N,N- Dimetyloformamid. Dokumentacja proponowanych wartości dopuszczalnych poziomów narażenia zawodowego

Sapota, A.; Ligocka, D.

Artykuł - szczegóły

Tytuł artykułu

N,N- Dimetyloformamid. Dokumentacja proponowanych wartości dopuszczalnych poziomów narażenia zawodowego

Autorzy

Sapota A. , Ligocka D.

Wybrane pełne teksty z tego czasopisma

www.ciop.pl/pimosp_teksty

Identyfikatory

Warianty tytułu

N,N-Dimetyloformamide

Języki publikacji

Abstrakty

Światowa produkcja DMF w 1995 r. wynosiła około 500 tys. ton. W Stanach Zjednoczonych, gdzie produkcja DMF w 1987 r. przekroczyła 250 tys. ton, liczba osób narażonych na ten związek wynosiła około 120.000 osób. W Polsce dokładna liczba osób narażonych na DMF nie jest znana. W 1995 r. w jednym z zakładów produkujących sztuczną skórę liczba narażonych zawodowo na ten związek wynosiła około 300 osób, w tym 50 osób narażonych na związek o stężeniach przekraczających dotychczas obowiązującą wartość NDS, tj. 10 mg/m3. Zgodnie z dyrektywą nr 92/32/EEC należy zaliczyć DMF do grupy związków szkodliwych. Na podstawie wyników badań na zwierzętach doświadczalnych nie stwierdzono, aby związek ten wykazał działanie drażniące czy uczulające; nie wykazano również jego działania rakotwórczego i teratogennego. W licznych testach in vitro i in vivo wykazano brak działania genotoksycznego związku. DMF w dużych dawkach wykazuje działanie hepatotoksyczne, które stwierdzono u wielu gatunków zwierząt po podaniu związku różnymi drogami i w różnym czasie. Obserwowano nasilanie się skutków działania hepatotok- sycznego DMF w zależności od stosowanych dawek. DMF ulega wchłanianiu w postaci par w drogach oddechowych i przez skórę. W badaniach eksperymentalnych na ochotnikach retencja DMF w płucach wynosiła około 90%. Ciekły DMF naniesiony na skórę wchłania się bardzo szybko, a wyznaczony u ludzi współczynnik wchłaniania wynosi 9 mg/cm2/h. Za efekt krytyczny działania tego związku przyjęto działanie układowe na wątrobę. W celu obliczenia i ustalenia wartości NDS przyjęto wartość NOEL dla szczurów w warunkach 2-letniego narażenia inhalacyjnego, która wynosiła 75 mg/m3. Po uwzględnieniu powyższych danych zaproponowano utrzymanie dotychczasowej wartości 10 mg/mJ jako wartości NDS DMF. Wyliczona wartość NDS związku powinna zapobiec skutkom zdrowotnym długotrwałego narażenia na DMF w warunkach narażenia zawodowego. Proponujemy ponadto przyjąć wartość DSB, podobnie jak w Niemczech i USA, gdzie wymagane jest oznaczanie w moczu jednego z głównych metabolitów DMF /V-metyloformamidu (NMF). Obowiązująca w Niemczech wartość NDS DMF wynosi 30 mg/m3, a wartość DSB - 15 mg /V-metyloforma- midu/1 moczu. Ze względu na prostoliniową zależność stężenia A^metyloformamidu w moczu od stężenia DMF w powietrzu, po odpowiednim przeliczeniu dla wartości proponowanego przez nas NDS (10 mg/mJ) DSB w Polsce powinno wynosić 5 mg NMF/1 moczu. Ze względu na duże wchłanianie DMF przez skórę w postaci ciekłej i w postaci par, proponujemy dodatkowe oznaczenie literami Sk. Nie ma podstaw do ustalenia wartości NDSCh N,N -dimetyloformamidu.

Dimethylformamide (DMF) is a colourless and hygroscopic liquid with a faint odour of amines. It is mainly used as a liquid and gas solvent in organic synthesis in the process of producing low - and high-molecular vinyl and acryl polymers, foil, fibres and coatings. IN 1995, the world production of DMF was about 500,000 tons. In the USA, where in 1987 DMF production exceeded 250,000 tons, about 120,000 people were exposed to this compound. In Poland the exact number of people exposed to DMF is unknown. In 1995, in one of the plants producing artificial leather, about 300 workers were occupationally exposed to this compound. 50 of them were exposed to concentrations exceeding the so far obligatory TLV value (10 mg/m3). According to European Union instruction No. 92/32/EEC DMF should be included in the group of harmful compounds. On the basis of the results of investigations on laboratory animals the compound does not demonstrate irritating, sensitizing, carcinogenic or teratogenic effect. In numerous in vitro and in vivo tests the compound showed no genotoxic effect. In high doses DMF reveals hepatotoxic effect observed in many animal species after administration of the compound in various ways and at different times. Intensification of DMF hepatotoxic effect was found depending on the applied doses. DMF is absorbed in the form of vapours in the airways and through skin. In experimental studies on volunteers, DMF retention in lungs w'as about 90%. Liquid DMF applied on skin is absorbed very quickly and the determined in humans absorption coefficient is 9 mg/cm2/h. Systemic activity on liver has been assumed to be critical effect of the compound. To calculate and establish a TLV value the NOEL value of 75 mg/m for rats in the condition of 2-year inhallatory exposure was ac¬cepted. Taking into consideration the above data, the so far used value 10 mg/nr’ has been suggested to be retained as a TLV value for DMF. The calculated TLV value of the compound should prevent health effects of long-term exposure to DMF in occupational exposure. Moreover, we suggest accepting a BEI value, like in Germany and the USA, where determination of iV-methylformamide (one of main DMF metabolites) in urine is required. In Germany, the obligatory TLV value for DMF is 30 mg/mJ and the BEI value is 15 mg /V-met- hylformamide/1 of urine. Due to rectilinear dependence of //-methylformamide urine concen¬tration on DMF concentration in the air after adequate calculation for the suggested by us TLV value (10 mg/nr’), the BEI value in Poland should be 5 mg NMF/1 of urine. Considering high DMF skin absorption in the liquid and vapour form we suggest an additional determina¬tion with letters Sk. There are no bases for establishing a STEL value.

Słowa kluczowe

N,N-dimetyloformamid toksykokinetyka wartość NDS

N,N-dimetyloformamide toxicokinetics NDS

Wydawca

Centralny Instytut Ochrony Pracy - Państwowy Instytut Badawczy

Czasopismo

Podstawy i Metody Oceny Środowiska Pracy

Rocznik

2003

Tom

Nr 1 (35)

Strony

61--82

Opis fizyczny

Bibliogr. 73 poz., rys., tab.

Twórcy

autor

Sapota A.

Uniwersytet Medyczny w Łodzi Zakład Toksykologii 90-151 Łódź ni dr. J. Muszyńskiego 1

autor

Ligocka D.

Instytut Medycyny Pracy prof. dr. med. Jerzego Nofera 90-950 Łódź św. Teresy 8

Bibliografia

1. ACGIH, American Conference of Govermental Industrial Hygienists (1991) Documentation of the threshold limit values for substances in workroom air. American Conference of Govermental Industrial Hygienists, P.O. Box 1937, Cincinnati 45201.
2. Antoine J.L. i in. (1983) [W:] Bua-Stoffdossier. N,N-dimethylformamid. Stand 04/91. Toxicol. 26, 207-212.
3. Arimoto S. i in. (1982) a solvent effect on the mutagenicity of tryptophan-pyrolysate mutagens in the salmonella/mammalian microsome assay. Mutat. Res. 102; 105-112 [cyt. za IUCLID 1996].
4. Bainova A. (1985) Toxicological problems due to the action of chemical substances on the skin (dermatotoxicology) [cyt za EHC 114, 1991; IUCLID 1996].
5. Baker R.S, Bonin A.M. (1981) Study of 42 coded compounds with the salmonella/mammalian microsome assay. [W:] Evaluation of short-term tests for carcinogens. Report of the Intemational Collaborative Program. Prog. Mutat. Res. 1; 249-260.
6. Bames J.R., Ranta K.E. (1972) The metabolism of dimethylformamide and dimethylacetamide. Toxicol. Appl. Pharmacol. 23, 271-276 [cyt. za EHC 114, 1991].
7. BASF AG (1977) Abteilung Toxikologie, unveroeffent1ichte Untersuchung. (XXIII/402) [cyt. za IUCLID 1996].
8. Becci PJ., i in. (1983) Subschronic feeding study of N,N-dimethyl formamide in rats and mice. J Amer. Coli. Toxicol. 2 (6) 371-378. -
9. Brams A. i in. (1987) A comparative study, with 40 chemicals, of the efficiency of the Salmonella Assay and the sos chromotest (Kit procedure). Toxicol. Lett., 38:123-133.
10. Brooks TM., Dean B.l. (1981) Mutagenie activity of 42 coded compounds in the SalmonellalMicrosome assay with preincubation. [W:] Evaluation of short-term tests for carcinogens. Report of the International Collaborative Program. Prog. Mutat. Res. 1; 261-270.
11. Cai S.X. i in. (1992) Occupational dimethylformamide exposure. 3. Health effects of dimethylformamide after occupational exposure at low concentrations. Int. Arch. Environ. Health. 63,461-468.
12. Chen J.L. i in. (1988) Cancer incidence of workers exposed to dimethylformamide and/or acrylonitrile. J. Occup. Med. 30; 813-818 [cyt. za IUCLID 1996].
13. Clayton J. W. i in. (1963) The inhalation toxicity of dimethyl formamide (DMF). Amer. Ind. Hyg. Assoc. J. 24,144-154.
14. Cragin D.W, Lewis S.C; McKee R.H. (1990) A dominant lethal test of dimethylformamide environ mutagen.15 (Suppl. 17), abstr. 44.
15. Craig D.K. i in. (1984) Subchronic inhalation taxicity of DMF in rats and mice. Drug. Chem. Taxicol. 7, 551-571[cyt. za NTP 1992].
16. Craig D.K. i in. (1984) Subchronic inhalation taxicity of dimethylformamide in rats and mice. Drug. Chem.Taxicol., vol7, lSS 6, P551-71.
17. Cross H. i in. (1990) N-alkylformamides are metabolized to N-alky1carbamoylating species by hepatic microsomesfrom rodents and humans. Chem. Res. Taxicol. 3, 357-362 [cyt. za NTP 1992].
18. DFG (1995) Biological exposure values for occupational toxicants and carcinogens. Vol. 2,51-57.
19. Druckrey H. i in. (1967) Organotrope carcinogene wirkungen bei 65 verschiedenen N-nitroso-verbindungenan BD ratten Zeistschrift fur Krebsforschung 69, 103-201.
20. Du Pont de Nemours Co. Inc. (1970) Wilmington, DeI. USA: DMF Produet Information [W:] Henschler D.: MAK-Wertbegruendung Dimethylformamid, Weinheim, (1990).
21. Eben A., Kimmerle G. (1976) Metabolism studies in N,N-dimethylformamide. III. Studies on the influence of ethanol in person s and laboratory animals. lnt. Arch. Occup. Environ. Health 36; 243-265 [cyt. za EnvironmentalHealth Criteria 114, WHO, Geneva, 1991].
22. Elvoara E., Marselos M., Vaino H. (1983) N,N-Dimethyl formami de induced effects on hepatic and renal xenobiotic enzymes with emphasis on aldelyde metabolism in the rat. Acta Pharmacol. Taxicol. 53 159- 165.
23. Germanova A.L i in. (1979) Adaption after continuous and intermittend exposure to dimethylformamide. [W:] Toksikologia novyh promyshlennyh himicheskih veshchtestv. Moskau 15, 69-76 [cyt. za IUCLID 1996].
24. Hellwig J. i in. (1991) Investigation on the prenatal taxicity of N,N-dimethylformamide (DMF) in maice, rats and rabbits [cyt. za EHC 114, 1991].
25. Hurtt M.E. i in. (1992) 13-week inhalation taxicity study of dimethylformamide (DMF) in cynomolgus monkeys. Fundam, Appl. Taxicol., voI. 18, lSS 4, P596-601.
26. HSDB (1996).
27. IARC(1989) Monographs on the evaluation of the corcinogenic risk of chemicals to man. Geneva, WHO, 47,171-197.
28. IUCLID-CD (1996) Ver. 1.0, International Uniform Chemical Information Database. Ed. 1.
29. Jagannath D.R., Vultaggio D.M., Brusick D.J. (1981) Genetic activity of 42 Coded Compounds in the :r. mitotic gene conversion assay using Saccharomyces cerevisiae strain D4. [W:] Evaluation of short-term tests for carcinogens. Report of the International Collaborative Program. Prog. Mutat. Res. 1; 456-467.
30. Jotz M.M., Mitchell A.D. (1981) Effects of 20 coded chemicals on the forward mutation frequency at the thymidine kinase locus. [W:] L5178y Mouse Lymphoma Cells. [W:] Evaluation of short-term tests for carcinogens. Report of the International Collaborative Program. Prog. Mutat. Res. 1; 580-593.
31. Kada T. (1981) Dna-darnaging activity of 42 coded compounds in the rec-assay. [W:] Evaluation of shortterm tests for carcinogens. Report of the International Collaborative Program. Prog. Mutat. Res. l; 175- 182.
32. Kawai T. i in. (1992) Occupational dimethylformamide exposure 2. Monomethylformamide excretion in urine after occupational dimethylformamide exposure. Int. Arch. Occup. Environ. Health. 63,7,455-460.
33. Kennedy G.L.Jr., Sherman H. (1986) Acute and subchronic taxicity of dimethylformamide and dimethylacetamide following various routes of administration. Drug. Chem. Taxicol., vol. 9, lSS 2, P147- 70
34. Kinimerle G., Eken A. (1975) Metabolism studies of N,N-dimethyl formamide. l studies in rats and dogs. Int. Arch. Arbeitsmed. 34, 109-126.
35. Kimmerle G., Machemer L (1975) Studies with N,N-dimethylformamide for embryotoxic and teratogenie effects on rats after dynamie inhalation. Int. Arch. Arbeitsmed. 34, 167-175 [cyt. za EHC 114, 1991].
36. Kiss G. (1979) Study of the irritative action of dimethylformamide [cyt. za EHC 114, 1991].
37.. Kommineni C. (1973) Pathologic studies of aflatoxin fractions and dimethylformamide in MRC rats Diss. Abstr. Int. B 34291 [cyt. za IUCLID, 1996].
38. Krivanek N.D., Mclaughlin M., Fayerweather WE. (1978) Monomethylformamide levels in human urine after repetitive exposure to dimethylformamide vapour. l. Occup. Med., 20, 179-182 [cyt. Za Environmental Health Criteria 114, WHO, Geneva 1991].
39. Lauwerys R.R. i in. (1980) Biological surveillance of workers exposed to dimethylformamide and the influence of skin protection on its percutaneous absorption. Int. Arch. Occup. Environ. Health 45, 189-203 [cyt. za Environmental Health Criteria 114, WHO, Geneva 1991].
40. Llewellyn G.C, Hastings WC, Kimbrough T.D. (1974) The effects of dimethyl formamide on female Mongolian gerbils Meriones unguliculatus. BulI. Environ. Contam. ToxicoI. 11 467-473 [cyt. za NTP, 1992].
41 Lundberg I. i in. (1981) Some observation on dimethylformamide hepatotoxicity. Toxicology 22, 1-7 [cyt. za NTP 1992].
42. Malley LA. i in. (1994) Chronic toxicity/oncogenieity with dimethylformamide in rats and mice. Fund. AppI. ToxicoI. 23, 268-279. .
43. Massmann W. (1956) Toxicologieal investigations on dimethy formamide. Brit. J. Ind. Med. 13 51-54 [cyt. za NTP 1992; IUCLID 1996].
44. Mathew T. i in. (1980) Hepatotoxicity of dimethylformamide and dimethylsulfoxide at and above the levels used in some aflatoxin studies. Lab. Invest. 42, 257-262 [cyt. za NTP 1992].
45. McGregor D. i in. (1988) Responses ofL5178Y tk+/tk- mouse lymphoma cell forward mutationassay: III. 72 coded chemicals. Environ. Molec. Mutagen. 12,85-154 [cyt. za IUCLID 1996].
46. McQueen C.A., Kreiser D.M., Williams G.M. (1983) The hepatocyte primary Culture/dna repair assay using mouse or hamster hepatocytes. Environ. Mutagen. 5; 1-8 [cyt. za IUCLID 1996].
47. Mohn G.R. i in. (1981) Studies on the mutagenic activity of 20 coded compounds in liquid tests using the multipurpose strain Escherichia coli K-12/343/113 and derivatives [W:] Evaluation of short-term tests for carcinogens. Report of the International Collaborative Program. Prog. Mutat. Res. l; 396-413 [cyt. Za IUCLID 1996].
48. Mortelmans K. i in. (1986) Salmonella mutagenicity Tests. 2. Results from the testing of 270 chemicals. Environ. Mutagen. 8 (Suppl 7); 1-119 [cyt. za IUCLID 1996].
49. Mraz: J. i in. (1989) Differences between rodents and humans in the metabolic toxication of N,Ndimethylformamide. ToxicoI. AppI. PharmacoI. 98 (3), 507-516.
50. Mraz: L, Nohova H. (1992) Absorption, metabolism and elimination of N,N-dimethylformamide in humans [cyt. za DFG 1995].
51. Natarajan A. T. i in. (1981) Mutagenic activity of 20 coded compounds in chromosome aberrations/sister chromatid exchanges assay using chinese hamster ovary (cho) cells. [W:] Evaluation of short-term tests for carcinogens. Report of the International Collaborative Program. Prog. Mutat. Res. l; 551-559 [cyt. Za IUCLID 1996].
52. NTP (1992) TR22 Toxieity studies of N,N-dimethylformamide CAS NO 68-12-2 administered by inhalation to F344/n rats and B6C3Fl mice. US National Toxicology Programme DHSS.
53. O’Berg M. T. i in. (1985) Epidemiologic study of workers exposed to acrylonitryle, an update. J. Occup. Med.27: 855-840 [cyt. za IUCLID 1996].
54. PotterH.P. (1973) Dimethylformamide induced abdominal pain and liver injury [cyt. za EHC 114, 1991].
55. Redlich C.A. i in. (1990) Clinical and pathological characteristics of hepatotoxicity associates with occupational exposure to dimethylformamide. Gastroent. 99, 748-757 [cyt. za NTP 1992].
56. Robinson D.E., Mitchell A.D. (1981) Unscheduled DNA synthesis response of human fibroblasts. Wi-38 Cells, To 20 Coded Chemicals. [W:] Evaluation of short-term tests for carcinogens: Report of the International Collaborative Program. Prog. Mutat. Res. 1,517-527 [cyt. za ruCLID 1996].
57. RTECS, Registry of Toxic Effects of Chemical Substances (1997) [komputerowa baza danych] The Nationl Institute for Occupational Safety and Health.
58. Salamone M.F., Heddle l.A., Kat: M. (1981) Mutagenic activity of 41 compounds in the in vivo rnicronucleus assay. [W:] Evaluation of short-term tests for carcinogens: Report of The International Collaborative Program. Prog. Mutat. Res. 1,686-697 [cyt. za ruCLID 1996].
59. Scailteur J.P. i in. (1981) Relationships between dimethylformamide metabolism and toxicity. [cyt. Za NTP 1992].
60. Scailteur J.P. Lauwerys R.R. (1984) In vivo metabolism of dimethylformamide and relationship to toxicity in the male rat. Arch. Toxicol. 56, 87-9 l.
61 Sharp D.C., Parry 1.M. (1981) Induction of mitotie gene conversion by 41 coded compounds using the yeast culture Jdl [W:] Evaluation of short-term tests for carcinogens. Report of the International Collaborative Program. Prog. Mutat. Res. 1,491-501 [cyt. za IUCLID 1996].
62. Sheveleva G.A. i in. (1979) Study of the embryotropic, mutagenic and gonadotropic effects of dirnethylformamide after inhibition exposure [cyt. za EHC 114, 1991].
63. Tweats D.J. (1981) Activity of 42 coded compounds in a differential killing test using Escherichia coli strains Wp2, Wp67 (Uvra Pola), and Cm871 (Uvra Lexa Reca). [W:] Evaluation of short-term tests for carcinogens: report of the International Collaborative Program. Prog. Mutat. Res. 1; 199-209 [cyt. Za IUCLID 1996].
64. Slatter 1.G. i in. (1991) Biotransformation of methyl isocyanate in the rat. Evidence for glutathione conjugation as a major pathway of metabolism and implications for isocyanate-mediated toxicities. Chem. Res. Toxicol. 4,157-161 [cyt. za NTP 1992].
65. Tanaka K.I. (1971) Toxicity of dimethyl formamide (DMF) to the young female rat. Int. Arch. Arbecksmed 28 98-105.
66. Tolot F. i in. (1968) Intoxication par la dimethylformamide. Arch. MaI. Prof. 29, 714-717.
67. Trueman R. W. (1981) Activity of 42 coded compounds in the Salmonella reverse mutation test. [W:] Evaluation of short-term tests for carcinogens: report of the International Collaborative Program. Prog. Mutat. Res. 1,343-350 [cyt. za IUCLID 1996].
68. Venitt S; Crofton-Sleigh C. (1981) Mutagenicity of 42 coded compounds in a bacterial assay using Escherichia coli and Salmonella typhimurium. [W:] Evaluation of short-term tests for carcinogens: Report ofthe International Collaborative Program. Prog. Mutat. Res. 1,351-360 [cyt. za IUCLID 1996].
69. Walrath l. i in. (1989) A case-control study of cancer among Du Pont employees with potential for exposure to dimehtylformamide. J. Occup. Med. 31.432-438.
70. Wang J.D. i in. (1991) Dimethylformamide induced liver damage among synthetic leather workers. Arch. Environ. Health. 46,161-166.
71. Wiles J.S., Narcisse J.K. Jr. (1971) The acute toxicity of dimethylformamides in several animaI stpecies. Am. Ind. Hyg. Assoc. J. 32: 539-545 [cyt. za EHC 114 1991].
72. William S.G.M., Mori H., McQueen CA. (1989) Structure activity relationships in the rat hepatocyte DNA repair test for 300 chemicals Mutat Res 221 263-286 [cyt. za IUCLID 1996].
73. Yonemoto J., Suzuki S. (1980) Relation of exposure to dimethylformamide vapour and the metabolite, methylformarnide, in urine of workers. lnt. Arch. Occup. Environ. Health. 46; 159-165 [cyt. za EHC 114 1991].

Typ dokumentu

Bibliografia

Identyfikator YADDA

bwmeta1.element.baztech-6bccec94-1629-429d-8e4f-a8b73b31780a