Karbaminian etylu : dokumentacja proponowanych dopuszczalnych wielkości narażenia zawodowego

• Autorzy: Szymańska J. , Bruchajzer E. , Frydrych B.

Warianty tytułu

EN

Ethyl carbamate : documentation of proposed values of occupational exposure limits (OELs)

• Języki publikacji: PL

Abstrakty

PL

Karbaminian etylu (uretan, nr CAS 51-79-6) jest ciałem stałym, bez zapachu, dobrze rozpuszczalnym w wodzie i rozpuszczalnikach organicznych. W środowisku występuje jako naturalny produkt powstający podczas fermentacji alkoholowej pokarmów i napojów zawierających alkohol. Są one głównym źródłem narażenia populacji generalnej. Techniczne preparaty karbaminianu etylu, otrzymywane na drodze syntezy organicznej, uzyskują wysoką czystość chemiczną. Karbaminian etylu jest stosowany głównie jako półprodukt w syntezie organicznej (m.in. do wytwarzania żywic aminowych), a jego wodne roztwory jako rozpuszczalniki: pestycydów, fumigantów, kosmetyków oraz środków farmaceutycznych stosowanych w weterynarii. Narażenie zawodowe w Polsce na karbaminiany etylu (drogą inhalacyjną i/lub przez kontakt ze skórą) występuje w kilku zakładach produkujących oraz stosujących go i obejmuje kilkadziesiąt osób rocznie. U ludzi nie stwierdzono zatruć ostrych karbaminianom etylu. W dostępnym piśmiennictwie nie ma informacji na temat jego toksyczności przewlekłej u ludzi narażonych zawodowo oraz danych epidemiologicznych. Wartość LD50 dla karbaminianu etylu podanego dożołądkowo szczurom wynosi 1810 mg/kg mc. W zatruciu ostrym zwierząt obserwowano działanie znieczulające i nasenne (wykorzystywane w weterynarii) oraz narkotyczne związku. Karbaminian etylu nie wykazywał działania drażniącego i uczulającego na zwierzęta. Podprzewlekłe narażenie szczurów i myszy na karbaminian etylu podawany w wodzie do picia (o stężeniach 110 ÷ 10 000 ppm, czyli w dawkach 8 ÷ 622 mg/kg mc./dzień dla szczurów oraz 18,3 ÷ 1667 mg/kg mc./dzień dla myszy) spowodowało, zależne od wielkości narażenia, działanie immunosupresyjne. U zwierząt obserwowano także nefropatię i kardiomiopatię, a u samców również uszkodzenie wątroby. Oprócz działania immunotoksycznego u myszy stwierdzono zmiany rozrostowe w układzie rozrodczym i płucach. Po 2-letnim narażeniu myszy na karbaminian etylu w wodzie do picia (o stężeniach 10 ÷ 90 ppm, co odpowiadało dawce 1,17 ÷ 12 mg/kg mc./dzień) zaobserwowano skutki toksycznego działania związku na: wątrobę, serce, płuca oraz macicę. Karbaminian etylu o stężeniach w wodzie wynoszących 30 lub 90 ppm (4 lub 12 mg/kg mc./ dzień) spowodował zwiększoną liczbę padnięć zwierząt. Na podstawie wyników standardowych testów, karbaminian etylu został sklasyfi kowany jako substancja o słabym działaniu mutagennym i genotoksycznym. Wyniki podprzewlekłych i przewlekłych badań nad toksycznością karbaminianu etylu podawanego w różny sposób i różnym gatunkom zwierząt laboratoryjnych, jednoznacznie wskazują na jego rakotwórcze działanie. Związek ten powodował: nowotwory płuc, wątroby, naczyń krwionośnych i skóry, a także chłoniaki i białaczki. Karbaminian etylu wpływa niekorzystnie na płodność. Stwierdzono jego działanie: embriotoksyczne, fetotoksyczne oraz teratogennie. Karbaminian etylu wchłania się do organizmu bardzo szybko i całkowicie po narażeniu w różny sposób i natychmiast podlega dystrybucji w organizmie. Większość karbaminianu etylu (ponad 90%) jest metabolizowana do: etanolu, amoniaku i ditlenku węgla, który jest wydalany z powietrzem wydychanym. Około 5% karbaminiany etylu podlega przemianom przy udziale enzymu CYP 2E1 do karbaminianu winylu, a następnie epoksytlenku karbaminianu winylu, który – przez wiązanie z zasadami DNA i RNA – jest odpowiedzialny za genotoksyczne i rakotwórcze działanie związku. Wydalanie metabolitów z moczem i kałem jest niewielkie i wynosi odpowiednio: 2 ÷ 8% oraz 0,3 ÷ 1%. Karbaminian etylu został zakwalifi kowany przez IARC (2010) do grupy 2.A, czyli czynników prawdopodobnie rakotwórczych dla ludzi. Unia Europejska zaklasyfi kowała go do grupy 1.B, czyli substancji, które mogą powodować raka. W żadnym państwie nie ustalono wartości najwyższego dopuszczalnego stężenia (NDS) dla karbaminianu etylu. W SCOEL dla karbaminiany etylu nie ustalono wartości OEL, gdyż związek zaliczono do grupy A rakotwórczości, tj. do genotoksycznych kancerogenów bez możliwości ustalenia wartości dopuszczalnej na podstawie skutku zdrowotnego. Karbaminian etylu wywołuje nowotwory złośliwe u szczurów i myszy w wielu narządach docelowych, po podaniu go w różny sposób. Karbaminian etylu jest substancją: toksyczną, mutagenną i klastogenną, zwłaszcza w obecności układu z aktywacją metaboliczną.

EN

Ethyl carbamate (urethane, CAS 51-79-6) is a solid, odorless and soluble in water and organic solvents. In an environment it occurs as a natural product produced during alcoholic fermentation of foods and beverages containing alcohol. They could be the main source of exposure of the general population. The technical formulations of ethyl carbamate, obtained through organic synthesis, achieve a high chemical purity. Ethyl carbamate is mainly used as an intermediate in organic synthesis (including manufacturing amino resin), and its aqueous solutions as solvents for pesticides, fumigants, cosmetics and pharmaceuticals used in veterinary medicine. In Poland, occupational exposure to ethyl carbamate (inhalation and/or skin contact) occurs in several plants producing and using it, and many people are exposed every year. In humans, no acute poisoning with ethyl carbamate was noticed. There is no information in the available literature about epidemiological data and chronic toxicity in humans occupationally exposed. The LD50 value of ethyl carbamate given intragastrically to rats is 1810 mg/kg of body weight. In acute intoxication in animals, narcosis and sedation (used in veterinary medicine) and narcotic effects were observed. Ethyl carbamate did not show irritation and sensitization for animals. Subchronic exposure of rats and mice on ethyl carbamate administered in drinking water (with concentrations of 110 — 10.000 ppm, or in doses of 8 — 622 mg/kg/day for rats and 18.3 — 1667 mg/kg/ day for mice) resulted in, depending on the size of the exposure, immunosuppressive activity. In animals, observed nephropathy and cardiomyopathy were also, and in males also damages to liver were observed. In addition to the immunotoxicity in mice, proliferation changes in the genital tract and in the lungs were observed . After 2-year exposure of mice for ethyl carbamate in drinking water (with concentrations of 10 to 90 ppm, corresponding to a dose of 1.17 to 12 mg/kg/day) the toxic effects for liver, heart, lung, and uterus were observed. Ethyl carbamate in concentration in water 30 or 90 ppm (4 or 12 mg/kg /day) caused an increasing number of deaths of animals. Based on the results of standardized tests, ethyl carbamate is classifi ed as a substance with a weak mutagenic and genotoxic effects. The results of subchronic and chronic toxicity studies of ethyl carbamate administered in various ways and various species of laboratory animals show its carcinogenic effect. The compound was found as a cause of cancer of lung, liver, blood vessels and skin, and lymphomas and leukemia. Ethyl carbamate cause a negative impact on fertility. It has embryotoxic, fetotoxic and teratogenic effects. Ethyl carbamate is absorbed into an organism rapidly and completely after exposure in different ways and is immediately subjected to distribution in a body. Majority of ethyl carbamate (90%) is metabolized to ethanol, ammonia and carbon dioxide, which is excreted in the expired air. About 5% of ethyl carbamate is transformed by CYP2E1 to the vinyl carbamate and then to vinyl carbamate epoxide which, by binding to DNA and RNA, is responsible for the genotoxic and carcinogenic effects of the compound. The excretion of metabolites in the urine and faeces is low and amounts 2 — 8% and 0.3 — 1%, respectively. Ethyl carbamate classifi ed by IARC (2010) as 2.A group — agents probably carcinogenic to humans. The European Union classifi ed it as 1.Bv group — substances that can cause cancer. The maximum allowable concentration (MAC) for ethyl carbamate was not set in any country. SCOEL did not established OEL values, since the compound is in Group A carcinogenicity, i.e., genotoxic carcinogens with no establish limit values based on health effect. Ethyl carbamate causes the cancer in rats and mice in many target organs following administration to a differently ways. Ethyl carbamate is toxic, mutagenic or clastogenic, especially in the presence of a metabolic activation.

Słowa kluczowe

PL

karbaminiany etylu; uretan; toksyczność; narażenie zawodowe; NDS

EN

ethyl carbamate; urethane; toxicity; occupational exposure; MAC (TWA)

• Wydawca: Centralny Instytut Ochrony Pracy - Państwowy Instytut Badawczy
• Czasopismo: Podstawy i Metody Oceny Środowiska Pracy
• Rocznik: 2015
• Tom: Nr 3 (85)
• Strony: 67--106
• Opis fizyczny: Bibliogr. 93 poz., rys., tab.

Twórcy

autor

Szymańska J.

• Uniwersytet Medyczny w Łodzi ul. J. Muszyńskiego 1 90-151 Łódź

autor

Bruchajzer E.

• Uniwersytet Medyczny w Łodzi ul. J. Muszyńskiego 1 90-151 Łódź

autor

Frydrych B.

• Uniwersytet Medyczny w Łodzi ul. J. Muszyńskiego 1 90-151 Łódź

Bibliografia

• 1.Abraham S.K., Singh S.P., Kesavan P.C. (1998) In vivo antigenotoxic effects of dietary agents and beverage co-administered with urethane: assessment of the role of glutathione S-transferase activity. Mutat. Res. 413, 103–110 [cyt. za IARC 2010].
• 2.Barbin A. (2000) Etheno-adduct-forming chemicals: from mutagenicity testing to tumor mutation spectra. Mutat. Res. 462, 55–69.
• 3.Bolt H.M. (2005) Vinyl chloride – a classical industrial toxicant of New interest. Crit. Rev. Toxicol. 35, 307–323, [cyt. za SCOEL 2012 streszczenie].
• 4.Boyland E., Nery R. (1965) The metabolism of urethane and related compounds. Biochem. J. 94, 198– 208. streszczenie [cyt. za Choy i in. 1995].
• 5.Burkhard W., Fritz-Niggli H. (1987) Antiteratogenic and anticarcinogenic effects of X-rays in urethane-treated NMR1 mice. Int. J Radiat. Biol. relat. Stud. Phys. Chem. Med. 51, 1031–1039
• 6.Cadranel J.F., Legandre C., Desaint B., Delamarre N., Florent C., Levy V.G. (1993) Liver disease from surreptitious administration of urethane. J. Clin. Gastroenterol. 17(1), 52–56.
• 7.Carlson G.P. (1994) The effect of inducers and inhibitors of urethane metabolism on its in vitro and in vivo metabolism in rats. Cancer Lett. 87, 145–150.
• 8.Centralny Rejestr Danych o Narażeniu na Substancje, Preparaty, Czynniki i Procesy Technologiczne o Działaniu Rakotwórczym lub Mutagennym. Korzystano z bazy GESTIS International limit value for chemical agent, Occupational exposure limits (OELs). Guide Occupational Values 2012, informacje tabelaryczne uzyskane z Biura ds. NDS, IMP, Łódź [http://www.dguv.de/ifa/en/gestis/limit_values. jsp].
• 9.Cha S.W., Lee H.J., Cho M.H., Lee M.H., Koh W.S., Han S., Kim J., Lee E., Nam D., Jeong T.C. (2001) Role of corticosterone in ethyl carbamate – induced mmunosuppression in famale BALB/c mice. Toxicol. Lett. 119, 173–181 [cyt. za IARC 2010].
• 10.Cha S.W., Gu H.K., Lee K.P. Lee M.H., Han S.S., Joeng T.C. (2000) Immunotoxicity of ethyl carbamate in female BALB/c mice: role of esterase and cytochrome P450. Toxicol. Lett. 115, 173–181.
• 11.Chieco-Bianchi L., De Benedictis G., Tridente G., Fiore-Donati L. (1963) Infl uence: Of age on susceptibility to licer carcinogenesis and skin initiating action by urethane in swiss mice. Br. J. Cancer 17, 672–680.
• 12.Choy W.N., Black W., Mandakas G., Mirro E.J., Black H.E. (1995) A pharmacokinetic study of ethanol inhibition of micronuclei induction by urethane in mouse bone marrow erythrocytes. Mutat. Res. 341, 255–263.
• 13.Dahl G.A., Miller E.C., Miller J.A. (1980) Comparative carcinogenicities and mutagenicities of vinyl carbamate, ethyl carbamate, and ethyl N-hydroxycarbamate. Cancer. Res. 40, 1194–1203.
• 14.Dahl G.A., Miller J.A., Miller E.C. (1978) Vinyl carbamate as a promutagen and a more carcinogenic analog of ethyl carbamate. Cancer. Res. 38, 3793–3804.
• 15.DECOS (2000) Dutch Expert Committee on Occupational Standards, a Committee of the Health Council of the Netherlands: Urethane (ethyl carbamate) – health based calculated occupational cancer risk values. Health Council of the Netherlands. The Hague; publication no. 2000/12OSH.
• 16.Della Porta G., Capitano J., Strambio de Castillia P. (1963) Studies on leukemogenesis in karbaminian etylu treated mice. Acta Un. Int. Cancer. 29, 783–785 [cyt. za Świdwińska-Gajewska i in. 2007].
• 17.Di Paolo J.A., Elis J. (1967) The comparison of teratogenic and carcinogenic effects of some carbamate compounds. Cancer Res. 27, 1696–1701 [cyt. za IARC 2010].
• 18.Doell R.G., Carnes H.W. (1962) Urethan induction of thymic lymphoma in C57bl mice. Nature 194, 588–589.
• 19.Dragani T.A., Sozzi G., Della Porta G. (1984) Comparison of urethane-induced sister-chromatid exchanges in various murine strains, and the effect of enzyme inducers. Mutat. Res. 121, 233–239.
• 20.EFSA (2007) European Food Safety Authority. Ethyl carbamate and hydrocyanic acid in food and beverages [1] – Scientifi c opinion of the Panel on Contaminants. The EFSA Journal 551, 1- 44 [cyt. za SCOEL 2012; http://www.efsa.europa.eu/EFSA/ efsa_locate-1178620753812_1178655060600.htm].
• 21.Ferm V.H., Hanover N.H. (1966) Severe developmental malformations. Malformations induced by urethane and hydroxyurea in the hamster. Arch. Pathol. 81, 174–177 [cyt. za IARC 2010].
• 22.Field K.J., Lang C.M. (1988) Hazards of urethane (ethyl carbamate): a review of the literature. Lab. Anim. 22(3), 255–262.
• 23.Fiore-Donati L. (1961) Leukaemogenesis by than in newborn Swiss mice. Nature 190, 278–279.
• 24.Fiore-Donati L., De Benedictis G., Chieco-Bianchi L., Maiorano G. (1962) Leukaemogenic activity of urathan in Swiss and AKR mice. Acta Un. Int. Cancer 18, 134–139.
• 25.Forkert P.G. (2010) Mechanisms of lung tumorigenesis by ethyl carbamate and vinyl carbamate. Drug Metab. Rev. 42(2), 355–378.
• 26.Fossa A.A., Baird W.M., Carlson G.P. (1985) Distribution of urethane and its binding to DNA, RNA and protein in Sencar and BALB/C mice following oral and dermal administration. J. Toxicol. Environ. Health 15, 635–654 [cyt. za Nomeir i in. 1989, streszczenie].
• 27.Frohlich A., Wurgler F.E. (1990) Genotoxicity of etyl carbamate in the Drosophila wing spot test: dependence on genotype-controlled metabolic capacity. Mutat. Res. 244, 201-208. [cyt. za Choy i in. 1995, streszczenie].
• 28.GESTIS-Soffdatenbank (2013) Urethane. IFA Institut für Arbeitsschutz der Deutschen Gezetzlichen Unfaliversicherung.
• 29.Hagmar L., Bellander T., Englander V., Ranstam J., Attwell R., Skerfving S. (1986) mortality and cancer morbidity among workers in a chemical factory. Scand. J. Work Environ. Health 12, 545–551.
• 30.Hirschboeck J.S., Lindsert M.C., Chase J., Calvy T.L. (1948) Effects of urethane in the treatment of leukemia and metastatic malignant tumors. J. Am. Med. Assoc. 136, 90–95 [cyt. za IARC 2010].
• 31.Hoffl er U., Dixon D., Peddada S., Ghanayem B.I. (2005): Inhibition of urethane-induced genotoxicity and cell proliferation in CYP2E1-null mice. Mutat. Res. 572, 58–72.
• 32.Hoffl er U., El-Masri H.A., Ghanayem B.I. (2003) Cytochrome P-450 2E1 (CYP 2E1) is the principal enzyme responsible for urethane metabolism: comparative studies using CYP 2E1-null and wild-type mice. J. Pharmacol. Exper. Ther. 305(2), 557–564.
• 33.Hoffl er U., Ghanayem B.I. (2005) Increased bioaccumulation of urethane in CYP 2E1-/- versus CYP 2E1+/+ mice. Drug Metab. Dispos. 33, 1144–1150.
• 34.Hollander C.F., Bentvelzen P. (1968) Enhancementof urethan induction of hepatomas in mice by prior partial hepatectomy. J. Nat. Cancer Inst. 41, 1303- 1306 [cyt. za Świdwińska-Gajewska i in. 2007].
• 35.HSDB (2014) Hazardous Substances Data Bank [komputerowa baza danych].
• 36.IARC (1974) Urethane. [W:] Monographs on the evaluation of carcinogenic risk of chemicals to man: some anti-thyroid and related substances – nitrofurans and individual chemicals, Vol. 7, 111-140, International Agency for Research on Cancer, Lyon, France.
• 37.IARC (2010) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Alcohol consumption and ethyl carbamate. Vol. 96, 1281–1424.
• 38.ICSC (2010) International Chemical Safety Cards ICSC:0314. NIOSH National Institute for Occupational safety and health [Komputerowa baza danych].
• 39.Ida N., Oda N., Yoda T., Kiyama T. (1962) Urethan (ethyl carbamate) as a multipotential carcinogen in BALB/C, ZB and DB female mice. Acta Med. Okayama 16, 253–264.
• 40.Inai K., Arihiro K., Takeshima Y., Yonchara S., Tachiyama Y., Khatun N., Nishisaka T. (1991) Quantitative risk assessment of carcinogenicity of urethane (ethyl carbamate) on the basis of long-term oral administration to B6C3F1 mice. Jpn. J. Cancer Res. 82, 380–385.
• 41.Ito T., Hoshino T., Sawauchi K. (1965) Further observation of urethan-induced thymic lymphoma in mice. Z. Krebsforsch 66, 552–558.
• 42.Kemper R.A., Myers S.R., Hurst H.E. (1995) Detoxifi cation of vinyl carbamate epoxide by glutathione: evidence for participation of glutathione S-transferases in metabolism of ethyl carbamate. Toxicol. Appl. Pharmacol. 135, 110–118.
• 43.Kommineni V.R.Ch., Greenblatt M., Mihailovich N., Vesselinovitch S.D. (1970) The signifi cance of perinatal age periods and the dose of urethan on the tumor profi le in the MRC Rat. Cancer Res. 30, 2552–2555.
• 44.Levin S.V. (1956) Infl uence of narcosis on sorption properties of cerebral cortical cells. [W:] Bulletin of Experimental Biology and Medicine, 1956, Springer Verlag, Heidelberg, Germany [cyt. za SCOEL 2012].
• 45.Luster M.I., Dean J.H., Boorman G.A., Dieter M.P., Hayes H.T. (1982) Immune functions in methyl and ethyl carbamate treated mice. Clin. Exp. Immunol. 50, 223–230.
• 46.Matsuyama M., Suzuki H., Nakamura T. (1969) Carcinogenesis in dd-I mice injected during suckling period with urethane, nitrogen mistard N-oxide, and nitroso-urethane. Br. J. Cancer 23, 167–171.
• 47.Matsuyama M., Suzuki H. (1970) Adrenal tumors and endocrine lesions induced in Syrian hamsters by urethane injected during suckling period. Br. J. Cancer 24, 312–317 [cyt. Za IARC 2010].
• 48.Merck Index (2000) [Red.] S. Budavari. Boca Raton, Fl, Chapman&Hall, 12th ed.
• 49.Merck Index (2001) [Red.] S. Budavari. Boca Raton, Fl, Chapman&Hall, 13th ed.
• 50.Miller Y.E. Dwyer-Nield L.D., Keith R.L., Franklin W.A., Malkinson A.M. (2003) Induction of a high incidence of lung tumors in C57BL/6 mice with multiple ethyl carbamate injections. Cancer Let. 198, 139–144.
• 51.Miller J.A. (1991) The need for epidemiologal studies of the medical exposure of Japonese patients to the carcinogen ethyl carbamate (urethane) from 1950 to 1975. Jpn. J. Cancer Res. 82, 1323–1324.
• 52.Nakane K., Kameyama Y. (1986) Effect of maternal urethane administration on the manifestation of cleft lip and palate in CL/Fr mice. J. Craniofac. Genet. Dev. Biol. Suppl. 2, 109–112.
• 53.Nettleship A., Henshaw P.S., Meyer H.L. (1943) Induction of pulmonary tumors in mice with ethyl carbamate (urethane). J. Nat. Cancer Inst. 4, 309–319, [cyt. za Świdwińska-Gajewska i in. 2007].
• 54.Nomeir A.A., Ioannou Y.M., Sanders J.M., Matthews H.B. (1989) Comparative metabolism and of ethyl carbamate (urethane) in male Fisher 344 rats and male B6C3F1 mice. Toxicol. Appl. Pharmacol. 97, 203–215.
• 55. Nomura T., Hayashi T., Masuyama T., Tanaka S., Nakajima H., Kurokawa N., Isa Y. (1990) Carcino-genicity of sublimed urethane in mice through the respiratory tract. Jpn. J. Cancer Res. 81, 742–746.
• 56. Nomura T. (1975a) Urethane (ethyl carbamate) as a cosolvent of drugs commonly used parenterally in humans. Cancer Res. 35, 2895–2899 [cyt. za Miller 1991].
• 57.Nomura T. (1975b) Letter: Transmission of tumors and malformations to the next generation of mice subsequent to urethan treatment. Cancer. Res. 35, 264–266.
• 58.Nomura T. (1988) X-Ray-and chemically induced germ-line mutation causing phenotypical anomalies in mice. Mutat. Res. 198, 309-320.
• 59.NTP (1996) Technical report on toxicity studies of urethane in drinking water and urethane in 5% ethanol administered to F344/N rats and B6C3F1 mice. Toxicity Report Series, Number 52, NIH Publication 96-3937, March 1996, United States Department of Health and Human Services, Public Health Service, National Institutes of Health.
• 60.NTP (2004) Technical report on toxicology and carcinogenesis studies of urethane, ethanol, and urethane/ethanol in B6C3F1 mice (drinking water studies). Technical Report Series, Number 510, NIH Publication 04-4444, August 2004, United States Department of Health and Human Services, Public Health Service, National Institutes of Health.
• 61.Ough C.S. (1976) Ethyl carbamate in fermented beverages and foods. I. Naturally occurring ethyl carbamate. Agric. Food Chem. 24, 323–328 [cyt. Za Miller 1991].
• 62.Park K-K., Liem A., Stewart B.C., Miller J.A. (1993) Vinyl carbamate epoxide, a major strong electrophilic, mutagenic and carcinogenic metabolite of vinyl carbamate and ethyl carbamate (urethane). Carcinogenesis 14, 441–450.
• 63.Paterson E., Haddow A., Thomas I.A., Watkinson J.M. (1946) Leukaemia treated with urethane compared with deep X-Ray therapy. Lancet 247, 677– 683 [cyt. za IARC 2010].
• 64.Pietra G., Rappaport M.D., Shubik P., Phil D. (1961) The effects of carcinogenic chemicals in newborn mice. Cancer 14, 308–317.
• 65.Pietra G., Shubik P. (1960) Induction of melanotic tumors in the Syrian golden hamster after administration of ethyl carbamate. J. Natl. Cancer Inst. 25, 627–630.
• 66.Port R., Schmahl D., Wahrendorf J. (1976) Some examples of dose-response studies in chemical carcinogenesis. Oncology 33(2), 6–71.
• 67.Roe F.J.C., Millican D., Mallett J.M. (1963) Induction of melanotic lesions of the iris in rats by urethane goven during the neonatal period. Nature, 199, 1201–1202.
• 68.Russell L.B., Hunsicker P.R., Oakberg E.F. Cummings C.C., Schmoyer R.L. (1987) Tests for urethane induction of germ-cell mutations and germ-cell killing in the mouse. Mutat. Res. 188, 335–342.
• 69.Salmon A.G., Zeise L. (1991) Risk of carcinogenesis from urethane exposure, Boca raton, FL, CRC Press [cyt. za IARC 2010; NTP 1996].
• 70.Schlatter J., Lutz W.K. (1990) The carcinogenic potential of ethyl carbamate (urethane): risk assessment at human dietary exposure levels. Food Chem. Toxicol. 28, 205–211.
• 71.Schmähl D., Port R., Wahrendorf J. (1977) A dose- -response study on urethane carcinogenesis in rats and mice. Int. J. Cancer 19, 77–80.
• 72.SCOEL (2012) Recommendation from the Scientifi c Committee on Occupational Exposure Limits for ethyl carbamate (urethane) SCOEL/SUM/172, March 2012.
• 73.Sharova L.V., Sharov A.A., Sura P. Gogal R.M., Smith B.J., Holladay S.D. (2003) Maternal immune stimulation reduces both placental morphologic damage and down-regulated placental growth-factor and cell cycle gene expression caused by urethane: are these events related to reduced teratogenesis? Int. Immunopharmacol. 3, 945–955.
• 74. Sinclair J.G. (1950) A specific transplacental effect of urethane in mice. Tex. Rep. Biol. Med. 8, 623–632.
• 75.Świdwińska-Gajewska A., Czerczak S., Szymczak W. (2007) Karbaminian etylu. Wytyczne Szacowania Ryzyka 1(24), 71–124.
• 76.Takaori S., Tanabe K., Shimamoto K. (1966) Developmental abnormalities of skeletal system induced by ethylurethan in the rat. Jpn. J. Pharmacol. 16, 63–73.
• 77.Tannenbaum A., Maltoni C. (1962) Neoplastic response of various tissues to the administration of urethan. Cancer Res. 22, 1105–1112.
• 78.Tannenbaum A., Silverstone H. (1958) Urethan (ethyl carbamate) as a multipotential carcinogen. Cancer Res. 18, 1225–1231.
• 79.Thorgeirsson U.P., Dalgard D.W., Reeves J., Adamson R.H. (1994) Tumor incidence in a chemical carcinogenesis study of nonhuman primates. Regul. Toxicol. Pharmacol. 19, 130–151.
• 80.Toth B., Della Porta G., Shubik P. (1961a) The occurrence of malignant lymphomas in karbaminian etylu-treated Swiis mice. Br. J. Cancer 15, 322–326.
• 81.Toth B., Tomatis L., Shubik P. (1961b) Multipotential carcinogenesis with urethan administration to newborn mice of different strains. Nature 202, 305–306.
• 82.Toth B. (1970) Tumor induction with single urethane injection in newborn and adult syrian golden hamsters. A study on age infl uence. I. Int. J. Cancer 15, 63-68.
• 83.Toth B. (1971) Tumor induction by repeated injections of urethan in newborn and adult hamsters: age infl uence. II. J. Natl. Cancer Inst. 46, 81-93.
• 84.Toth B., Boreisha I. (1969) Tumorigenesis with isonocotinic acid hydrazide and urethan in the Syrian golden hamster. Eur. J. Cancer 5, 164–171.
• 85.Trainin N., Precerutti A. (1964) Law Lw, trends in carcinogenesis by urethan administration to newborn mice of different strains. Nature 202, 305–306.
• 86.Tutikawa K., Harada Y. (1972) Teratogenicity and nonmutagenicity of urethane. Teratology [abstract], August 123 [cyt. za IARC 2010].
• 87.Vesselinovitch S.D., Mihailovich N., Richter W.R. (1970) The induction of malignant melanomas in Syrian white hamster by neonatal exposure to urethan. Cancer Res. 30, 2543–2547.
• 88.Vesselinovitch S.D., Mihailovich N. (1966) Significance of newborn age and dose of urethan in leukemogenesis. Cancer Res. 26, 1643–1647.
• 89.Vesselinovitch S.D., Mihailovich N. (1967) The neonatal and infant age periods as biologic factors which modify multicarcinogenesis by urethan. Cancer Res. 27, 1422–1429.
• 90.Vesselinovitch S.D., Mihailovich N. (1968) The induction of bening and malignant liver tumors by urethan in newborn rats. cancer Res. 28, 881–887.
• 91.Yamamoto T., Pierce W.M., Hurst H.E., Chen D., Waddell W.J. (1988) Inhibition of the metabolism of urethane by ethanol. Drug Metab. Dispos. 16, 355–358.
• 92.Yu W., Sipowicz M.A., Haines D.C., Birely L. Diwan B.A., Riggs C.W., Kasprzak K.S., Anderson L.M. (1999) Preconception urethane or chromium(III) treatment of male mice: multiple neoplastic and non-neoplastic changes in offspring. Toxicol. Appl. Pharmacol. 158, 161–176.
• 93.Zimmerli B., Schlatter J. (1991) Ethyl carbamate: analytical methodology, occurrence, formation, biological activity and risk assessment. Mutat. Res. 259, 325–350.