1

N,N-Dimethylformamide
1

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 Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established 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 distinguished 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

________________________

1This document was prepared by the AEGL Development Team composed of Claudia Troxel (Oak Ridge National Laboratory) and Loren Koller and George Woodall (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee 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).



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



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 13
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 13
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 13
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 13
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 13
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 13
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 13
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 13
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 13
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 13
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 13
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 13
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 13
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 13
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 13
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 13
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 13
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 13
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 13
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 13
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 13
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.