Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 10 (2011) / Chapter Skim
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1 N,N-Dimethylformamide
1 N,N-Dimethylformamide
Pages 13-71
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From page 13... ...
Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels.
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From page 14... ...
Reports of both accidental and chronic daily workplace inhalation exposures to DMF describe signs and symptoms, including abdominal pain, nausea, and vomiting, and liver toxicity as indicated by elevated serum enzymes and histologic evaluation. Epidemiologic studies suggest a causal association between DMF exposure and testicular germ cell tumors.
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Repeated inhalation exposure of rats, mice, and cats to DMF generally resulted in reduced body weight, and hepatotoxicity indicated by increased liver enzymes and histopathologic changes including degeneration and necrosis. However, repeated inhalation 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.
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From page 16... ...
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.
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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)
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. 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 extrapolate from longer to shorter exposure periods.
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Human data are available from reports of accidental and controlled inhalation 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 induction of hepatotoxicity.
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The studies were conducted to assess metabolism, and no adverse effects of inhaled DMF exposure 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)
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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 symptoms were not evaluated by the study authors.
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. In the re-evaluation, the defined exposure population consisted of subjects who were male, Hispanic, and who worked in jobs with DMF exposure.
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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.
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No workplace air or biologic monitoring data were reported that could be used to document the extent of DMF exposure; therefore, the late deaths could not be attributed to DMF.
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Each case was matched to two controls based on sex, salary, birth year, and plant location. Each job with possible DMF exposure was identified, and exposure rankings were assigned based on industrial hygiene monitoring of DMF, monitoring of urinary DMF metabolites, and knowledge of work practices and plant operations.
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From page 26... ...
The authors stated that "all animals appeared normal shortly after exposure and remained so even if subsequently dying." Body weight at 0, 7, or 14 days postexposure was comparable in the male and female rats exposed for 1 or 3 h. Necropsy was not performed.
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Histopathologic examination was conducted on all rats either upon death or at the termination of the 10-day period. Clinical signs among exposed rats consisted of progressive weakness, discomfort, and body-weight loss.
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SDH and GDH levels were maximally increased by 24 h in rats exposed at 153, 313, or 441 ppm, with SDH levels increased approximately 2-fold in the 153-ppm group, and SDH and GDH levels increased approximately 6-fold and 10.5-fold in the 313- and 441-ppm group, respectively. In contrast, SDH and GDH levels in rats exposed at 991 ppm peaked at 48 h, having increases of 140-fold and 130-fold, respectively and no significant increases at 24 h.
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. Twenty-four hours following termination of DMF exposure, rats were killed and blood was collected to measure serum GDH, AST, and SDH.
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Developmental toxicity was evident in the 450-ppm group because of significant reductions in mean fetal body weight compared with weight in the concurrent controls and significant increases in the litter incidence of total external malformations, total skeletal variations, and total malformations (external, soft tissue, and skeletal combined)
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Mean fetal body weight was reduced (p <0.05) in the 221- and 522-ppm groups.
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b Body weights recorded on GD 0, 4, 11, 15, and 20; therefore, body-weight gain over the exposure interval of GD 4-8 could not be calculated. c Percent decrease or increase compared with controls; calculated by reviewer.
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The only effect observed in fetuses was reduced mean fetal body weight in the 172-ppm group (3.78 g vs. 4.07 g for controls; p <0.01)
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Clinical signs were recorded daily during exposure, and body weight was recorded 1 day before exposure, on study day 8, and after the last exposure. Blood was collected for hematology and clinical chemistry analysis 1 day before exposure at the end of the first exposure day and following the last exposure day.
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Relative liver weight was increased in male rats exposed at ≥100 ppm and in female rats exposed at ≥200 ppm. Histopathologic examination revealed increased hepatic single-cell necrosis in male and female rats exposed at ≥200 ppm and in centrilobular hypertrophy in male and female rats exposed at ≥400 ppm.
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High-dose female rats had an increased length of estrous cycle compared with controls. No definitive exposure-related effects were observed in renal function, blood pressure, or electrocardiogram readings or in male reproductive parameters.
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Centrilobular degeneration was present in male mice exposed at ≥200 ppm and in female mice exposed at ≥800 ppm. In the 13-week study, males exhibited reduced body weight and increased relative liver weight at all DMF concentrations and a reduction in feed
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. Body-weight gain was decreased in male and female rats exposed at 800 ppm.
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. Female rats exposed at 400 ppm and male rats exposed at 100 or 400 ppm had decreased absolute body weight, and body-weight gain was reduced in males and females at 100 or 400
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A concentration-related reduction in absolute body weight was observed in DMF-exposed male and female rats, and females exposed at 800 ppm reduced their food consumption. Clinical chemistry revealed a concentrationrelated increase in AST, ALT, GGT, and AP activity in male and female rats, and males at 800 ppm had increased LDH.
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* Non-neoplastic lesions Centrilobular hypertrophy 0 39*
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From page 42... ...
However, 6-h exposures of monkeys to DMF at 500 ppm did not result in any measurable effects. Developmental toxicity studies reported maternal effects of reduced maternal body weight, and developmental effects included reduced fetal weight; increases in the litter incidence of total external, skeletal, and visceral malformations and skeletal variations; and an increased number and percentage of dead implants.
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From page 43... ...
Duration Effect Reference Rat 3,700 1, 3 h 3/3 males and 3/3 females survived; Shell Oil excessive grooming Company 1982 7h 2/3 males and 3/3 females died; excessive grooming, lethargy 5,000 4 or 8 h No mortality (within 24 h) Lundberg et al.
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1984 1,200 5d/wk, Variations in hepatic nuclear size and 12 wk cytoplasmic variations at 300 ppm and above; increased cholesterol at 600 ppm and above; 1 male and 1 female died, liver necrosis; surviving rats, decreased body weight, liver necrosis 100, 200, 400 6 h/d, No clinical signs at any concentration Senoh et al. 800, 1,600 5 d/wk, Decreased growth rate at 400 ppm and above 2003 2 wk Centrilobular single-cell necrosis 3 males and 7 females died within 10 exposures; massive hepatic necrosis 50, 100 6 h/d, Increased liver enzymes at 50 ppm and above Senoh et al.
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From page 45... ...
800, 1,600 5 d/wk, Increased relative liver weight at 200 ppm 2003 2 wk and above Decreased growth rate, focal hepatic necrosis at 1,600 ppm 50, 100, 200, 6 h/d, Decreased growth rate and increased liver Senoh et al. 400, 800 5 d/wk, weight in all exposed groups; centrilobular 2003 13 wk hypertrophy in males at 50 ppm and above Increased liver enzymes at 100 ppm and above Decreased food consumption, single-cell necrosis in liver, centrilobular hypertrophy in females at 800 ppm 50, 100, 200, 6 h/d, Mild centrilobular hepatocellular hypertophy NTP 1992 400, 800 5 d/wk, at ≥50 ppm 13 wk Significant increase in liver weight at ≥200 ppm Decreased growth rate at 800 ppm 150, 300, 600, 6 h/d, 1 died; hepatic cytomegaly around central Craig et al.
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From page 46... ...
(1989) reported that the absorbed dose by humans following inhalation exposure to DMF at 20 ppm for 8 h was one-half of that absorbed by male mice, rats, and hamsters after a single intraperitoneal injection of DMF at 0.1, 0.7, or 7 mmol/kg of body weight.
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From page 47... ...
However, it has since been determined that the conditions used in those early gas-chromatographic analyses resulted in thermolytic degradation of the HMMF metabolite to NMF. Studies measuring plasma concentrations of DMF and its metabolites in monkeys, rats, and mice following acute inhalation exposure reported that both HMMF and NMF are recovered when appropriate methods are used, and the concentrations of each in relation to the other vary; however, HMMF was the primary urinary metabolite recovered (Hundley et al.
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From page 48... ...
to air containing a measured concentration of DMF at 20 ppm (reported as 60 mg/m3) for 8 h, and these investigators also gave male mice, rats, and hamsters DMF at 0.1, 0.7, or 7 mmol/kg of body weight via intraperitoneal injection.
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During the inhalation exposure, the volunteers sat outside the exposure chamber and inhaled air containing DMF from the exposure chamber. Chamber DMF concentrations were monitored every 10 min using a gas chromatograph.
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The precise mechanism of the disulfiram-like symptoms that occur with combined ethanol consumption and DMF exposure is not known. Disulfiram
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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 include clinical signs, body weight, hematology and serum chemistry analyses, urinalysis, semen analysis, and gross necropsy findings) (Hurtt et al.
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From page 52... ...
DATA ANALYSIS FOR AEGL-1 5.1. Summary of Human Data Relevant to AEGL-1 The controlled human exposures in which the metabolism of DMF was investigated were not designed to assess the toxicity of DMF exposure (Kimmerle and Eben 1975b; Mraz et al.
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From page 53... ...
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 controls. Developmental toxicity was evident at 450 ppm as increases in external malformations and total malformations (external, soft tissue, and skeletal combined)
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From page 54... ...
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 measurable adverse effects (parameters examined included clinical signs, body weight, hematology and serum chemistry analyses, urinalysis, semen analysis, and gross necropsy findings)
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From page 55... ...
because DMF exposure can result in hepatotoxicity, those individuals with chronic liver disease may be at increased risk. Application of a total uncertainty factor of 10 produces AEGL-2 values that are inconsistent with the available human data (values for the 10-min, 30min, 1-h, 4-h, and 8-h AEGL-2 using default time-scaling would be 49, 34, 27, 17, and 11 ppm, respectively)
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From page 56... ...
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)
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From page 57... ...
because DMF exposure can result in hepatotoxicity, those individuals with chronic liver disease may be at increased risk. Therefore, a total uncertainty factor of 10 is applied.
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From page 58... ...
DMF Toxicity - All Data 10000.0 Human - No Effect Human - Discomfort 1000.0 Human - Disabling AEGL-3 Animal - No Effect ppm 100.0 Animal - Discomfort AEGL-2 Animal - Disabling 10.0 Animal - Some Lethality Animal - Lethal AEGL 1.0 0 60 120 180 240 300 360 420 480 Minutes FIGURE 1-1 Category plot of animal toxicity data compared with AEGL values.
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From page 59... ...
Occupational workplace standards lie below the 8-h AEGL-2 levels. TABLE 1-16 Extant Standards and Guidelines for DMF Exposure Duration Guideline 10 min 30 min 1h 4h 8h AEGL-1 NR NR NR NR NR AEGL-2 110 ppm 110 ppm 91 ppm 57 ppm 38 ppm AEGL-3 970 ppm 670 ppm 530 ppm 280 ppm 140 ppm ERPG-1 (AIHA)
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Nonlethal acute inhalation effects in animals were limited to measurements of alterations in liver enzymes; livers from animals subjected to a single exposure were not examined histologically. Histologic analyses of tissues from animals that died following acute DMF exposure were generally not available.
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1998. N-methylcarbamoyl adducts at the N-terminal valine of globin in workers exposed to N,N-dimethylformamide.
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1993a. Dimethylformamide pharmacokinetics following inhalation exposure to rats and monkeys.
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1992. Developmental toxicity of dimethylformamide in the rat following inhalation exposure.
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2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals.
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From page 65... ...
2003. Toxicity due to 2- and 13-wk inhalation exposures of rats and mice to N,N-dimethylformamide.
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From page 66... ...
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) Time-scaling: Cn × t = k (default of n = 3 for longer to shorter exposure periods; n = 1 for shorter to longer exposure periods)
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From page 67... ...
/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: 10-min AEGL-3: C3 × 0.167 = 151,959,000 ppm-h C3 = 909,934,132 ppm C = 969 ppm = 970 ppm 30-min AEGL-3: C3 × 0.5 = 151,959,000 ppm-h C3 = 303,918,000 ppm C = 672 ppm = 670 ppm 1-h AEGL-3: C3 × 1 h = 151,959,000 ppm-h C3 = 151,959,000 ppm C = 534 ppm = 530 ppm 4-h AEGL-3: C1× 4 h = 1,110 ppm-h C1 = 277.5 ppm C = 280 ppm 8-h AEGL-3: C1× 8 h = 1,110 ppm-h C1 = 138.8 ppm C = 140 ppm
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From page 68... ...
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)
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From page 69... ...
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.
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From page 70... ...
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.
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From page 71... ...
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.
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