United States
Environmental Protection
1=1 m m Agency
EPA/690/R-11/049F
Final
9-27-2011
Provisional Peer-Reviewed Toxicity Values for
3-(N,N-Dimethylamino)propionitrile
(CASRN 1738-25-6)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Jeff Swartout, National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
National Center for Environmental Assessment, Cincinnati, OH
This document was externally peer-reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300).

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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS	ii
BACKGROUND	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVS	1
INTRODUCTION	2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER)	4
HUMAN STUDIES	8
Oral Exposures	8
Inhalation Exposures	8
Long-term Studies	8
ANIMAL STUDIES	12
Oral Exposures	12
Subchronic Studies	12
Chronic Studies	13
Developmental Studies	13
Reproductive Studies	13
Carcinogenicity Studies	13
Inhalation Exposures	14
Subchronic Studies	14
Chronic Studies	14
Developmental Studies	14
Reproductive Studies	14
Carcinogenicity Studies	14
Other Studies	14
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)	15
Tests Evaluating Carcinogenicity, Genotoxicity, and/or Mutagenicity	19
Other Toxicity Studies (Exposures Other Than Oral and Inhalation)	19
Short-term Studies	19
Toxicokinetics	20
DERIVATION 01 PROVISIONAL VALUES	21
DERIVATION OF ORAL REFERENCE DOSES	22
Derivation of Subchronic Provisional RfD (Subchronic p-RfD)	22
Derivation of Chronic Provisional RfD (Chronic p-RfD)	22
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS	22
Derivation of Subchronic Provisional RfC (Subchronic p-RfC)	23
Derivation of Chronic Provisional RfC (Chronic p-RfC)	23
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTION	23
MODE-OF-ACTION (MOA) DISCI SSION	23
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES	24
Derivation of Provisional Oral Slope Factor (p-OSF)	24
Derivation of Provisional Inhalation Unit Risk (p-IUR)	24
APPENDIX A. PROVISIONAL SCREENING VALUES	25
APPENDIX B. DATA TABLES	26
APPENDIX C. BMD OUTPUTS	37
APPENDIX D. REFERENCES	38
i	3-(N,N-dimethylamino)propionitrile

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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMD
benchmark dose
BMCL
benchmark concentration lower bound 95% confidence interval
BMDL
benchmark dose lower bound 95% confidence interval
HEC
human equivalent concentration
HED
human equivalent dose
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
POD
point of departure
RfC
reference concentration (inhalation)
RfD
reference dose (oral)
UF
uncertainty factor
UFa
animal-to-human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete-to-complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
11

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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
3-(N,N-DIMETHYLAMIN0)PR0PI0NITRILE (CASRN 1738-25-6)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database (http://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (www.epa.gov/iris), the respective PPRTVs are removed
from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
QUESTIONS REGARDING PPRTVS
Questions regarding the contents and appropriate use of this PPRTV assessment should
be directed to the EPA Office of Research and Development's National Center for
Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300).
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INTRODUCTION
3-(N,N-Dimethylamino)propionitrile (DMAPN) is used as a catalyst in the manufacture
of polyurethane or as a polymerization stimulator in the production of polyacrylamide gels
(HSDB, 2003). It belongs to a class of chemicals called propionitriles, which have the basic
structure of (X-CH2-CH2-CN). These compounds have a wide variety of toxic effects that
depend on the identity of the X moiety (Pestronk et al., 1980). DMAPN (see Figure 1) has been
shown to have neurotoxic properties. The neurotoxic effects of DMAPN were first identified
during an epidemic of urinary retention, sexual dysfunction, and peripheral neuropathy that
occurred when workers in polyurethane foam manufacturing plants were exposed to this
compound in 1976 and 1977 (Keogh, 1983; Keogh et al., 1980; Kreiss et al., 1980; Baker et al.,
1981). Most affected workers recovered promptly, but some had persisting neuropathy, sexual
and bladder dysfunction, and central nervous system (CNS) symptoms. The outbreak ceased
abruptly when DMAPN use was stopped. The catalyst that caused the problem—NIAX catalyst
ESN (a mixture of 95% DMAPN/dimethylaminopropionitrile and 5% bis-dimethylaminoethyl
ether)—was withdrawn from the market in the United States after rapid governmental action
(Keogh, 1983). Table 1 provides a list of the selected physicochemical properties for DMAPN.
N
Figure 1. 3-(N,N-dimethylamino)propionitrile Structure
2
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Table 1. Physicochemical Properties of 3-(N,N-dimethylamino)propionitrile
(CASRN 1738-25-6)a
Property (unit)
Value
Boiling point (°C)
171
Melting point (°C)
-44.6
"3
Density (g/cm )
0.8701 at 20°C
Vapor pressure (hPa at 30°C)
2.4
pH (unitless)
10.8 at lOOg/Land 20°C
Solubility in water (g/100 mL at 25°C)
Miscible
Relative vapor density (air =1)
ND
Molecular weight (g/mol)
98.2
aIUCLID (2000).
ND = no data
No Reference Dose (RfD), Reference Concentration (RfC), or cancer assessment for
DMAPN is included in the United States Environmental Protection Agency (U.S. EPA)
Integrated Risk Information System (IRIS) (U.S. EPA, 2010) or on the Drinking Water
Standards and Health Advisories List (U.S. EPA, 2009). No RfD or RfC values are reported in
the Health Effects Assessment Summary Tables (U.S. EPA, 2003). The Chemical Assessments
and Related Activities (CARA) list does not include any EPA documents for DMAPN
(U.S. EPA, 1994). The California Environmental Protection Agency (CalEPA, 2008, 2009) has
not derived toxicity values for exposure to DMAPN.
The toxicity of DMAPN has not been reviewed by the Agency for Toxic Substances and
Disease Registry (ATSDR, 2010) or the World Health Organization (WHO, 2011). No
occupational exposure limits for DMAPN have been derived or recommended by the American
Conference of Governmental Industrial Hygienists (ACGIH, 2010), the National Institute of
Occupational Safety and Health (NIOSH, 2011), or the Occupational Safety and Health
Administration (OSHA, 2006). However, in May 1978, OSHA and NIOSH jointly published the
Current Intelligence Bulletin (CIB) 26: NIAX® Catalyst ESN (NIOSH, 2011). In this CIB,
OSHA and NIOSH recommended that occupational exposure to NIAX® Catalyst ESN, its
components, DMAPN and bis(2-(dimethylamino)ethyl)ether, as well as formulations containing
either component, be minimized. They stated that exposures should be limited to as few workers
as possible, while minimizing workplace exposure concentrations with effective work practices
and engineering controls. In addition, exposed workers should be carefully monitored for
potential disorders of the nervous and genitourinary system (NIOSH, 2011). The Registry of
Toxic Effects of Chemical Substances (RTECS, 2007) reports a Russian short-term occupational
exposure limit of 10 mg/m3 for DMAPN.
The HEAST (U.S. EPA, 2011) does not report any cancer values for DMAPN. The
International Agency for Research on Cancer (IARC, 2010) has not reviewed the carcinogenic
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potential of DMAPN; the compound is not included in the 12th Report on Carcinogens (NTP,
2011), and CalEPA (2008) has not prepared a quantitative estimate of carcinogenic potential for
DMAPN.
Literature searches were conducted on sources published from 1900 through
August 2011, for studies relevant to the derivation of provisional toxicity values for
3-(N,N-dimethylamino)propionitrile, CAS Number (1738-25-6). Searches were conducted using
U.S. EPA's Health and Environmental Research Online (HERO) database of scientific literature.
HERO searches the following databases: AGRICOLA; American Chemical Society; BioOne;
Cochrane Library; DOE: Energy Information Administration, Information Bridge, and Energy
Citations Database; EBSCO: Academic Search Complete; GeoRef Preview; GPO: Government
Printing Office; Informaworld; IngentaConnect; J-STAGE: Japan Science & Technology;
JSTOR: Mathematics & Statistics and Life Sciences; NSCEP/NEPIS (EPA publications
available through the National Service Center for Environmental Publications (NSCEP) and
National Environmental Publications Internet Site (NEPIS) database); PubMed: MEDLINE and
CANCERLIT databases; SAGE; Science Direct; Scirus; Scitopia; SpringerLink; TOXNET
(Toxicology Data Network): ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART, EMIC,
EPIDEM, ETICBACK, FEDRIP, GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS, ITER,
LactMed, Multi-Database Search, NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI, and
TSCATS; Virtual Health Library; Web of Science (searches Current Content database among
others); World Health Organization; and Worldwide Science. The following databases outside
of HERO were searched for risk assessment values: ACGIH, ATSDR, CalEPA, U.S. EPA IRIS,
U.S. EPA HEAST, U.S. EPA HEEP, U.S. EPA OW, U.S. EPA TSCATS/TSCATS2, NIOSH,
NTP, OSHA, and RTECS.
REVIEW OF POTENTIALLY RELEVANT DATA
(CANCER AND NONCANCER)
Table 2 provides an overview of the relevant database for DMAPN and includes all
potentially relevant repeated short-term-, subchronic-, and chronic-duration studies. NOAELs,
LOAELs, and BMDL/BMCL are provided in HED/HEC units for comparison except that oral
noncancer values are not converted to HEDs and are identified in parentheses as (Adjusted)
rather than HED/HECs. Principal studies are identified. Following the table, important aspects
of all the studies in the table are provided in the same order as the table. Reference can be made
to details provided in Table 2. The phrase, "statistical significance," used throughout the
document, indicates ap-walue of <0.05.
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Table 2. Summary of Potentially Relevant Data for 3-(N,N-Dimethylamino)Propionitrile (CASRN 1738-25-6)
Notes3
Category
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
Human
1. Oral (mg/kg-d)b
NA
Subchronic
ND
NA
Chronic
ND
NA
Developmental
ND
NA
Reproductive
ND
NA
Carcinogenicity
ND
2. Inhalation (mg/m3)b
NA
Subchronic
ND
PR
Long-term
139/2 workers at
Facility A,
64/11 workers at
Facility B, work
exposure, ~9 mo
NA
Symptoms of urinary retention among
workers at both facilities were
reported. These included straining,
hesitancy, decreased flow, intermittent
flow, bladder distension, and the need
for manual pressure to empty the
bladder.
Increased incidence of sexual
dysfunction also was found among
workers working in the production
line.
NA
DU
NA
Keogh et al.
(1980)
5
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Table 2. Summary of Potentially Relevant Data for 3-(N,N-Dimethylamino)Propionitrile (CASRN 1738-25-6)
Notes3
Category
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
PR

213 (no. sex not
reported), work
exposure, ~9 mo
NA
Symptoms were identified among
104 workers, most of whom worked at
the production line. These symptoms
were
-neurogenic bladder dysfunction,
characterized by hesitancy, need to
strain, decreased stream, and
increased duration of urination.
-sexual difficulties.
NA
DU
NA
Kreiss et al.
(1980)
PR
11 (mostly male), ~9 mo
NA
Decrease in the overall prevalence of
urologic and neurological symptoms
for the 11 persons interviewed 2 yr
after the exposure; however, high rates
of some persistent symptoms were
observed (sexual dysfunction).
NA
DU
NA
Baker et al.
(1981)
NA
Developmental
ND
NA
Reproductive
ND
NA
Carcinogenicity
ND
Animal
1. Oral (mg/kg-d)b
NPR
Subchronic
6 (no. sex not reported),
Sprague-Dawley, rat,
diet, 7 d/wk, 56 d
0 or 175 mg/kg-d
(Adjusted)
No deaths occurred, no skeletal
changes of weanlings, no lathyrogenic
(type of neurological) effects.
NDr
DU
NDr
Bachhuber et al.
(1955)
NPR
Chronic
(no. animals, sex, species
not reported), rat,
drinking water, 2-9 mo
450 mg/kg-d
(Adjusted)
Enlarged distal motor and spindle
axons with disordered neurofilaments
and enlarged motor nerve terminals
were observed.
NDr
DU
NDr
Pestronk et al.
(1979, as cited
in Pestronk et
al., 1980)
6
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Table 2. Summary of Potentially Relevant Data for 3-(N,N-Dimethylamino)Propionitrile (CASRN 1738-25-6)
Notes3
Category
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
NA
Developmental
ND
NPR
Reproductive
0/2, Sprague-Dawley,
rat, diet, at 17th d of
pregnancy
150 mg/kg-d
(Adjusted)
No toxic effects were reported.
Normal litters were born.
NDr
DU
NDr
Stamler (1955)
NA
Carcinogenicity
ND
2. Inhalation (mg/m3)b
NA
Subchronic
ND
NA
Chronic
ND
NA
Developmental
ND
NA
Reproductive
ND
NA
Carcinogenicity
ND
aNotes: IRIS = utilized by IRIS, date of last update; PS = principal study; PR = peer reviewed; NPR = not peer reviewed.
bDosimetry: NOAEL, BMDL/BMCL, and LOAEL values are converted to human equivalent dose (HED in mg/kg-day) or human equivalent concentration (HEC in
mg/m3) units.
DU = data unsuitable; NA = not applicable; ND = No data; NDr = Not determined; NR = Not reported; NR/Dr = Not reported, but determined from data.
7
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HUMAN STUDIES
Oral Exposures
No studies investigating the effects oral exposure to DMAPN in humans have been
identified.
Inhalation Exposures
The effects of inhalation exposure of humans to DMAPN have been evaluated in two
occupational studies (Keogh et al., 1980; Kreiss et al., 1980) and in one follow-up study
(Baker et al., 1981).
Long-term Studies
Keogh et al., 1980
Keogh et al (1980) performed a clinical investigation on workers who had been
occupationally exposed to a catalyst containing 95% DMAPN, 5%
bis(2-(dimethylamino)ethyl)ether, and <1% acrylonitrile and dimethylamine at two polyurethane
foam manufacturing plants in the United States (Maryland and Massachusetts plants). The
investigation was conducted after complaints of dizziness, weakness, temporary clouding of
vision, and paresthesias were reported in workers at these plants. The cause of these symptoms
was thought to be due to a new catalyst NIAX-catalyst ESN, which had been introduced in large
quantities into the production line of polyurethane in August 1977, some months before the
epidemic began. Based on this, the use of the catalyst was stopped in the plant and the study
authors carried out their clinical investigation on all workers at the affected plant (Plant A,
Maryland) to explore the potential health effects of DMAPN exposure. They also examined
workers at a nearby plant (Plant B, Massachusetts) owned by the same company, which made
polyurethane but used little of the suspected catalyst in production.
Of 234 eligible employees (across the plant from production line, finishing, supply,
storage, laboratory, and clerical areas), 216 agreed to participate in the study (141 employees
from Plant A [139 men and 2 women] and 75 employees from Plant B [64 men and 11 women]).
Workers were thought to have experienced dermal as well as inhalation exposures. The workers
were tested between April 11 and May 2, 1978, almost 1 year after the introduction of the ESN
catalyst (August 1977). Participants were asked to complete questionnaires focused mainly on
symptoms observed on the skin, the lungs, the CNS, and the genitourinary system. They were
asked specifically about straining, hesitancy, decreased flow, intermittent flow, distension,
frequency of urination, the need for manual pressure to empty the bladder, and sexual function.
Complete physical examination was conducted on all participants and the results were recorded
on a standard form. Limited neurological assessments were carried out. These included testing
for cranial nerves and examining motor strength, deep tendon reflexes, and vibratory sensation at
the ankles, station, and gait. Pulmonary function was assessed by performing a spirometry test in
all participants. An intravenous pyelography (IVP) with postvoid film was ordered for workers
who had persisting symptoms of urinary retention. Laboratory analyses including routine blood
and complete urine tests were also performed. The prevalence of specific symptoms was
assessed individually. Statistical analyses included the x test to analyze symptoms and clinical
signs.
The results of the clinical and physical examinations indicated that occupational exposure
to unknown concentrations of the ESN catalyst for 8 months resulted in neurological and
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urologic effects (e.g. urinary retention, paresthesias, weakness, impotence, irritability, and
insomnia). The prevalence of a variety of symptoms reported by the exposed groups is shown in
Table B. 1. Among the reported symptoms, urinary retention and irritability were the most
common symptoms. Also, the prevalence of these symptoms in Plant A workers was
significantly higher (p < 0.01) than that found in Plant B workers (see Table B. 1). After
exposure was discontinued, these symptoms decreased or disappeared as reported by the exposed
workers. Among all subjects, 65 workers were identified to undergo an IVP. Seventeen of these
workers had abnormal postvoid retention of contrast material in the bladder (see Table B.2).
However, the study authors stated that this finding was not conclusive evidence of bladder
dysfunction. Therefore, the bladder dysfunction was further assessed by performing cystoscopy
and cystometrograms (CMGs) in exposed workers whose symptoms, examination, and
roentgenograms suggested intervention might be needed to prevent hydronephrosis. As a result,
bladder dysfunction was diagnosed in only four workers as confirmed by CMG tests but none
needed surgical intervention. Decreased sensation in lower sacral dermatomes and hands and
feet was reported in three workers. The findings of other examinations (nerve conduction
studies, urinalysis, and blood tests) were reported to be normal. A clear association between jobs
having the highest exposure to warm foam containing ESN and the incidence of urinary retention
was observed (see Table B.3). Production line employees were reported to have a high incidence
of urinary retention as compared with those working in the supervisory and clerical areas.
In addition to the above, other symptoms such as visual disturbances, upper respiratory
tract irritation, dermatitis, and pulmonary symptoms were also reported by workers in both
plants. A significantly higher (p < 0.01) incidence of these symptoms was observed at Plant A
(see Table B.4). Visual disturbances were the most common problem reported. The results of
the spirometry assessment of pulmonary function were abnormal in many workers. This
incidence of this abnormality showed no relation to the length of employment and was explained
by the study authors to be due to the presence of other factors such as toluene diisocyanate (TDI,
the monomer employed in polyurethane foam production) and cotton. A high incidence of upper
respiratory tract irritation and dermatitis was also observed at both plants. This was considered
by the study authors to be due to high exposure to irritant fumes and the lack of protective
clothing or adequate respiratory protection worn at the plants. The severity and frequency of
these symptoms were not decreased after the removal of the catalyst.
In summary, increased incidence of urinary retention, muscle weakness, paresthesia,
insomnia, and sexual dysfunction were observed in employees working in the manufacture of
polyurethane foam. The highest rates of illness occurred in production workers who were
exposed to the greatest amounts of warm foam with ESN. The study authors concluded that the
new catalyst ESN was the causative agent for these symptoms. The reasons for their conclusion
were (1) there was a temporal relationship between the introduction of the catalyst and the onset
of the epidemic, (2) the symptoms of retention, paresthesia, weakness, insomnia, and sexual
dysfunction were largely confined to the plant where the catalyst was used most heavily
(Plant A) and (3) no new cases occurred after the use of catalyst was stopped. The study authors
also stated that DMAPN, the major component of the catalyst, was probably the neurotoxin
responsible for these effects. Because the level of exposure to DMAPN was not measured in the
study, no NOAEL or LOAEL could be identified.
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Kreiss et al., 1980
Kreiss et al. (1980) investigated the extent of an epidemic discovered among workers
employed in another polyurethane manufacture plant in Massachusetts. The outbreak occurred
in a plant that manufactured automobile seat cushions from polyurethane foam. The study
authors stated that a new catalyst, DMAPN, which was recently introduced into the
manufacturing process, could be the cause of this epidemic. The investigation was conducted 8
to 13 days after the catalyst was withdrawn from the manufacturing process (March 29, 1978).
Of 230 eligible employees (across the plant), 213 agreed to precipitate in the study
(number of men and women participants were not reported). The median age of the cases at
entry into the cohort was 37.9 years for females and 31.3 years for males. Participants were
administered a questionnaire that collected information on medical history and general
symptoms. Information on job description, use of protective equipment, personal hygiene, and
genitourinary and neurological symptoms were collected by personal interview. Blood sampling
and urinalyses were performed. The blood was analyzed for complete blood cell count,
differential white blood cell (WBC) count, and levels of electrolytes, glucose, blood urea
nitrogen (BUN), creatinine, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic
pyruvic transaminase (SGPT), lactic dehydrogenase, alkaline phosphatase, bilirubin, calcium,
and uric acid and for antinuclear antibody titer. Neurologic examinations were performed on
eight symptomatic workers (five men and three women) 2V2 weeks after cessation of DMAPN
exposure. The neurological examinations included testing for cranial nerves, reflexes,
coordination, sensory system and gait (e.g., skin temperature-nerve conduction studies), and
mental status. The criteria for clinical neuropathy included upper and lower extremity
distribution of one abnormality, or the occurrence of at least two of the following: numbness,
paresthesia, decreased pinprick sensation, decreased vibratory sensation, decreased tendon
reflexes, and muscle weakness. The urologic evaluation included cystometrography. Bladder
dysfunction was characterized by hesitancy, need to strain, decreased stream, and increased
duration of urination. The study authors defined a case of bladder dysfunction as any employee
who experienced any two of these four symptoms. A late improver case was defined as a worker
who had persistent urinary symptoms at the 3 month reinterview. The employees were grouped
and analyzed according to the departments in which they worked. Workers from the production
or finishing rooms were considered to be at higher risk of exposure to DMAPN than those
working in the nonmanufacturing areas such as the warehouse.
Of 213 workers who participated in the study, the symptoms of 208 employees' were
analyzed. Of these, 166 employees (36 women and 130 men) were identified to be at risk for
developing bladder dysfunction while no risk was associated with the remaining 42. The
prevalence of a variety of urinary tract symptoms reported by the exposed groups is shown in
Table B.5. There were 104 employees who met the case definition of bladder dysfunction.1 The
case rates for women and men were 55.6% and 64.5%, respectively. No increase in this case rate
with age was observed. Also, there were no sex-specific differences in the proportion of cases
experiencing specific urinary tract symptoms. A high rate of bladder dysfunction was mainly
observed among the production line workers (the specific rate could not be determined as the
data were represented in the original study as a graph without individual data points). Most of
the affected employees were second- and third-shift workers where the workers were exposed to
1 Case defined by the study authors is an employee who experienced any two of the four symptoms of bladder
dysfunction (hesitancy, need to strain, decreased stream, and increased duration of urination).
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more scrap and waste foam than on the first shift. Bladder symptoms were observed in subjects
with and without significant skin contact with the catalyst or foam product. Based on this, the
study authors suggested that inhalation could be the possible route of exposure. There was also a
clear association between the amount of catalyst used (from June 1977-April 1978) and the
number of cases of bladder dysfunction reported in plant workers (data were represented in the
original study as a graph). Most patients (85%) experienced no improvements in their symptoms
as long as DMAPN was still in use. However, 8-13 days after exposure to the catalyst had been
discontinued, 51% of the patients showed improvement, and an additional 21% were back to
normal. Three months later, 86% of the cases were asymptomatic and the remainder reported
improvement. Only 14 cases were identified as late improvers (4 women and 10 men).
Neurologic testing of eight cases of bladder dysfunction revealed that seven lacked either
detrusor reflex or normal sensation of bladder filling; seven had a subclinical sensory
abnormality; three had prolonged sacral-evoked responses; and two of these three had limb
motor neuropathies (see Tables B.6, B.7, and B.8). Results of urinalysis and blood tests did not
reveal any abnormalities. Other symptoms reported included pain and burning on urination, as
well as impotence. Sexual difficulties were noted in 23 cases and in 6 noncases (employees who
had no bladder dysfunction symptoms) while dysuria was noted in all 14 late improver cases.
These 14 patients were older, on average, than the other patients, with a mean age of 36.4 years
(ages ranged from 21 to 54 years).
The above results suggested that there was an association between occupational exposure
to the DMAPN catalyst and signs and symptoms of bladder neuropathy. The investigators stated
that the results of this study were in line with the occurrence of similar epidemics in at least five
other polyurethane foam plants that had introduced the catalyst. Accordingly, DMAPN was
identified as the cause of this outbreak. Employees exposed to the catalyst experienced
symptoms of bladder dysfunction, sexual dysfunction, and CNS symptoms. The urinary
symptoms, however, occurred with greater frequency than somatic nerve symptoms and sexual
dysfunction. Follow-up evaluations performed 3 months after the substance was removed from
the workplace revealed that approximately 85% of the workers who were initially symptomatic
had recovered. In conclusion, DMAPN was identified by the study authors as a unique industrial
neurotoxin because of its effect in producing bladder dysfunction without producing frequent
complaints of other organ or nerve dysfunction. Because no environmental measurements were
obtained while DMAPN was used in production, the quantitative exposures associated with this
epidemic were unknown. Therefore, no NOAEL or LOAEL can be identified from this study.
Baker etal., 1981
Baker et al. (1981) performed a follow-up investigation in 1980 at the Massachusetts
polyurethane foam factory that had been examined in 1978 by Kreiss et al. (1980). The study
focused on the evaluation of long-term morbidity among the 14 patients who were identified as
late improvers in the Kreiss et al. (1980) 3-month follow-up interview (July 1978). The study
design was similar to that of Kreiss et al. (1980). Briefly, clinical and laboratory examinations
included personal interviews to obtain information on medical history (1978-1980), job history,
urinary symptoms, alcohol consumption, medication, and sexual history. Physical, neurological,
and urological examinations were performed in the same laboratory under similar conditions
and, in most instances, by the same physician as in 1978. For nerve conduction testing, a group
of 29 age- and sex-matched machinists, nonexposed to neurotoxins were used as a reference
group. Also for the neurological testing, four out of eight subjects that previously were tested in
1978 were reexamined again (these eight subjects are the eight cases of bladder dysfunction that
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were selected by Kreiss et al. [1980] for neurological examinations, see Tables B.7 and B.8). In
total, 11 of the 14 late improver participants were interviewed and 10 of them underwent
complete physical, neurological, and urological examinations.
Based on the clinical history, the 11 late improvers continued to report urologic and
abnormal symptoms (see Table B.9). Of these, 9 were male, English speaking and relatively
young (median age 36). The overall prevalence of these symptoms was less than in 1978 except
for an increase in sexual difficulties and paresthesias (see Table B.9). No clear associations
between job category, age, or demographic characteristics and disease persistence were seen.
Neurological abnormalities (sensorimotor neuropathy and hyperreflexic knee jerks) were
observed in three out of ten as confirmed by physical examination. Follow-up neurological
examinations and testing for the four subjects that were tested in 1978 revealed that three of the
four who had signs of sensory or sensorimotor neuropathy in 1978 were normal 2 years later (see
Table B. 10). However, signs of sensorimotor neuropathy persisted in one of the three
individuals while all three workers still had abnormalities affecting the lower limbs (see
Table B. 10). These results correlated weakly with the urologic studies that showed clear
improvement associated with a reduction in the intensity of urologic symptoms among the four
individuals after 2 years (see Table B.l 1). Compared with the referent group, no significant
differences in the nerve conduction tests were observed (see Table B. 12).
In summary, persistent symptoms of urinary tract dysfunction, along with some
neurological damage, were observed in a small group of workers exposed to the industrial
catalyst DMAPN 2 years previously. Their symptoms improved considerably after removal
from exposure to the substance but continued improvement ceased. The study authors were
unable to identify any individual factor that would account for the persistence of symptoms in
this group compared with the vast majority of workers at the plant who recovered without
residual effects. No quantitative data with regard to the exposure level are reported in the study,
and, therefore, no NOAEL or LOAEL can be identified.
ANIMAL STUDIES
Oral Exposures
The effects of oral exposure of animals to DMAPN have been evaluated in one
subchronic-duration (i.e., Bachhuber et al., 1955), one chronic-duration (i.e., Pestronk et al.,
1979, as cited in Pestronk et al., 1980), and one reproductive study (i.e., Stamler, 1955). These
studies provide very limited information.
Subchronic Studies
Bachhuber et al., 1955
Bachhuber et al. (1955) evaluated the subchronic lathyrism toxicity of DMAPN
administered to rats in the diet. (Lathyrism is a neurotoxic disease which results from excessive
consumption of the pea, Lathyrus sativus, and certain related species). The assay was part of a
study investigating the lathyrism effects of Beta-aminopropionitrile (BAPN) and related
compounds since BAPN is known to be the causative agent in producing skeletal deformities in
rats fed Lathyrus odoratus. The study authors performed a series of toxicity assays on
substances chemically related to BAPN to investigate the relation between the structure and the
biological activity. With regard to the DMPAN assay, a group of six Sprague-Dawley rats (sex
and age were not provided) was given a synthetic diet (consisting of casein, dried brewer's yeast,
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and cerelose) to which DMAPN was added at a concentration of 0.35% for 56 days,
corresponding to an average dietary intake of 175 mg/kg-day (as reported in the secondary
source IUCLID [2000]; the primary reference did not report the mg/kg-day equivalent). Control
rats (five) were given the same synthetic diet for 55-64 days. The animals were observed daily
for mortality and body weight was recorded weekly. In the control rats, weight gain was poor
and skeletal abnormalities were not observed. Alteration in skeletal deformities, malformation of
the femurs, hind limb paralysis, hernias and spontaneous aortic ruptures were assessed. No
further information was provided by the study authors on data obtained on this assay. No
mortality was seen in animals given DMAPN in the diet at 175 mg/kg-day for 56 days. In
addition, no changes in body weight or skeletal alterations were observed. Only one rat showed
a presence of bronchopneumonia, which was an unusual observation. Based on the results of the
assays on the BAPN-related chemicals, including DMAPN, the study authors stated that if one or
two methyl groups are incorporated on the amino group in BAPN, this results in a loss of
biological activity. Thus, the lathyrism activity of BAPN is not due solely to the presence of a
nitrile group and is greatly influenced by the presence of a reactive amino group. Based on the
study design (only one dose was applied), no NOAEL/LOAEL can be determined.
Chronic Studies
Pestronk et al., 1979, as cited in Pestronk et al., 1980
Pestronk et al. (1979, as cited in Pestronk et al., 1980) investigated the long-term effects
of DMAPN administered to rats in drinking water. Rats fed 0.5% DMAPN in drinking water
(equivalent to 450 mg/kg-day, as reported in the secondary source IUCLID [2000] which cites
Keogh, 1983 which cites Pestronk et al., 1980; neither of which report the mg/kg-day
equivalents) for 2 to 9 months showed enlarged motor nerve terminals. Electron microscopy
showed enlarged distal motor and spindle axons with disordered neurofilaments. No further
information was provided in the secondary sources. Due to the lack of information on this study,
no NOAEL/LOAEL can be determined.
Developmental Studies
No studies investigating the developmental effect of oral exposure to DMAPN in animals
have been identified
Reproductive Studies
Stamler, 1955
In a study investigating the reproductive effects on rats fed Lathyrus peas or aminonitriles
by Stamler (1955), normal litters (total of 9 litters) were born to female rats (two albino
Sprague-Dawley rats) fed a diet containing 0.3% of DMAPN (equivalent to 150 mg/kg-day as
reported in the secondary source IUCLID [2000)]; the primary reference did not report the
mg/kg-day equivalent) when given beginning the 17th day of pregnancy. No further information
was provided on this particular experiment. It was stated in IUCLID (2000) that only three
maternal animals were used, and the study was inadequately reported and not carried out in
accordance with current guidelines. No NOAEL or LOAEL could be determined.
Carcinogenicity Studies
No oral carcinogenic studies were identified for DMAPN.
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Inhalation Exposures
Data on DMAPN-induced toxicity in animals following inhalation exposure are limited
to one short-term study (i.e., BASF, 1989, as cited in IUCLID, 2000; see Other Data section
below).
Subchronic Studies
No inhalation subchronic studies were identified for DMAPN.
Chronic Studies
No inhalation chronic studies were identified for DMAPN.
Developmental Studies
No inhalation developmental studies were identified for DMAPN.
Reproductive Studies
No inhalation reproductive studies were identified for DMAPN.
Carcinogenicity Studies
No inhalation carcinogenic studies were identified for DMAPN.
Other Studies
Mumtaz et al. (1991b) describe the in vitro and in vivo metabolism of DMAPN, but
present no relevant information for the derivation of reference values. Llorens et al. (2011) pose
a unifying hypothesis for the neurotoxic effects of nitriles but also do not present information
useful for deriving reference values for DMAPN.
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OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
A few studies on genotoxicity, exposures other than oral or inhalation, short-term toxicity and toxicokinetics of DMAPN are available.
These are summarized in Tables 3A and 3B.
Table 3A. Summary of DMAPN Genotoxicity
Endpoint
Test System
Dose
Concentration"
Resultsb
Comments
References
Without
Activation
With
Activation
Genotoxicity studies in prokaryotic organisms
Reverse mutation
Salmonella typhimurium TA98, TA100,
TA1535, TA1537
20-5000
(ig/plate


None
BASF, 1989
(as cited in
IUCLID,
2000)
SOS repair
induction
ND
Genotoxicity studies in nonmammalian eukaryotic organisms
Mutation
ND
Recombination
induction
ND
Chromosomal
aberration
ND
Chromosomal
malsegregation
ND
Mitotic arrest
ND
Genotoxicity studies in mammalian cells—in vitro
Mutation
ND
Chromosomal
aberrations
ND
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Table 3A. Summary of DMAPN Genotoxicity
Endpoint
Test System
Dose
Concentration"
Resultsb
Comments
References
Without With
Activation Activation
Sister chromatid
exchange (SCE)
ND
DNA damage
ND
DNA adducts
ND
Genotoxicity studies in mammals—in vivo
Chromosomal
aberrations
ND
Sister chromatid
exchange (SCE)
ND
DNA damage
ND
DNA adducts
ND
Mouse biochemical
or visible specific
locus test
ND
Dominant lethal
ND
Genotoxicity studies in subcellular systems
DNA binding
ND
aLowest effective dose for positive results, highest dose tested for negative results.
b+ = positive, ± = equivocal or weakly positive, - = negative, T = cytotoxicity, NA = not applicable, ND = no data, NDr = Not determined, NR = Not reported,
NR/Dr = Not reported, but determined from data
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Table 3B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Other toxicity
studies (exposures
other than oral or
inhalation)
Five male rats were administered daily dosage
level of 0.01, 0.1, 0.25, 0.5, or 1.0 mL/kg of
DMAPN for 2 wk (i.p.).
Five male mice were administered daily dosage
level of 0.25, 0.5, or 1.0 mL/kg of DMAPN
(i.p.) for 2 wk (i.p.).
Death occurred in both mice and rats at the
two highest doses (1.0 and 0.5 mL/kg). At
0.01 mL/kg—loss of micturition reflex in
rats; at 0.25 mL/kg—tremors, convulsions,
and cardiovascular effects.

Gadetal. (1979)

Rats were administered a mixture of ESN
catalyst (95% DMAPN and 5% A-99/bis-
dimethylaminoethyl ether) (i.p.) at 0.2 or
2.0 mL/kg.
Rats were administered a mixture of ESN
catalyst (95% DMAPN and 5% A-99/bis-
dimethylaminoethyl ether) by gavage at 0.31 or
0.62 mL/kg for 3 d.
In the i.p. experiment; high dose
(2.0 mL/kg) rapidly produced CNS
excitation followed by depression and
death. In the gavage study, urinary
bladder lesions were observed at both
doses tested (0.31 and 0.62 mL/kg).
ESN catalyst with
DMAPN as the most
prominent
components is toxic
to rats.
Jaeger et al. (1980)

In both experiments, the doses were given to
the rats twice for one day. The animals were
sacrificed on Day 3.



Short-term studies
LD50 studies in rats, mice, and rabbits
1305-2600 mg/kg (oral) in rats and
1500 mg/kg (oral) in mice.
1227-1410 mg/kg (dermal) in rabbits,
435-1740 mg/kg (i.p. in rats), and
180 mg/kg (i.v.) in mice.

BASF, undated; Deckert et al.,
1982; BASF, 1975; RTECS,
undated, Patty, 1962;
Smyth et al., 1962; all as cited
in IUCLID, 2000 ; Pestronk et
al., 1980

12 rats were administered DMAPN by
inhalation for 3-8 hr and 6 rats were
administered DMAPN by inhalation for 8 hr
12 rats: No deaths at 3 hr and 1 death at
8 hr; 6 rats: No deaths at 8 hr.

BASF, 1975; Smyth etal.,
1962; as cited in IUCLID, 2000
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Table 3B. Other Studies
Test
Materials and Methods
Results
Conclusions
References

5 male Sprague-Dawley rats were administered
DMAPN orally at dose level of 350 mg/kg-d,
5 d/wk for 2 wk or 525 mg/kg-d once a day for
2d.
Decrease in body weight, high water
consumption during the first 7 d (2 wk
study); kidney effects, increased urea
nitrogen, creatinine in plasma, decreased
urea nitrogen, creatinine in urine (2 d
study).

Mumtazetal., 1991a
Short-term studies
Rats were exposed to inhaled DMAPN at doses
of 0, 0.01, 0.1, or 1 mg/L, 6 hr/d, 5 d/wk, for
2 wk.
No deaths occurred. Decrease in body
weight gain and changes of behavior such
as reduced fright reactions were observed
at the highest dose.

BASF, 1989 as cited in
IUCLID, 2000
Metabolism/
toxicokinetic
Male Sprague-Dawley rats were administered
0, 75, 350, or 525 mg/kg DMAPN by gavage
and an in vitro study was also done.
Metabolites were identified as
beta-aminopropionitrile, cyanide,
formaldehyde, and cyanoacetic acid and
metabolism occurred in the microsomal
fraction of the liver, kidney, and bladder.
About 44% of the dose was excreted
unchanged in 5 d.
DMAPN is primarily
metabolized via the
cytochrome
P450-dependent
mixed function
oxidase system.
Mumtazetal., 1991b

Rats were administered DMAPN (174 mg/kg)
i.p. and an in vitro study was also done.
Thiocyanate was identified in the urine of
rats. An in vitro study reported cyanide
and formaldehyde as intermediates.

Froines et al., 1985

Rats and mice were administered orally 0, 175,
350, or 700 mg/kg DMAPN twice on Day 1.
Animals were killed at 36 hr posttreatment.
In another study, rats were administered
525 mg/kg once daily for 2 d.
An increase in the bladder urine retention
with an increase in the DMAPN dosage
was observed. In mice, maximal urine
retention was observed at 350 mg/kg; at
700 mg/kg urine retention was not
observed.
Rats excreted about 44% of the unchanged
DMAPN and mice excreted about 6% of
the unchanged DMAPN. Mice
metabolized DMAPN to a higher extent to
beta-aminopropionitrile and cyanoacetic
acid.
DMAPN-induced
urinary retention
in rats and mice was
time dependent.
Mice metabolize
DMAPN more than
rats.
Mumtazetal., 1991a
ND = No data
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Tests Evaluating Carcinogenicity, Genotoxicity, and/or Mutagenicity
The genotoxic effects of DMAPN were assessed in vitro in Salmonella typhimurium
strains TA98, TA100, TA1535, and TA 1537—both with and without metabolic activation
systems (BASF, 1989, as cited in IUCLID, 2000). Negative results were reported. No other
genotoxicity data (either in vitro or in vivo) were identified for DMAPN.
Other Toxicity Studies (Exposures Other Than Oral and Inhalation)
Several studies have examined intraperitoneal (i.p.) exposure to DMAPN in rats and
mice. Gad et al. (1979) administered DMAPN at 0.01-1.0 mL/kg, and reported a loss of
micturition reflex in rats at 0.01 mL/kg and tremors, convulsions, and cardiovascular effects in
rats and mice at 0.25 mL/kg. Jaeger et al. (1980) administered a mixture of 95% DMAPN and
5% A-99/bis dimethylaminoethyl ether to male Holtzman rats at doses of 0.2 or 2.0 mL/kg twice
in 1 day. Doses of 2.0 mL/g produced central nervous system excitation, depression, and then
death. At 0.2 mL/kg, reduction in motor activity, rapid breathing, and prostration were observed.
These signs disappeared in survivors over a period of 10-15 minutes.
Short-term Studies
Several studies have evaluated the acute toxicity of DMAPN in animals following oral,
inhalation, i.p., or dermal exposure (BASF, undated; Deckert et al., 1982; BASF, 1975; Patty,
1962; RTECS, undated; Smyth et al., 1962; all as cited in IUCLID, 2000; Pestronk et al., 1980).
Two week oral and inhalation animal studies were also identified (Mumtaz et al., 1991a, as cited
in IUCLID, 2000; BASF, 1989, as cited in IUCLID, 2000)
Oral LD50 values in rats ranged from 1305-2600 mg/kg (BASF, undated; Deckert et al.,
1982; BASF, 1975, 1982; RTECS, undated; all as cited in IUCLID, 2000) and an LD50 value of
1500 mg/kg was reported in mice (Patty, 1962; RTECS, undated; all as cited in IUCLID, 2000).
No mortality was observed when 12 rats were exposed for 3 hours by inhalation to DMAPN,
while 1 rat died within 8 hours in this study (BASF, 1975, as cited in IUCLID, 2000). In an
additional inhalation study, no mortality was observed when 6 rats were exposed for 8 hours to
DMAPN (Smyth et al., 1962, as cited in IUCLID, 2000).
Dermal LD50 values in rabbits were reported at 1227 and 1410 mg/kg (Smyth et al., 1962;
RTECS, undated; all as cited in IUCLID, 2000 and Pestronk et al., 1980). The i.p. LD50 values
in rats ranged from 435-1740 mg/kg (BASF, undated; Deckert et al., 1982; BASF, 1975, 1982;
all as cited in IUCLID, 2000) and an intravenous (i.v.) LD50 value in mice was reported at
180 mg/kg (RTECS, undated; as cited in IUCLID, 2000).
Mumtaz et al. (1991a) administered groups of five male Sprague-Dawley rats 0 or
350 mg/kg DMAPN orally, once a day, 5 days/week, for 2 weeks. Animal weight, water
consumption, and urine volume were recorded every 24 hours and morphologic and histologic
studies on the liver, bladder, and kidney were done at the end of the 2-week study. Rats who
received 350 mg/kg showed a gradual decrease in body weight between Day 6 and 12 and a
sharp decrease between Day 12 and 15. Water consumption of rats at 350 mg/kg was slightly—
but significantly—higher than controls during the first 7 days and greatly decreased after that and
urine volume followed the same pattern. Histological examination of the bladder showed
submucosal and subserosal edema, severe congestion of submucosal capillaries, and petechial
hemorrhages. No quantitative data were available in the 2-week study. In another study by
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Mumtaz et al. (1991a), male Sprague-Dawley rats were administered 525 mg/kg DMAPN once a
day for 2 days. Hydronephrosis in the kidney, characterized by marked dilation of the renal
pelvis with blunting of the renal papilla, was observed. Plasma levels of urea nitrogen and
creatinine were significantly increased above control values, and urinary levels of urea nitrogen
and creatinine were decreased below control values.
BASF (1989), an unpublished study, as cited in IUCLID (2000), documented the effect of
short-term inhalation of DMAPN to rats. The study authors exposed rats (number, sex and strain
not provided) to 0, 0.01, 0.1, or 1 mg/L DMAPN for 6 hours per day, 5 days per week, for
2 weeks. No further information with regard to the data obtained was reported in the secondary
source. IUCLID (2000) reported that no deaths were observed during the treatment and a
decrease in body weight gain and changes of behavior such as reduced fright reactions were
observed at the highest dose.
Toxicokinetics
Limited information is available on the toxicokinetics of DMAPN. Mumtaz et al.
(1991b) administered 0, 75, 350, or 525 mg/kg DMAPN by gavage to male Sprague-Dawley rats
and P-aminopropionitrile was identified as a metabolite. About 44% of the dose of DMAPN was
excreted unchanged in rats after 5 days, and peak excretion occurred during the first 12 hours.
The excretion of P-aminopropionitrile increased with time until 24 hours after dosing. In the in
vitro part of this study, DMAPN was shown to be metabolized to cyanide, formaldehyde, and
cyanoacetic acid. Metabolism took place in the microsomal fraction of the liver, kidney, and
urinary bladder and was dependent on the cytochrome P450 mixed function oxidase system.
Froines et al. (1985) reported an in vivo study in which rats were administered DMAPN by i.p.
exposure and thiocyanate was found in the urine and an in vitro study on the metabolism of
DMAPN which demonstrated the generation of cyanide and formaldehyde. In Mumtaz et al.
(1991a), rats and mice were administered 0, 175, 350, or 700 mg/kg DMAPN and in a
time-course study, male rats were administered 525 mg/kg. The time-course study showed that
rats excreted about 44% of unchanged DMAPN and mice excreted only about 6% of the dose of
DMAPN.
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DERIVATION OF PROVISIONAL VALUES
Tables 4 and 5 present a summary of noncancer and cancer reference values, respectively. IRIS data are indicated in the table, if
available.
Table 4. Summary of Reference Values for 3-(N,N-dimethylamino)propionitrile (CASRN 1738-25-6)
Toxicity Type (units)
Species/Sex
Critical Effect
p-Reference
Value
POD
Method
POD
UFc
Principal Study
»Yubchronic p-RfD (mg/kg-d)
NDr
NDr
NDr
NDr
NDr
NDr
NDr
Chronic p-RfD (mg/kg-d)
NDr
NDr
NDr
NDr
NDr
NDr
NDr
Subchronic p-RfC (mg/m3)
NDr
NDr
NDr
NDr
NDr
NDr
NDr
Chronic p-RfC (mg/m3)
NDr
NDr
NDr
NDr
NDr
NDr
NDr
NDr = Not determinable
Table 5. Summary of Cancer Values for 3-(N,N-dimethylamino)propionitrile (CASRN 1738-25-6)
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF
NDr
NDr
NDr
NDr
p-IUR
NDr
NDr
NDr
NDr
NDr = Not determinable
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DERIVATION OF ORAL REFERENCE DOSES
No reports of human ingestion of DMAPN were identified. The available oral toxicity
studies in laboratory animals are too limited in scope to be used to identify NOAEL or LOAEL
values for DMAPN as only one dose level was employed in each study (Bachhuber et al., 1955;
Pestronk et al., 1979, as cited in Pestronk et al., 1980; Stamler, 1955). Both Stamler (1955) and
Bachhuber et al. (1955) studies were reported in very limited detail with respect to the
experimental design (whether it was compliant with GLP), endpoints measured, and number of
animals. Also no DMAPN treatment-related effects were observed in these studies. With regard
to Pestronk et al. (1979, as cited in Pestronk et al., 1980), the study was unpublished and the
results were briefly reported in the secondary sources (Pestronk et al., 1980; Keogh, 1983;
IUCLID, 2000). Based on this, the available studies on the oral toxicity of DMAPN in animals
are not sufficient for deriving RfD or screening RfD values for DMAPN.
Derivation of Subchronic Provisional RfD (Subchronic p-RfD)
A subchronic p-RfD was not derived for DMAPN due to inadequate data.
Derivation of Chronic Provisional RfD (Chronic p-RfD)
A chronic p-RfD was not derived for DMAPN due to inadequate data.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
The available data concerning health effects in humans following inhalation exposure to
DMAPN are derived from workers exposed occupationally to the catalyst ESN-NIAX, which
consists approximately 95% dimethylaminopropionitrile in the period of 1977-1978 at two
polyurethane foam-manufacturing plants in the United States (Keogh et al., 1980; Kreiss et al.,
1980). Workers were thought to have experienced dermal (skin absorption) as well as inhalation
exposure. Data taken from these studies showed that workers exposed for up to 6 months to
unknown concentrations of this compound experienced urinary problems, impotence, and
peripheral neuropathies. The urinary problems consisted of difficulty in initiating urination,
decreased force of urine stream, urgency, and dysuria while peripheral neuropathies included
paresthesia in feet and hands. Urinary retention was the predominant symptom in exposed
workers. Impotence and decreased libido were the next most remarkable findings. These
symptoms are largely reversible and disappeared once exposure was eliminated. Upon follow-up
of the exposed workers 2 years after the end of the exposure, a majority of the symptomatic
workers were normal and showed full recovery, although some individuals had persistent
symptoms of difficulty in urinating and sexual dysfunction (Baker et al., 1981).
Because levels of exposure to DMAPN were not provided in these studies, NOAELs or
LOAELs could not be established for the observed urological and neurological effects in the
occupationally exposed workers. Accordingly, health effects data in these workers are
unsuitable for derivation of an RfC.
Animal studies on the toxicity of DMAPN following inhalation exposure were limited to
one short-term study (2 weeks). The study was unpublished and the results were briefly reported
in the secondary source (IUCLID, 2000) with no adequate information on the experimental
design, endpoints measured, number of animals and GLP status were provided. Thus, this study
is considered inadequate for derivation of an RfC.
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Derivation of Subchronic Provisional RfC (Subchronic p-RfC)
A subchronic p-RfC was not derived for DMAPN due to inadequate data.
Derivation of Chronic Provisional RfC (Chronic p-RfC)
A chronic p-RfC was not derived for DMAPN due to inadequate data.
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTION
The U.S. EPA has not assigned a carcinogenicity classification for DMAPN under the
2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005). In accordance with these
guidelines, data are inadequate for an assessment of the human carcinogenic potential of
DMAPN (see Table 6). This WOE determination is based on the fact that no adequate data, such
as reliable human epidemiological studies or well-conducted, long-term animal studies are
available to perform a carcinogenicity assessment for DMAPN.
Table 6 identifies the cancer WOE descriptor for DMAPN.
Table 6. Cancer WOE Descriptor for 3-(N,N-dimethylamino)propionitrile.
Possible WOE
Descriptor
Designation
Route of Entry
(Oral, Inhalation, or
Both)
Comments
"Carcinogenic
to Humans "
NA
NA
There are no human data available.
"Likely to Be
Carcinogenic to
Humans "
NA
NA
There is not enough evidence to
support this statement.
"Suggestive
Evidence of
Carcinogenic
Potential"
NA
NA
There is not enough evidence to
support this statement.
"Inadequate
Information to
Assess
Carcinogenic
Potential"
Selected
NA
No adequate information available
to assess the carcinogenic potential
by the inhalation or oral routes of
exposure.
"Not Likely to
Be Carcinogenic
to Humans "
NA
NA
There is not enough evidence to
support this statement.
NA = not applicable
MODE-OF-ACTION (MOA) DISCUSSION
The Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005) define MOA as "A
sequence of key events and processes starting with the interaction of an agent with a cell,
proceeding through operational and anatomical changes, and resulting in cancer formation"
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(p. 10). Examples of possible modes of carcinogenic action include mutagenic, mitogenic,
antiapoptotic (inhibition of programmed cell death), cytotoxic with reparative cell proliferation,
and immune suppression.
There are no studies available that examine the mode of carcinogenic activity of
DMAPN.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Derivation of Provisional Oral Slope Factor (p-OSF)
No p-OSF can be derived due to a lack of carcinogenicity data.
Derivation of Provisional Inhalation Unit Risk (p-IUR)
No p-IUR can be derived due to a lack of carcinogenicity data.
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APPENDIX A. PROVISIONAL SCREENING VALUES
Appendix A is not applicable.
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APPENDIX B. DATA TABLES
Table B.l. Prevalence of Neurologic and Urologic Symptoms Reported by
Workers in Polyurethane Manufacturing Plants A and Ba
Symptoms
Plant A (n = 141)
Average Age, 31.6 yr
Plant B (« = 75)
Average Age, 34.6 yr
pit
Number
Percent
Number
Percent
Urinary retention
85
60
6
8
<0.01
Urinary frequency
2
1
1
1
NS
Impotence or decreased libido
49
35
6
8
<0.01
Constipation
13
9
3
4
NS
Insomnia
44
31
3
4
<0.01
Irritability
71
50
16
21
<0.01
Muscle weakness
32
22
4
5
<0.01
Paresthesias
37
26
1
1
<0.01
Headaches
40
28
14
19
NS
aKeogh et al. (1980)
*Determined by x2-
NS = not specified
Table B.2. Prevalence Of Postvoid Residual On Intravenous Pyelograms (IVPs)
Among Workers Working in both Polyurethane Manufacturing Plants"
Description
Number
Workers with symptoms of urinary retention
91
Workers who had IVPs (« = 65)
with Normal IVP
48
with IVP showing postvoid retention of contrast material
17
Workers with IVP showing postvoid retention of contrast material (« = 17)
Large residual
3
Moderate residual
9
Minimal residual
5
aKeogh et al. (1980).
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Table B.3. Number of Workers* Reporting Symptoms at Plant A
with Regard to Their Working Area"
Work Area, No.
Average
Age (yr)
No. (%) of Workers with Symptoms
Urinary
Retention
Muscle
Weakness
Paresthesias
Insomnia
Sexual
Dysfunction
Bridge (n = 7)
31.3
5(71)
1(14)
2 (28)
2 (28)
5(71)
Section cuttingb
(;n = l)
31.6
6 (85)
0(0)
3 (42)
3 (42)
4(57)
Hole-boring back
roomb (n= 13)
33.5
10 (76)
4(31)
4(31)
5 (38)
4(31)
Material-handling
back roomb
(;n = 7)
24.5
3 (42)
1(14)
0(0)
1(14)
0(0)
Peelingb (n = 63)
30.5
39 (61)
15 (23)
18 (29)
17 (26)
21 (33)
Quality control
peelingb (n = 5)
33.4
4 (80)
2(40)
2(40)
3 (60)
3 (60)
Compressing13
(n = 5)
31.4
1(20)
1(20)
0(0)
0(0)
1(20)
Shipping (n = 9)
26.4
5 (55)
1(18)
1(18)
3 (33)
3 (33)
Maintenance
(n = 6)
37.6
3 (50)
3 (50)
2(33)
3 (50)
0(0)
Scrap baling
(n = 3)
39.0
1(33)
0(0)
0(0)
0(0)
0(0)
Supervisory and
clerical (n = 16)
36.5
7 (43)
4(25)
5(31)
7 (43)
6(37)
aKeogh et al. (1980).
*Total number of workers reported symptoms at Plant A is 141.
* Areas of highest exposure
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Table B.4. Prevalence of Other Symptoms Reported by Workers in Polyurethane
Manufacturing Plants A and Ba
Symptoms
Plant A (n = 141)
Average Age, 31.6 yr
Plant B (« = 75)
Average Age, 34.6 yr
pit
Number
Percent
Number
Percent
Visual disturbances
113
80
36
48
<0.01
Dermatitis
92
65
32
43
<0.01
Bad taste
58
41
17
23
<0.01
Sore throat
55
39
14
19
<0.01
Cough
42
30
21
28
NS
Wheezing
64
45
21
28
<0.02
Chest tightness
79
56
23
31
<0.01
aKeogh et al. (1980)
*Determined by x2-
NS = not specified
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Table B.5. The Prevalence of Urinary Tract Symptoms Reported by Workers in
Polyurethane Manufacturing Plant (Massachusetts, 1978)a'b
Symptoms
Number of Cases0
(« = 104)
Number of Noncasesd
(« = 104)
Increased duration
102
1
Hesitance
98
0
Need to strain
98
0
Decreased stream
94
4
Subjective retention
70
4
Dysuria
70
13
Abdominal discomfort
61
6
Urgency
47
3
Decreased frequency
47
1
Increased frequency
44
23
Urethral discharge
19/84
2/80
Nocturia
15
10
Gross hematuria
12
4
aKreiss etal. (1980).
bTotal number of workers reported their symptoms was 208.
°Case as defined by the study authors is an employee who experienced any two of the four symptoms of bladder
dysfunction (hesitancy, need to strain, decreased stream, and increased duration of urination). Of the 208, 104
employees met this case definition and are considered as cases.
dNoncase: an employee who did not experience any two of the four symptoms of bladder dysfunction. Of the 208,
104 employees were identified as noncases.
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Table B.6. Results of the Neurological Examinations of Eight Cases of Bladder
Dysfunction Identified in Polyurethane Foam Manufacturing Plant (Massachusetts, 1978)a
Age/Sex
Sensory Abnormalities
Motor Abnormalities
Clinical
Impression
26/M
Numbness; decreased vibration, both
lower extremities
Hyporeflexia; absent
ankle jerks
Sensorimotor
neuropathy
45/M
Decreased vibration; proprioception;
light touch in toes
Decreased ankle jerks
Sensorimotor
neuropathy
23/M
Decreased vibration, left lower
extremity
None
Probably normal
30/M
Decreased proprioception, lower
extremities
None
Sensory
abnormality
42/M
Numbness; decreased light-touch,
pinprick, both lower extremities
None
Sensory neuropathy
29/F
Minimal decreased vibration, all limbs
distally
None
Sensory neuropathy
37/F
Mid hyperesthesia, feet
None
Sensory
abnormality
24/F
Decreased light-touch, pinprick, both
lower extremities distally
None
Sensory neuropathy
aKreiss etal. (1980).
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Table B.7. Results of the Neurological Testing of Eight Cases of Bladder Dysfunction
Identified in Polyurethane Foam Manufacturing Plant (Massachusetts, 1978)a
Age/Sex
Electrodiagnostic Neurological Testing
Peroneal Motor Nerve
Sural Nerve
Motor Velocity
(m/s)
Distal Latency
(m/s)
Amplitude
(mv)
Sensory Velocity
(m/s)
Amplitude
(mv)
Ankle
Knee
26/M
43.4
6.8*
0.65*
0.65*
32.5*
21.0
45/M
47.3
4.3
4.0
4.0
35.0*
3.5*
23/M
48.6
4.6
2.8
2.8
46.6
14.0
30/M
44.6, 46.0
5.5
5.6
5.0
38.8*
6.0
42/M
49.5
4.0
3.0
3.0
43.5
NR
29/F
63.0
5.0
3.5
3.5
48.8
NR
37/F
58.5
3.9
9.0
7.5
46.0
25
24/F
54.6
4.0
7.5
7.5
56.0
33
Normal
range
38-59
3-6.5
2.2-14.8
40-54.7
6-42
aKreiss etal. (1980).
*Outside the normal range.
NR = Not reported
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Table B.8. Results of the Urological Testing of Eight Cases of Bladder Dysfunction
Identified in Polyurethane Foam Manufacturing Plant (Massachusetts, 1978)a

Electrodiagnostic Testing
Cystometrogram

Age/Sex
Sacral
Latency
(ms)
Sphincter
Electromyogram
First Sensation
of Filling
(mL)
Detrusor
Reflex
(mL)
Comments
26/M
43*
Increased
polyphasia
100
Absent
Positive bethanecol test
45/M
120*
Increased
polyphasia
175*
Absent
Negative bethanecol
test; impotence;
testicular discomfort,
800-mL urinary
retention
23/M
38
Normal
50
Absent
NC
30/M
38
Normal
50
Absent
Negative bethanecol test
42/M
50*
Normal
80
Present at
275
Impotence; testicular
discomfort
29/F
37
Normal
100
Absent
Negative bethanecol test
37/F
NR
Normal
150*
Present at
450
NC
24/F
35, high
threshold
Normal
300*
Present at
425
NC
Normal
<42

<125


range





aKreiss etal. (1980).
*Outside the normal range.
NR = Not reported; NC = No comments provided
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Table B.9. Prevalence of Symptoms Reported by Late Improvers in 2 Years
Follow Up Study"

Number with Symptoms (« = 11)
Symptoms
1978
1980
Urinary hesitancy
11
7
Need to strain to urinate
11
5
Incomplete bladder emptying
9
6
Sexual difficulties
3
5
Paresthesias
3
6
Dry mouth
5
1
Weakness in arms/legs
5
5
"Baker etal. (1981).
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Table B.10. Results of the Neurological Testing of Dimethylaminopropionitrile-Exposed
Workers in 1978 and 1980a
Age/Sex
Electrodiagnostic Neurological Testing
Peroneal Motor Nerve
Sural nerve
Motor Velocity
(m/s)
Distal Latency
(m/s)
Amplitude
(mv)
Sensory Velocity
(m/s)
Amplitude
(mv)
Ankle
Knee
47/M
1978
47.3
4.3
4.0
4.0
35*
3.5*
1980
46.0
8.5*
4.0
3.0
Absent
Absent *
29/M
1978
43.4
6.8*
0.6*
0.6*
32.5*
21.0
1980
45.0
6.4
o
*
o
*
46.0
11.0
32/M
1978
46.0
5.5
5.6
5.0
38.8*
6.0
1980
44.2
5.0
6.0
6.0
38.0*
12.0
44/M
1978
49.5
4.0
3.0
3.0
43.5
—
1980
50.8
4.2
2.0*
2.0*
44.8
25.0
Normal
range
38-59
3-6.5
2.2-14.8
40-54.7
6-42
"Baker etal. (1981).
*Outside the normal range.
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Table B.ll. Results of the Urological Testing of Dimethylaminopropionitrile-Exposed
Workers in 1978 and 1980a
Age/Sex
Electrodiagnostic testing
Cystometrogram
Sacral
Latency (ms)
Sphincter
Electromyogram
First Sensation of
Filling (mL)
Detrusor Reflex
(mL)
47/M
1978
120*
Increased polyphasia
175*
Absent
1980
38
Normal
Not done
Not done
29/M
1978
43*
Increased polyphasia
100
Absent
1980
33
Normal
200*
700
32/M
1978
38
Normal
50
Absent
1980
28
Normal
250*
450
44/M
1978
50
Normal
80
275
1980
35.2
Normal
100
325
Normal
range
<42

<125

"Baker etal. (1981).
*Outside the normal range.
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Table B.12. Results of the Nerve Conducting Study on Workers Exposed to
Dimethylaminopropionitrile and Referents"
Group
Nerve
Peroneal Motor Nerve
Sural Nerve
Motor
Velocity
(m/s)
Distal
Latency
(m/s)
Amplitude
(mv)
Sensory
Velocity
(m/s)
Amplitude
(mv)
Ankle
Knee
Exposed (n = 10)
Mean
49.44
4.73
4.04
3.78
40.58
18.1
SD
4.60
1.60
2.03
2.15
14.57
12.25
Referents (n = 29)
Mean
48.87
4.17
5.69
5.33
47.75
13.88
SD
4.34
0.86
2.39
2.33
5.12
6.58
t-Value
0.033
1.06
1.81b
1.91b
1.22
1.09
"Baker etal. (1981).
hp < 0.05, one-tailed /-test.
36
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APPENDIX C. BMD OUTPUTS
Appendix C is not applicable.
37
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