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Determination of Noncancer Chronic Reference Exposure Levels Batch 2A December 2000 N,N-DIMETHYLFORMAMIDE
CAS Registry Number: 68-12-2
Chronic Toxicity Summary
Inhalation reference exposure level 80 µg/m3 (30 ppb)
Liver dysfunction and respiratory irritation in Chemical Property Summary (HSDB, 1994)
Soluble in alcohol, ether, acetone, benzene, Major Uses and Sources
Dimethylformamide (DMF) is primarily used as a solvent in the production of polyurethaneproducts and acrylic fibers. It is also used in the pharmaceutical industry, in the formulationof pesticides, and in the manufacture of synthetic leathers, fibers, films, and surface coatings(Howard, 1993; Gescher, 1993; Redlich et al., 1988). DMF may be emitted to theenvironment as a result of its use in a variety of petrochemical industries (Howard, 1993). Theannual statewide industrial emissions from facilities reporting under the Air Toxics Hot SpotsAct in California based on the most recent inventory were estimated to be 18,249 pounds ofDMF (CARB, 2000).
Effects of Human Exposure
Among 100 workers occupationally exposed to DMF for at least one year (mean exposure of5 years; range = 1-15 years), a statistically significant incidence of hepatic impairment, asindicated by elevated gamma-glutamyl transpeptidase levels and digestive disturbances, wasnoted (Cirla et al., 1984). Other changes, that were not statistically significant, included Determination of Noncancer Chronic Reference Exposure Levels Batch 2A December 2000 increased SGOT and SGPT and enlarged livers. The mean time-weighted averageconcentration of DMF was 22 mg/m3 (range = 8-58 mg/m3). Symptoms of irritationoccurring only during work at statistically significantly higher incidences included wateryeyes, dry throat, and coughing. Also, the exposed workers reported a reduced sense of smelland dry coughs at home with a statistically significant difference as compared to controls.
Several of the DMF exposed workers also reported alcohol intolerance characterized by adisulfiram-type reaction (facial flushing and palpitations following alcohol ingestion).
Alcohol consumption, a potential confounder, was controlled for in the study design.
A similar study was conducted on workers who had been employed in an acrylic acid fiberplant for more than 5 years (Cantenacci et al., 1984). Concentrations to which the workerswere exposed were characterized as either an 8-hour TWA of 18 mg/m3 or an 8-hour TWA of3 mg/m3. Measures of liver function including SGOT, SGPT, gamma-glutamyl transferase,and alkaline phosphatase levels were not significantly different between exposed andunexposed workers. However, the U.S. EPA cautions that because only 54 matched pairs ofworkers were examined, the power of this study was not high enough to reliably detect adifference in enzyme levels.
Redlich et al. (1988) characterized a plant-wide outbreak of liver disease among workers in afactory coating fabric with polyurethane. Fifty-eight of 66 (88%) workers participated andeach had standard liver screening function tests done at least once. At the work site DMF wasbeing used in poorly ventilated areas without appropriate skin protection. No other majorknown hepatotoxic exposure was identified. Overall, 36 of 58 (62%) workers tested hadelevations of either aspartate aminotransferase (AST) or alanine aminotransferase (ALT)levels. Enzyme abnormalities occurred almost exclusively in production workers (35 out of46 abnormal). Only 1 of 12 non-production workers showed elevations in enzyme levels (p <0.0001). Serologic tests excluded known infectious causes of hepatitis in all but 2 workers.
Changes, characteristic of liver injury, were confirmed by histologic examination of biopsyspecimens from 4 workers. Improvement in liver enzyme abnormalities and symptoms inmost patients were seen, after modification of work practices and removal of workers mostseverely affected from exposure. However, some patients showed persistent elevations ofenzyme levels. No measurements or estimates of DMF exposure levels were reported.
Wang et al. (1991) investigated the prevalence of liver injury associated with DMF exposurein 183 of 204 (76%) employees of a synthetic leather factory by performing medicalexaminations, liver function tests, and creatine phosphokinase (CPK) determinations. Airconcentrations were measured with personal samplers and gas chromatography. Theconcentration of DMF in air to which each worker was exposed was categorized as high(DMF exposure index 2: 25-60 ppm; 75-180 mg/m3), medium (index 1: 10-40 ppm), and low(index 0: <10 ppm). High exposure concentrations were significantly associated withelevated alanine aminotransferase (ALT) levels (i.e., greater than or equal to 35 InternationalUnits/liter), a result that did not change after stratification by hepatitis B carrier status.
Logistic regression analysis indicated that exposure to high DMF levels was associated withelevated ALT (p = 0.01), whereas hepatitis B surface antigen (HBsAg) was slightly butindependently associated with elevated ALT (p = .07). Workers with normal ALT values hadsignificantly higher mean ALT and aspartate aminotransferase (AST) activities, especially Determination of Noncancer Chronic Reference Exposure Levels Batch 2A December 2000 among those who were not HBsAg carriers. A significant association existed betweenelevated CPK levels and exposure to DMF. However, an analysis of the CPK isoenzymeamong 143 workers did not reveal any specific damage to muscles. Thus the authors ascribedthe liver injury to DMF.
U.S. EPA (1994) states that subjective evidence of liver toxicity, such as digestive impairmentand alcohol intolerance, is often observed at exposures below those that cause clinicalchanges in liver enzymes. Thus, the symptoms may be more sensitive indicators of hepaticimpairment.
Three unexplained cases of small-for-date third trimester intrauterine deaths were observed ina group of women working as quality control analysts in the pharmaceutical industry(Farquhason et al., 1983). This represented a 30% stillbirth rate as compared with the averagefor the general population of about 0.26%. While the authors concluded that the occurrenceof stillbirth in these women was not likely due to chance, the effects cannot be solelyattributed to DMF because the women were exposed to other agents in addition to DMF.
Effects of Animal Exposure
Malley et al. (1994) exposed male and female Crl:CD rats and mice to 0, 25, 100, or 400 ppmDMF for 6 hr/day, 5 days/week for 18 months (mice) or 2 years (rats). No compound-relatedeffects on clinical observations or survival were observed. Body weights of rats exposed to100 (males only) and 400 ppm were reduced, while body weights were increased in 400 ppmmice. No hematologic changes were observed in either species. Serum sorbitoldehydrogenase activity was increased in rats exposed to 100 or 400 ppm. DMF-relatedmorphological changes were observed only in liver. Exposure of rats to 100 and 400 ppmproduced increased relative liver weights, centrilobular hepatocellular hypertrophy,lipofuscin/hemosiderin accumulation in Kupffer cells, and centrilobular single cell necrosis(400 ppm only). In mice, increased liver weights (100 ppm males, 400 ppm both sexes),centrilobular hepatocellular hypertrophy, accumulation of lipofuscin/hemosiderin in Kupffercells, and centrilobular single cell necrosis were observed in all exposure groups. Theseobservations occurred in a dose-response fashion and were minimal at 25 ppm. No increasein hepatic cell proliferation was seen in mice or female rats. Slightly higher proliferation wasseen in male rats exposed to 400 ppm at 2 weeks and 3 months but not at 12 months. Thus 25ppm was a chronic NOAEL for both rats and mice.
A developmental toxicity study using three species (mice, rabbits, and rats) and four routes ofadministration (oral, inhalation, dermal, and intraperitoneal) identified the rabbit as the mostsensitive of the three species. Groups of 15 pregnant rabbits were exposed for 6 hours per dayon days 8-20 of gestation to 50, 150, or 450 ppm (150, 449, or 1350 mg/m3) DMF (Hellwig etal., 1991). Slight maternal toxicity, as indicated by non-statistically significant decreases inmaternal body weight gain, was observed in the 450 ppm exposure group. An increasednumber of total malformations per litter was observed in the 450 ppm exposure group.
Malformations observed at statistically higher incidences compared to controls includedhernia umbilicalis, external variations, pseudoankylosis of the forelimbs, and skeletal Determination of Noncancer Chronic Reference Exposure Levels Batch 2A December 2000 variation and retardation. The authors conclude that there was a clear teratogenic effect inrabbits following maternal exposure to 450 ppm DMF and a marginal effect followingexposure to 150 ppm DMF. A NOAEL of 50 ppm for fetal and maternal effects was reported.
Inhalation exposure to 150 ppm was calculated by the authors to approximate a daily dose of45 mg/kg/day, which coincides with previous work on this compound in this species.
Derivation of Chronic Reference Exposure Level
Cirla et al., 1984; Catenacci et al., 1984 Digestive disturbances and slight hepatic 8 hr/day (10 m3/day), 5 days/week (assumed) 7.9 mg/m3 for LOAEL group (22 x 10/20 x 5/7) Inhalation reference exposure level The U.S. EPA (1994) based its RfC of 30 µg/m3 on the same study but included a ModifyingFactor (MF) of 3 due to lack of reproductive toxicity data in the DMF database. The criteriafor use of modifying factors are not well specified by U.S. EPA. Such modifying factors werenot used by OEHHA. Intermediate uncertainty factors were used for LOAEL to NOAEL andsubchronic to chronic extrapolation because of the mild nature of the effects observed and theless than chronic exposure duration.
For comparison Hellwig et al. (1991) found a developmental NOAEL of 50 ppm in rabbitsexposed 6 hours per day on gestation days 8-20, equivalent to continuous exposure of 12.5ppm. Multiplication by an RGDR of 1 and division by a UF of 30 (3 for interspecies and 10for intraspecies) results in a REL estimate of 400 ppb. The NOAEL of 25 ppm for rats andmice in the chronic study of Malley et al. (1994) leads to a REL estimate of 150 ppb.
Data Strengths and Limitations for Development of the REL
The major strength of the REL for N,N-dimethylformamide is the availability of humanhealth effects data over several years of exposure. The major uncertainties are the difficulty Determination of Noncancer Chronic Reference Exposure Levels Batch 2A December 2000 in estimating exposure patterns and magnitude, the lack of a NOAEL observation, and thelack of complete reproductive and developmental toxicity data.
VIII. References
CARB. 2000. California Air Resources Board. California Emissions Inventory Developmentand Reporting System (CEIDARS). Data from Data Base Year 1998. February 12, 2000.
Catenacci G, Grampella D, Terzi R, Sala A, and Pollini G. 1984. Hepatic function in subjectsexposed to environmental concentrations of DMF lower than the actually proposed TLV. G.
Ital. Med. Lav. 6(3-4):157-158.
Cirla AM, Pisati G, Invernizzi E, and Torricelli P. 1984. Epidemiological study on workersexposed to low dimethylformamide concentrations. G. Ital. Med. Lav. 6(3-4):149-156.
Farquharson RG, Hall MH, and Fullerton WT. 1983. Poor obstetric outcome in three qualitycontrol laboratory workers. Lancet 1(8331):983-984. [cited in U.S. EPA, 1994].
Gescher A. 1993. Metabolism of N,N-dimethylformamide: key to the understanding of itstoxicity. Chem. Res. Toxicol. 6(3):245-251.
HSDB. 1994. Hazardous Substances Data Bank. National Library of Medicine, Bethesda, MD(TOMES CD-ROM Version). Denver, CO: Micromedex, Inc. (Edition expires 11/31/94).
Hellwig J, Merkle J, Klimisch HJ, and Jackh R. 1991. Studies on the prenatal toxicity of N,N-dimethylformamide in mice, rats and rabbits. Food Chem. Toxicol. 29(3):192-201.
Howard PH. (ed) 1993. Handbook of Environmental Fate and Exposure Data for OrganicChemicals. Vol. IV: Solvents 2. Chelsea, MI: Lewis Publishers Inc.
Malley LA, Slone TW Jr, Van Pelt C, Elliott GS, Ross PE, Stadler JC, and Kennedy GL Jr.
1994. Chronic toxicity/oncogenicity of dimethylformamide in rats and mice followinginhalation exposure. Fundam. Appl. Toxicol. 23(2):268-279.
Redlich C, Beckett WS, Sparer J, Barwick KW, Riely CA, Miller H, Sigal SL, Shalat SL, andCullen MR. 1988. Liver disease associated with occupational exposure to the solventdimethylformamide. Ann. Intern. Med. 108:680-686.
U.S. EPA. 1994. U.S. Environmental Protection Agency. IRIS. 1994. Integrated RiskInformation System (IRIS). Reference concentration for chronic inhalation exposure (RfC) forN,N,-Dimethylformamide. Available online at http://www.epa.gov/ngispgm3/iris Wang JD, Lai MY, Chen JS, Lin JM, Chiang JR, Shiau SJ, and Chang WS. 1991.
Dimethylformamide-induced liver damage among synthetic leather workers. Arch. Environ.
Health 46(3):161-166.

Source: http://www.zemus.co.kr/pud/chronic%20toxicity%20summary.pdf

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