Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 13
1
N,N-Dimethylformamide1
Acute Exposure Guideline Levels
PREFACE
Under the authority of the Federal Advisory Committee Act (FACA) P.L.
92-463 of 1972, the National Advisory Committee for Acute Exposure Guide-
line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab-
lished to identify, review, and interpret relevant toxicologic and other scientific
data and develop AEGLs for high-priority, acutely toxic chemicals.
AEGLs represent threshold exposure limits for the general public and are
applicable to emergency exposure periods ranging from 10 minutes (min) to 8
hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for
each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin-
guished by varying degrees of severity of toxic effects. The three AEGLs are
defined as follows:
AEGL-1 is the airborne concentration (expressed as parts per million or
milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is
predicted that the general population, including susceptible individuals, could
experience notable discomfort, irritation, or certain asymptomatic, nonsensory
1
This document was prepared by the AEGL Development Team composed of Claudia
Troxel (Oak Ridge National Laboratory) and Loren Koller and George Woodall (Na-
tional Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous
Substances). The NAC reviewed and revised the document and AEGLs as deemed neces-
sary. Both the document and the AEGL values were then reviewed by the National Re-
search Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC com-
mittee concludes that the AEGLs developed in this document are scientifically valid
conclusions based on the data reviewed by the NRC and are consistent with the NRC
guidelines reports (NRC 1993, 2001).
13
OCR for page 14
14 Acute Exposure Guideline Levels
effects. However, the effects are not disabling and are transient and reversible
upon cessation of exposure.
AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a
substance above which it is predicted that the general population, including sus-
ceptible individuals, could experience irreversible or other serious, long-lasting
adverse health effects or an impaired ability to escape.
AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a
substance above which it is predicted that the general population, including sus-
ceptible individuals, could experience life-threatening health effects or death.
Airborne concentrations below the AEGL-1 represent exposure concentra-
tions that could produce mild and progressively increasing but transient and
nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen-
sory effects. With increasing airborne concentrations above each AEGL, there is
a progressive increase in the likelihood of occurrence and the severity of effects
described for each corresponding AEGL. Although the AEGL values represent
threshold levels for the general public, including susceptible subpopulations,
such as infants, children, the elderly, persons with asthma, and those with other
illnesses, it is recognized that individuals, subject to idiosyncratic responses,
could experience the effects described at concentrations below the correspond-
ing AEGL.
SUMMARY
N,N-Dimethylformamide (DMF) is a clear-to-slightly yellow liquid with a
faint amine (fishy) odor. Odor thresholds have been reported to range from 0.47
to 100 ppm. DMF is a polar compound used as a solvent in the manufacturing of
many products. American manufacturers consumed 32 million pounds of DMF
in 1993 (TURI 2001). The primary end-users of DMF are manufacturers of
pharmaceuticals (12 million pounds), electronic components (10 million
pounds), butadiene (3 million pounds), and urethanes (3 million pounds). It is
also used as a resin cleanup solvent, reaction solvent, and processing solvent in
the manufacture of polyimides, optical brightners, semipermeable membranes,
and pesticides.
Human data were limited to controlled inhalation exposures or accidental
workplace exposures. Although no adverse effects were reported in the con-
trolled studies, these studies were designed to assess DMF metabolism, and fol-
low-up physical evaluations of the volunteers were not carried out. Reports of
both accidental and chronic daily workplace inhalation exposures to DMF de-
scribe signs and symptoms, including abdominal pain, nausea, and vomiting,
and liver toxicity as indicated by elevated serum enzymes and histologic evalua-
tion. Epidemiologic studies suggest a causal association between DMF exposure
and testicular germ cell tumors.
OCR for page 15
15
N,N-Dimethylformamide
Single inhalation exposures of mice and rats to high concentrations of
DMF (approaching or at saturation of the chemical in air) resulted in mortality
(Stasenkova 1961; Shell Oil Company 1982), and inhalation exposure of rats to
low and intermediate concentrations resulted only in alterations of liver enzymes
(Brondeau et al. 1983; Lundberg et al. 1986; Roure et al. 1996). The cause of
death following acute inhalation exposure was not identified. Repeated inhala-
tion exposure of rats, mice, and cats to DMF generally resulted in reduced body
weight, and hepatotoxicity indicated by increased liver enzymes and histopa-
thologic changes including degeneration and necrosis. However, repeated inha-
lation exposure of monkeys to DMF at 500 ppm for 6 h/day, 5 days per week,
for up to 13 weeks failed to result in any measurable adverse effects (Hurtt et al.
1991, 1992). Inhalation developmental toxicity studies reported reduced mater-
nal body weight. Developmental effects included reduced fetal weight; increases
in the litter incidence of total external, skeletal, and visceral malformations and
skeletal variations; and increased number and percentage of dead implants
(BASF 1974a,b,c; Kimmerle and Machemer 1975; BASF 1989; Hellwig et al.
1991; Lewis et al. 1992). Genotoxicity testing of DMF has generally been nega-
tive (Antoine et al. 1983; NTP 1992). One study found no evidence of carcino-
genicity when mice and rats inhaled DMF up to 400 ppm for 2 years (E.I. Du-
pont de Nemours & Co. 1992); a more recent study found that chronically
inhaled DMF produced hepatocellular adenomas and carcinomas in rats at 400
ppm or 800 ppm, respectively, and hepatoblastomas and hepatocellular adeno-
mas and carcinomas in mice at 200 ppm and above (Senoh et al. 2004).
An AEGL-1 value was not recommended because data pertaining to end
points relevant to the AEGL-1 definition were not available.
The AEGL-2 derivation was based on the study in which groups of 15
pregnant Himalayan rabbits were exposed to DMF at 0, 50, 150, or 450 ppm for
6 h/day on gestation days (GD) 7-19 (Hellwig et al. 1991). Over GD 7-19, mean
maternal body-weight gain was reduced in dams exposed to DMF at 150 ppm
compared with controls, while dams in the 450-ppm group lost weight; mean
maternal body-weight gain over the entire study period of GD 0-29 was also
decreased in dams from the 150- and 450-ppm DMF groups compared with con-
trols. Developmental toxicity was evident at 450 ppm as increases in external
malformations and total malformations (external, soft tissue, and skeletal com-
bined). Other effects included a reduction in fetal weight (86% of controls) and
statistically significant increases in the litter incidence of skeletal variations,
including splitting of skull bones, fused sternebrae, irregular shaped sternebrae,
and bipartite sternebrae. An increase in fetal deaths did not occur. No develop-
mental effects were observed at 150 ppm. To protect against irreversible devel-
opmental effects (malformations), the rabbit no-observed-adverse-effect level
(NOAEL) of 150 ppm for 6 h was used as the point of departure for derivation
of AEGL-2 values (Hellwig et al. 1991).
A total uncertainty factor of 3 was applied to the point of departure of 150
ppm for 6 h: 1 for interspecies variability and 3 for intraspecies variability. An
interspecies uncertainty factor of 1 was applied because it appears that primates
OCR for page 16
16 Acute Exposure Guideline Levels
are not as sensitive as rodents. Monkeys inhaled DMF at 500 ppm for 6 h/day, 5
days/week, for up to 13 weeks with no measurable adverse effects (parameters
examined included clinical signs, body weight, hematology and serum chemistry
analyses, urinalysis, semen analysis, and gross necropsy findings). In contrast,
subchronic DMF inhalation exposure produced significant hepatic effects in rats
at concentrations of 200 ppm (Senoh et al. 2003), 300 ppm (Craig et al. 1984),
and 400 ppm (NTP 1992) and in mice at 100 ppm (Senoh et al. 2003), 150 ppm
(Craig et al. 1984), and 200 ppm (NTP 1992). Indexes of toxicity after repeated
DMF exposure ranged from elevated serum enzymes indicative of liver injury to
hepatic degeneration and necrosis. From these exposure data, humans would be
expected to be less sensitive than laboratory animals (rodents). Because the
mechanism of hepatotoxicity is believed to be related to the metabolism of DMF
to a reactive intermediate, fetal toxicity is expected to result from exposure to
the parent DMF or metabolites. An oral study assessing the tissue and metabo-
lite distribution of DMF in pregnant rats indicated that DMF and its metabolites
were transferred across the placenta by passive diffusion and that maternal
plasma, embryo or fetus, placenta, and amniotic fluid belonged to the same
compartment (Saillenfait et al. 1997). Therefore, the fetus and placenta will not
provide any additional protection or enhancement of DMF toxicity because ex-
posure to DMF and its metabolites will depend on the metabolism by the
mother.
An intraspecies uncertainty factor of 10 would normally be applied be-
cause a host of interindividual differences could affect the manifestation of
DMF toxicity: (1) activity of CYP2E1, an enzyme that plays a pivotal role in the
metabolism of DMF to reactive intermediates, can be induced by ethanol con-
sumption, obesity, diabetes, and other lifestyle and genetic factors (Gonzalez
1990; Song et al. 1990; Lucas et al.1998; McCarver et al. 1998), and increased
CYP2E1 levels increase the toxic metabolites of DMF; (2) prior consumption of
ethanol can exacerbate DMF toxicity in individuals; (3) on the basis of the pro-
posed mechanism of action, detoxification of the reactive intermediate is partly
dependent on conjugation with glutathione; therefore, if glutathione levels are
depleted for other reasons, the potential exists for greater exposure to the reac-
tive intermediate; and (4) because DMF exposure can result in hepatotoxicity,
individuals with chronic liver disease may be at increased risk. However, appli-
cation of a total uncertainty factor of 10 produces AEGL-2 values that are in-
consistent with the available human data. (Values for the 10-min, 30-min and 1-,
4-, and 8-h AEGL-2 using default time-scaling would be 49, 34, 27, 17, and 11
ppm, respectively.) Humans were exposed by inhalation to DMF at 87 ppm for 4
h or at 81 ppm for 2 h to assess the metabolism of DMF (Kimmerle and Eben
1975b; Eben and Kimmerle 1976). These single-exposure studies were con-
ducted to assess DMF metabolism, and no adverse effects were reported; thus,
the concentration can be considered an acute exposure concentration unlikely to
result in adverse effects in healthy adults. Therefore, the intraspecies uncertainty
factor is reduced to 3, resulting in a total uncertainty factor of 3.
OCR for page 17
17
N,N-Dimethylformamide
The experimentally derived exposure value is scaled to AEGL time frames
using the concentration-time relationship given by the equation Cn × t = k, where
C = concentration, t = time, k is a constant, and n generally ranges from 1 to 3.5
(ten Berge et al. 1986). The value of n was not empirically derived because of
inadequate data; therefore, the default value of n = 1 was used for extrapolating
from shorter to longer exposure periods, and a value of n = 3 was used to ex-
trapolate from longer to shorter exposure periods. The 30-min AEGL-2 value
was set equal to the 10-min value because of the uncertainty in extrapolating
from a 6-h exposure duration to a 10-min duration.
The AEGL-3 derivation was based on the study in which groups of three
male and three female rats were exposed to DMF at 3,700 ppm for 1 or 3 h with
no mortality, while exposure for 7 h resulted in 83% mortality (Shell Oil Com-
pany 1982). Clinical signs were limited to excess grooming in all exposure
groups, with lethargy also noted in rats exposed for 7 h. The end point of no
mortality in rats exposed at 3,700 ppm for 3 h was chosen for the derivation.
A total uncertainty factor of 10 was applied to the point of departure for
the AEGL-3: 1 for interspecies variability and 10 for intraspecies variability.
The total uncertainty factor of 10 should protect against all but hypersensitive
human hepatotoxic effects. An interspecies uncertainty factor of 1 was applied
because it appears that primates are not as sensitive as rodents. Monkeys inhaled
DMF at 500 ppm for 6 h/day, 5 days/week, for up to 13 weeks with no measur-
able adverse effects (parameters examined included clinical signs, body weight,
hematology and serum chemistry analyses, urinalysis, semen analysis, and gross
necropsy findings). In contrast, subchronic DMF inhalation exposure produced
significant hepatic effects in rats at concentrations of 200 ppm (Senoh et al.
2003), 300 ppm (Craig et al. 1984), and 400 ppm (NTP 1992) and in mice at 100
ppm (Senoh et al. 2003), 150 ppm (Craig et al. 1984), and 200 ppm (NTP 1992).
Indexes of toxicity after repeated DMF exposure ranged from elevated serum
enzymes indicative of liver injury to hepatic degeneration and necrosis. From
these exposure data, humans would be expected to be less sensitive than labora-
tory animals (rodents). An intraspecies uncertainty factor of 10 is applied be-
cause a host of interindividual differences could affect the manifestation of
DMF toxicity: (1) activity of CYP2E1, an enzyme that plays a pivotal role in the
metabolism of DMF, to reactive intermediates, can be induced by ethanol con-
sumption, obesity, diabetes, and other lifestyle and genetic factors (Gonzalez
1990; Song et al. 1990; Lucas et al. 1998; McCarver et al. 1998), and increased
CYP2E1 levels increase the toxic metabolites of DMF; (2) prior consumption of
ethanol can exacerbate DMF toxicity in individuals; (3) on the basis of the pro-
posed mechanism of action, detoxification of the reactive intermediate is partly
dependent on conjugation with glutathione; therefore, if glutathione levels are
depleted for other reasons, the potential exists for greater exposure to the reac-
tive intermediate; (4) because DMF exposure can result in hepatotoxicity, indi-
viduals with chronic liver disease may be at increased risk. Therefore, a total
uncertainty factor of 10 is applied.
OCR for page 18
18 Acute Exposure Guideline Levels
The experimentally derived exposure value is scaled to AEGL time frames
using the concentration-time relationship given by the equation Cn × t = k, where
C = concentration, t = time, k is a constant, and n generally ranges from 1 to 3.5
(ten Berge et al. 1986). The value of n was not empirically derived because of
inadequate data; therefore, the default value of n = 1 was used for extrapolating
from shorter to longer exposure periods, and a value of n = 3 was used to ex-
trapolate from longer to shorter exposure periods.
There is a high potential for DMF to be absorbed dermally, so this route of
exposure should be considered along with inhalation.
The calculated values are listed in Table 1-1 below.
1. INTRODUCTION
DMF is a clear-to-slightly yellow liquid with a faint amine (fishy) odor. It
can be synthesized in a one-stage process by reacting dimethylamine in metha-
nol with carbon monoxide in the presence of sodium methylate or with metal
carbonyls; it also can be synthesized in a two-stage process from reacting
methanol with carbon monoxide in the presence of sodium methylate, followed
by reaction with dimethylamine (IARC 1989). DMF is a polar compound used
as a solvent in manufacturing acrylic fibers, films, surface coatings, synthetic
leather, polyurethane, and wire enamels based on polyimides or polyurethanes
(Trochimowicz et al. 1994). It is also used as a solvent for certain epoxy resin
curing agents. DMF has applications in hydrocarbon separations (such as recov-
ery or removal of acetylene and extraction of butadiene from hydrocarbon
streams) and in selective solvent extractions (such as separating nonparaffinic
from paraffinic hydrocarbons in petroleum processing and in the separation of
polycarboxylic acids) (IARC 1989; Trochimowicz et al. 1994).
TABLE 1-1 Summary of AEGL Values for DMFa
Classification 10 min 30 min 1h 4h 8h End Point (Reference)
NRb
AEGL-1 NR NR NR NR
(nondisabling)
AEGL-2 110 ppm 110 ppm 91 ppm 57 ppm 38 ppm 150 ppm for 6 h in
(disabling) (330 (330 (270 (170 (110 rabbits to protect against
mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) irreversible effects
(malformations)
(Hellwig et al. 1991)
AEGL-3 970 ppm 670 ppm 530 ppm 280 ppm 140 ppm No mortality in 6 rats
(lethal) (2,900 (2,000 (1,600 (840 (420 exposed to 3,700 ppm
mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) for 3 h (Shell Oil
Company 1982)
a
There is a high potential for DMF to be absorbed dermally, so this route of exposure
should be considered along with inhalation.
b
NR, not recommended. Absence of an AEGL-1 does not imply that exposure below the
AEGL-2 is without adverse effects.
OCR for page 19
19
N,N-Dimethylformamide
American manufacturers used 32 million pounds of DMF in 1993 (TURI
2001). The primary end users of DMF are manufacturers of pharmaceuticals (12
million pounds), electronic components (10 million pounds), butadiene (3 mil-
lion pounds), and urethanes (3 million pounds). DMF is also used as a resin
cleanup solvent, reaction solvent, and processing solvent in the manufacture of
polyimides, optical brightners, semipermeable membranes, and pesticides.
Human data are available from reports of accidental and controlled inhala-
tion exposures and from epidemiologic studies investigating consequences of
chronic exposure. Animal data consisted of acute inhalation studies with mice
and rats and studies designed to examine the mode of action responsible for in-
duction of hepatotoxicity. Repeat-exposure studies were available for monkeys,
rats, mice, and cats.
The chemical and physical data on DMF are presented in Table 1-2.
TABLE 1-2 Chemical and Physical Data
Parameter Data Reference
Synonyms N,N-dimethylformamide, DMF
CAS registry no. 68-12-2
Chemical formula C3H7NO
Molecular weight 73.09 Budavari et al. 1996
Physical state Liquid Budavari et al. 1996
Color Colorless to slightly yellow Budavari et al. 1996
Melting point −61°C Budavari et al. 1996
Boiling point760 153°C Budavari et al. 1996
Solubility in water Miscible with water and most Budavari et al. 1996
common organic solvents
Vapor pressure 2.6 mmHg (20°C) Trochimowicz et
3.7 mmHg (25°C) al. 1994
IARC 1989
Saturated vapor pressure 3,755 ppm at 20°C Shell Oil
5,000 ppm at at 25°C Company 1982
Lundberg et al. 1986
Liquid density (water =1) 0.9445 Budavari et al. 1996
3
Conversion factors 1 ppm = 2.99 mg/m NIOSH 2005
1 mg/m3 = 0.33 ppm
OCR for page 20
20 Acute Exposure Guideline Levels
2. HUMAN TOXICITY DATA
2.1. Acute Lethality
No acute lethality data in humans were found in the searched literature.
2.2. Nonlethal Toxicity
2.2.1. Controlled Exposures
DMF has a faint amine odor (Budavari et al. 1996). Odor thresholds range
from 0.47 to 100 ppm (EPA 1992). The 0.47-ppm concentration was the thresh-
old for recognition; no data were provided for the 100-ppm concentration. Tro-
chimowicz et al. (1994) reported an odor threshold of 21.4 ppm, and Amoore
and Hautala (1983) reported a threshold of 2.2 ppm; they stated that less than
50% of distracted individuals could perceive odor at the Threshold Limit Value
(TLV) of 10 ppm.
A number of controlled human inhalation exposures to DMF are available,
and these metabolism studies are discussed in Section 4.2. The studies were
conducted to assess metabolism, and no adverse effects of inhaled DMF expo-
sure were reported at the concentrations and durations of exposure examined. A
summary of the following data is found in Table 1-3: 10 healthy volunteers (five
males and five females, ages 25-56 years) were exposed to DMF at 3, 10, or 20
ppm for 8 h (Mraz and Nohova 1992); 10 healthy human volunteers (five males
and five females, ages 26-56) were exposed at 20 ppm for 8 h (Mraz et al.
1989); four volunteers (three males and one female, ages 20-50) were exposed
to DMF at 53 ± 32 ppm for 2 h (Eben and Kimmerle 1976); and four volunteers
were exposed at 26 ± 8 ppm (four males, ages 25-50) or 87 ± 25 ppm for 4 h
(three males and one female, ages 20-50) or 21 ± 4 ppm (four males, ages 25-50)
for 4 h/day for 5 consecutive days (Kimmerle and Eben 1975b). Alcohol intoler-
ance was not observed when four volunteers (three males and one females; ages
20-50) drank 19 g of ethanol (50 mL of a 38% schnaps or gin) followed by a 2-h
exposure to DMF at 82 ± 20 ppm (Eben and Kimmerle 1976). This observation
is significant in light of evidence that sufficiently high concomitant DMF and
ethanol exposures can result in disulfiram-like symptoms (see Section 4.3).
2.2.2. Case Reports
Potter (1973) described an accidental DMF exposure in a 52-year-old man
where DMF splashed on approximately 20% of the victim’s body, after which
he washed the affected skin, put his clothes back on, and drove home (45 min).
The intense odor of DMF was noted in the factory following the accident and in
his car. Immediate symptoms were limited to dermal irritation and hyperemia,
with anorexia developing 1-2 days later. Sixty-two hours after the accident, he
OCR for page 21
21
N,N-Dimethylformamide
developed epigastric pain that spread throughout his abdomen, chest, and thighs,
and episodes of vomiting followed. On admission to the hospital, he presented
with hypertension, and he complained of weakness and incoordination of his
legs, but no objective neurologic changes were apparent. Minimal abdominal
tenderness was noted. Increased white blood cells and serum conjugated and
total bilirubin, glutamic oxaloacetic transaminase, and glutamic pyruvic transa-
minase were observed. Urine tested positive for porphobilinogen for the 3 days
the patient experienced abdominal pain. Minimal S-T segment and T-wave de-
pressions were noted during electrocardiograms, but the abnormalities returned
to normal before discharge. An aspiration biopsy of the liver 11 days after the
exposure revealed minimal septal fibrosis and an accumulation of mononuclear
cells. Upon discharge from the hospital 15 days postexposure, the patient was
free of any symptoms.
A 21-year-old man was hospitalized following accidental exposure to
DMF at work (exposure quantity and route not characterized) (Chary 1974). On
hospital admission, he experienced upper abdominal pain radiating in his back.
Nausea and vomiting, epigastric tenderness, and an erythematous rash on his
hands and forearms (possibly suggesting direct skin contact with DMF) devel-
oped. Serum amylase levels were increased to 2,400 I.U./liter (L), but a chole-
cystogram and intravenous cholangiogram were normal. Following the accident,
a search of factory records found that a 28-year-old male coworker had previ-
ously been admitted to the hospital following accidental exposure to DMF.
Again, the exposure route was not characterized, but this patient too had an ery-
thematous rash on his hands and forearms, and suffered from upper abdominal
pain, nausea and vomiting, and epigastric tenderness. Serum amylase levels
were not measured, but a cholecystogram was normal. Follow-up of the patient
revealed continuing complaints of epigastric pain. The three remaining workers
in the factory were then questioned about symptoms. All admitted intermittent
gastrointestinal symptoms, erythema of exposed parts, and pruritus, particularly
after consuming ethanol.
TABLE 1-3 Summary of Controlled Human Exposures to DMFa
Number of Subjects Duration Concentration (ppm) Reference
10 (5 males, 5 females) 8h 3 Mraz and Nahova 1992
10
20
10 (5 males, 5 females) 8h 20 Mraz et al. 1989
4 (4 males) 4h 26 Kimmerle and Eben 1975b
4 (3 males, 1 female) 87
4 (4 males) 4 h/d for 5 d 21
4 (3 males, 1 female) 2h 53 Eben and Kimmerle 1976
82b
a
Because these studies were designed only to assess metabolism, clinical signs and symp-
toms were not evaluated by the study authors.
b
Exposure occurred following consumption of ethanol.
OCR for page 22
22 Acute Exposure Guideline Levels
2.2.3. Epidemiologic Studies
Fiorito et al. (1997) conducted a cross-sectional study investigating the
prevalence of liver function abnormalities in workers exposed to DMF in a syn-
thetic leather factory. The study consisted of 75 exposed workers (average em-
ployment 3.8 years) and 75 unexposed individuals matched for age, sex, social
status, and place of residence. Although these workers were generally exposed
to less than 10 ppm DMF, biologic monitoring revealed that occasional overex-
posure was possible. Fifty percent of the DMF-exposed workers complained of
gastrointestinal symptoms, and 40% of exposed workers also complained of
disulfiram-like symptoms (facial flushing [38%], palpitation [30%], headache
[22%], dizziness [22%], body flushing [15%], and tremors [14%]) after ethanol
consumption. Covariance analysis of clinical chemistry parameters revealed
increased alanine aminotransaminase (ALT), aspartate aminotransferase (AST),
gamma glutamyl transpeptidase (GGT), and alkaline phosphatase (AP) in DMF-
exposed workers compared with the reference group. Twenty-three percent of
DMF-exposed workers had abnormal transaminase values, compared with 4% of
controls. The study authors concluded that repeated occupational exposure to
DMF at levels less than 10 ppm for 8-h TWAs can impair liver function.
In response to a case of suspected toxic hepatitis in a worker from a fabric
coating factory, a clinical-epidemiologic investigation and environmental as-
sessment of the patient’s workplace was conducted (Redlich et al. 1988). A total
of 58 workers participated in the study: All had at least one liver function test;
46 completed a questionnaire addressing demographic background, job history,
and symptoms; and 27 underwent an extensive clinical evaluations to assess
liver function. Workers were exposed to DMF in the process of coating fabric in
poorly ventilated areas, and little effort was made to control direct skin contact
with the solvent. Results from the questionnaire and clinic interviews revealed
complaints of gastrointestinal problems (31 of 46), headache and dizziness (18
of 46), and alcohol intolerance characterized by facial flushing and palpitations
after drinking ethanol (11 of 46; total number consuming ethanol not provided).
Clinical chemistry analyses revealed that 36 of 58 workers had increased AST or
ALT levels, 19 having elevations greater than twice normal, and 9 of the 19 hav-
ing increases greater than five times normal. All but one of these employees
were production-line workers (35 of 46, vs. 1 of 12 nonproduction-line work-
ers). Histologic examination of liver biopsies from four workers confirmed toxic
liver injury. Serologic testing and a ratio of AST to ALT of less than one ruled
out infectious hepatitis in all but two workers and alcoholic liver disease in all
but one worker, respectively.
The cohort described by Redlich et al. (1988) was re-evaluated by Fleming
et al. (1990). In the re-evaluation, the defined exposure population consisted
of subjects who were male, Hispanic, and who worked in jobs with DMF expo-
sure. An unexposed population of 111 individuals was chosen from a pre-
employment population for comparison. A complete liver enzyme profile was
determined for each individual. Analysis of the data revealed a statistically sig-
OCR for page 23
23
N,N-Dimethylformamide
nificant (p <0.0001) increase in ALT and a decrease in the AST:ALT ratio (ratio
of <1.0) in the DMF-exposed group compared with the referent group, but there
was no difference in AST levels. Continued surveillance of the workplace over
the next 14 months failed to identify any additional cases of liver dysfunction;
this observation was coincident with changes in several engineering and indus-
trial hygiene changes and a reduction in the quantity of DMF used in the proc-
ess. The study authors therefore concluded that the outbreak of liver damage
was “almost certainly” causally related to workplace exposure to DMF.
Wrbitzky (1999) measured liver function in workers exposed to DMF
alone or after ethanol consumption. The study involved 126 male workers ex-
posed to DMF in their job and 54 comparable unexposed male employees. DMF
concentrations measured in workplace air ranged from <0.1 to 37.9 ppm, and the
concentrations of the DMF metabolite N-methylformamide (NMF)measured in
the urine of exposed workers ranged from 0.05 to 22.0 mg/L preshift and 0.9 to
100.0 mg/L post shift. Facial flushing following ethanol consumption was noted
by 70% of the DMF-exposed workers compared with 4% of unexposed controls.
Exposed workers had significant increases in GGT and ALT activities. Exposed
workers were further categorized as having high (0.1-100 ppm) or low expo-
sures (0.1-13.7 ppm) to DMF, and alcohol consumption was assigned using the
criteria of consuming no alcohol, consuming 50
g/day. A ranking sum value based on GGT, AST, and ALT levels was deter-
mined for all groups. The results demonstrated that chronic occupational DMF
exposure can impair liver function, and drinking alcohol was synergistic with
the hepatotoxicity of DMF.
Catenacci et al. (1984) found no alterations in hepatic function in 54
workers employed for at least 5 years in an acrylic fiber plant and exposed to
DMF at <10 ppm for 8-h TWAs. Hepatic parameters included assessment of
serum ALT, AST, GGT, and AP.
A cohort study by E.I. Dupont de Nemours & Co. (1973) investigated the
association between DMF exposure and adverse health effects. Workers at two
DuPont plants (Waynesboro and Camden) were categorized into three groups
based on work history: currently exposed to DMF, previously exposed to DMF,
or never exposed to DMF. The DMF-exposed workers were compared with the
referent group for history of chronic disease, findings at periodic health exami-
nations, and sickness absenteeism over a 5-year period. Although all illnesses
were investigated, the liver, gastrointestinal system, and cardiovascular system
were of particular focus. Because differences were observed in the distribution
of age and race among the DMF-exposed and the referent groups, comparisons
were made by age categories and by computing age-adjusted rates. The study
authors concluded that there was no significant excess in any of the parameters
examined. However, a significant reduction in the prevalence of hypertension
was found in workers currently exposed to DMF at the Waynesboro plant, but
this finding was not observed in workers previously exposed to DMF. Although
it appeared that a similar reduction in the prevalence of hypertension may have
OCR for page 61
61
N,N-Dimethylformamide
Amoore, J.E., and E. Hautala. 1983. Odor as an aid to chemical safety: Odor thresholds
compared with threshold limit values and volatilities for 214 industrial chemicals
in air and water dilution. J. Appl. Toxicol. 3(6):272-290.
Angerer, J., T. Goen, A. Kramer, and H.U. Kafferlein. 1998. N-methylcarbamoyl adducts
at the N-terminal valine of globin in workers exposed to N,N-dimethylformamide.
Arch. Toxicol. 72(5):309-313.
Antoine, J.L., J. Arany, A. Leonard, J. Henrotte, G. Jenar-Dubuisson, and G. Decat. 1983.
Lack of mutagenic activity of dimethylformamide. Toxicology 26(3-4):207-212.
BASF. 1974a. Report on the Study of the Prenatal, Perinatal, and Postnatal Toxicity of
Dimethylformamide in Rats on Repeated Inhalation (1st Communication) with At-
tachments and Sheet Dated 06/12/89. EPA Document No. 86-890000648. Micro-
fiche No. OTS 0521154. U.S. Environmental Protection Agency, Washington, DC.
BASF. 1974b. Report on the Study of the Prenatal, Perinatal, and Postnatal Toxicity of
Dimethylformamide in Rats on Repeated Inhalation (2nd Communication) with
Attachments and Sheet Dated 06/12/89. EPA Document No. 86-890000649. Mi-
crofiche No. OTS 0521155. U.S. Environmental Protection Agency, Washington,
DC.
BASF. 1974c. Report on the Study of Dimethylformamide for a Teratogenic Effect on
Rats after Repeated Inhalation with Attachments and Cover Sheet Dated 06/12/89.
EPA Document No. 86-890000650. Microfiche No. OTS 0521156. U.S. Environ-
mental Protection Agency, Washington, DC.
BASF. 1989. Prenatal Toxicity of Dimethylformamide in Rabbits after Inhalation, Vol-
ume I-II (Draft Report) with Attached Supplement to the Report and Cover Sheet
Dated 06/12/89. EPA Document No.86-890000632. Microfiche No. OTS0521138.
U.S. Environmental Protection Agency, Washington, DC.
Brondeau, M.T., P. Bonnet, J.P. Guenier, and J. de Ceaurriz. 1983. Short-term inhalation
test for evaluating industrial hepatotoxicants in rats. Toxicol. Lett. 19(1-2):139-
146.
Budavari, S., M.J. O'Neil, A. Smith, P.E. Heckelman, and J.F. Kinneary, eds. 1996. P.
549 in The Merck Index: An Encyclopedia of Chemicals, Drug, and Biologicals,
12th Ed. Whitehouse Station, NJ: Merck.
Catenacci, G., D. Grampella, R. Terzi, A. Sala, and G. Pollini. 1984. Hepatic function in
subjects exposed to environmental concentrations of DMF lower than the actually
proposed TLV. G. Ital. Med. Lav. 6(3-4):157-158.
Chary, S. 1974. Dimethylformamide: A cause of acute pancreatitis? Lancet 2(7876):356.
Clayton, J.W., Jr., J.R. Barnes, D.B. Hood, and G.W. Schepers. 1963. The inhalation
toxicity of dimethylformamide (DMF). Am. Ind. Hyg. Assoc. J. 24:144-154.
Craig, D.K., R.J. Weir, W. Wagner, and D. Groth. 1984. Subchronic inhalation toxicity
of dimethylformamide in rats and mice. Drug Chem. Toxicol. 7(6):551-571.
DFG (Deutsche Forschungsgemeinschaft). 2002. List of MAK and BAT Values 2002.
Maximum Concentrations and Biological Tolerance Values at the Workplace Re-
port No. 38. Weinheim, Federal Republic of Germany: Wiley VCH.
Ducatman, A.M., D.E. Conwill, and J. Crawl. 1986. Germ cell tumors of the testicle
among aircraft repairmen. J. Urol. 136(4):834-836.
Eben, A., and G. Kimmerle. 1976. Metabolism studies of N,N-dimethylformamide. III.
Studies about influence of ethanol in persons and laboratory animals. Int. Arch.
Occup. Environ. Health 36(4):243-265.
E.I. Dupont de Nemours & Co. 1944. The Toxicity of Dimethylformamide with Cover
Sheets and Dated 09/24/84 (sanitized). EPA Document 86-890000768S. Micro-
fiche No. OTS 0520887. U.S. Environmental Protection Agency, Washington, DC.
OCR for page 62
62 Acute Exposure Guideline Levels
E.I. Dupont de Nemours & Co. 1973. An Epidemiology Study of Workers Exposed to
Dimethylformamide with Attachments and Cover Sheets Dated 09/24/84. EPA
Document No. 86-890000788. Microfiche No. OTS 0521260. U.S. Environmental
Protection Agency, Washington, DC.
E.I. Dupont de Nemours & Co. 1992. Long-Term Inhalation Oncogenicity Study with
Dimethylformamide in Rats and Mice (11 Volumes) with Cover Letter Dated
01/04/93. EPA Document No. 86-930000085. Microfiche Number OTS 0544841.
U.S. Environmental Protection Agency, Washington, DC.
EPA (U.S. Environmental Protection Agency). 1990. N,N-Dimethylformamide. Inte-
grated Risk Information System, U.S. Environmental Protection Agency [online].
Available: http://www.epa.gov/iris/subst/0511.htm [accessed Oct. 22, 2010].
EPA (U.S. Environmental Protection Agency). 1992. Reference Guide to Odor Thresh-
olds for Hazardous Air Pollutants Listed in the Clean Air Act Amendments of
1990. EPA/600/R-92/047. Office of Research and Development, U.S. Environ-
mental Protection Agency, Washington, DC. March 1992 [online]. Available: http:
//cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=40610 [accessed Oct. 22, 2010].
Farquharson, R.G., M.H. Hall, and W.T. Fullerton. 1983. Poor obstetric outcome in three
quality control laboratory workers. Lancet 1(8331):983-984.
Fiorito, A., F. Larese, S. Molinari, and T. Zanin. 1997. Liver function alterations in syn-
thetic leather workers exposed to dimethylformamide. Am. J. Ind. Med. 32(3):255-
260.
Fleming, L.E., S.L. Shalat, and C.A. Redlich. 1990. Liver injury in workers exposed to
dimethylformamide. Scand. J. Work Environ. Health 16(4):289-292.
Gescher, A. 1993. Metabolism of N,N-dimethylformamide: Key to the understanding of
its toxicity. Chem. Res. Toxicol. 6(3):246-251.
Gonzalez, F.J. 1990. Molecular genetics of the P-450 superfamily. Pharmacol. Ther.
45(1):1-38.
Hardman, J.G., and L.E. Limbird, eds. 2001. Goodman and Gilman’s The Pharmacologi-
cal Basis of Therapeutics, 10th Ed. New York: McGraw-Hill Professional.
Hellwig, J., J. Merkle, H.J. Klimisch, and R. Jackh. 1991. Studies on the prenatal toxicity
of N,N-dimethylformamide in mice, rats and rabbits. Food Chem.Toxicol.
29(3):193-201.
Hundley, S.G., P.H. Lieder, R. Valentine, L.A. Malley, and G.L. Kennedy, Jr. 1993a.
Dimethylformamide pharmacokinetics following inhalation exposure to rats and
monkeys. Drug Chem. Toxicol. 16(1):21-52.
Hundley, S.G., K.T. McCooey, P.H. Lieder, M.E. Hurtt, and G.L. Kennedy, Jr. 1993b.
Dimethylformamide pharmacokinetics following inhalation exposure in monkeys.
Drug Chem. Toxicol. 16(1):53-79.
Hurtt, M.E., K.T. McCooey, M.E. Placke, and G.L. Kennedy. 1991. Ten-day repeated-
exposure inhalation study of dimethylformamide (DMF) in cynomolgus monkeys.
Toxicol. Lett. 59(1-3):229-237.
Hurtt, M.E., M.E. Placke, J.M. Killinger, A.W. Singer, and G.L. Kennedy, Jr. 1992. Thir-
teen-week inhalation toxicity study of dimethylformamide (DMF) in cynomolgus
monkeys. Fundam. Appl. Toxicol. 18(4):596-601.
IARC (International Agency for Research on Cancer). 1989. Dimethylformamide. Pp.
171-197 in Some Organic Solvents, Resin Monomers and Related Compounds,
Pigments and Occupational Exposures in Paint Manufacture and Painting. IARC
Monographs on the Evaluation of Carcinogenic Risks to Humans Vol. 47. Lyon,
France: IARC.
OCR for page 63
63
N,N-Dimethylformamide
Kafferlein, H.U., and J. Angerer. 2001. N-methylcarbamoylated valine of hemoglobin in
humans after exposure to N,N-dimethylformamide: Evidence for the formation of
methyl isocyanate? Chem. Res. Toxicol. 14(7):833-840.
Kennedy, G.L. 1986. Biological effects of acetamide, formamide, and their monomethyl
and dimethyl derivatives. Crit. Rev. Toxicol. 17(2):129-182.
Kennedy, G.L., and H. Sherman. 1986. Acute and subchronic toxicity of dimethylforma-
mide and dimethylacetamide following various routes of administration. Drug
Chem. Toxicol. 9(2): 147-170.
Kestell, P., M.D. Threadgill, A. Gescher, A.P. Gledhill, A.J. Shaw, and P.B. Farmer.
1987. An investigation of the relationship between hepatotoxity and the metabo-
lism of N-alkylformamides. J. Pharmacol. Exp. Ther. 240(1):265-270.
Kimmerle, G., and A. Eben. 1975a. Metabolism studies of N,N-dimethylformamide. I.
Studies in rats and dogs. Int. Arch. Arbeitsmed. 34(2):109-126.
Kimmerle, G., and A. Eben. 1975b. Metabolism studies of N,N-dimethylformamide. II.
Studies in persons. Int. Arch. Arbeitsmed. 34(2):127-136.
Kimmerle, G., and L. Machemer. 1975. Studies with N,N-dimethylformamide for em-
bryotoxic and teratogenic effects on rats after dynamic inhalation. Int. Arch. Ar-
beitsmed. 34(3):167-175.
Levin, S.M, D.B. Baker, P.J. Landrigan, S.V. Monaghan, E. Frumin, M. Braithwaite, and
W. Towne. 1987. Testicular cancer in leather tanners exposed to dimethylforma-
mide. Lancet 2(8568):1153.
Lewis, S.C., R.E. Schroeder, and G.L. Kennedy, Jr. 1992. Developmental toxicity of
dimethylformamide in the rat following inhalation exposure. Drug Chem. Toxicol.
15(1): 1-14.
Lucas, D., C. Farez, L.G. Bardou, J. Vaisse, J.R. Attali, and P. Valensi. 1998. Cyto-
chrome P450 2E1 activity in diabetic and obese patients as assessed by chlorzoxa-
zone hydroxylation. Fundam. Clin. Pharmacol. 12(5):553-558.
Lundberg, I., A. Pehrsson, S. Lundberg, T. Kronevi, and V. Lidums. 1983. Delayed di-
methylformamide biotransformation after high exposures in rats. Toxicol. Lett.
17(1-2): 29-34.
Lundberg, I., M. Ekdahl, T. Kronevi, V. Lidums, and S. Lundberg. 1986. Relative hepa-
totoxicity of some industrial solvents after intraperitoneal injection or inhalation
exposure in rats. Environ. Res. 40(2):411-420.
Lynch, D.W., M.E. Placke, R.L. Persing, and M.J. Ryan. 2003. Thirteen-week inhalation
toxicity study of , N-dimethylformamide in F344/N rats and B6C3F1 mice. Toxi-
col. Sci. 72(2): 347-358.
Malley, L.A., T.W. Slone, C. Van Pelt, G.S. Elliott, P.E. Ross, J.C. Stadler, and G.L.
Kennedy. 1994. Chronic toxicity/oncogenicity of dimethylformamide in rats and
mice following inhalation exposure. Fundam. Appl. Toxicol. 23(2):268-279.
Massmann, W. 1956. Toxicological investigations on dimethylformamide. Br. J. Ind.
Med. 13(1): 51-54.
McCarver, D.G., R. Byun, R.N. Hines, M. Hichme, and W. Wegenek. 1998. A genetic
polymorphism in the regulatory sequences of human CYP2E1: Association with
increased chlorzoxazone hydroxylation in the presence of obesity and ethanol in-
take. Toxicol Appl. Pharmacol. 152(1):276-281.
Mraz, J., and H. Nohova. 1992. Absorption, metabolism and elimination of N,N-
dimethylformamide in humans. Int. Arch. Occup. Environ. Health 64(2):85-92.
Mraz, J., and F. Turecek. 1987. Identification of N-acetyl-S-(N-methylcarbamoyl) cys-
teine, a human metabolite of N,N-dimethylformamide and N-methylformamide. J.
Chromatogr. 414(2):399-404.
OCR for page 64
64 Acute Exposure Guideline Levels
Mraz, J., H. Cross, A. Gescher, M.D. Threadgill, and J. Flek. 1989. Differences between
rodents and humans in the metabolic toxication of N,N-dimethylformamide. Toxi-
col. Appl. Pharmacol. 98(3):507-516.
Mraz, J., P. Jheeta, A. Gescher, R. Hyland, K. Thummel, and M.D. Threadgill. 1993.
Investigation of the mechanistic basis of N,N-dimethylformamide toxicity. Me-
tabolism of N,N-dimethylformamide and its deuterated isotopomers by cytochrome
P450 2E1. Chem. Res. Toxicol. 6(2):197-207.
MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst
2004: Dimethylformamide. Den Haag: SDU Uitgevers [online]. Available:
http://www.lasrook.net/lasrookNL/maclijst2004.htm [accessed Oct. 21, 2010].
NIOSH (National Institute for Occupational Safety and Health). 1996. Documentation
for Immediately Dangerous to Life or Health Concentrations (IDLH): NIOSH
Chemical Listing and Documentation of Revised IDLH Values (as of 3/1/95)-
Dimethylformamide. U.S. Department of Health and Human Services, Centers
for Disease Control and Prevention, National Institute for Occupational Safety
and Health. August 1996 [online]. Available: http://www.cdc.gov/niosh/idlh/
68122.html [accessed Oct. 21, 2010].
NIOSH (National Institute for Occupational Safety and Health). 2005. NIOSH Pocket
Guide to Chemical Hazards: Dimethylformamide. U.S. Department of Health
and Human Services, Centers for Disease Control and Prevention, National Insti-
tute for Occupational Safety and Health, Cincinnati, OH. September 2005
[online]. Available: http://www.cdc.gov/niosh/npg/npgd0226.html [accessed Oct.
21, 2010].
Nomiyama, T., V. Haufroid, J.P. Buchet, H. Miyauchi, S. Tanaka, T. Yamauchi, S. Ima-
miya, Y. Seki, K. Omae, and D. Lison. 2001a. Insertion polymorphism of CYP2E1
and urinary N-methylformamide after N,N-dimethylformamide exposure in Japa-
nese workers. Int. Arch. Occup. Environ. Health 74(7):519-522.
Nomiyama, T., H. Nakashima, Y. Sano, L.L. Chen, S. Tanaka, H. Miyauchi, T. Yamau-
chi, H. Sakurai, and K. Omae. 2001b. Does the polymorphism of cytochrome P-
450 2E1 affect the metabolism of N,N-dimethylformamide? Comparison of the
half-lives of urinary N-methylformamide. Arch. Toxicol. 74(12):755-759.
NRC (National Research Council). 1993. Guidelines for Developing Community Emer-
gency Exposure Levels for Hazardous Substances. Washington, DC: National
Academy Press.
NRC (National Research Council). 2001. Standing Operating Procedures for Developing
Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na-
tional Academy Press.
NTP (National Toxicology Program). 1992. Toxicology Studies of N,N-Dime-
thylformamide (CAS No. 68-12-2) Administered by Inhalation to F344/N Rats and
B6C3F1 Mice. NTP TR 22. NIH 93-3345. U.S. Department of Health and Human
Services, Public Health Service, National Institutes of Health, National Toxicology
Program, Research Triangle Park, NC [online]. Available: http://ntp.niehs.nih.gov/
ntp/htdocs/ST_rpts/tox022.pdf [accessed Oct. 22, 2010].
Potter, H.P. 1973. Dimethylformamide-induced abdominal pain and liver injury. Arch.
Environ. Health 27(5):340-341.
Redlich, C.A., W.S. Beckett, J. Sparer, K.W. Barwick, C.A. Riely, H. Miller, S.L. Sigal,
S.L. Shalat, and M.R. Cullen. 1988. Liver disease associated with occupational ex-
posure to the solvent dimethylformamide. Ann. Intern. Med. 108(5):680-686.
OCR for page 65
65
N,N-Dimethylformamide
Roure, M.B., A.M. Lambert, C. Cour, P. Bonnet, and A.M. Saillenfait. 1996. Hepatotox-
icity of N,N-dimethylformamide in rats following intraperitoneal or inhalation
routes of administration. J. Appl. Toxicol. 16(3):265-267.
Saillenfait, A.M., J.P. Payan, D. Beydon, J.P. Fabry, I. Langonne, J.P. Sabate, and F.
Gallissot. 1997. Assessment of the developmental toxicity, metabolism, and pla-
cental transfer of N,N-dimethylformamide administered to pregnant rats. Fundam.
Appl. Toxicol. 39(1):33-43.
Scailteur, V., and R.R. Lauwreys. 1987. Dimethylformamide (DMF) hepatotoxicity.
Toxicology 43(3):231-238.
Senoh, H., T. Katagiri, H. Arito, T. Nishizawa, K. Nagano, S. Yamamoto, and T. Matsu-
shima. 2003. Toxicity due to 2- and 13-wk inhalation exposures of rats and mice to
N,N-dimethylformamide. J. Occup. Health 45(6):365-375.
Senoh, H., S. Aiso, H. Arito, T. Nishizawa, K. Nagano, S. Yamamoto, and T. Matsu-
shima. 2004. Carcinogenicity and chronic toxicity after inhalation exposure of rats
and mice to N,N-dimethylformamide. J. Occup. Health 46(6):429-439.
Shell Oil Company. 1982. Test Standardization: Inhalation Toxicity Testing of 8 Chemi-
cals According to the OECD Inhalation Hazard Test. EPA Document No.
878212113. Microfiche No. OTS0205969. U.S. Environmental Protection Agency,
Washington, DC.
Smyth, H.F., and C.P. Carpenter. 1948. Further experience with the range finding test in
the industrial toxicology laboratory. J. Ind. Hyg. Toxicol. 30(1):63-68.
Song, B.J., R.L. Veech, and P. Saenger. 1990. Cytochrome P450IIE1 is elevated in lym-
phocytes from poorly controlled insulin-dependent diabetics. J. Clin. Endocrinol.
Metab. 71(4): 1036-1040.
Stasenkova, K.P. 1961. Toxicity of dimethylformamide [in Russian]. Toksikol. Nov.
Prom. Khim. Vesh. 1:54-69.
Tanaka, K.I. 1971. Toxicity of dimethylformamide (DMF) to the young female rat. Int.
Arch. Occup. Health 28(2):95-105.
ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality
response relationship of irritant and systemically acting vapors and gases. J. Haz-
ard. Mater. 13(3): 301-309.
Tietz, N., ed. 1995. Clinical Guide to Laboratory Tests, 3rd Ed. New York: W.B. Saun-
ders.
Trochimowicz, H.J., G.L. Kennedy, Jr., and N.D. Krivanek. 1994. Heterocyclic and mis-
cellaneous nitrogen compounds: Aromatic Compounds- dimethylformamide. Pp.
3464-3521 in Patty’s Industrial Hygiene and Toxicology, Vol. II E, Toxicology,
4th Ed., G.D. Clayton, and F.E. Clayton, eds. New York: John Wiley & Sons.
TURI (Massachusetts Toxics Use Reduction Institute). 2001. Dimethylformamide. Mas-
sachusetts Chemical Fact Sheet. Toxics Use Reduction Institute, University of
Massachusetts, Lowell [online]. Available: http://www.turi.org/library/turi_publi
cations/massachusetts_chemical_fact_sheets/dimethylformamide [accessed Oct.
21, 2010].
Walrath, J., W.E. Fayerweather, P.G. Gilby, and S. Pell. 1989. A case-control study of
cancer among DuPont employees with potential for exposure to dimethylforma-
mide. J. Occup. Med. 31(5):432-438.
Wrbitzky, R. 1999. Liver function in workers exposed to N,N-dimethylformamide during
the production of synthetic textiles. Int. Arch. Occup. Environ. Health 72(1):19-25.
OCR for page 66
66 Acute Exposure Guideline Levels
APPENDIX A
DERIVATION OF AEGL VALUES FOR N,N-DIMETHYLFORMAMIDE
Derivation of AEGL-1 Values
An AEGL-1 value was not derived because it was not appropriate. No data
pertaining to end points relevant to the AEGL-1 definition were available. 10-
and 30-min and 1-, 4-, and 8-h AEGL-1: not recommended.
Derivation of AEGL-2 Values
Key studies: Hellwig et al. 1991; BASF 1989
Toxicity end points: No developmental effects seen in rabbits exposed to
150 ppm for 6 h; exposure at 450 ppm for 6 h resulted in
irreversible developmental effects (malformations)
Cn × t = k (default of n = 3 for longer to shorter exposure
Time-scaling:
periods; n = 1 for shorter to longer exposure periods)
[(150 ppm)/3]1 × 6 h = 300 ppm-h
[(150 ppm)/3]3 × 6 h = 750,000 ppm-h
Uncertainty factors: 1 for interspecies variability
3 for intraspecies variability
Combined uncertainty factor of 3
Modifying factor: Not applicable
Calculations:
10-min AEGL-2: Set equal to 30-min value due to uncertainty in
extrapolating from 6 h exposure duration to 10 min
C3 × 0.5 h = 750,000 ppm-h
30-min AEGL-2:
C3 = 1,500,000 ppm
C = 114 ppm = 110 ppm
C3 × 1 h = 750,000 ppm-h
1-h AEGL-2:
C3 = 91 ppm
C3 × 4 h = 750,000 ppm-h
4-h AEGL-2:
C2 = 187,500 ppm
C = 57 ppm
OCR for page 67
67
N,N-Dimethylformamide
C1 × 8 h = 300 ppm-h
8-h AEGL-2:
C1 = 37.5 ppm
C = 38 ppm
Derivation of AEGL-3 Values
Key studies: Shell Oil Company 1982
Toxicity end points: Goup of three male and three female rats survived a 3-h
exposure to DMF at
3,700 ppm
Cn × t = k (default of n = 3 for longer to shorter exposure
Time-scaling:
periods; n = 1 for shorter to longer exposure periods)
[(3,700 ppm)/10]1 × 3 h = 1,110 ppm-h
[(3,700 ppm)/10]3 × 3 h = 151,959,000 ppm-h
Uncertainty factors: 1 for interspecies variability
10 for intraspecies variability
Combined uncertainty factor of 10
Modifying factor: Not applicable
Calculations:
C3 × 0.167 = 151,959,000 ppm-h
10-min AEGL-3:
C3 = 909,934,132 ppm
C = 969 ppm = 970 ppm
C3 × 0.5 = 151,959,000 ppm-h
30-min AEGL-3:
C3 = 303,918,000 ppm
C = 672 ppm = 670 ppm
C3 × 1 h = 151,959,000 ppm-h
1-h AEGL-3:
C3 = 151,959,000 ppm
C = 534 ppm = 530 ppm
C1× 4 h = 1,110 ppm-h
4-h AEGL-3:
C1 = 277.5 ppm
C = 280 ppm
C1× 8 h = 1,110 ppm-h
8-h AEGL-3:
C1 = 138.8 ppm
C = 140 ppm
OCR for page 68
68 Acute Exposure Guideline Levels
APPENDIX B
ACUTE EXPOSURE GUIDELINE LEVELS FOR
N,N-DIMETHYLFORMAMIDE
Derivation Summary N,N-Dimethylformamide
AEGL-1 VALUES
10 min 30 min 1h 4h 8h
Not Not Not Not Not
recommended recommended recommended recommended recommended
Reference: Not applicable
Test species/Strain/Number: Not applicable
Exposure route/Concentrations/Durations: Not applicable
Effects: Not applicable
End point/Concentration/Rationale: Not applicable
Uncertainty factors/Rationale: Not applicable
Modifying factor: Not applicable
Animal-to-human dosimetric adjustment: Not applicable
Time-scaling: Not applicable
Data adequacy: No human or animal data pertaining to end points relevant to the
AEGL-1 definition were available. Absence of an AEGL-1 does not imply that
exposures below the AEGL-2 values are without adverse effects.
AEGL-2 VALUES
10 min 30 min 1h 4h 8h
110 ppm 110 ppm 91 ppm 57 ppm 38 ppm
Key references:
Hellwig, J., J. Merkle, H.J. Klimisch, and R. Jackh. 1991. Studies on the prenatal
toxicity of N,N-dimethylformamide in mice, rats and rabbits. Food Chem. Toxicol.
29(3):193-201.
BASF. 1989. Prenatal Toxicity of Dimethylformamide in Rabbits after Inhalation,
Volume I-II (Draft Report) with Attached Supplement to the Report and Cover Sheet
Dated 06/12/89. EPA Document No.86-890000632. Microfiche No. OTS0521138.
U.S. Environmental Protection Agency, Washington, DC.
Test species/Strain/Number: 15 Himalayan rabbits per group
Exposure route/Concentrations/Durations: Inhaled DMF at 0, 50, 150, or 450 ppm
for 6 h/d over GD 7-19
(Continued)
OCR for page 69
69
N,N-Dimethylformamide
AEGL-2 VALUES Continued
10 min 30 min 1h 4h 8h
110 ppm 110 ppm 91 ppm 57 ppm 38 ppm
Effects: (1) Maternal toxicity evident at 150 and 450 ppm as decreased body-weight
gain or weight loss over GD 7-19 and GD 0-29. (2) Developmental toxicity evident
at 450 ppm as increase in external malformations and total malformations (external,
soft tissue, and skeletal combined), as decrease in fetal weight (86% of controls), and
as increase in litter incidence of skeletal variations (splitting of skull bones; fused,
irregular shaped, and bipartite sternebrae). No developmental effects were observed
at 150 ppm.
End point/Concentration/Rationale: 150 ppm for 6 h to protect against irreversible
developmental effects (malformations)
Uncertainty factors/Rationale:
Total uncertainty factor: 3
Interspecies: 1was applied because it appears that primates are not as sensitive as
rodents. Monkeys inhaled DMF at 500 ppm for 6 h/d, 5 d/wk, for up to 13 weeks
with no measurable adverse effects. In contrast, subchronic DMF inhalation
exposure produced significant hepatic effects in rats at concentrations of 200 ppm
(Senoh et al. 2003), 300 ppm (Craig et al. 1984) and 400 ppm (NTP 1992) and in
mice at 100 ppm (Senoh et al. 2003), 150 ppm (Craig et al. 1984), and 200 ppm
(NTP 1992). Indexes of toxicity after repeated DMF exposure ranged from elevated
serum enzymes indicative of liver injury to hepatic degeneration and necrosis. From
these exposure data, humans are expected to be less sensitive than laboratory
animals (rodents). Because the mechanism of hepatotoxicity is thought to be related
to the metabolism of DMF to a reactive intermediate, fetal toxicity is expected to
result from exposure to the parent DMF or metabolites. An oral study assessing the
tissue and metabolite distribution of DMF in pregnant rats indicated that DMF and
its metabolites were transferred across the placenta by passive diffusion and that
maternal plasma, embryo or fetus, placenta, and amniotic fluid belonged to the same
compartment (Saillenfait et al. 1997). Therefore, the fetus and placenta will not
provide any additional protection or enhancement of DMF toxicity because exposure
to DMF and its metabolites will depend on the metabolism by the mother.
Intraspecies: 3, an intraspecies uncertainty factor of 10 would normally be applied
because a host of interindividual differences could affect the manifestation of DMF
toxicity: (1) activity of CYP2E1, an enzyme that plays a pivotal role in the
metabolism of DMF to reactive intermediates, can be induced by ethanol
consumption, obesity, diabetes, and other lifestyle and genetic factors (Gonzalez
1990; Song et al. 1990; Lucas et al. 1998; McCarver et al. 1998), and increased
CYP2E1 levels increase the toxic metabolites of DMF;(2) prior consumption of
ethanol can exacerbate DMF toxicity in individuals; (3) on the basis of the proposed
mechanism of action, detoxification of the reactive intermediate is partly dependent
on conjugation with glutathione; therefore, if glutathione levels are depleted for
other reasons, the potential exists for greater exposure to the reactive
(Continued)
OCR for page 70
70 Acute Exposure Guideline Levels
AEGL-2 VALUES Continued
10 min 30 min 1h 4h 8h
110 ppm 110 ppm 91 ppm 57 ppm 38 ppm
intermediate; (4) because DMF exposure can result in hepatotoxicity, individuals
with chronic liver disease may be at increased risk. However, application of a total
uncertainty factor of 10 produces AEGL-2 values that are inconsistent with the
available human data (values for the 10- and 30-min and1-, 4-, and 8-h AEGL-2
using default time-scaling would be 49, 34, 27, 17, and 11 ppm, respectively).
Humans were exposed by inhalation of DMF at 87 ppm for 4 h or at 81 ppm for 2 h
to assess the metabolism of DMF (Kimmerle and Eben 1975b; Eben and Kimmerle
1976). These single-exposure studies were conducted to assess DMF metabolism,
and no adverse effects were reported; the concentration can be considered an acute
exposure concentration unlikely to result in adverse effects in healthy adults.
Therefore, the intraspecies uncertainty factor is reduced to 3.
Modifying factor: Not applicable
Animal-to-human dosimetric adjustment: Not applicable
Time-scaling: Default time-scaling using n = 3, 1. The 30-min AEGL-2 value was
set equal to the 10-min value because of the uncertainty in extrapolating from a 6-h
exposure duration to a 10-min duration.
Data quality and support for the AEGL values: Data meeting the definition of an
AEGL-2 end point were limited to developmental toxicity studies. Other nonlethal
acute health effects in animals were limited to alterations in liver enzymes because
livers from animals following a single exposure were not examined histologically.
Histologic analysis of tissues from animals that died following acute exposure was
not available to determine the cause of death.
AEGL-3 VALUES
10 min 30 min 1h 4h 8h
970 ppm 670 ppm 530 ppm 280 ppm 140 ppm
Key reference: Shell Oil Company. 1982. Test Standardization: Inhalation Toxicity
Testing of 8 Chemicals According to the OECD Inhalation Hazard Test. EPA
Document No. 878212113. Microfiche No. OTS0205969. U.S. Environmental
Protection Agency, Washington, DC
Test species/Strain/Number: groups of three male and three female Wistar rats
Exposure route/Concentrations/Durations: exposed to 3,700 ppm DMF for 1, 3, or
7 h and observed for mortality for 14 days postexposure
Effects: 1- or 3-h exposure at 3,700 ppm, no mortality; 7-h exposure at 3,700 ppm,
killed 2/3 males and 3/3 females
End point/Concentration/Rationale: exposure for 3 h to 3,700 ppm did not result in
mortality
(Continued)
OCR for page 71
71
N,N-Dimethylformamide
AEGL-3 VALUES Continued
10 min 30 min 1h 4h 8h
970 ppm 670 ppm 530 ppm 280 ppm 140 ppm
Uncertainty factors/Rationale:
Total uncertainty factor: 10
Interspecies: 1 was applied because it appears that primates are not as sensitive as
rodents. Monkeys inhaled DMF at 500 ppm for 6 h/d, 5 d/wk, for up to 13 weeks
with no measurable adverse effects. In contrast, subchronic DMF inhalation
exposure produced significant hepatic effects in rats at concentrations of 200 ppm
(Senoh et al. 2003), 300 ppm (Craig et al. 1984), and 400 ppm (NTP 1992) and in
mice at 100 ppm (Senoh et al. 2003), 150 ppm (Craig et al. 1984), and 200 ppm
(NTP 1992). Indexes of toxicity after repeated DMF exposure ranged from elevated
serum enzymes indicative of liver injury to hepatic degeneration and necrosis. From
these exposure data, humans are expected to be less sensitive than laboratory
animals (rodents). Because the mechanism of hepatotoxicity is thought to be related
to the metabolism of DMF to a reactive intermediate, fetal toxicity is expected to
result from exposure to the parent DMF or metabolites. An oral study assessing the
tissue and metabolite distribution of DMF in pregnant rats indicated that DMF and
its metabolites were transferred across the placenta by passive diffusion and that
maternal plasma, embryo or fetus, placenta, and amniotic fluid belonged to the same
compartment (Saillenfait et al. 1997). Therefore, the fetus and placenta will not
provide any additional protection or enhancement of DMF toxicity because exposure
to DMF and its metabolites will depend on the metabolism by the mother.
Intraspecies: 10 was applied because a host of interindividual differences could
affect the manifestation of DMF toxicity: (1) activity of CYP2E1, an enzyme that
plays a pivotal role in the metabolism of DMF to reactive intermediates, can be
induced by ethanol consumption, obesity, diabetes, and other lifestyle and genetic
factors (Gonzalez 1990; Song et al. 1990; Lucas et al. 1998; McCarver et al. 1998),
and increased CYP2E1 levels increase the toxic metabolites of DMF; (2) prior
consumption of ethanol can exacerbate DMF toxicity in individuals; (3) on the basis
of the proposed mechanism of action, detoxification of the reactive intermediate is
partly dependent on conjugation with glutathione; therefore, if glutathione levels are
depleted for other reasons, the potential exists for greater exposure to the reactive
intermediate; and (4) because DMF exposure can result in hepatotoxicity,
individuals with chronic liver disease may be at increased risk.
Modifying factor: Not applicable
Animal-to-human dosimetric adjustment: Not applicable
Time-scaling: Default time-scaling using n = 3, 1
Data quality and support for the AEGL values: Quality data for derivation of the
AEGL-3 value were sparse. The AEGL-3 level is based on a study in which groups
of only 3 rats of each sex were used, as opposed to 10 animals per group. The other
studies investigating lethality following acute exposure to DMF did not observe
animals for 14 days postexposure and did not report reliable exposure
concentrations. However, the lethality data provided in the key study is
consistent with the weight of evidence.
