U.S. Environmental Protection Agency
Hazard Characterization Document
December, 2012
SCREENING-LEVEL HAZARD CHARACTERIZATION
SPONSORED CHEMICAL
l,7-Bis(l,3-dimethylbutylidene)diethylenetriamine (CASRN 10595-60-5)
SUPPORTING CHEMICALS
Diethylenetriamine (CASRN 111-40-0)
Methyl isobutyl ketone (CASRN 108-10-1)
The High Production Volume (HPV) Challenge Program1 was conceived as a voluntary initiative
aimed at developing and making publicly available screening-level health and environmental
effects information on chemicals manufactured in or imported into the United States in quantities
greater than one million pounds per year. In the Challenge Program, producers and importers of
HPV chemicals voluntarily sponsored chemicals; sponsorship entailed the identification and
initial assessment of the adequacy of existing toxicity data/information, conducting new testing if
adequate data did not exist, and making both new and existing data and information available to
the public. Each complete data submission contains data on 18 internationally agreed to "SIDS"
1 2
(Screening Information Data Setl ' ) endpoints that are screening-level indicators of potential
hazards (toxicity) for humans or the environment.
The Environmental Protection Agency's Office of Pollution Prevention and Toxics (OPPT) is
evaluating the data submitted in the HPV Challenge Program on approximately 1400 sponsored
chemicals by developing hazard characterizations (HCs). These HCs consist of an evaluation of
the quality and completeness of the data set provided in the Challenge Program submissions.
They are not intended to be definitive statements regarding the possibility of unreasonable risk of
injury to health or the environment.
2 3
The evaluation is performed according to established EPA guidance ' and is based primarily on
hazard data provided by sponsors; however, in preparing the hazard characterization, EPA
considered its own comments and public comments on the original submission as well as the
sponsor's responses to comments and revisions made to the submission. In order to determine
whether any new hazard information was developed since the time of the HPV submission, a
search of the following databases was made from one year prior to the date of the HPV
Challenge submission to the present: (ChemID to locate available data sources including
Medline/PubMed, Toxline, HSDB, IRIS, NTP, AT SDR, IARC, EXTOXNET, EPA SRS, etc.),
STN/CAS online databases (Registry file for locators, ChemAbs for toxicology data, RTECS,
Merck, etc.), Science Direct and ECHA4. OPPT's focus on these specific sources is based on
their being of high quality, highly relevant to hazard characterization, and publicly available.
OPPT does not develop HCs for those HPV chemicals which have already been assessed
internationally through the HPV program of the Organization for Economic Cooperation and
Development (OECD) and for which Screening Initial Data Set (SIDS) Initial Assessment
1	U.S. EPA. High Production Volume (HPV) Challenge Program; http://www.epa.gov/chemrtk/index.htm.
2	U.S. EPA. HPV Challenge Program - Information Sources; http://www.epa.gov/chemrtk/pubs/general/guidocs.htm.
3	U.S. EPA. Risk Assessment Guidelines; http://cfpub.epa.gov/ncea/raf/rafguid.cfm.
4	European Chemicals Agency, http://echa.europa.eu.

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Reports (SIAR) and SIDS Initial Assessment Profiles (SIAP) are available. These documents are
presented in an international forum that involves review and endorsement by governmental
authorities around the world. OPPT is an active participant in these meetings and accepts these
documents as reliable screening-level hazard assessments.
These hazard characterizations are technical documents intended to inform subsequent decisions
and actions by OPPT. Accordingly, the documents are not written with the goal of informing the
general public. However, they do provide a vehicle for public access to a concise assessment of
the raw technical data on HPV chemicals and provide information previously not readily
available to the public.	
Chemical Abstract Service Registry Number
(CASRN)
10595-60-5
Chemical Abstract Index Name
Diethylenetriamine, l,7-bis(l,3-
dimethylbutylidene)
CH, CH,
Structural Formula
H,C'
CH, CH,
CH,
Summary
l,7-bis(l,3-dimethylbutylidene) diethylenetriamine is an intermediate used to produce a resin
that is a component of paint products. It cannot be isolated as a pure substance, but rather it is
produced as a liquid in the presence of excess methyl isobutyl ketone (-30%). If isolated, 1,7-
bis(l,3-dimethylbutylidene) diethylenetriamine would be expected to possess low vapor
pressure and low solubility. It is expected to have low mobility in soil. Volatilization is low
since this substance would be expected to exist as a cation under environmental conditions and
cations do not volatilize. Hydrolysis is rapid and represents the dominant environmental fate
process for l,7-bis(l,3-dimethylbutylidene) diethylenetriamine. Due to the rapid rate of
hydrolysis, l,7-bis(l,3-dimethylbutylidene) diethylenetriamine is expected to have low
persistence (PI) and low bioaccumulation potential (Bl).
Adequate studies are available for all endpoints for the hydrolysis products of
diethylenetriamine and methyl isobutyl ketone.
The acute oral and acute dermal toxicity of l,7-bis(l,3-dimethylbutylidene) diethylenetriamine
is low in rats and rabbits, respectively. Following repeated oral exposures to the
dihydrochloride salt of diethylenetriamine in the diet for 90 days, decreased body weight,
increased kidney, liver weights, increased mean corpuscular volume and hemoglobin, decreased
blood glucose, increased white blood cells and lymphocytes and increased urine pH were	
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observed at > 530-620 mg/kg-day; the NOAEL was 70-80 mg/kg-day. Rats and mice were
exposed to methyl isobutyl ketone for 6 hrs/day, 5 days/week for 14 week and showed no
adverse effects; the NOAEC is 4.1 mg/L (highest dose tested). In another study, rats were
exposed to methyl isobutyl ketone for 13 weeks via inhalation resulting in a NOAEC is 6.1
mg/L (highest dose tested).
In an oral gavage reproductive toxicity study in rats, exposure to diethylenetriamine resulted in
decreased body weight was seen in parents at 300 mg/kg-day; the NOAEL for systemic toxicity
is 100 mg/kg-day and the NOAEL for reproductive/developmental toxicity is 30 mg/kg-day. In
a 2-generation inhalation reproductive toxicity study in rats with methyl isobutyl ketone, parents
had decreased body weight at 8.2 mg/L; the NOAEC for systemic toxicity is 4.1 mg/L.
However, no reproductive effects were observed and the reproductive NOAEC is 8.2 mg/L. F1
offspring had clinical signs of neurotoxicity at 8.2 mg/L when exposure began at post natal day
(PND) 22. Based on these neurological signs, the NOAEC for developmental toxicity is 4.1
mg/L.
Diethylenetriamine induced gene mutations in mammalian cells in vitro and bacteria but not in
yeast. Methyl isobutyl ketone did not induce gene mutations in bacteria. Diethylenetriamine
did not induce chromosomal aberrations in an in vitro test using Chinese hamster ovary cells or
micronuclei in mice in vivo but induced sister chromatid exchanges in vitro. Methyl isobutyl
ketone did not induce chromosomal aberrations in rat liver (RL4) cells in vitro, mitotic
recombination, unscheduled DNA synthesis in vitro or micronuclei in mice in vivo. Methyl
isobutyl ketone induced mutations in mouse lymphoma cells.
Diethylenetriamine is corrosive to rabbit skin and eyes and a dermal sensitizer in guinea pigs.
Methyl isobutyl ketone is irritating to rabbit skin and eyes and is not a dermal sensitizer.
Methyl isobutyl ketone induced cell transformation in BALB/3T3 mouse embryo cells in vitro.
Diethylenetriamine did not induce an increase in tumor formation following repeated dermal
exposures over the lifetime of rats and mice. Methyl isobutyl ketone showed some evidence of
carcinogenicity in mice and male rats and equivocal evidence in female rats. Some neurological
signs have been seen in humans and other species exposed to methyl isobutyl ketone.
The aquatic toxicity of l,7-bis(l,3-dimethylbutylidene) diethylenetriamine, based on the
supporting chemicals diethylenetriamine and methyl isobutyl ketone, for fish is 248 mg/L (96-h
LC50), for aquatic invertebrates is 16 mg/L (48-h EC50), and for aquatic plants is 187 mg/L for
biomass(72-h EC50). The 21-day NOEC and LOEC for chronic toxicity to aquatic invertebrates,
based on the supporting chemicals is 5.6 and 11.3 mg/L, respectively. The 28-day NOEC for
chronic toxicity to fish, based on the supporting chemicals is 10 mg/L.	
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The sponsor, Air Products and Chemicals, Inc. and PPG Industries, Inc., submitted a Test Plan
and Robust Summaries to EPA for diethylenetriamine, l,7-bis(l,3-dimethylbutylidene) (CASRN
10595-60-5; 9th CI name: 1,2-ethanediamine, N-(l,3-dimethylbutylidene)-N'-[2-[(l,3-
dimethylbutylidene)amino]ethyl]-]) on February 13, 2003. EPA posted the submission on the
ChemRTK HPV Challenge website on February 14, 2003
(http://www.epa.gov/chemrtk/pubs/summaries/ditribis/cl4300tc.htm). EPA comments on the
original submission were posted to the website on July 2, 2003. Public comments were also
received and posted to the website. The sponsor submitted updated/revised documents on
September 15, 2003, which were posted to the ChemRTK website on November 3, 2003.
Justification for Supporting Chemicals
The sponsor provided test data for the supporting chemicals, diethylenetriamine (DETA,
CASRN 111-40-0) and methyl isobutyl ketone (MIBK, CASRN 108-10-1) to fill data gaps for
the sponsored substance. For health effects, EPA agrees that these data can be used because 1,7-
bis(l,3-dimethylbutylidene)diethylenetriamine undergoes rapid hydrolysis in water (< 5 minutes
at pH 7; < 30 minutes at pH 1.2) to form these two chemicals. For aquatic toxicity endpoints,
however, EPA believes that since the two chemicals were tested separately, data may
underestimate the potential toxicity of the sponsored substance. Testing the sponsored substance
or a mixture of the hydrolysis products would better examine potential synergy, additivity or
antagonism in the toxicities of the hydrolysis products.
Information available for the supporting chemicals includes published documents from the
OECD Cooperate Chemicals Assessment Program (formerly OECD HPV Program). Documents
for diethylenetriamine are available at:
http://www.chem.unep.ch/irptc/sids/OECDSIDS/111400.pdf. Documents for methyl isobutyl
ketone are available at: http://webnet.oecd.org/hpv/UI/SIDS Details.aspx?Kev=fc0c677f-097a-
40bl-9364-87bl914eclf3&idx=0. In addition, methyl isobutyl ketone has been assessed in
EPA's Integrated Risk Information System (IRIS). IRIS document for this chemical can be
found at: http://www.epa.gov/iris/toxreviews/0173tr.pdf.
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1. Chemical Identity
1.1 Identification and Purity
To produce this substance, an excess of methyl isobutyl ketone (-30%) was used. Thus, the
product tested was 70% of the sponsored substance with 30% methyl isobutyl ketone. Chemical
structures of the sponsored substance plus the two supporting chemicals are listed in Table 1.
Table 1: Chemicals Structures of Sponsored Chemical and Supporting Chemicals
SPONSORED CHEMICAL
l,7-Bis(l,3-dimethylbutylidene)
diethylenetriamine
(CASRN 10595-60-5)
SUPPORTING CHEMICAL
Diethylenetriamine
(CASRN 111-40-0)
SUPPORTING CHEMICAL
Methyl isobutyl ketone (CASRN
108-10-1)
CH, CH, CH, CH,
l\L M
XX
1.2 Physical-Chemical Properties
The physical-chemical properties of l,7-bis(l,3-dimethylbutylidene) diethylenetriamine are
summarized in Table 2. This chemical is an intermediate used to produce a resin that is a
component of paint products. It cannot be isolated as a pure substance, but rather it is produced
as a liquid in the presence of excess methyl isobutyl ketone (-30%). If isolated, l,7-bis(l,3-
dimethylbutylidene) diethylenetriamine would be expected to possess low vapor pressure and
low solubility.
Table 2. Physical-Chemical Properties of
l,7-Bis(l,3-dimethylbutylidene)diethylenetriamine1
Property
Value
CASRN
10595-60-5
Molecular Weight
267.46
Physical State
Light yellow liquid
Melting Point
Not applicable
Boiling Point
>300°C (estimated)2'3
The pure substance would probably decompose before boiling.
Vapor Pressure
6.3xlO"4 mm Hg at 25°C (estimated)2'3
Dissociation Constant
(pKa)
9.63 (estimated)3'4
Henry's Law Constant
2.2xl0"6 atm-m3/mole (estimated)2'3
Water Solubility
0.0058 mg/L at 25°C (estimated)2'3
Log Kow
7.63 (estimated)2'3
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1 Air Products and Chemicals Inc. and PPG Industries Inc. 2003. Revised Test Plan and Robust Summary for
Diethylenetriamine, l,7-bis(l,3-dimethylbutylidene). Available online at
http://www.epa. gov/chemrtk/pubs/summaries/ditribis/c 14300tc.htm as of December 12, 2011.
2U.S. EPA. 2011. Estimation Programs Interface Suite™ for Microsoft® Windows, v4.10. U.S. Environmental
Protection Agency, Washington, DC, USA. Available online at
http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm as of December 12, 2011.
31,2-Ethanediamine, Nl-(l,3-dimethylbutylidene)-N2-[2-[(l,3-dimethylbutylidene)amino]ethyl]- is produced as a
70% solution with 30% MIBK and cannot be isolated; therefore, all properties are estimated because measurements
on the pure substance is not possible.
4 SPARC. 2011. Online pKa/Property Calculator, w4.2.1405-s4.2.1408. University of Georgia, Athens, GA, USA.
Available online at http://ibmlc2,chem.uga.edu/sparc/ as of January 3, 2012.
2. General Information on Exposure
2.1	Production Volume and Use Pattern
CASRN 10595-60-5 had an aggregated production and/or import volume in the United States
between 1 and 10 million pounds during calendar year 2005.
Non-confidential information in the IUR indicates that the industrial processing and uses of the
chemical include automobile and light duty motor vehicle manufacturing as adhesives and
binding agents; and paints and coating manufacturing as "other." Non-confidential commercial
and consumer uses of this chemical include paints and coatings.
2.2	Environmental Exposure and Fate
The environmental fate properties of l,7-bis(l,3-dimethylbutylidene) diethylenetriamine are
provided in Table 3. The sponsored chemical is expected to have low mobility in soil. No
biodegradation data were available for this substance. The dominant environmental fate process
for this compound is hydrolysis. The hydrolysis half-life of l,7-bis(l,3-dimethylbutylidene)
diethylenetriamine (70% and 30% MIBK) was 34 minutes, 5.04 minutes and <1 minute at pH 4,
7 and 9, respectively, and 20EC. Volatilization would be low since this substance hydrolyzes
rapidly and is expected to exist as a cation under environmental conditions, and cations do not
volatilize. The rate of atmospheric photooxidation is considered rapid. Due to the rapid rate of
hydrolysis, l,7-bis(l,3-dimethylbutylidene) diethylenetriamine is expected to have low
persistence (PI) and low bioaccumulation potential (Bl).
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Table 3. Environmental Fate Characteristics of
l,7-Bis(l,3-dimethylbutylidene) diethylenetriamine 1
Property
Value
Photodegradation Half-
life
1.3 hours (estimated)
Hydrolysis Half-life3
34 minutes at pH 4 and 20EC;
5.04 minutes at pH 7 and 20EC;
0.972 minutes at pH 9 and 20EC
Biodegradation
No data.
Bioaccumulation
Factor
BAF = 1.3 x 106 (estimated)2; however, due to rapid hydrolysis it will
not bioaccumulate
Log Koc
4.8 (estimated)2
Fugacity
(Level III Model)2
Air (%)
Water (%)
Soil (%)
Sediment (%)
0.1
13.9
69.0
17.0
Persistence4
PI (low)
Bioaccumulation4
Bl (low)
1 Air Products and Chemicals Inc. and PPG Industries Inc. 2003. Revised Test Plan and Robust Summary for
Diethylenetriamine, l,7-bis(l,3- dimethylbutylidene). Available online at
http://www.epa. gov/chemrtk/pubs/summaries/ditribis/c 14300tc.htm as of December 12, 2011.
2U.S. EPA. 2011. Estimation Programs Interface Suite™ for Microsoft® Windows, v4.10. U.S. Environmental
Protection Agency, Washington, DC, USA. Available online at
http://www.epa. gov/opptintr/exposure/pubs/episuitedl.htm as of December 12, 2011.
3Tested as a 70% solution with 30% methyl isobutyl ketone.
4Federal Register. 1999. Category for Persistent, Bioaccumulative, and Toxic New Chemical Substances. Federal
Register 64, Number 213 (November 4, 1999) pp. 60194-60204.
Conclusion: l,7-bis(l,3-dimethylbutylidene) diethylenetriamine is an intermediate used to
produce a resin that is a component of paint products. It cannot be isolated as a pure substance,
but rather it is produced as a liquid in the presence of excess methyl isobutyl ketone (-30%). If
isolated, l,7-bis(l,3-dimethylbutylidene) diethylenetriamine would be expected to possess low
vapor pressure and low solubility. It is expected to have low mobility in soil. Volatilization is
low since this substance would be expected to exist as a cation under environmental conditions
and cations do not volatilize. Hydrolysis is rapid and represents the dominant environmental fate
process for l,7-bis(l,3-dimethylbutylidene) diethylenetriamine. Due to the rapid rate of
hydrolysis, l,7-bis(l,3-dimethylbutylidene) diethylenetriamine is expected to have low
persistence (PI) and low bioaccumulation potential (Bl).
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3. Human Health Hazard
Acute Oral Toxicity
Diethylenetriamine, l,7-bis(l,3-dimethylbutylidene) (CASRN10595-60-5)
Albino rats (5/sex/dose) were administered diethylenetriamine via gavage at 1, 2 or 4 mL/kg-bw
(~ 876, 1752 or 3504 mg/kg-bw) and observed for 14 days. Mortalities occurred at 2 and 4
mL/kg-bw.
LD50 ~ 1664 mg/kg
Acute Dermal Toxicity
Diethylenetriamine, l,7-bis(l,3-dimethylbutylidene) (CASRN 10595-60-5)
New Zealand white rabbits (2/sex/dose, strain not specified) were administered
diethylenetriamine, l,7-bis(l,3-dimethylbutylidene) via the dermal route at 2.0 mL/kg-bw (~
1752 mg/kg-bw) to abraded dorsal skin under semi-occlusive conditions for 24 hours. After
dosing, animals were observed for 14 days. No mortality occurred. Severe erythema, severe
eschar and necrosis were observed.
LD50 > -1752 mg/kg
Repeated-Dose Toxicity
Diethylenetriamine (CASRN 111-40-0, supporting chemical)
(1) Male and female Fischer 344 rats (number not specified) were administered
diethylenetriamine dihydrochloride salt in the diet at nominal concentrations of 0, 1000, 7500 or
15,000 ppm for 90 days (~ 0, 70, 530 or 1060 mg/kg-bw/day for males and 0, 80, 620 or 1210
mg/kg-bw/day for females). Decreased food consumption was seen at the high dose and
decreased body weight or weight gain was noted at the two highest doses. Increased mean
corpuscular volume (MCV) and mean corpuscular hemoglobin were observed in males in the
mid- and high-dose groups. In females, decreased glucose and albumin and increased MCV
were noted in the high-dose group. Similar changes in glucose and MCV were seen in the mid-
dose group. Dose-related increases in white blood cells and lymphocytes were noted in the mid
and high dose females. Increased urine pH in females from mid and high dose groups and/or
excretion of test material was observed after 13 weeks of exposure. Increased kidney and liver
weights were observed in the mid- and high-dose females and increased adrenal weights in high
dose females (OECD http://www.chem.unep.ch/irptc/sids/OECDSIDS/111400.pdf).
LOAEL = 530 - 620 mg/kg-bw/day (based on decreased body weight, increased kidney and
liver weights, increased mean corpuscular volume and hemoglobin, decreased blood glucose,
white blood cells and lymphocytes and increased urine pH)
NOAEL = 70-80 mg/kg-bw/day
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(2)	Rabbits were administered diethylenetriamine in drinking water at nominal doses of 1 or 10
mg/kg-bw/day for 6 months. In the high-dose group, prothrombin activity decreased to 62% of
control values and ASAT and ALAT activities increased up to 3 times compared to controls. No
other details were provided (OECD
http://www.chem.unep. ch/irptc/sids/OECDSIDS/111400.pdf).
LOAEL = Not established
NOAEL = 10 mg/kg-bw/day (based on no adverse effects at the highest dose tested)
(3)	New Zealand white rabbits (10/sex/dose) were administered diethyl enetriamine dermally at
doses of 20 or 400 mg/L (2 or 40% wt/v) for 28 and 8 days, respectively. The high dose group
was terminated due to severe irritation. In the high dose group, hemoglobin, hematocrit and red
blood cells were slightly higher and bilirubin and cholesterol were elevated. The low dose group
had higher incidence and/or severity of erythema, atonia, dequamation, fissuring, eschar
formation and exfoliation compared with controls. Body weight at 20 mg/L was 9-15% lower
than controls. Both doses had lower testes and epidymides weights (absolute and relative)
compared with controls. There was no information on the amount administered in mg/kg-bw
(OECD http://www.chem.unep.ch/irptc/sids/OECDSIDS/111400.pdf).
Methyl isobutyl ketone (CASRN108-10-1, supporting chemical)
(1)	Sprague-Dawley rats (30/sex/dose) were administered methyl isobutyl ketone via gavage at
0, 50, 250 or 1000 mg/kg-day, 7 days/week for 13 weeks. Reversible lethargy was seen at 1000
mg/kg-day a few hours after dosing, which decreased in incidence and severity throughout the
study. Males had significantly decreased body weight gains at the highest dose (by 9%),
whereas females had significantly increased body weight gain; both sexes had increased food
consumption during the second half of the exposure period. Significantly (but slightly) increased
hemoblogin (by 6%) and hematocrit (by 8%) were observed at sacrifice in females at the highest
dose. A 15% decrease in lymphocyte counts were seen in high-dose males. Increased liver and
kidney weights were observed at the highest concentration in males and females; there were no
corresponding histopathological lesions present in the liver. A general nephropathy was seen in
both male and female rats at 1000 mg/kg-day. These effects seen at the highest dose were
present to a lesser extent in both sexes in the mid-dose group (IRIS -
http://www.epa.gov/iris/toxreviews/0173tr.pdf).
LOAEL = Not established
NOAEL = 1000 mg/kg-day (based on no adverse effects at the highest dose tested)
(2)	Fischer 344 rats and B6C3Fi mice (14/sex/concentration) were exposed via inhalation to 0,
50, 252 and 1002 ppm (0, 0.205, 1.033 and 4.106 mg/L) for 6 hrs/day, 5 days/week for 14 weeks.
A variety of hematology, clinical chemistry, urinalysis, organ weight, body weight (increase)
changes were observed, which were not considered adverse. The only effect seen upon
microscopic examination was renal hyaline droplet formation in males; it was presumed that this
was due to alpha2U-globulin accumulation that is unique to the male rat and probably not relevant
to humans (IRIS - http://www.epa.gov/iris/toxreviews/0173tr.pdf).
LOAEC (rats and mice) = Not established
NOAEC (rats and mice) = 4.1 mg/L-day (based on no adverse effects at the highest dose
tested)
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(3)	Sprague-Dawley rats (20/sex/concentration) were exposed via inhalation to 0, 250, 750 or
1400 ppm (0, 1.024, 3.073 or 6.146 mg/L) methyl isobutyl ketone for 6 hrs/day, 5 days/week for
13 weeks. Half were given restricted diets and the other half were fed ad libitum. The rats
underwent daily schedule-controlled operant behavioral (SCOB) testing. No histopathology was
conducted, and there was no mention of clinical chemistry, hematology or urinalysis
measurements. Reduced activity was seen in the first 8 or 10 weeks in rats at the mid- and
highest concentration, respectively. In creased body weights were observed (which was
statistically significant in the restricted-diet group). Increased mean relative liver (both dietary
groups) and kidney (restricted diet rats only) weights were observed but not always in a dose-
related manner. No significant differences were observed in any of the SCOB measures (IRIS -
http://www.epa.gov/iris/toxreviews/0173tr.pdf).
LOAEC = Not established
NOAEC = 6.1 mg/L-day (based on no adverse effects at the highest dose tested)
(4)	Five female HLA Wistar rats were given 1.3% methyl isobutyl ketone in drinking water
(approximately 1040 mg/kg-day) for 120 days. In addition to general examinations (body
weight, food consumption, clinical sings), selected tissues were examined histologically
(including selected nervous system tissues). Neurobehavioral and neuromuscular function tests
were also conducted. It was not stated whether hematology, clinical chemistry or urinalysis were
conducted. The only statistically significant finding was increased mean absolute and relative
kidney weights. Renal tubular cell hyperplasia was seen in one treated female (IRIS -
http://www.epa.gov/iris/toxreviews/0173tr.pdf).
LOAEL = Not established
NOAEL ~ 1040 mg/kg-bw/day
(5)	Additional oral and inhalation studies that had limited information, used single/low
concentrations, no control groups or were conducted for short durations (e.g., 7 or 9 days)
showed minimal effects that were not considered adverse (IRIS -
http://www.epa.gov/iris/toxreviews/0173tr.pdf).
Reproductive Toxicity
Diethylenetriamine (CASRN111-40-0, supporting chemical)
Wistar rats (number per sex not specified) were administered diethylenetriamine via gavage at 0,
30, 100 or 300 mg/kg-day during a 2-week premating period, through mating and gestation up to
day 4 post-partum. The total exposure period was 29 - 54 days. No mortality occurred. Male
and female parental body weight was decreased at the high-dose level. Increased duration of
gestation, increased post-implantation loss and reduced mean litter size were observed at 100 and
300 mg/kg-day. No treatment-related effects on pup body weights or clinical and necropsy
observations were observed.
LOAEL (systemic toxicity) = 300 mg/kg-day (based on decreased body weight)
NOAEL (systemic toxicity) = 100 mg/kg-day
LOAEL (reproductive/developmental toxicity) = 100 mg/kg-day (based on in increased
duration of gestation, increased post-implantation loss and reduced mean litter size)
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NOAEL (reproductive/developmental toxicity) = 30 mg/kg-day
Methyl isobutyl ketone (CASRN108-10-1, supporting chemical)
In a two-generation reproductive study, F0 Sprague-Dawley rats (30/sex/concentration) were
exposed to methyl isobutyl ketone via whole-body inhalation at 0, 500, 1000 or 2000 ppm (0,
2.012, 4.093 and 8.187 mg/L actual concentrations) for 6 hrs/day for 70 days prior to mating and
through mating. F0 females were further exposed until gestation day 20 and again during
lactation days 5 to 21 and pups were not directly exposed during lactation. On lactation day 4,
litters were culled to 4/sex. At lactation day 21, 30 rats/sex/concentration were randomly
selected for the F1 parents and were exposed using the same concentrations (actual
concentrations of 0, 2.073, 4.105, and 8.219 mg/L) and exposure schedule as the F0 parents.
In parents, transient decreased body weight gains were seen in high-dose females only in weeks
0-2 but no accompanying changes in body weight were seen. Decreased food consumption
(statistically significant) was also seen during weeks 0 to 1 in the F0 parents (both sexes) at the
highest dose. One F1 male rat at 8.2 mg/L died on post-natal day 22. F1 parental females had
slightly decreased body weights through mating and post-lactation at 8.2 mg/L. F1 parental
males had decreased body weight at 4.1 mg/L with a transient reduction at 2.0 mg/L. Decreased
food consumption was seen at 8.2 mg/L in F1 adults (both sexes) during the first week of
measurement. F1 males had decreased final body weights at 8.2 mg/L. In F0 rats, there were
increases in the number of rats with absent or decreased responses to novel sound stimuli at 1000
and 2000 ppm (4.1 and 8.2 mg/L) but rats were normal at 1 hour post-exposure. There were no
clinical signs of note (such as unsteady gait).
There were increased absolute and relative liver weights at the highest concentration (both F0
and F1 generations) and increased absolute and relative kidney weights (F0 and F1: males at all
doses). F1 parental females had increased relative kidney weights at the highest dose.
Significantly increased relative adrenal weights were seen in F0 females at the highest dose and
significant increased relative and absolute ovarian weights (both by more than 20%) were seen in
F0 females at the highest dose (p < 0.01). Increased seminal vesicle weights were seen in F0
males at the highest dose. F1 parental males had increased kidney weights at all doses, increased
liver weights at the highest dose and increased seminal vesicles at the highest dose. Incidence of
rats with centrilobular hepatocellular hypertrophy (which was considered to be adaptive by the
authors) was increased in F0 males at all doses (0 in controls, vs. 3, 15 and 26 at 2.0, 4.1 and 8.2
mg/L).
Prevalence of nephropathy (characterized by inflamed and thickened basophilic tubule
membranes) in parents was significantly higher in F0 and F1 males at the highest two doses. F1
parental males also had acidophilic spherical inclusions/droplets in the renal cortical tubular
epithelium at the two highest doses but the authors noted that there was no indication of fully
developed alpha2U-globulin-related renal tubular lesions.
In offspring, on postnatal day 22 (the first exposure day for F1 generation), 7 males and 11
females at 8.2 mg/L in the F1 generation showed clinical signs of neurological/neuromuscular
toxicity 1 hour after exposure (rocking, lurching or swaying when trying to walk); 5 males and 2
females were prostrate, and 3 males had half-closed eyelids. Of these rats, 9 males and 10
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females had bilateral lacrimation. Due to this mortality and the CNS signs, exposures for all F1
rats were suspended and reinitiated on postnatal day 28; after reinitiation, 6 males at 8.2 mg/L
showed clinical signs of sedation 1 hour after exposure, but CNS depression was transient and
not seen on subsequent days. No recurrence of neurological clinical signs were seen in females
after exposure was resumed; upon reinitiation of exposure, F1 rats at 4.1 and 8.2 mg/L had
absent or diminished response to novel sound stimulus.
In offspring, decreases in mean body weights (-5%) were seen on day 14 post-partum in F1 rats
at all concentrations and in F2 pups at the high concentration. However, pup body weights were
not different from controls on days 7 and 21 post-partum. Internal (skeletal, visceral)
examinations were not conducted; these would have been done only in any pups with abnormal
external changes, which were not reported (Nemec et al., 2004; IRIS -
http://www.epa.gov/iris/toxreviews/0173tr.pdf).
LOAEC (parental systemic toxicity) = 8.2 mg/L (based on decreased body weights)
NOAEC (parental systemic toxicity) = 4.1 mg/L
LOAEC (reproductive toxicity) = Not established
NOAEC (reproductive toxicity) = 8.2 mg/L (based on no adverse affects at the highest dose
tested)
LOAEC (developmental) = 8.2 mg/L (based on neurological/clinical signs in F1 offspring)
NOAEC (developmental) = 4.1 mg/L
Developmental Toxicity
Methyl isobutyl ketone (CASRN108-10-1, supporting chemical)
(1) Pregnant Fischer 344 rats (35/concentration) were exposed to methyl isobutyl ketone via
inhalation at concentrations of 0, 300, 1000 or 3000 ppm (~ 0, 1.229, 4.106 or 12.292 mg/L) for
6 hours/day on gestation days 6 through 15. Animals were sacrificed on gestation day 21.
Exposure to 3000 ppm resulted in maternal toxicity including clinical signs (CNS-type effects
and others), decreased body weight and body weight gain, increased relative (to body) kidney
weight and decreased food consumption. Signs of fetotoxicity, including reduced fetal body
weight per litter and reductions in skeletal ossification, were seen at 3000 ppm. No exposure-
related effects were observed in numbers of corpora lutea, total implants, percent implantation
loss, live fetuses per litter, non-viable implants per litter, percent live fetuses, and sex ratio. No
increases in malformations were observed (supplemented with information from IRIS
http://www.epa.gov/iris/toxreviews/0173tr.pdf).
LOAEC (maternal toxicity) = 12.3 mg/L/day (based on clinical signs of toxicity, decreased
body weight and body weight gain, increased relative kidney weight and decreased food
consumption)
LOAEC (developmental toxicity) = 12.3 mg/L/day (based on reduced fetal body weight per
litter and reductions in skeletal ossification)
NOAEC (maternal and developmental toxicity) = 4.1 mg/L/day
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(2) Pregnant CD-I mice (30/concentration) were exposed to methyl isobutyl ketone via
inhalation at concentrations of 0, 300, 1000 or 3000 ppm (~ 0, 1.229, 4.106 or 12.292 mg/L) for
6 hours/day on gestation days 6 through 15. Animals were sacrificed on gestation day 18.
Exposure to 3000 ppm resulted in maternal toxicity including apparent exposure related
increases in deaths (12%; 3/25 dams), clinical signs (CNS-type effects and others) and increased
absolute and relative (to body) liver weights. Signs of fetotoxicity included increased incidence
of dead fetuses, reduced fetal body weight per litter and reductions in skeletal ossification. No
exposure-related effects were observed in numbers of corpora lutea, total implants, percent
implantation loss, live fetuses per litter, non-viable implants per litter, percent live fetuses, and
sex ratio. No increases in fetal malformations were observed (summary supplemented with
information from IRIS http://www.epa.gov/iris/toxreviews/0173tr.pdf).
LOAEC (maternal toxicity) = 12.3 mg/L/day (based on death, clinical signs and increased
relative and absolute liver weights)
LOAEC (developmental toxicity) = 12.3 mg/L/day (based on increased incidence of dead
fetuses, reduced fetal body weight per litter and reductions in skeletal ossification)
NOAEC (maternal and developmental toxicity) = 4.1 mg/L/day
Genetic Toxicity — Gene Mutations
In vitro
Diethylenetriamine (CASRN111-40-0, supporting chemical)
(1)	In three studies, S. typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 were
exposed to diethylenetriamine at concentrations up to 10,000 |j,g/plate in the presence of
metabolic activation and up to 500 |j,g/plate in the absence of metabolic activation. No details
regarding cytotoxicity, precipitation or response of positive controls were provided (OECD -
http://www.chem.unep.ch/irptc/sids/OECDSIDS/111400.pdf).
Diethylenetriamine was not mutagenic in these assays.
(2)	S. typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 were exposed to
diethylenetriamine at concentrations of 10 - 1000 |j,g/plate in the absence of metabolic activation
and 100 - 5000 |j,g/plate in the presence of metabolic activation. Increases in mutations (1.6-2-
fold) were seen without metabolic activation in TA98, TA100 and TA1537. Retesting with
concentrations of 200 - 500 |j,g/plate was positive in TA1537 without metabolic activation. No
details regarding cytotoxicity, precipitation or response of positive controls were provided
(OECD - http://www.chem.unep.ch/irptc/sids/OECDSIDS/111400.pdf).
Diethylenetriamine was mutagenic in this assay.
(3)	S. typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 were exposed to
diethylenetriamine at concentrations ranging from 0.001 to 10 (iL/plate in the presence and
absence of metabolic activation. No cytotoxicity was observed. Positive (but not dose-related)
increases were observed in strains TA1537 and TA1538 without metabolic activation. No details
regarding precipitation or response of positive controls were provided (OECD -
http://www.chem.unep. ch/irptc/sids/OECDSIDS/111400.pdf).
Diethylenetriamine was mutagenic in this assay.
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(4)	S. typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 were exposed to
diethylenetriamine at concentrations of 1000, 1500, 2000, 2500 or 3000 |j,g/plate in the presence
and absence of metabolic activation. Increased mutations (3.7-fold higher than controls) were
seen in strain TA98 in the absence of metabolic activation. No details regarding cytotoxicity,
precipitation or response of positive controls were provided (OECD -
http://www.chem.unep. ch/irptc/sids/OECDSIDS/111400.pdf).
Diethylenetriamine was mutagenic in this assay.
(5)	S. cerevisiae D4 were exposed to diethylenetriamine at concentrations up to 5.0 |jl/plate in
the presence and absence of metabolic activation. No details regarding cytotoxicity,
precipitation or response of positive controls were provided (OECD -
http://www.chem.unep. ch/irptc/sids/OECDSIDS/111400.pdf).
Diethylenetriamine was not mutagenic in this assay.
(6)	Chinese hamster ovary (CHO) cells were exposed to diethylenetriamine (commercial grade)
(as well as two other diethylenetriamine compounds) in an HGPRT assay at concentrations of
0.0125, 0.025, 0.05, 0.1, 0.2 or 0.4% (v/v) in the presence and absence of metabolic activation.
The 0.4% level was cytotoxic. Diethylenetriamine (commercial grade) showed a positive result
at 0.2% in a second test with concentrations of 0.0125 - 0.2% in the presence of metabolic
activation. No details regarding precipitation or response of positive controls were provided
(OECD - http://www.chem.unep.ch/irptc/sids/OECDSIDS/111400.pdf).
Diethylenetriamine was mutagenic in this assay.
Methyl isobutyl ketone (CASRN108-10-1, supporting chemical)
(\)Salmonella typhimurium strains TA97, TA98, TA100, and TA1535were exposed to methyl
isobutyl ketone in dimethyl sulfoxide at concentrations from 100 to 6667 |ig/plate in the
presence and absence of metabolic activation. Positive and negative controls were included, and
showed appropriate responses. Slight toxicity was seen in cultures both with and without
activation for four strains. For the fifth strain (TA97), some toxicity was also seen with and
without activation at 3333 (or 3334) |ig/plate (http://ntp-
apps.niehs.nih.gov/ntp tox/index.cfm?searchterm=108-10-
l&fuseaction=ntpsearch.searchresults)
Methyl isobutyl ketone was not mutagenic in this assay.
(2) In six studies, Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538
were exposed to methyl isobutyl ketone at concentrations of up to 8000 |j,g/plate in the presence
and absence of metabolic activation. No details regarding cytotoxicity, precipitation or response
of positive controls were provided.
Methyl isobutyl ketone was not mutagenic in these assays.
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Genetic Toxicity — Chromosomal Aberrations
In vitro
Diethylenetriamine (CASRN111-40-0, supporting chemical)
CHO cells were exposed to diethylenetriamine at 250, 833 or 2500 |j,g/mL in the presence and
absence of metabolic activation. No details regarding cytotoxicity, precipitation or response of
positive controls were provided (OECD -
http://www.chem.unep. ch/irptc/sids/OECDSIDS/111400.pdf).
Diethylenetriamine did not induce chromosomal aberrations in this assay.
Methyl isobutyl ketone (CASRN 108-10-1, supporting chemical)
In a chromosome aberrations assay, rat liver (RL4) cells were exposed to methyl isobutyl ketone
at concentrations up to 1000 |j,g/mL. No details regarding toxicity or use and response of
positive controls were provided.
Methyl isobutyl ketone did not induce chromosomal aberrations in this assay.
In vivo
Diethylenetriamine (CASRN 111-40-0, supporting chemical)
Male and female CD-I mice (number and sex ratio not specified) were administered
diethylenetriamine via gavage at 85, 283 or 850 mg/kg-bw and sacrificed after 24, 48 or 72
hours. Bone marrow was sampled for presence of increased micronucleated polychromatic
erythrocytes. No details regarding toxicity or use and response of positive controls were
provided (OECD - http://www.chem.unep.ch/irptc/sids/OECDSIDS/111400.pdf).
Diethylenetriamine did not induce micronuclei in this assay.
Methyl isobutyl ketone (CASRN 108-10-1, supporting chemical)
(1)	Mice (strain and number not specified) were administered methyl isobutyl ketone via
intraperitoneal injection at 0.73 mL/kg-bw (IRIS -
http://www.epa.gov/iris/toxreviews/0173tr.pdf).
Methyl isobutyl ketone did not induce micronuclei in this assay.
(2)	CD-I mice (5/sex/group) were administered methyl isobutyl ketone via intraperitoneal
injection at 585 mg/kg-bw and sacrificed at 12, 24 and 48 hours. No details regarding toxicity or
use and response of positive controls were provided.
Methyl isobutyl ketone did not induce micronuclei in this assay.
Genetic Toxicity — Other
In vitro
Diethylenetriamine (CASRN 111-40-0, supporting chemical)
(1) In a sister chromatid exchange assay, CHO cells were exposed to diethylenetriamine at
concentrations of 100 - 400 |j,g/plate in the absence of metabolic activation and 400 - 700
Hg/plate in the presence of metabolic activation. Positive effects were observed in the absence of
metabolic activation and marginally positive effects were observed in the presence of activation.
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No details regarding cytotoxicity, precipitation or response of positive controls were provided
(OECD - http://www.chem.unep.ch/irptc/sids/OECDSIDS/111400.pdf).
Diethylenetriamine induced sister chromatid exchanges in this assay.
(2)	In a sister chromatid exchange assay, CHO cells were exposed to diethylenetriamine
(commercial grade) at 0, 0.0125, 0.025, 0.05, 0.1 or 0.2% (v/v) in the presence and absence of
metabolic activation. Positive effects were observed in the absence of metabolic activation at the
high concentration. No details regarding cytotoxicity, precipitation or response of positive
controls were provided (OECD - http://www.chem.unep.ch/irptc/sids/OECDSIDS/111400.pdf).
Diethylenetriamine induced sister chromatid exchanges in this assay.
(3)	In an unscheduled DNA synthesis assay, rat hepatocytes were exposed to diethylenetriamine
(commercial grade) at 0.0001, 0.001, 0.003, 0.01, 0.03 or 0.1% (v/v). No cytotoxicity was
observed at the highest dose. No details regarding precipitation or use and response of positive
controls were provided (OECD - http://www.chem.unep.ch/irptc/sids/OECDSIDS/111400.pdf).
Diethylenetriamine did not induce unscheduled DNA synthesis in this assay.
Methyl isobutyl ketone (CASRN108-10-1, supporting chemical)
(1)	In a mitotic recombination assay, methyl isobutyl ketone was negative when tested in
Saccharomyces cerevisiae in the presence and absence of metabolic activation (IRIS -
http://www.epa.gov/iris/toxreviews/0173tr.pdf).
Methyl isobutyl ketone did not induce mitotic recombination in this assay.
(2)	Methyl isobutyl ketone was negative in an unscheduled DNA synthesis assay (IRIS -
http://www.epa.gov/iris/toxreviews/0173tr.pdf).
Methyl isobutyl ketone did not induce unscheduled DNA synthesis in this assay.
(3)	In a cell transformation assay in BALB/3T3 mouse embryo cells, methyl isobutyl ketone
induced morphological transformations at the highest exposure in the absence of metabolic
activation. No effects were observed in the presence of activation. No other details were
available (IRIS - http://www.epa.gov/iris/toxreviews/0173tr.pdf).
Methyl isobutyl ketone induced cell transformation in this assay.
(4)	In a cell transformation assay in BALB/3T3 mouse embryo cells, methyl isobutyl ketone was
negative for in the presence and absence of metabolic activation. No further details were
available (IRIS - http://www.epa.gov/iris/toxreviews/0173tr.pdf).
Methyl isobutyl ketone did not induce cell transformation in this assay.
(5)	Mouse lymphoma cells L51784 TK +/- were exposed to methyl isobutyl ketone at
concentrations ranging from 0.4 to 6.0 |j,l/mL in the presence and absence of metabolic
activation. No details regarding cytotoxicity, precipitation or response of positive controls were
provided.
Methyl isobutyl ketone was not mutagenic in this assay.
(7) Mouse lymphoma cells L51784 TK +/- were exposed to methyl isobutyl ketone at
concentrations up to 3368 |j,g/mL in the presence and absence of metabolic activation. Three
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non-activated cultures exhibited mutant frequencies that were greater than the mean mutant
frequency of the solvent controls, but didn't exhibit a dose-response relationship. Growth
appeared to be inhibited in some cultures (not specified). No details regarding precipitation or
response of positive controls were provided.
Methyl isobutyl ketone was mutagenic in this assay.
(8) Mouse lymphoma cells L51784 TK +/- were exposed to concentrations of methyl isobutyl
ketone at concentrations up to 2967 |j,g/mL in the presence and absence of metabolic activation.
Four non-activated cultures exhibited mutant frequencies 2x the solvent controls, but did not
show a dose-response relationship. Growth appeared to be inhibited in some cultures (not
specified). No details regarding precipitation or response of positive controls were provided.
Methyl isobutyl ketone was mutagenic in this assay.
Additional Information
Skin Irritation
Diethylenetriamine (CASRN111-40-0, supporting chemical)
In multiple tests, diethylenetriamine was corrosive to rabbit skin (OECD -
http://www.chem.unep.ch/irptc/sids/OECDSIDS/111400.pdf).
Diethylenetriamine was corrosive to rabbit skin.
Methyl isobutyl ketone (CASRN 108-10-1, supporting chemical)
Slight dermal irritation was seen in rabbits (OECD-
http://webnet.oecd.org/hpv/UI/SIDS Details.aspx?Key=fc0c677f-097a-40b 1-9364-
87bl914eclf3&idx=0Y
Methyl isobutyl ketone was irritating to rabbit skin.
Eye Irritation
Diethylenetriamine (CASRN 111-40-0, supporting chemical)
In multiple tests, diethylenetriamine was corrosive to rabbit eyes (OECD -
http://www.chem.unep. ch/irptc/sids/OECDSIDS/111400.pdf).
Diethylenetriamine was corrosive to rabbit eyes.
Methyl isobutyl ketone (CASRN 108-10-1, supporting chemical)
(1)In	rabbits, methyl isobutyl ketone was shown to be irritating (inflammation, swelling up to 24
hours) (OECD - http://webnet.oecd.org/hpv/UI/SIDS Details.aspx?Kev=fc0c677f-097a-40b 1-
9364-87bl914eclf3&idx=0y
Methyl isobutyl ketone was irritating to rabbit eyes.
(2)	In an experiment of acute inhalation exposures to methyl isobutyl ketone via full face mask
by human volunteers, irritation (eye, nose and throat) was seen after 7 minutes (followed by
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Hazard Characterization Document
another 7-minute exposure two weeks later). The threshold for irritation was determined to be
1.39 mg/L (IRIS - http://www.epa.gov/iris/toxreviews/0173tr.pdf).
Humans exhibited irritation in this study.
Respiratory Irritation
Methyl isobutyl ketone (CASRN108-10-1, supporting chemical)
In one test, sensory (e.g., throat) irritation was seen at air concentrations of 0.01 mg/L and higher
(IRIS - http://www.epa.gov/iris/toxreviews/0173tr.pdf).
Humans exhibited irritation in this study.
Skin Sensitization
Diethylenetriamine (CASRN 111-40-0, supporting chemical)
(1)Diethylenetriamine	was sensitizing to guinea pigs in two guinea pig maximization tests and
one patch test in guinea pigs. Limited details were provided for these studies (OECD -
http://www.chem.unep. ch/irptc/sids/OECDSIDS/111400.pdf).
Diethylenetriamine was a dermal sensitizer under the conditions of these assays.
(2)Diethylenetriamine	was not sensitizing to guinea pigs one test (not specified). Only limited
details were provided (OECD - http://www.chem.unep.ch/irptc/sids/OECDSIDS/111400.pdf).
Diethylenetriamine was a not a dermal sensitizer under the conditions of this assay.
Methyl isobutyl ketone (CASRN 108-10-1, supporting chemical)
In a guinea pig maximization test, methyl isobutyl ketone administered at unspecified
concentrations was not sensitizing to guinea pigs.
Methyl isobutyl ketone was not a dermal sensitizer under the conditions of this assay.
Respiratory Sensitization
Diethylenetriamine (CASRN 111-40-0, supporting chemical)
(1)	Although little information specific to this chemical is available, an industry submission to
EPA states that human subjects working with "these chemicals" (including diethylenetriamine)
indicates "some or all of them sometimes cause a hypersensitivity following prolonged and
repeated exposures with liquid or with vapors" that may manifest as asthma (or dermatitis)
(TSCATS - OTS84003A).
(2)	A study of chemical workers exposed to aliphatic polyamines (diethylenetriamine, ethylene
diamine, and triethylene tetramine), dimer acids, various other fatty acids, and a variety of other
compounds was conducted at a specific factory to determine respiratory effects compared with
unexposed workers. Exposed workers had significantly increased cough, phlegm, and wheezing,
and the study authors described the prevalence of symptoms as 'extraordinarily high'. There
were also significantly increased mean and maximum diurnal variations in peak expiratory flow
rates (DV-PEFR%s) compared with unexposed workers. No differences, however, were seen in
common respiratory measures such as forced expiratory volume in 1 second (FEVi), forced vital
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capacity (FVC), or FEV1/FVC (Ng et al., 1995). Because of the additional compound
exposures, no firm conclusions can be made with respect to the association of diethylenetriamine
with increased asthma-type symptoms.
Cell Transformation
Methyl isobutyl ketone (CASRN108-10-1, supporting chemical)
(1)	In a cell transformation assay in BALB/3T3 mouse embryo cells, methyl isobutyl ketone
induced morphological transformations at the highest exposure in the absence of metabolic
activation. No effects were observed in the presence of activation. No other details were
available (IRIS - http://www.epa.gov/iris/toxreviews/0173tr.pdf).
Methyl isobutyl ketone induced cell transformation in this assay.
(2)	In a cell transformation assay in BALB/3T3 mouse embryo cells, methyl isobutyl ketone was
negative for in the presence and absence of metabolic activation. No further details were
available (IRIS - http://www.epa.gov/iris/toxreviews/0173tr.pdf).
Methyl isobutyl ketone did not induce cell transformation in this assay.
Carcinogenicity
Diethylenetriamine (CASRN 111-40-0, supporting chemical)
C3H/HeJ mice (50 males/group) were administered diethylenetriamine in water via the dermal
route at 0 or 1.25 mg/animal/day (~ 0 or 62.5 mg/kg-bw/day) 3 days/week for the lifetime of the
animals. No treatment-related skin tumors or increased incidence of any internal tumors were
observed. The survival time and mortality rates were not markedly different between the treated
and control groups (OECD http://www.chem.unep.ch/irptc/sids/OECDSIDS/111400.pdf).
Diethylenetriamine was negative for carcinogenicity in this study.
Methyl isobutyl ketone (CASRN 108-10-1, supporting chemical)
In studies conducted by the National Toxicology Program, Fischer 344/N rats and B6C3Fi mice
(50/sex/concentration) were exposed via inhalation for 6 hrs/day, 5 days/week for 104 weeks to
0, 450, 900 or 1800 ppm methyl isobutyl ketone (equivalent to 0, 1.84, 3.68 or 7.36 mg/L).
Survival of male rats at the highest concentration was significantly less than for controls. In rats,
non-neoplastic lesions of the kidneys of males were characteristic of alpha2u-globulin although
nephropathy was also observed in female rats. There was some evidence of carcinogenic activity
in male rats based on increased incidences of renal tubule neoplasms. Male rats at 1800 ppm
may have had some increased incidence of mononuclear cell leukemia. There was equivocal
evidence of carcinogenic activity in female rats based on occurrence of renal mesenchymal
tumors at the highest concentration. There was some evidence of carcinogenic activity in male
and female mice based on increased liver neoplasms
(http://ntp.niehs.nih.gov/files/538 Web.pdf).
Methyl isobutyl ketone showed some evidence (mice, male rats) and equivocal evidence of
carcinogenicity (female rats) in these studies.
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Neurotoxicity
Methyl isobutyl ketone (CASRN108-10-1, supporting chemical)
(1)	In three separate 2-hour exposures of human volunteers to methyl isobutyl ketone via
inhalation, neurological symptoms (headache, nausea and vertigo) occurred during exposure with
cessation shortly after exposure ended. One of eight volunteers had vertigo at 0.01 mg/L and
three of eight had vertigo and headache at 0.1 or 0.2 mg/L. No decrement in task performance
was seen (IRIS - http://www.epa.gov/iris/toxreviews/0173tr.pdf).
Humans exhibited some neurological signs in this study.
(2)	In a double-blind study of male and female volunteers exposed to 0.41 mg/L via inhalation
for two consecutive 2-hr periods, no changes on performance tests or percent of subjects with
neurological symptoms were seen (IRIS - http://www.epa.gov/iris/toxreviews/0173tr.pdf).
Humans exhibited no neurological signs in this study.
(3)	In a study of volunteers exposed to methyl isobutyl ketone for 2-hr exposure periods at 1-
week intervals for an unspecified total number of exposures, an index of prevalence and intensity
of neurological symptoms was significantly increased at 0.2 mg/L compared with 0.01 mg/L
(considered to be the control).
Humans exhibited some neurological signs in this study.
(4)In	three separate 2-hour exposures of human volunteers to methyl isobutyl ketone via
inhalation, neurological symptoms (headache, nausea and vertigo) occurred during exposure with
cessation shortly after exposure ended. One of eight volunteers had vertigo at 0.01 mg/L and
three of eight had vertigo and headache at 0.1 or 0.2 mg/L. No decrement in task performance
was seen (IRIS - http://www.epa.gov/iris/toxreviews/0173tr.pdf).
Humans exhibited some neurological signs in this study.
(5)	In rats exposed to methyl isobutyl ketone via inhalation for 13 weeks (6 hrs/day, 5
days/week), overall activity was reduced for the first 8 and 10 weeks at 3.1 and 6.1 mg/L,
respectively. No evidence of behavioral test performance or gross pathologies in nervous system
tissues was found. Histopathology was not conducted (IRIS -
http://www.epa.gov/iris/toxreviews/0173tr.pdf).
Rats exhibited lethargy in this study.
(6)	Six young adult rats (strain and sex not specified) were exposed via whole-body inhalation to
methyl isobutyl ketone (with ~ 3% methyl n-butyl ketone) 6 hrs/day, 5 days/week for up to 5
months at 1500 ppm (6.146 mg/L). Slight narcosis was seen but no cumulative neurological
effects were seen after 5 months of exposure. Increased minimally dilated mitochondrial
remnants in the most distal portions of tibial and ulnar nerves. The neurological signs may have
been due to the presence of methyl n-butyl ketone (IRIS -
http://www.epa.gov/iris/toxreviews/0173tr.pdf).
Rats exhibited equivocal neurological effects in this study.
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(7)	Swiss OF1 mice were exposed via whole-body inhalation to 0, 662, 757, 807 or 892 ppm (0,
2.712, 3.102, 3.307 or 3.655 mg/L) methyl isobutyl ketone for single 4-hour exposures. A
statistically-significant dose-related decrease in immobility in a behavioral despair swimming
test was seen during the first 3 minutes after beginning of exposure (IRIS -
http://www.epa.gov/iris/toxreviews/0173tr.pdf).
Mice exhibited neurobehavioral effects in this assay.
(8)	No clear effect on mean variable interval response rate was seen in Sprague-Dawley rats in a
SCOB battery immediately after a 3-hr exposure to 25 ppm (0.102 mg/L; 7 rats exposed) or 50
ppm (0.205 mg/L; 1 rat exposed). No other effects were seen in tests conducted up to 12 days
after exposure (IRIS - http://www.epa.gov/iris/toxreviews/0173tr.pdf).
Rats did not exhibit neurobehavioral effects in this assay.
(9)	Studies in baboons yielded conflicting results. In juvenile baboons exposed via whole-body
inhalation to 0, 25, 35, 50 or 75 ppm (0, 0.102, 0.143, 0.205 or 0.307 mg/L) methyl isobutyl
ketone over a period of 7 days (exact details not available), no clear exposure-related effects
were observed in task performance. However, one baboon at 0.205 mg/L consistently showed an
increased extra response compared with controls in 5 testing sessions over 7 days. In a similar
match-to-sample task performance study, results indicated depressed extra response time in 3 of
4 baboons vs. controls and increased mean response time in all 4 baboons at 0.205 mg/L when
comparing pre- and post-exposure responses. The animals had been exposed to methyl ethyl
ketone 1 month previously, which may have affected some results (IRIS -
http://www.epa.gov/iris/toxreviews/0173tr.pdf).
Baboons exhibited neurological effects in these assays.
Conclusion: No endpoints have been identified as data gaps under the HPV Challenge Program
for the hydrolysis products of diethylenetriamine and methyl isobutyl ketone.
The acute oral and acute dermal toxicity of l,7-bis(l,3-dimethylbutylidene) diethylenetriamine is
low in rats and rabbits, respectively. Following repeated oral exposures to the dihydrochloride
salt of diethylenetriamine in the diet for 90 days, decreased body weight, increased kidney, liver
weights, increased mean corpuscular volume and hemoglobin, decreased blood glucose,
increased white blood cells and lymphocytes and increased urine pH were observed at > 530-620
mg/kg-day; the NOAEL was 70-80 mg/kg-day. Rats and mice were exposed to methyl isobutyl
ketone for 6 hrs/day, 5 days/week for 14 week and showed no adverse effects; the NOAEC is 4.1
mg/L (highest dose tested). In another study, rats were exposed to methyl isobutyl ketone for 13
weeks via inhalation resulting in a NOAEC is 6.1 mg/L (highest dose tested).
In an oral gavage reproductive toxicity study in rats, exposure to diethylenetriamine resulted in
decreased body weight was seen in parents at 300 mg/kg-day; the NOAEL for systemic toxicity
is 100 mg/kg-day and the NOAEL for reproductive/developmental toxicity is 30 mg/kg-day. In
a 2-generation inhalation reproductive toxicity study in rats with methyl isobutyl ketone, parents
had decreased body weight at 8.2 mg/L; the NOAEC for systemic toxicity is 4.1 mg/L.
However, no reproductive effects were observed and the reproductive NOAEC is 8.2 mg/L. F1
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offspring had clinical signs of neurotoxicity at 8.2 mg/L when exposure began at post natal day
(PND) 22. Based on these neurological signs, the NOAEC for developmental toxicity is 4.1
mg/L.
Diethylenetriamine induced gene mutations in mammalian cells in vitro and bacteria but not in
yeast. Methyl isobutyl ketone did not induce gene mutations in bacteria. Diethylenetriamine did
not induce chromosomal aberrations in an in vitro test using Chinese hamster ovary cells or
micronuclei in mice in vivo but induced sister chromatid exchanges in vitro. Methyl isobutyl
ketone did not induce chromosomal aberrations in rat liver (RL4) cells in vitro, mitotic
recombination, unscheduled DNA synthesis in vitro or micronuclei in mice in vivo. Methyl
isobutyl ketone induced mutations in mouse lymphoma cells.
Diethylenetriamine is corrosive to rabbit skin and eyes and a dermal sensitizer in guinea pigs.
Methyl isobutyl ketone is irritating to rabbit skin and eyes and is not a dermal sensitizer.
Methyl isobutyl ketone induced cell transformation in BALB/3T3 mouse embryo cells in vitro.
Diethylenetriamine did not induce an increase in tumor formation following repeated dermal
exposures over the lifetime of rats and mice. Methyl isobutyl ketone showed some evidence of
carcinogenicity in mice and male rats and equivocal evidence in female rats. Some neurological
signs have been seen in humans and other species exposed to methyl isobutyl ketone.
The aquatic toxicity of l,7-bis(l,3-dimethylbutylidene) diethylenetriamine, based on the
supporting chemicals diethylenetriamine and methyl isobutyl ketone, for fish is 248 mg/L (96-h
LC50), for aquatic invertebrates is 16 mg/L (48-h EC50), and for aquatic plants is 187 mg/L for
biomass(72-h EC50). The 21-day NOEC and LOEC for chronic toxicity to aquatic invertebrates,
based on the supporting chemicals is 5.6 and 11.3 mg/L, respectively. The 28-day NOEC for
chronic toxicity to fish, based on the supporting chemicals is 10 mg/L.
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Table 4. Summary of the Screening Information Data Set under the U.S. HPV Challenge
Program - Human Health Data

SPONSORED
CHEMICAL
SUPPORTING
CHEMICAL
SUPPORTING
CHEMICAL
Endpoints
1,7-Bis(l,3-
dimethylbutylidene)
diethylenetri amine
(CASRN 10595-60-5)
Diethylenetri amin
(CASRN 1 1 1-40-0)
Methyl isobutyl ketone
(CASRN 108-10-1)
Acute Toxicity
Oral LD50 (mg/kg)
-1664


Acute Toxicity
Dermal LD50
(mg/kg)
-1752


Repeated-Dose
Toxicity
NOAEL/LOAEL
Oral (mg/kg-day)
NOAEL = 70-80
LOAEL = 530 - 620
(RA)
NOAEL = 70-80
LOAEL = 530 - 620
(rat)
NOAEL = 1000
LOAEL = NE
(rat)
Repeated-Dose
Toxicity
N O AEC/LO AEC
Inhalation (mg/L-
day)
NOAEC = 6.1
LOAEC = NE
(RA)
—
NOAEC = 6.1
LOAEC = NE
(rat)
Reproductive
Toxicity
NOAEL/LOAEL
Oral (mg/kg-bw/day)
Systemic Toxicity

NOAEL = 100
LOAEL = 300

Reproductive
Toxicity

NOAEL = 30
LOAEL = 100

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Table 4. Summary of the Screening Information Data Set under the U.S. HPV Challenge
Program - Human Health Data

SPONSORED
CHEMICAL
SUPPORTING
CHEMICAL
SUPPORTING
CHEMICAL
Endpoints
1,7-Bis(l,3-
dimethylbutylidene)
diethylenetri amine
(CASRN 10595-60-5)
Diethylenetri amin
(CASRN 1 1 1-40-0)
Methyl isobutyl ketone
(CASRN 108-10-1)
Reproductive
Toxicity
NOAEL/LOAEL
Inhalation (mg/L-
day)
Systemic Toxicity
NOAEC ~ 4.1
LOAEC ~ 8.2

NOAEC ~ 4.1
LOAEC ~ 8.2
Reproductive
Toxicity
NOAEC -8.2
LOAEC = NE

NOAEC ~ 8.2
LOAEC = NE
Developmental
Toxicity
NOAEC -4.1
LOAEC - 8.2
(RA)

NOAEC ~ 4.1
LOAEC ~ 8.2
Developmental
Toxicity
NOAEL/LOAEL
Inhalation (mg/L-
day)
Maternal Toxicity
NOAEC-4.1
LOAEC - 12.3

NOAEC ~ 4.1
LOAEC ~ 12.3
Developmental
Toxicity
NOAEC-4.1
LOAEC - 12.3
(RA)

NOAEC ~ 4.1
LOAEC ~ 12.3
Genetic Toxicity -
Gene Mutation
In vitro
Positive
(RA)
Positive
Negative
Genetic Toxicity -
Chromosomal
Aberrations In vitro
Negative
(RA)
Negative
Negative
Genetic Toxicity -
Chromosomal
Aberrations In vivo
Negative
(RA)
Negative
Negative
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U.S. Environmental Protection Agency
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Table 4. Summary of the Screening Information Data Set under the U.S. HPV Challenge
Program - Human Health Data

SPONSORED
CHEMICAL
SUPPORTING
CHEMICAL
SUPPORTING
CHEMICAL
Endpoints
1,7-Bis(l,3-
dimethylbutylidene)
diethylenetri amine
(CASRN 10595-60-5)
Diethylenetri amin
(CASRN 1 1 1-40-0)
Methyl isobutyl ketone
(CASRN 108-10-1)
Genetic Toxicity -
Other
Mitotic
Recombination
Unscheduled DNA
Synthesis


Negative
Negative
Mouse lymphoma
Sister Chromatid
Exchange

Positive
Positive
Additional
Information
Skin Irritation
Eye Irritation
Skin Sensitization
Cell Transformation
Carcinogenicity
Neurotoxicity
—
Corrosive
Corrosive
Positive
Negative
Irritating
Irritating
Negative
Positive
Positive
Positive
NE = not established
- this endpoint was not addressed for this chemical and read-across was not used
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4. Hazard to the Environment
A summary of aquatic toxicity data submitted for SIDS endpoints is provided in Table 5.
Acute Toxicity to Fish
Diethylenetriamine (CASRN111-40-0, supporting chemical)
In two studies, guppies (Poecilia reticulata) were exposed to diethylenetriamine at unspecified
concentrations under static conditions for 96 hours.
96-h LC50 = 248 - 332 mg/L
Methyl isobutyl ketone (CASRN 108-10-1, supporting chemical)
(1)	In five studies, fathead minnows (Pimephalespromelas) were exposed to methyl isobutyl
ketone at unspecified concentrations under unspecified conditions for 96 hours.
96-h LC50 = 505 - 780 mg/L
(2)	Rainbow trout (Salmo gairdneri) were exposed to methyl isobutyl ketone at unspecified
concentrations under unspecified conditions for 96 hours.
96-h LC50 = 600 mg/L
Acute Toxicity to Aquatic Invertebrates
Diethylenetriamine (CASRN 111-40-0, supporting chemical)
(1)	In three studies, water fleas (Daphnia magna) were exposed to diethylenetriamine at
unspecified concentrations under unspecified conditions for 48 hours.
48-h EC50= 16 - 64.6 mg/L
(2)	Water fleas (Daphnia magna) were exposed diethylenetriamine at unspecified concentrations
under static conditions for 48 hours.
48-h EC50 = 53.5 mg/L
Methyl isobutyl ketone (CASRN 108-10-1, supporting chemical)
In two studies, water fleas (Daphnia magna) were exposed to methyl isobutyl ketone
diethylenetriamine at unspecified concentrations under unspecified conditions for 48 hours.
48-h EC50 = 170 - > 1000 mg/L
Toxicity to Aquatic Plants
Diethylenetriamine (CASRN 111-40-0, supporting chemical)
(1)	Green algae (Pseudokirchneriella subcapitata) were exposed to diethylenetriamine at
unspecified concentrations for 96 hours.
96-h EC50 (growth) = 346 mg/L
(2)	Green algae (Scenedesmus subspicatus) were exposed to diethylenetriamine at unspecified
concentrations for 96 hours.
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96-h EC50 (growth) = 592 mg/L
(3) Green algae (Pseudokirchneriella subcapitata) were exposed to diethylenetriamine at
unspecified concentrations for 72 hours.
72-h EC50 (growth) = 1164 mg/L
72-h EC50 (biomass) = 187 mg/L
Methyl isobutyl ketone (CASRN108-10-1, supporting chemical)
(1)	Green algae (.Pseudokirchneriella subcapitata) were exposed to methyl isobutyl ketone at
unspecified concentrations for 96 hours.
96-h EC50 (growth) = 400 mg/L
(2)	Green algae (Scenedesmus subspicatus) were exposed to methyl isobutyl ketone at
unspecified concentrations for 48 hours.
48-h EC50 = 980 mg/L
Chronic Toxicity to Fish
Diethylenetriamine (CASRN 111-40-0, supporting chemical)
In a fish early-life stage study, three-spined sticklebacks (Gasterosteus aculeatus) were exposed
to diethylenetriamine at unspecified concentrations under static-renewal conditions for 28 days.
No effects were observed on weight or length.
NOEC = 10 mg/L
Methyl isobutyl ketone (CASRN 108-10-1, supporting chemical)
Fathead minnow (Pimphalespromelas) were exposed to methyl isobutyl ketone at unspecified
concentrations under unspecified conditions for 31 days. Weight of young fish was the only
endpoint evaluated.
NOEC = 57 mg/L
LOEC = 105 mg/L
MATC = 77.4 mg/L
Chronic Toxicity to Aquatic Invertebrates
Diethylenetriamine (CASRN 111-40-0, supporting chemical)
In a reproduction rate study, water fleas (Daphnia magna) were exposed to diethylenetriamine at
unspecified concentrations under static-renewal conditions for 21 days.
LOEC = 11.3 mg/L
NOEC = 5.6 mg/L
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Methyl isobutyl ketone (CASRN108-10-1, supporting chemical)
In a reproduction rate study, water fleas (Daphnia magna) were exposed to methyl isobutyl
ketone at unspecified concentrations under unspecified conditions for 21 days.
NOEC = 78 mg/L
Conclusion: The aquatic toxicity of diethylenetriamine, l,7-bis(l,3-dimethylbutylidene), based
on the supporting chemicals Diethylenetriamine and Methyl isobutyl ketone, for fish is 248 mg/L
(96-h LC50), for aquatic invertebrates is 16 mg/L (48-h EC50), and for aquatic plants is 187 mg/L
for biomass (72-h EC50). The 21-day NOEC and LOEC for chronic toxicity to aquatic
invertebrates for diethylenetriamine, l,7-bis(l,3-dimethylbutylidene), based on the supporting
chemicals is 5.6 and 11.3 mg/L, respectively. The 28-day NOEC for chronic toxicity to fish for
diethylenetriamine, l,7-bis(l,3-dimethylbutylidene), based on the supporting chemicals is 10
mg/L. No endpoints have been identified as data gaps under the HPV Challenge Program for the
hydrolysis products of diethylenetriamine and methyl isobutyl ketone.
Table 5. Summary of the Screening Infor
Challenge Program - Ac
mation Data Set under the U.S. HPV
uatic Toxicity Data
Endpoints
SPONSORED
CHEMICAL
1,7-bis( 1,3-(limethy 1-
butylidcnc)
(10595-60-5)
SUPPORTING
CHEMICAL
Diethylenetriamine
(111-40-0)
SUPPORTING
CHEMICAL
Methyl isobutyl ketone
(108-10-1)
Fish
96-h LC50 (mg/L)
No data
248
(RA)
248
505
Aquatic Invertebrates
48-h EC?o (mg/L)
No data
16
(RA)
16
170
Aquatic Plants
72-h EC50 (mg/L)
Growth rate
Biomass
No data
187
(RA)
1164
187
400
(96-h)
Chronic Toxicity to Fish
28-d LC50 (mg/L)
No Data
NOEC = 10 mg/L
(RA)
NOEC = 10 mg/L
NOEC = 57 mg/L
LOEC = 105 mg/L
MATC = 77.4 mg/L
Chronic Toxicity to
Aquatic Invertebrates
21-d LC?» (mg/L)
No Data
LOEC = 11.3 mg/L
NOEC = 5.6 mg/L
(RA)
LOEC = 11.3 mg/L
NOEC = 5.6 mg/L
NOEC = 78 mg/L
\A = Read across; Bold = experimentally derived data.
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References
Nemec, M.D., J.A. Pitt, D.C. Topping, R. Gingell, K.L. Pavkov, E.J. Rauckman, and S.B. Harris.
2004. Inhalation two-generation reproductive toxicity study of methyl isobutyl ketone in rats.
International Journal of Toxicology. 23(2):127-143.
Ng, T.P., H.S. Lee, M.A. Malkik, C.B.E. Chee, T.H. Cheong, and Y.T. Wang. 1995. Asthma in
chemical workers exposed to aliphatic polyamines. Occup. Med. 45(l):45-48.
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