mL/kg
group; all rats died on day 1 of the 2.0
mL/kg group.

10

Acute Oral
Neopentanoic acidMale Sprague34.6, 120, 417, 1450,
Dawley rats (n=5)
5000, or 10000 mg/kg
in corn oil by gavage

Wistar rats (4/sex)

Similar to OECD Guideline 420(Acute Oral Toxicity - Fixed Dose
Method). Rats were observed for 14
days after dosing.

10

0.5, 1.0 or 2.0 mL/kg

Fixed dose procedure. Rats wereobserved for 9 days after dosing. No
further details were provided.

Dose not specified, a“suitable vehicle”(e.g. water, corn oil,or semi-sold agar
suspension) was used
1, 4.64, 6.81, 10 g/kg
(vehicle=water)

Single dose administered by gastricintubation to non-fasted rats; rats
observed for 14 days post-dosing

An estimated LD50 of 5.89 g/kg ± 1.96
standard deviations was reported, LD50
range reported was 5.38 to 6.44 g/kg

71

Procedures followed were inaccordance with OECD TG 401(Acute Oral Toxicity); single dose
administered by gavage; animals
observed for 14 days post-dosing

72

Guinea Pig (notspecified)

Not Specified

Not Specified

Mouse (notspecified)

Not Specified

Not Specified

Rabbit (notNot Specified

Not Specified

LD50 = 10 g/kg for males and females; 1
death in 24 h (6.81 g/kg dose), 3 deaths in
24 h (10 g/kg dose), no deaths at two lower
doses; reduced weight gain early in study;
gross pathology revealed acute dilation of
the heart and congestive hyperemia, bloody
stomach ulcerations, diarrhetic andhematonic gut content, and abnormal
bladder content; clinical signs: reduced
state, staggering, paresis, spastic gait,
salivation, exsiccosis
LD50 = 4.6 g/kg; somnolence, excitement,
and muscle weakness noted details
provided)
LD50 = 6.3 g/kg; somnolence, excitement,
and muscle weakness noted (details
provided)
LD50 = 6.3 g/kg; somnolence, excitement,

1,5 Pentanediol
Carworth-Wistar
rat (5)Sprague-Dawley
rat (12 males andfemales)

73

73

73

Table 4. Available toxicity studies for the hydrolysis product of Diethylpentanediol Dineopentanoate, neopentanoic
acid, and on 1,5 pentanediol and isopentyldiol.
Animal (n)specified)
Isopentyldiol
CD-1 mouse(5/sex)Dose/
Concentration(s)2 g/kg and 5 g/kg
(vehicle= water)

Methods

Procedures followed were inaccordance with OECD TG 401(Acute Oral Toxicity); necropsy
performed

Results
and muscle weakness noted (no further
details provided)

Reference

LD50 > 5 g/kg; no mortality; gross necropsy
revealed no abnormalities; no signs of
toxicity reported

74

LC50 > 5.3 mg/L
During exposure, decreased respiratory rate
was observed in all rats. On removal fromthe chamber all rats exhibited decreased
respiratory rate and ataxia. 1 h postexposure, a slight recovery was evident in
all animals as ataxia was no longer
apparent.
Signs of hunched posture and piloerection
were observed in rats for short periods onremoval from the chamber. Wet fur wascommonly recorded both during and for ashort period after exposure. Rats recovered
quickly to appear normal on day 2 or 3
post-exposure. These observations are
considered to be associated with therestraint procedure and, in isolation, are notindicative of toxicity.
Mice-LC100 = 4.0 mg/L
Rats-LC50 = < 4 mg/L
Guinea pig-LC50 = < 4 mg/L
All mice died within 24 h of exposure. 2
rats (on day 2 and 5 post exposure) and 1
guinea pig (between 8 and 24 h post
exposure) died.

10

No deaths were reported for up to 8 h ofinhalation exposure71

LC0 = 0.078 mg/l air for 7 h for males andfemales was reported; no mortality; grosspathology revealed no findings

72

Generally, rabbits in the low-dose group
showed an overall body weight gain; in thehigh-dose group, an overall slight weightloss was noted. Gross pathological findings
at necropsy consisted of parasitic cysts inthe liver and fibrous, pitted kidneys,
congestion of the lungs, and congestion of
the pancreas.
Dermal: low-dose group showed slight ormoderate erythema, atonia, anddesquamation. Exposed skin of 1 rabbit
showed slight edema following the third

10

Acute Inhalation
Neopentanoic acid
Wistar rats (3/sex) 5.30 mg/L for 4 h

Male Swiss mice,
Wistar rats,
Hartley guinea
pigs (10)1,5 Pentanediol
Albino rat (6/sex)Sprague-Dawley
rat (6/sex)

Nose only application. Rats were
examined for clinical signs hourly
during exposure and daily for 14 days.

4.0 mg/L for 6 hMice, rats and guinea pigs exposed tovaporized test substance in wholebody inhalation chambers for 6 hours
at the nominal concentration of 4
mg/L. All groups were monitored for
14 days for clinical signs of toxicity.

Concentrated vapor(concentration in air
not specified)

Rats were exposed to a stream of air
containing the concentrated vapor;vapor was produced by passing driedair (2.5 liters/min) through a glass discimmersed in 1 inch of 50 ml 1,5Pentanediol; duration of inhalation
exposure was up to 8 h; rats observedfor 14 days post-exposure
Procedures followed were inaccordance with OECD TG 403(Acute Inhalation Toxicity); animals
exposed for 7 h; animals observed for
14 days post-exposure; necropsy
performed

0.11 g (no vehicle)

10

Short-term Dermal Toxicity
Neopentanoic acidRabbit (4)30 or 300 mg/kg for
24 h under occlusion

10 exposure, 5 days/week over 2
weeks.

Table 4. Available toxicity studies for the hydrolysis product of Diethylpentanediol Dineopentanoate, neopentanoic
acid, and on 1,5 pentanediol and isopentyldiol.
Animal (n)Dose/
Concentration(s)Methods

Results
and fourth application and a circumscribedarea of corrosion during the last 4 days ofthe study. High-dose group rabbits
generally showed moderate erythema
following all applications, slight to marked
edema following the first 5 applications,and moderate or marked atonia anddesquamation following the last 7
applications. In 3 of the rabbits discolored
areas which subsequently became necrotic
were noted following the third application.
The necrosis persisted throughout the
study.

Reference

NOAEL = 30 mg/kg/day
Immediately after dosing the 100 or 300
mg/kg/day groups, rats were observed tosneeze and produce a dark nasal discharge,
probably resulting from a mild irritanteffect of the volatile acid test substance on
nasal mucosa. A slightly lower bodyweightin the 300 mg/kg/day dose group females
was considered to be of uncertain relation
to treatment. There was no effect on male
bodyweight, food intake, hematologicalparameters, or histopathologicalobservations at any dose level. Changes inalkaline phosphatase, cholesterol,creatinine and bilirubin in females
suggested a slight change in liver function
at the 100 and 300 mg/kg/day doses,
however, there was no associatedhistopathological changes. Minor
differences in hepatic macroscopic
appearance, liver weight and kidney weight
were not accompanied by any
histopathological change. These differenceswere considered to be related to adaptive orfunctional changes and not a toxic effect.
There was no evidence of a cumulative
toxic effect at any dose level. However,transient irritancy or adaptive changes wereseen at 30, 100 and 300 mg/kg/day. Minor
differences in liver and kidney weight wereseen at 10 mg/kg/day; these were of
uncertain relationship with treatment.

10

Negative with and without metabolic
activation

10

Negative with and without metabolic
activation

10

Negative

10

Short-term Oral Toxicity
Neopentanoic acid
Fischer 344 rats
10, 30, 100, or 300(7/sex)
mg/kg/d; 5 mL/kg inwater/PEG 200 (50/50
v/v)

OECD Guideline 407 (Repeated Dose
28-Day Oral Toxicity in Rodents)

Genotoxicity
Neopentanoic acidS. typhimurium
TA 1535, TA
1537, TA 98, TA
100 and E. coli
WP250.0, 150, 500, 1500
and 5000 μg per platein water with andwithout metabolic
activation

L5178Y/TK+/Mouse
Lymphoma

3.99, 7.98, 16.0, 31.9,
63.8, 128, 255, 511
and 1021 μg/mL

Chinese Hamster
Ovary (CHO)
Cells

100, 250, 500, 750,
1020 µg/mL

OECD Guideline 471 (Bacterial
Reverse Mutation Assay)
Positive controls: 9-aminoacridine, 2nitrofluorene, sodium azide,
methylmethanesulfonate, and 2aminoanthracene
OECD Guideline 476 (In Vitro
Mammalian Cell Gene MutationTest). Positive controls:
7,12-dimethylbenzanthracene
methylmethanesulfonate
OECD Guideline 473 (In Vitro
Mammalian Chromosome Aberration
Test)

Table 4. Available toxicity studies for the hydrolysis product of Diethylpentanediol Dineopentanoate, neopentanoic
acid, and on 1,5 pentanediol and isopentyldiol.
Animal (n)Dose/
Concentration(s)1,5 Pentanediol
Salmonella
typhimurium(TA98, TA100,
TA1535,
TA1537)0, 20, 100, 500, 2500,
5000 µg/plate (vehicle= water; application
by agar plate
incorporation)

Salmonella
typhimurium(TA98, TA100,
TA1535,
TA1537)0, 20, 100, 500, 2500,
5000 µg/plate (vehicle= water; applicationby preincubation @37°C for 20 min)Isopentyldiol
S. typhimurium:
TA98, TA100,
TA1535, TA1537;
E. coli: WP2
uvrA (pKM101)

Bacillus subtilis(M45, H17)

33 to 10,000 µg/plate(vehicle = DMSO)

6.25, 12.5, 25, 50, 100
mg/plate (vehicle =DMSO)

Methods

Results

ReferenceAmes Test was performed, with andwithout metabolic activation, in
accordance with GLP and OECD TG
471 (Bacterial Reverse Mutation
Assay); negative, vehicle, and positive
controls were used
Ames Test was performed, with andwithout metabolic activation, in
accordance with GLP and OECD TG
471 (Bacterial Reverse Mutation
Assay); negative, vehicle, and positive
controls were used

Negative; controls performed as expected

72

Negative; controls performed as expected

72

Bacterial reverse mutation assay was
performed , with and without
metabolic activation, in accordancewith OECD TG 471 (Bacterial
Reverse Mutation Test) and EC
Directive 2000/32/EC B.12/14
Mutagenicity-Reverse Mutation Test
using Bacteria; 10,000 µg/plateexceeds the 5000 µg/plate limit
recommended for non-cytotoxic
substances; positive controls wereusedPreliminary rapid streak test was
conducted to determine dose levels;
liquid suspension assay was
performed with and without metabolic
activation; negative, vehicle, andpositive controls were used

Negative; controls performed as expected

74

No toxicity reported in preliminary test;
liquid suspension assay was negative forgenotoxicity; controls performed as
expected

74

Mean erythema score: 3.61 out of 4; mean
edema score: 1.83 out of 4.
Topical application elicited severe
erythema in one rabbit, moderate to severe
erythema in two rabbits, well-definederythema in one rabbit and very slighterythema in two rabbits at 45 min after
application. Erythema then increased. At
24 h, four rabbits had severe erythema, one
rabbit with well-defined erythema and one
with slight erythema. Erythema increased
again at 48 and 72 h. Erythema increasedslightly again at day 7 where all rabbits
were noted with severe erythema. Changes
in erythema were accompanied by changes
in edema.
Highly irritating10

Dermal Irritation
Neopentanoic acid
New Zealand
100%; 0.5 mL
White rabbit (6)OECD Guideline 404 (Acute Dermal
Irritation/Corrosion)

New ZealandWhite rabbit (8)100%; 0.5 mLApplied to intact and abraded skin for
24 h under occlusion.

Undiluted or insolutions of water,
propylene glycol, or
acetone (no further
specifications
provided)
Undiluted

Fur was clipped from skin; 0.1 ml test
substance was applied and left
uncovered for 24 h, at which point
skin was examined

Non-irritating (rated grade 1 on a scalefrom 1-non-irritating to 10-necrosis)

71

Procedures followed (non-GLP) werein accordance with OECD TG 404(Acute Dermal Irritation/ Corrosion);
1 ml of test substance saturated on a
cotton patch (2.5 x 2.5 cm area) was

Non-irritating: For the 24, 48, and 72 h
post-application time points the meanerythema score was 0.5 (very slight effect)
and mean edema score was 0.1 (very slighteffect); this erythema and edema were72

1,5 Pentanediol
Albino rabbit (5)Vienna White
Rabbit (1 male, 5females)10

Table 4. Available toxicity studies for the hydrolysis product of Diethylpentanediol Dineopentanoate, neopentanoic
acid, and on 1,5 pentanediol and isopentyldiol.
Animal (n)Human (30)

Isopentyldiol
New ZealandWhite rabbit(3/sex)Dose/
Concentration(s)5% in a topicalformulation

Undiluted

Male New
Zealand White
rabbit (9)Not specified

Human (13 males
and 17 females)

Not specified

Methods
applied to intact or scarified back skinand occlusively covered for 20 h, thenpatch was removed and skin waswashed with 50% polyethylenglycol
in water; skin was examined for
irritation 24, 48, and 72 h postapplication and also 7 days postapplication
Patch test was performed; test
substance was applied (single
application) to inner forearms andocclusively covered with a patch; 24 hpost-application the patch wasremoved and skin was immediately
assessed and assessed again 48 and 72
h after patch removal; standard light
conditions used

Results
reversible within 48 h; additional findings
were at 48 h spotted appearance (scarified
skin of 2 animals), at 72 h desquamation(scarified skin of 3 animals), and at 7 days
observation desquamation (scarified skin of
4 animal)

Non-irritating, no indications ofhypersensitivity or photo-sensitivity

75

Procedures followed were a variationof OECD TG 404 (Acute Dermal
Irritation/Corrosion); test substance
was applied and occlusively coveredfor 24 h, then the patch was removed;skin was examined at 24 and 72 h
post-application
15 µl of test substance was applied todorsal trunk area (clipped) while
another site in the vicinity was used asa control; sites were covered (semiocclusively) for 24 h, then patches
were removed and skin examined;
another treatment of test substance
was applied to the same site andprocedures used during the first
application were repeated each day for
28 days; at the completion of the study
the animals were killed and skin cells
examined

Non-irritating74

No substantial irritation with repeated skinapplication
On day 10 of study an animal died (cause
was gastrointestinal disease and unrelated
to treatment) and another was added to test
group; an animal died on day 22, but cause
was unknown
On days 15, 18, and 27 slight erythema
and/or edema was observed in 4 animals,
but by the following day irritation had
resolved
At the treatment site of 4 animals, mild
inflammatory cell infiltration was reported,but in 2 of those 4 animals the control sites
yielded similar results
Isopentyldiol slightly irritating; slighterythema reported 30 min after Finn
chamber removal (in 66 yr old female andin 49 yr old female), but this resolved
within 24 h

74

OECD Guideline 406 (Skin
Sensitization)/guinea pig
maximization test

Not sensitizing

10

Scalp wash was used ≥ 2 times/day for
4 weeks (no other products were usedon hair during this time); scalp skin
was assessed periodically throughout
study; after 4 weeks, test substance
was applied (single application) to
inner forearms and occlusively

Non-irritating, non-sensitizing

75

An unspecified concentration of
Isopentyldiol, 1,3-Butanediol, andwater (control) were soaked into filter
paper and applied to medial brachiumarea of skin and covered with a Finn
chamber; 48 h post-application the test
substance/Finn chamber were
removed and skin examined at 30 min,24 h, and up to 7 days

Reference

74

Sensitization
Neopentanoic acid
Guinea pig
Induction Intradermal(10/sex; controls,
induction: 0.05% w/v;
5/sex)
Topical induction:
25% w/v;
Topical challenge:
10% w/v in corn oil
1,5 Pentanediol
Human (20 males)

5% in a scalp wash
formulation

Table 4. Available toxicity studies for the hydrolysis product of Diethylpentanediol Dineopentanoate, neopentanoic
acid, and on 1,5 pentanediol and isopentyldiol.
Animal (n)Human (30)

Isopentyldiol
Dunkin-Hartley
Guinea Pig (20,
10 controls)

Dose/
Concentration(s)25% in a topicalformulation

Main Study:
Intradermal Induction:
10% in distilled water
Topical Induction:
100% undiluted
Challenge: 50% in
distilled water

Methods
covered with a patch; 24 h postapplication, the patch was removed
and skin was immediately assessed
and assessed again 48 and 72 h after
patch removal
Single application of test substance toinner forearms and occlusively
covered with a patch; 24 h postapplication, the patch was removed
and skin was immediately assessed
and assessed again 48 and 72 h after
patch removal; this patch test was
repeated 1 week later and at week 6

Guinea pig maximization test was
performed in accordance with OECD
TG 406 (Skin SensitizationMagnusson & Kligman)
Preliminary study was conductedusing an intradermal concentration of
10% test substance in distilled waterand a topical induction concentrationof 50% test substance in distilledwater; these were the maximum nonirritating concentrations
Induction Phases: test substance wasapplied at indicated concentrations(volumes were not specified)
Challenge: test substance was applied
at indicated concentration (volumes
were not specified); skin was
examined 24 and 48 h post-challenge
application; positive and negative
controls were used

Results

Reference

Non-irritating, non-sensitizing

75

Induction Phases: moderate and confluent
erythema was reported 24 h postapplication at intradermal injection sites
and topical application sites; controls
showed slight or discrete erythema
Challenge: Non-sensitizing; no reactionsin test group or negative controls; positive
controls performed as expected74

Photosensitization/Phototoxicity
1,5 Pentanediol
Human (30)

Isopentyldiol
Dunkin-Hartley
Guinea Pig (10test animals, 10
controls)

Dunkin-Hartley
Guinea Pig (10test animals, 10

5% in a topicalformulation

Test substance was applied (single
application) to inner forearms; testsites on skin were then exposed to
UV-A light (30 J/cm2) and UV-B light(0.05 J/cm2); test skin sites werecovered with occlusive patch for 24 hand then patch was removed; skin wasassessed immediately after patch
removal and again at 48, 72, and 96 h
post-application

Non-phototoxic and non-photosensitizer;
study authors stated that 1,5-pentanediol
does not absorb in long-wave ultra-violet
range

75,76

Undiluted

To the shaved back of each animal
0.025 ml of test substance and apositive control (8-methoxysporalen
or 8-MOP) were applied
epicutaneously to test animals;
animals were exposed to 20 J/cm2 of
UVA radiation (320-400 nm); when
exposure of UVA radiation reached2.5 J/cm2 the positive control site wasconcealed with lightproof tape;control animals were not exposed to
UVA radiation; skin of all animals
examined 24, 48, and 72 h postapplication
Induction: to the shaved andchemically depilated back of each test
animal, 0.025 ml of test substance was

Isopentyldiol was a not a photoirritant;positive control performed as expected74

Isopentyldiol was non-photosensitizing; 1
animal was killed before challenge becauseof probable pneumonia; no skin reactions

74

Undiluted (used on
test animals during
induction andTable 4. Available toxicity studies for the hydrolysis product of Diethylpentanediol Dineopentanoate, neopentanoic
acid, and on 1,5 pentanediol and isopentyldiol.
Animal (n)controls)

Dose/
Concentration(s)challenge); distilledwater (controls); 0.1%
tetrachlorosalicylanilide in petrolatum(positive controls)

Methods
epicutaneously applied; animals were
exposed to 485 mJ/cm2 of UVA
radiation and 185 mJ/cm2 of UVB
radiation for 10 min; this procedure
was repeated 5x every 48 h for a totalof 6 applications in 2 weeks (animals
were shaved/depilated as needed);
control and positive control animals
were similarly treated except with
distilled water andtetrachlorosalicylanilide, respectively;
skin was examined 24, 48, and 72 h
post-application
Challenge: 12 days after induction
phase was complete, test substance
was applied epicutaneously (open) tothe backs (shaved/depilated) of test
and control animals following thesame procedures used in the induction
phase; 30 min post-application test
and control animals were exposed to
10 J/cm2 of UVA radiation, then test
substance was applied to a nearby skinsite of the test and control animals andno radiation exposure applied to thosesites; skin of all animals was
examined 24, 48, and 72 h postapplication of test substance, distilledwater, or positive control substance

Results
post-application of treatment during
induction or challenge phases; positive
controls performed as expected

Reference

Ocular Irritation
Neopentanoic acid
New ZealandWhite rabbit (4)New ZealandWhite rabbit (6)1,5 Pentanediol
Rabbit (6)Rabbit (notspecified)
Vienna White
rabbit (2 male, 4female)100%; 0.2 mLOECD Guideline 405 (Acute Eye
Irritation/Corrosion)

100%; 3 mg

OECD Guideline 405

Unknown

Test substance was instilled into the
conjunctival sac (no further details
specified)

Not specified

Not specified

Undiluted

Procedures followed (non-GLP) werein accordance with OECD TG 405(Acute Eye Irritation/ Corrosion); 0.1
ml test substance was instilled into the
conjunctival sac of one eye (remaining
eye served as control); eye were
unwashed; examination of eyes
occurred 24 to 72 h post-applicationand for up to 8 days post-application

Mean overall irritation score: 3.8 out of 16
over 7 days.
There was a severe pain response.
Highly irritating.
Minimal signs of eye irritation were
present after exposure. Immediately
following application, the rabbits exhibited
blinking and preening. Responses consistedof moderate conjunctivitis in all rabbits at 1h, which gradually diminished in severity
and was clear by day 4 post exposure.
Slight iritis in two rabbits persisted for 2 h.
Transient dullness in one rabbit andopacity of cornea in another rabbit withsome sloughing or corneal epithelium at 24
and 48 h. All signs of irritation resolved
after day 4 and confirmed by negative
fluorescein examination on day 7 post
exposure.

10

On a scale of 1 (very small area of
necrosis) to 10 (a severe burn) 1,5Pentanediol application resulted in a ratingof 2, suggesting mild irritation
Mildly irritating

71

Results were considered to be nonirritating; average eye ratings were: slightirritation, fully reversible by 72 h forcornea, iris, conjunctivae, chemosis

72

10

77

Table 4. Available toxicity studies for the hydrolysis product of Diethylpentanediol Dineopentanoate, neopentanoic
acid, and on 1,5 pentanediol and isopentyldiol.
Dose/
Concentration(s)Animal (n)Isopentyldiol
New ZealandWhite rabbit (6)Methods

Results

Reference

74
Procedures followed were in
Non-irritating
accordance with OECD TG 405(Acute Eye Irritation/ Corrosion); eyes
were examined at 1, 24, 48, and 72 h
and up to 7 days post-applicationa
One place in the study says “rat,” another says “rabbit.” The rest of the name “New Zealand White” in the summary is usually associated withrabbits.

Not specified

Table 5. Frequency of use according to duration and exposure of monoalkylglycol dialkyl acid esters. 23,24
Use type

Total/range
Duration of usea
Leave-on
Rinse-off
Diluted for (bath)use
Exposure type
Eye area
Incidental
ingestion
Incidental
Inhalation-sprays
Incidental
inhalation-powders
Dermal contact
Deodorant(underarm)
Hair-noncoloring
Hair-coloring
Nail
MucousMembraneBaby

Maximum
Concentration
Uses(%)
Butylene Glycol
Dicaprylate/Dicaprate
93
1.3-10Maximum
Concentration
Uses(%)
Diethylpentanediol
Dineopentanoate
NR
1

93
NR

1.3-10
NR

NR
NR

NR
1

NR
NR

5
NR

NR
NR

1.3
NR

NR

NR

NR

NR

NR

NR

NR

NR

1

1.3-9

NR

NR

NR

NR

NR

NR

Uses

Maximum
Concentration(%)

Glycol Diethylhexanoate
NR
5

Uses

Maximum
Concentration(%)

Glycol Dilaurate
NR
1.3

1

NR

NR

NR

NR

NR

NR

NR

51; 5b;
13c

10

NR

NR

NR

NR

NR

NR

2d; 13c10; 8d

NR

NR

NR

NR

NR

1.3d

92

NR

NR

1

NR

5

NR

1.3

NR

NR

NR

NR

NR

NR

NR

NR

NR
NR
NR

NR
NR
NR

NR
NR
NR

NR
NR
NR

NR
NR
NR

NR
NR
NR

NR
NR
NR

NR
NR
NR

1

NR

NR

NR

NR

NR

NR

NR

2

NR

NR

NR

NR

NR

NR

NR

Table 5. Frequency of use according to duration and exposure of monoalkylglycol dialkyl acid esters. 23,24
Use type

Total/range
Duration of use
Leave-on
Rinse-off
Diluted for (bath)use
Exposure type
Eye area
Incidental
ingestion
Incidental
Inhalation-sprays
Incidental
inhalation-powders
Dermal contact
Deodorant(underarm)
Hair-noncoloring
Hair-coloring
Nail
MucousMembrane
Baby

Total/range
Duration of use
Leave-on
Rinse-off
Diluted for (bath)use
Exposure typea
Eye area
Incidental
ingestion
Incidental
Inhalation-sprays
Incidental
inhalation-powders
Dermal contact
Deodorant(underarm)
Hair-noncoloring
Hair-coloring
Nail
MucousMembraneBaby

Maximum
Concentration
Uses(%)
Neopentyl Glycol
Dicaprate
69
0.1-50Maximum
Concentration
Uses(%)
Neopentyl Glycol
Dicaprylate/Dicaprate
102
0.017-22.7

Maximum
Concentration
Uses(%)
Neopentyl Glycol
Diethylhexanoate
77
0.9-57

Maximum
Concentration
Uses(%)
Neopentyl Glycol
Diheptanoate
415
1-33

64
5

0.1-400.24-5091
100.045-22.7
0.017-15

71
6

0.9-57
1.5-11

409
6

1-33
1.9-9

NR

11

1

NR

NR

NR

NR

NR

5

3.5-502

0.094-18.9

14

1-36.520

2.8-18

17

5-40

27

1.9-22.712

3.1-11.3

43b; 7c6; 3.5-6b19b; 17c

0.045-0.9b8b; 6c7c

2.5-16.8;
1-28.5d0.1-501d; 17c1; 2.2d

1; 6c

650.017-19

57

52

e

f

7
b

3.6-9.3;
0.9-7.5d
1.1-2;
3-57d
0.9-57

6; 295 ;
54c
54c
405

5-19.5;
3-19.5b2.4;
1-20.7d1-33

NR

0.1 ; 4

NR

NR

NR

NR

NR

NR

NR
NR
NR

1-6
3.5
NR

10
NR
NR

0.045-0.9
NR
NR

8
NR
NR

1.5-9.3
1.8
NR

6
NR
NR

1.9-19.5
NR
NR

17

5-40

28

0.017-22.7

13

3.1-11.3

6

7-9

NR

NR

1

NR

NR

NR

NR

1.2-2.2

Neopentyl Glycol
Diisostearate
30.2-1.1

Propanediol Dicaprylate
71

Propanediol
Dicaprylate/Caprate
1
13.5

Trimethyl Pentanyl
Diisobutyrate
399
0.1-9.83
NR

0.9-1.1
0.2

6
1

1
NR

1
NR

13.5
NR

399
NR

0.1-9.8
2

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

2

NR

NR

NR

NR

NR

1

NR

NR

NR

NR

NR

NR

NR

1b

NR

2b; 2c

NR

1b

NR

NR

0.9

d

c

d

2

1

NR

NR

NR

13.5

d

NR

NR

2

0.9-1.1

7

1

1

13.5

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR
NR
NR

NR
0.2
NR

NR
NR
NR

NR
NR
NR

NR
NR
NR

NR
NR
NR

NR
NR
399

NR
NR
0.1-9.8

1

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR = Not Reported; Totals = Rinse-off + leave-on+diluted for (bath) use product uses.
aBecause each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure types may not equal the sum of
total uses.
b
It is possible these products may be sprays, but it is not specified whether the reported uses are sprays.
c
Not specified whether a powder or a spray, so this information is captured for both categories of incidental inhalation.
d
It is possible these products may be powders, but it is not specified whether the reported uses are powders.
e
Not spray.
fSprayTable 6. Current and historical frequency and concentration of use of monoalkylglycol dialkyl acid esters according toduration and exposure.4,23,24# of Uses

Max Conc of Use (%)

2017

2001

Totals*Duration of Use
Leave-On
Rinse-Off
Diluted for (Bath) Use
Exposure TypeEye Area
Incidental Ingestion
Incidental Inhalation-Spray
Incidental Inhalation-Powder
Dermal Contact
Deodorant (underarm)
Hair - Non-Coloring
Hair-Coloring
Nail
Mucous Membrane
Baby Products

2016# of Uses

Max Conc of Use (%)

2001

2017

2009

1663

Glycol Distearate
28
0.5-13.1

0.2-9

Neopentyl Glycol Diisononanoate
NR
NR
1.3-5

2016

2009
1

59
1531
73

1
26
1

0.2-13.1
0.05-10
0.2-5

1-6
0.2-9
0.4-3

NR
NR
NR

NR
NR
NR

1.3
2-5
NR

NR
1
NR

1
NR
1; 17a; 14b
14b
621
NR
539
502
NR
432
15

NR
NR
NR
NR
19
NR
9
NR
NR
16
NR

0.2-13.1
NR
1-2.5a2.5; 2-5.4c
0.05-13.1
NR
0.39-10
0.5-8
2
0.2-5
0.4-0.6

3
NR
2-6 b
2-6 b
0.2-6
NR
2-9
0.2-0.5
NR
0.4-3
1

NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR

NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR

NR
NR
NR
NR
1.3-5
NR
NR
NR
NR
NR
NR

NR
NR
NR
NR
1
NR
NR
NR
NR
NR
NR

*Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure types may not equal the sum of total uses.
NR – no reported usea
It is possible these products are sprays, but it is not specified whether the reported uses are sprays.
b
Not specified whether a spray or a powder, but it is possible the use can be as a spray or a powder, therefore the information is captured in both categoriesc
It is possible these products are powders, but it is not specified whether the reported uses are powders.

Table 7. Monoalkylglycol dialkyl acid esters with no reported
use.4,23,24
Butylene Glycol Diisononanoate
Dioctadecanyl
Ditetradecyloctadecanoate
Glycol Dioleate
GlycolDipalmate/Rapeseedate/Soyate
Glycol Ditallowate
Neopentyl Glycol
Dicaprylate/Dipelargonate/Dicaprate
Propanediol Diisostearate

Dioctadecanyl Didecyltetradecanoate
Glycol Dibehenate
Glycol Dipalmate/Palm
Kernelate/Olivate/Macadamiate
Glycol Dipivalate
Hexanediol Distearate
Neopentyl Glycol Dilaurate
Propanediol Dipelargonate

Table 8. Code of Federal Regulations that apply to monoalkylglycol dialkyl acid esters in this safety assessment.
Ingredient(s)Trimethyl Pentanyl
Diisobutyrate

Glycol Distearate

Glycol Distearate, Glycol
Ditallowate

Regulation
21CFR175.105 – may be used as a stabilizer in adhesives used in food packaging.
21CFR177.1200 - For use only in cellophane coatings and limited to use at a level not to exceed 10% by weight of thecoating solids except when used as provided in § 178.3740 of this Chapter.
21CFR178.3740 - For use only in cellulosic plastics in an amount not to exceed 15% by weight of the finished foodcontact article, provided that the finished plastic article contacts food only of the types identified in § 176.170(c) of thischapter, table 1, under Categories I, II, VI-B, VII-B, and VIII.
I. Nonacid, aqueous products; may contain salt or sugar or both (pH above 5.0).
II. Acid, aqueous products; may contain salt or sugar or both, and including oil-in-water emulsions of low- or high-fat
content.
VI. Beverages: B. Nonalcoholic.
VII. Bakery products other than those included under Types VIII or IX of this table: B. Moist bakery products withsurface containing no free fat or oil.
VIII. Dry solids with the surface containing no free fat or oil (no end test required).
21CFR73.1 - …[M]ay be safely used as diluents in color additive mixtures for food use exempt from certification, subject
to the condition that each straight color in the mixture has been exempted from certification or, if not so exempted, isfrom a batch that has previously been certified and has not changed in composition since certification. If a specification
for a particular diluent is not set forth in this part 73, the material shall be of a purity consistent with its intended use.
(a) General use. (1) Substances that are generally recognized as safe under the conditions set forth in section 201(s) of theact.
(2) Substances meeting the definitions and specifications set forth under subchapter B of this chapter, and which are used
only as prescribed by such regulations.
(2) Diluents in color additive mixtures for coloring shell eggs. Items listed in paragraph (a) of this section and thefollowing, subject to the condition that there is no penetration of the color additive mixture or any of its components
through the eggshell into the egg [as diethylene glycol distearate and ethylene glycol distearate].
21CFR176.210 - Defoaming agents may be safely used in the manufacture of paper and paperboard intended for use inpackaging, transporting, or holding food in accordance with the following prescribed conditions:(a) The defoaming agents are prepared from one or more of the substances named in paragraph (d) of this section, subject
to any prescribed limitations.
(b) The defoaming agents are used to prevent or control the formation of foam during the manufacture of paper andpaperboard prior to and during the sheet-forming process.
(c) The quantity of defoaming agent or agents added during the manufacturing process shall not exceed the amountnecessary to accomplish the intended technical effect.
(d) Substances permitted to be used in the formulation of defoaming agents include substances subject to prior sanctions
or approval for such use and employed subject to the conditions of such sanctions or approvals, substances generally
recognized as safe for use in food, substances generally recognized as safe for use in paper and paperboard, andsubstances listed in this paragraph, subject to the limitations, if any, prescribed.
(1) Fatty triglycerides, and the fatty acids, alcohols, and dimers derived therefrom:
Beef tallow.
Diethylene glycol (esters).

Table 9. Acute toxicity studies of monoalkylglycol dialkyl acid esters.
Ingredient

Animal (n)Trimethyl Pentanyl
Diisobutyrate

Hartley guinea pigs (n= 3)Trimethyl Pentanyl
Diisobutyrate
Trimethyl Pentanyl
Diisobutyrate

Guinea pigs (notspecified)
New Zealand White
rabbits (n = 5/sex)

Glycol Distearate

New Zealand White
rabbits (n = 3/sex)

Glycol Distearate

New Zealand White
rabbits (n = 3)

Methods; Results
Dermal100%; 5, 10, or 20 mL/kg (4.63, 9.26, or 18.53 g/kg). Following depilation of
abdomens, a single dose of undiluted test material was applied under occlusion for 24
h. Guinea pigs were observed on days 2, 7, and 14 after removal. There were noclinical signs. Two guinea pigs lost weight. LD50 > 20 mL/kg.
5 mg/kg. Slightly irritating.
100% (2000 mg/kg). OECD TG 402 (Acute Dermal Toxicity). Test substance wasadministered to clipped skin, approximately 10% of the body surface, under semiocclusion for 24 h. Residual test substance was removed with paper towels soaked intap water. There were no mortalities. Clinical signs were: instances of diarrhea, few
feces, and soiling of the anogenital area, which were resolved by day 14. Bodyweightgains were normal.
At necropsy results were normal in 3 males and 3 females. Abnormalities included
small spleen in 1 male, slight or scattered red areas in the thymus of 1 male, andslight or scattered red areas in the pancreas of 1 male and 2 females.
LD50 > 2000 mg/kg.
100% (0.5 g) was applied to shaved and abraded skin (2.5 cm2) under occlusion for
25 h. All rabbits appeared active and healthy. There were no signs of gross toxicity,
adverse pharmacologic effects or abnormal behavior.
100%. Amount and duration not specified. Observed at 1, 24, 48 and 72 h and 7 days.
No signs of systemic effects.

Reference
7,18,34

18

7,34

5

5

Table 9. Acute toxicity studies of monoalkylglycol dialkyl acid esters.
Ingredient

Animal (n)Trimethyl Pentanyl
Diisobutyrate

Rats (n = 2)

Trimethyl Pentanyl
Diisobutyrate

Female Wistar rats (n= 5)Trimethyl Pentanyl
Diisobutyrate

Mice (n = 2)

Diethylpentanediol
Dineopentanoate

Female SpragueDawley CD rats (n =6)Glycol Distearate

Sprague-Dawley rats
(n = 5/sex)

Glycol Distearate

Rats (not specified)

Glycol Distearate

Female Swiss mice (n= 5)Neopentyl Glycol
Dicaprate
Neopentyl Glycol
Diethylhexanoate

Female Sprague
Dawley CD rats (n =6)Male and female rats
(not specified)

Neopentyl Glycol
Diethylhexanoate

Female Swiss mice (n= 5)Neopentyl Glycol
Diheptanoate

Male and female
Alderley Park (Alpk:
APfSD) albino rats
(not specified)Methods; Results
Oral
800, 1600, or 3200 mg/kg by gavage and observed for 2 weeks. There were no
mortalities. Effects were observed at 3200 mg/kg. Weight gains were normal.
Clinical signs: moderate weakness and some vasodilatation following dosing.
2000 mg/kg by gavage and observed for 2 weeks. There were no mortalities. Weightgains were normal. Wet anogenital areas were observed on Days 0 and 1. Necropsies
were unremarkable. LD50 > 2000 mg/kg.
400, 800, 1600, 3200 or 6400 mg/kg by gavage and observed for 2 weeks. 1 mousedied within 1 day (not known which group but not in 6400 mg/kg group). Weightgains were normal. No clinical abnormalities were observed.
OECD TG 423 (Acute Oral Toxicity). The rats were treated by oral gavage with an
undiluted dose of 2000 mg/kg and observed for 14 days. There were no mortalities.
Ataxia and/or hunched posture were observed after treatment; all rats recovered 1 day
after dosing. Weight gains were as expected and no abnormalities were observed at
necropsy.
LD50 was estimated to be > 2500 mg/kg
5000 mg/kg (2.5% in CMC) by oral gavage in two 2.2 - 2.3 mL doses within 24 h.
Observed for 14 days. No mortalities or clinical signs of toxicity. LD50 > 5000
mg/kg.
OECD TG 401 (Acute Oral Toxicity)
LD50 > 2000 mg/kg
Single dose at 5000 mg/kg by gavage. LD50 > 5000 mg/kg.
No mortalities or clinical signs of toxicity were observed up to the end of the 14-day
observation period.
OECD TG 423 (Acute Oral Toxicity). Single dose at 2000 mg/kg neat after fasting.
LD50 > 2000 mg/kg.
No mortalities or clinical signs of toxicity were observed.
Single dose at 2000 mg/kg in corn oil by gavage.
OECD TG 401 (Acute Oral Toxicity)
LD50 > 2000 mg/kg
No mortalities or clinical signs of toxicity were observed.
Single dose at 2 mL/kg (no details on administration)
No mortalities or clinical signs of toxicity were observed up to the end of the 14-day
observation period.
LD50 > 2000 mL/kg (> 1880 mg/kg)
Single dose at 2000 mg/kg in corn oil by gavage; OECD TG 401 (Acute Oral
Toxicity).
No mortalities or clinical signs of toxicity were observed up to the end of the 14-day
observation period.

Reference
7,18,347,34

7,18,34

16,36

5

37

5

17

9

9

8

Inhalation
7,34
Whole body apparatus at 0.12 mg/L (10 ppm) for 6 h and observed for 14 days.
There were no mortalities or clinical signs. Weight gains were normal. LC lo > 0.12
mg/L.
7,18,34
Trimethyl Pentanyl
Rats (n = 3)
Whole body apparatus at 5300 mg/L (453 ppm) for 6 h and observed for 14 days.
Diisobutyrate
There were no mortalities. Discolored (pink) extremities were observed. Weightgains were normal. LClo > 5300 mg/L.
6,8
Neopentyl Glycol
RccHanTM;Wist rats
Nose only apparatus for 4 h and observed for 14 days. Mean achieved test
Diheptanoate(n = 3/sex)
atmosphere concentration = 2.14 mg/mL (13.5 mg/L nominal). MMAD/GSD: 1.42
µm/2.56 µm. No mortalities. Clinical signs included: hunched posture andpiloerection for short period after removal from exposure chamber. Increased
respiratory rate was observed in all rats. On removal from chamber and 1 h postexposure, all rats exhibited increased respiratory rates and ataxia. One day after
exposure, all rats still showed increased respiratory rate and hunched posture withoccasional instances of piloerection. All rats appeared normal at days 5 to 8 postexposure. At necropsy, no macroscopic abnormalities were observed. LC 50 > 5.22
mg/L (analytical).
CMC = carboxymethyl cellulose; GDS = Geometric standard deviation; MMAD = Mass median aerodynamic diameter; OECD TG = Organisation for
Economic Co-operation and Development Test Guidelines
Trimethyl Pentanyl
Diisobutyrate

Rats (n = 3)

Table 10. In vitro genotoxicity studies of monoalkylglycol dialkyl acid esters.
Test Article
Trimethyl Pentanyl
Diisobutyrate

Trimethyl Pentanyl
Diisobutyrate

Concentration/Vehicle
Without metabolic activation:
0,10, 15, 20, 25, 30, and 40µg/mL
With metabolic activation: 0,
250, 500, 750, 1000, 1500, 2000
µg/mL
DMSO
Not specified

ProcedureOECD TG 476 (In Vitro
Mammalian Cell
Mutation Assay)

Test System
CHO cells

Results
Negative with andwithout metabolic
activation.
Controls had
expected response.

ReferenceOECD TG 476 (In Vitro
Mammalian Cell
Mutation Assay)
EU Method B.13/14(Mutagenicity - Reverse
Mutation Test Using
Bacteria) [Ames test]

CHO cells

Negative with andwithout metabolic
activation.
Negative with andwithout metabolic
activation.
Controls had
expected response.
Negative with andwithout metabolic
activation.
Negative with andwithout metabolic
activation.
Negative with andwithout metabolic
activation.
Controls had
expected response.

34

CHO cells

Negative with andwithout metabolic
activation.

34

CHO cells

Negative with andwithout metabolic
activation.
Cytotoxic at 0.018
and 0.04 mg/mL
with and without
metabolicactivation,
respectively.
Negative

18

Trimethyl Pentanyl
Diisobutyrate

100, 250, 500, 1000, 2500, 5000
µg/plate
DMSO

Trimethyl Pentanyl
Diisobutyrate

Not specified

OECD TG 471 (Bacterial
Reverse Mutation Test)

S. typhimurium and E. coli(strains not specified)

Trimethyl Pentanyl
Diisobutyrate

0, 312.5, 625, 1250, 2500 or
5000 μg/plate

Japanese Guideline for
Screening Mutagenicity

Trimethyl Pentanyl
Diisobutyrate

Without metabolic activation:
6.25, 12.5, 17.5, 25.0, 37.5, 50.0
µg/mL
With metabolic activation: 125,
175, 250, 350, 500, 1000 µg/mL
DMSO

Trimethyl Pentanyl
Diisobutyrate

Not specified

Trimethyl Pentanyl
Diisobutyrate

Not specified

OECD TG 473 (In vitro
Mammalian
Chromosome AberrationTest), OPPTS 870.5375
and EU B.10
(Mutagenicity - In Vitro
Mammalian
Chromosome Aberration
Test)
OECD TG 473 (In vitro
Mammalian
Chromosome Aberration
Test)
Japanese Guideline for
Screening Mutagenicity

S. typhimurium (TA98,
TA100, TA1535, TA1537,
TA1538); E. coli (uvrA)
CHO cells

Diethylpentanediol
Dineopentanoate

312.5, 625, 1250, 2500, and5000 µg/plate with and without
metabolic activation

Ames test

Glycol Distearate

Experiment 1:
8, 40, 200, 1000 and 5000
µg/plate with and without
metabolic activation

Ames test; 3 days of
exposure

Glycol Distearate

Glycol Distearate

Experiment 2:61.73, 185.19, 555.56, 1666.67
and 5000 µg/plate with andwithout metabolic activation
Experiment 1:
0.1, 0.3, 1.0, 3.0, 10.0, 33.0,
100.0 and 333.0 µg/mL with andwithout metabolic activation
Experiment 2:
3.0, 10.0, 33.0, 100.0, 125.0,
140.0 and 175.0 µg/mL without
metabolic activation
0, 0.1, 0.3, 1.0, 3.0, 10.0, 33.0,
100.0 and 333.0 µg/mL withmetabolic activation
Not specified

Ames test;
Experiment 1:
3 h of exposure

S. typhimurium (TA98,
TA100, TA1535, andTA1537); E. coli (WP2
uvr A pKM 101)

S. typhimurium (TA98,
TA100, TA1535, andTA1537); E. coli (WP2
uvr A pKM 101)
S. typhimurium (TA98,
TA100, TA1535, andTA1537)

7

34

18

5

16,36

Negative with andwithout metabolic
activation.
Controls had
expected response.

5

S. typhimurium (TA98,
TA100, TA1535, andTA1537)

Negative with andwithout metabolic
activation.
Controls had
expected response.

5

Not specified

Negative

37

Experiment 2:
24 h of exposure without
metabolic activation; 3 hof exposure withmetabolic activation

OECD TG 471 (Bacterial

7

Table 10. In vitro genotoxicity studies of monoalkylglycol dialkyl acid esters.
Test Article

Concentration/Vehicle

Glycol Distearate

Not specified

Neopentyl Glycol
Dicaprate

5 concentrations: 50-5000µg/plate in acetone

Neopentyl Glycol
Diethylhexanoate

Experiment 1:
0.03, 0.1, 0.3, 1, 3, 10, 33, 100µg/mL with and without
metabolic activation

Neopentyl Glycol
Diethylhexanoate

Neopentyl Glycol
Diethylhexanoate

Experiment 2:
0.03, 0.1, 0.3, 1, 3, 10, 33, 100µg/ml (with metabolic
activation;
0.3, 1, 3, 10, 33, 66, 85, 100,
125, 150 µg/mL:
1, 5, 10, 17.5, 25, 75, 100, 125,
50, 175, 200, 225, 250, 275 and300 µg/mL; and0.3, 1, 3, 10, 33, 100, 200, 300,
400, 500 and 600 µg/mL without
metabolic activation.
Pretest: 0.15, 0.5, 1.5, 5, 15, 50,
150, 500, 1500 and 5000
µg/plate without metabolic
activation
Main test: 50, 150, 500, 1500
and 5000 µg/plate with andwithout metabolic activation in
acetoneRange finding study:
3 h: 3, 10, 33, 100 and 333µg/mL with and without
metabolic activation
24 and 48 h: 3, 10, 33, 100, 333,
1000 and 3333 µg/mL without
metabolic activation

Procedure
Reverse Mutation Test)
OECD TG 476 (In vitro
Mammalian Cell Gene
Mutation Test)
OECD TG 471 (Bacterial
Reverse Mutation Test)

Test System

Reference

Not specified

Negative

37

S. typhimurium (TA98,
TA100, TA1535, andTA1537)

Negative. An oily
precipitate wasobserved at ≥ 1500
µg/plate.
Fluctuations incytotoxicity
without metabolic
activation.
Negative with andwithout metabolic
activation.
Controls had
expected response.

17

Precipitation at
and above 1500
µg/plate. Negativewith and without
metabolicactivation.
Controls had
expected response.
Cytotoxic at 100µg/mL without
metabolicactivation at 48 h.
Negative with andwithout metabolic
activation.
Controls had
expected response.

9OECD TG 476 (In vitro
Mammalian Cell Gene
Mutation Test), EU
Method B.17
(Mutagenicity-In Vitro
Mammalian Cell Gene
Mutation Test)

Mouse lymphoma L5178Y
cells

EPA OPPTS 870.5265(The Salmonella
typhimurium Bacterial
Reverse Mutation Test)

S. typhimurium (TA98,
TA100, TA102, TA1535,
and TA1537)

OECD TG 473 (In vitro
Mammalian
Chromosome AberrationTest), EU Method B.10
(Mutagenicity - In Vitro
Mammalian
Chromosome Aberration
Test)

Cultured peripheral human
lymphocytes

Experiment 1:
3 h: 3, 10, 33, 100 and 333µg/mL with and without
metabolic activation
Experiment 2:
3 h: 50, 100 and 350 µg/mL withmetabolic activation
24 and 48 h: 5, 10, 50, 150 and
200 µg/mL without metabolic
activation
48 h: 10, 30, 50, 60, 70, 80, 90
and 100 µg/mL without
metabolic activation
In ethanol
25, 75 and 150 µg/mL with andwithout metabolic activation

Results

99

9
Negative with andwithout metabolic
activation.
Controls had
expected response.
38
Propanediol
0.005 mL/plate
Ames test without
S. typhimurium (TA 97a,
Negative with andDicaprylate/Caprate
metabolic activation; 3 hTA98, TA100, TA102, and without metabolicof exposure with
TA1535)
activation.
metabolic activation
Controls had
expected response
CHO = Chinese hamster Ovary cells; DMSO = Dimethyl sulfoxide; OECD TG = Organisation for Economic Co-operation and Development Guidelines

Neopentyl Glycol
Diethylhexanoate

Chromosome aberration

Human lymphocytes fromsingle male donorTable 11. Animal dermal irritation studies of monoalkylglycol dialkyl acid esters.
Ingredient(concentration/dose)
Trimethyl Pentanyl
Diisobutyrate (100%; 5, 10,
or 20 mL/kg; 4.63, 9.26, or
18.53 g/kg)
Trimethyl Pentanyl
Diisobutyrate (100%; 2000
mg/kg)

Test
Population
Hartley guinea
pigs (n = 3)

Trimethyl Pentanyl
Diisobutyrate (100%; 0.5
mL)

New ZealandWhite rabbits (n= 1 male, 2females)

Diethylpentanediol
Dineopentanoate (neat)

New Zealandwhite rabbits (n= 3)Glycol Distearate (100%;
0.5 g)New ZealandWhite rabbits (n= 3/sex)

Glycol Distearate (100%)

New ZealandWhite rabbits (n= 3)Glycol Distearate (notspecified)
Glycol Distearate (25%,50%, 75%, and 100% inwater)
Neopentyl Glycol
Diethylhexanoate (notspecified, tested neat)
Neopentyl Glycol
Diethylhexanoate (notspecified, tested neat)

Rabbits (notspecified)
Pirbright guinea
pigs (n = 3)

Neopentyl Glycol
Diheptanoate (100%; 0.5
mL)

New ZealandWhite rabbits (n= 3)New ZealandWhite rabbits (n= 5/sex)New ZealandWhite rabbits (n= 3)New ZealandWhite rabbits (n= 3)Procedure
Administered to depilated
abdomens under occlusion for
24 h. Observed on days 2, 7,
and 14 after removal.
Administered to the clippedskin, approximately 10% ofbody surface under semiocclusion for 24 h. Residual
test substance was removed
with paper towels soaked intap water.

Administered to shaved skinunder semi-occlusion for 4 h
in accordance with OECD TG
404 (Acute Dermal Irritation/
Corrosion)
Administered to intact skinunder semi-occlusion for 24 hin accordance with OECD TG
404 (Acute Dermal Irritation/
Corrosion)
Applied to shaved andabraded skin (2.5 cm2) underocclusion for 25 h. Test site
was observed at removal and
72 h after removal.
Applied to skin underocclusion; amount andduration not specified. Testsite was observed at 1, 24, 48
and 72 h and 7 days afteradministration.
OECD TG 404 (Acute
Dermal Irritation/ Corrosion)
Applied under occlusion for 6
h. 100% was applied in a few
drops of distilled water.
No further details were
provided
4 h of exposure

Administered to shaved skinunder semi-occlusion for 4 h
in accordance with OECD TG
404 (Acute Dermal
Irritation/Corrosion).
Application site examined at
1, 24, 48 and 72 h.
OECD GL = Organisation for Economic Co-operation and Development Guidelines

Results
At the 24- to 48-h examinations, slight to moderateedema and/or erythema with some hemorrhage wasobserved. Only desquamation was observed at the 1- and2-week examinations.
At removal, there was no erythema or edema observed in
two males and one female. Very slight erythema (Grade1) was present in one male and three females, and welldefined erythema (Grade 2) was observed in one female.
Very slight edema (Grade 1) was present in two males
and one female and slight edema (Grade 2) was observed
one male and two female. Seven days after removal oftest substance, all males and three females were normal;
two females had severe erythema (Grade 4) with flaking
skin. One female had slight edema (Grade 2) and one
had very slight edema (Grade 1).
There were no signs of irritation observed during study.
Conclusion: not considered an irritant or corrosive.

Reference

At 24, 48, and 72 h, the mean erythema/eschar scores
were 0.67, 1.00, and 1.33, respectively; the edema scores
were 0.00, 0.33, and 0.33, respectively. Signs of
irritation were resolved at 7 days after exposure. No
other clinical signs were observed. Classified as a nonirritant to rabbit skin.
There were no signs of erythema or edema during study
period. Draize scores for erythema and edema were 0 out
of 4.

16,36

No effects on skin were observed during study period in
any rabbit. Draize scores for erythema and edema were 0
out of 4.

5

Not irritating.

37

No signs of irritation.

5

Erythema and edema scores were 0 at 24, 48, and 72 h
after administration

9

Erythema scores were 0 at 24, 48, and 72 h afteradministration. Edema scores were 0.33, 0, and 0,
respectively. No signs of irritation were observed in two
rabbits. Slight erythema and transient slight edema wereobserved in third rabbit, which was completely resolved
2 days after removal of test substance.
No signs of erythema or edema were observed during thetest period.

9

7

7

7,34

5

8

Table 12. Animal sensitization studies of monoalkylglycol dialkyl acid esters
Ingredient
Trimethyl Pentanyl
Diisobutyrate

Concentration
1% in acetone

Animal (n)guinea pigs (4, 5solvent control, 4
positive control)

Assay
Induction and challenge
were by open epicutaneous
exposure. Positive control
was phenylhydrazine.
Examinations at 24 and 48
h after the challenge dose.

Trimethyl Pentanyl
Diisobutyrate

1% in organic solvent

Guinea pigs (3),Diethylpentanediol
Dineopentanoate

Injected 25% (0.1 mL inparaffin oil and Freund’s
adjuvant) then treated
topically with 100%.
Challenge was topicalapplication at 100% (0.5mL)
100% in a few drops ofwater for both induction
and challenge
Not specified, assumed
100%
Induction phase wasconducted at 100%,challenge at 30% in corn
oil and 100%.

Male albino Hartley
guinea pigs (10;controls = 5)

Dermal sensitization study.
No further details were
provided.
In accordance with OECD
TG 406 (skin sensitization)

Glycol Distearate

Glycol Distearate
Neopentyl Glycol
Diheptanoate

Results
No positive sensitization
reactions in the test or
negative control groups.
Positive control group
had the expected
response. Not
considered a skinsensitizer in this study.
No signs of sensitization

Reference

No reactions wereobserved in any oftreated guinea pig. Test
substance was a nonsensitizer.

16,36

7

34

Pirbright guinea pigs
(20; 10 controls)

Test sites were examined
24 and 48 h after challenge

No signs ofsensitization.

5

Guinea pigs (notspecified)Male Dunkin-Hartley
guinea pigs (20; 10
controls)

In accordance with OECD
TG 406
In accordance with OECD
TG 406

Not sensitizing37

One guinea pig had mild
redness at 24 h after thehigh-dose challenge;
there were no signs of
any type of reaction at
the test sites at 48 h.
Not sensitizing

6,8OECD TG = Organization for Economic Co-operation Guidelines

Table 13. HRIPTs of monoalkylglycol dialkyl acid esters.
Ingredient
Trimethyl Pentanyl
Diisobutyrate

Details
1.0% in acetone. Occlusive patches were applied
to backs of subjects for 24 h each 3 times per
week for a total of 9 applications. Challenge
patch was applied after 10-17 days to a naïve site.

n102

Trimethyl Pentanyl
Diisobutyrate

1.0% in acetone. Semi-occlusive patches wereapplied 3 times per week for 3 weeks. After a 2week rest, the challenge patch was applied to anaïve site.
1.0% in acetone. Semi-occlusive patches wereapplied 3 times per week for 3 weeks. Patches
were in place for 24 h. Challenge was applied
after a two-week rest.

200

100%; 0.2 mL, 0.2 mg. Test substance wasapplied to upper back of subjects 3 times per
week for 3 weeks. Patches were left in place for
24 h. A challenge patch was applied to naïve site
after a 10- to 14-day rest. Reactions were scored24-48 h after application of test material.
100%; 0.2 mL-Webril adhesive patches wereapplied 3 times per week for 9 applications andleft in place for 24 h. Challenge was applied after
approximately 14 days.

50

100%; 0.2 mL, 0.2 mg. Test substance wasapplied to upper back of subjects 3 times per
week for 3 weeks. Patches were left in place for
24 h. A challenge patch was applied to naïve site
after a 10- to 14-day rest. Reactions were scored24-48 h after application of test material.
Propanediol Dipelargonate
100%; 0.2 mL, 0.2 mg. Test substance wasapplied to upper back of subjects 3 times per
week for 3 weeks. Patches were left in place for
24 h. A challenge patch was applied to naïve site
after a 10- to 14-day rest. Reactions were scored24-48 h after application of test material.
HRIPT = Human repeated insult patch test

50

Trimethyl Pentanyl
Diisobutyrate

Neopentyl Glycol
Diethylhexanoate

Neopentyl Glycol
Diethylhexanoate

Propanediol
Dicaprylate/Caprate

203

96

50

Results
At 48 h after challenge, 2 subjects exhibited"slight, confluent or patchy erythema", which
persisted to 96 h. One subject experienced aspreading reaction beyond patch area with all test
articles (assumed multiple tests were being
conducted at once), which developed into apapular rash of the entire torso; subject described ahistory of such reactions, and was discontinued
from study and followed to resolution. Anothersubject exhibited slight reactions at challenge,
which was generally consistent with irritation.
Isolated instances of slight to mild redness wereobserved during induction. There were3 instancesof slight redness during challenge phase. Test
substance was non-sensitizing.
Two subjects exhibited slight erythema to test
substance on at least 5 occasions out of the 9
exposures. None of the subjects had a reaction atchallenge. Test material was reported to be nonsensitizing.
No adverse reactions of any kind were observed
during the course of this study; the test substance
was not an irritant or a sensitizer.

Reference

During the induction phase one subject exhibited
faint, minimal erythema. No reactions wereobserved during the rest and challenge phases ofthe experiment. No sensitizing reactions werereported.
No adverse reactions of any kind were observed
during the course of this study.

9

No adverse reactions of any kind were observed
during the course of this study.

7

34

41

40

42

43

Table 14. Ocular irritation studies on New Zealand White rabbits.
Concentration
(%)
100

n
6

Diethylpentanediol
Dineopentanoate

Neat; 0.1 mL

3Glycol Distearate

100

3/sex

0.1 g. Instilled into one eye,other eye served as control.
Eyes were examined at 24,
48 and 72 h after instillation

Glycol Distearate

Not specified,tested neat3

Instilled into one eye, othereye served as control. Eyes
were examined at 24, 48 and
72 h after instillation.

Neopentyl Glycol
Diethylhexanoate

Not specified,tested neat3

Eyes were examined at 4,
24, 48, 72 h and 7 days after
instillation.

Neopentyl Glycol
Diethylhexanoate

Not specified,tested neat

3a

Ingredient
Trimethyl Pentanyl
Diisobutyrate

Method
0.1 mL. Instilled into oneeye, the other served as thecontrol. 3 were washedimmediately, 3 were not.
Observed at 1, 24, 48, and72 h.
OECD TG 405 (Acute Eye
Irritation/Corrosion). Eyes
were not rinsed.

Results
There was slight redness for 1 unwashed eye and 3
washed eyes at the 1 h. There was no staining inunwashed or washed eyes when tested withfluorescein dye at 24 h. There were no abnormal
systemic signs noted during the observation period.

Reference

All eyes were normal at 24 h after treatment.
Maximum score of 4.0 (Class 3 on a 1 to 8 scale)according to a modified Kay and Calandra scale.
Minimal irritant
After 24 h, 4 rabbits had mild redness and 2 of 6 hadmoderate redness. At 48 h, 4 rabbits had mild
redness visible, which was fully reversible in 2
rabbits and persistent up to 72 h in 2 rabbits. After
24 h, 1 rabbit had mild chemosis, which was fully
reversible within 48 h. Average irritation scores (outof 4) for redness, swelling, iris corrosion, and cornea
corrosion were 0.78, 0.06, 0.0, and 0.0, respectively.
Not an ocular irritant.
No effects on cornea and iris were observed during
the study period in any rabbit. At 1 h after
instillation, moderate conjunctivae reactions wereobserved; these conjunctivae reactions were reduceat 24 and 48 h, and all effects were fully resolved in
all rabbits at 72 h. Average irritation scores forconjunctivae, iris corrosion, and cornea corrosion
were 0.7, 0.0, and 0.0, respectively. Not an ocular
irritant.
Conjunctival reactions were observed in all 3
animals after 4 h, which resolved within 24 h in 1
rabbit and within 48 h in other 2 rabbits. Not
irritating.
Slight erythema was observed in all rabbits 1 h after
instillation, which was resolved in 2 rabbits at 1 day
and the third at day 2. Erythema was observed in 1
rabbit and discharge was observed in all 3 rabbits
only at 1 h after instillation. Not irritating.
No effects on cornea or iris observed. Moderate(grade 2) conjunctival irritation was observed inboth rabbits 1 h after treatment. At 24 h, only
minimal conjunctival irritation (grade 1) waspresent, which was resolved at 48 h. Not irritating.

16,36Instilled into one eye, otherserved as the control. Theeyes were examined at 1h
and 1, 2, and 3 days after
instillation.
Neopentyl Glycol
100; 0.1 mL
2OECD TG 405 (Acute Eye
Diheptanoate
males Irritation/Corrosion); EU
Method B.5 (Acute
Toxicity: Eye Irritation /Corrosion). Eyes were
examined at 1, 24, 48 and 72
h after instillation.
OECD TG = Organisation for Economic Co-operation and Development Test Guidelinesa
Strain of rabbit not specified.

7,34

5

5

9

9

8

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