Document BRjGYZ5y1aQdw6Xq7EGwOJOz8

CINCINNATI, OHIO AMERICAN CONFERENCE OF GOVERNMENTAL INDUSTRIAL H YG ENISTS INC. ISBN 0-036712-31-7 @ 1962,1966, 1971 by American Conference of Governmental Industrial Hygenists, Cincinnati, OH. @ 1980 by American Conference ofGovernmental Industrial Hygenists, Inc., Cincinnati. OH. All rights reserved. N o part of this book may be reproduced in any form or by any means without written permission from the Executive Secretary, American Conference of Governmental lndusrrial Hygenists, Inc., 6500 Glenway, Bldg. D-5, Cincinnati, OH.45211. , . Printed in the U.S.A. I' -- BENOMYL - Methyl 1-(butylcarbamoyl)-2-benzimidazolecarbamate; TLV, 10 mg/m3 STEL, 15 mg/rn3 c Benomyl i s a white crystalline solid, which has a molecular weight of 290.32. It decomposes without melting and has a negligible vapor pressure, indicating exposure would be in particulate form. Very slightly soluble in water, i t is soluble in xylene, acetone, dimethylformamide and chloroform.(') Fluorometric and colorimetrid2tandliquid chromatographiclj) procedures for determining residues of benomyl have been published. Benomyl is the common name for this fungicide and ascaricide. The acute oral LDw for the rate i s 210,OOO mg/kg. The acute skin absorption LDw for the rabbit is 210,OOO mg/kg. Application to the shaved intact skin of ten male guinea pigs, at each level as aqueous suspensions containing 5, 12.5 and 25% benomyl as the active ingredient in a 50% wettable powder, resulted i n negligible irritation. One of ten guinea pigs had mild erythema two days after application at the high rate. All guinea pigs at the two lower rates and in a control showed no irritation after two days.(4) Instillation into the eyes of rabbits of 10 mg of dry 50% powder or 0.1 mL of 10%suspension i n mineral oil caused only temporary mild conjunctival irritation.11) The acute inhala- tion LCw i s 22000 mg/m3 (22 mg/L) for rat111 and i s equivalent to 2825 mg/m' ( 20.825 mg/L) for dog(`) for four-hour exposures. Histologically, there was reduction of spermatogenic activity i n some animals. With regard to this activity, no-effect levels for benomyl for four-hour expo- sures are equivalent to 2100 <410 mg/mj (> 0.7 20.41 mg/L) for the rat and 2 3 2 5 5825 mg/m' ( 20.325 50.825 mg/L) for the dog. Additionally fifteen four-hour inhala- tion exposures at the equivalent of 100 mg/m' (0.1 mg/L) of benomyl over a period of three weeks produced no clinical or histopathologic indication of accumulative effects in the rat.(4) A low order of toxicity has been found i n chronic studies. In two-year feeding studies no-effect levels i n the diet are 2500 ppm (0.25%) for rats (highest level fed) and 500 ppm (0.05%) for dogs. Pesticide residue tolerances have been established in many food crops. They are as high as 15 ppm for stone fruits and food additive tolerances are as high as 50 ppm for raisins.(') In a three-generation rat reproduction study no compound-related reproduction or lactation differences were observed among control and test groups even at 2500 ppm (0.25%), the highest dietary level fed. In a teratogenic study in rat neither the outcome of pregnancy nor embryonal development was affected even at 5000 ppm (0.50%),the highest dietary level fed. In a dominant lethal mutagenic study i n the rat, benomyl was not mulagenic at 2500 ppm (0.25?6), the highest dietary level fed.cs) Cardiner et a P showed that rat and dog eliminated 29% o f single, oral doses of 2-l4Cbenomyl via the urine and feces within 72 hours. The major metabolite was methyl 5-hydroxy-2-benzimidazole-carbamate which was present i n the urine as glucuronide and/or sulfate conjugates. Residue data on dog and rat tissues from two-year chronic feeding studies demonstrated that benomyl and its metabolites do not accumulate i n animal tissues. In view of the low order of acute and chronic toxicity the TLV of 10 mg/m3 and the STEL of 15 mg/m3 appear appropriate. References: 1. E.I. du Pont de Nemours & Co.. lnc.: Technical data sheet (lune 1974). 2. Pease, H.L, Halt, R.F.: 1. Assoc. Offic. Anal. Chem. 54(6):1399-1402 (1971). 3. Kirkland, 1.1., Halt, RJ., Pease, H.L: 1. Agr. food Chem. 27(3):368-371 (1973). 4. E.1. du Pont de Nemours & Co., Inc.: Unpublished data. 5. Sherman, H., Culik, R., lackson, R.A.: TOX.~ p p l f.harm. 32:305315 (1975). 6. Cardiner, I& Kirkland, M., Klopping H.L.: 1. Agr. food Chem. 22(3):419-427 (1974). BENZENE 6H6 -TLV, 10 ppm ( x 30 rng/m'), Appendix A2 Suspected Carcinogen STEL, 25 ppm ( rz 75 mg/mJ), Appendix A2 iiumerous organic chemicals. It is found i n gasoline from -trace amounts to as much as 30% concentration i n some countries. As an acute poison benzene produces narcotic effects comparable to those of toluene; it is a more potent narcotic than the alkanes or naphthenes of similar boiling points. But the effect of chronic exposure to this compound i s by far the most serious disease caused by any of the common hydrocarbon solvents. Its action on the bone marrow may result i n detectable alterations, and, i n some instances, aplastic anemia. Xhe reported LDSOorally i n young adult rats i s 3.8mL/kg.(l) It is unique among hydrocarbons as a myelotoxicant.(2) More than 140 fatal cases of benzene poisoning had been recorded prior t o 1959.(')Vigliani and Saita(4) listed 26 deaths from chronic benzene poisoning in two provinces in Italy between 1960 and 1963.Eleven of these were diagnosed as leukemia, which may develop several years after cessation o f exposure to benzene. Most deaths from benzene have resulted from expo- sures of the order of 200 ppm or more. In a few instances concentrations of lo00 or even 2000 ppm have been rec- orded in workplaces where deaths occurred. Some of these are: Leggejs) 210 to 7050 pprn: Greenburgp) 70 to 1800 ppm, with over half above 200; Bowdi~ch)~1)00 to 200+ measured; one leukemia case described by Hunter(*) and Mallory(9)six years after exposure at over 200 ppm; Creenburg)lQ 25 to loo0 pprn in four rooms; Helmer,W 140 to 200 ppm after improvements; Savilahtijl2) 318,433and 170 ppm; Kozlova)13) 47 to 310 ppm; Vigliani,W 190 to 660 pprn, after four years death from leukemia; Juzwiakj14)31 to 156 pprn; Aksoy,W 150 to 650 ppm, and 210 to 650 p p m p 26 patients with acute leukemia or preleukemia; Ikeda)17) 7 0 0 to 800 ppm, 7 deaths, all females, none from leukemia. WinsIow)'a) however, reported blood changes in workers where concentrations of benzene vapor below 100 ppm were found. Heimann and Ford(19)found one death and three cases with blood changes where air analysis for benzene showed a concentration of 105 ppm. Wilson(20) reported three fatal cases in a plant where the average concentration of benzene vapor was 100 ppm. In a fifth room, associated with benzene poisoning, Greenburg`lo) found 11 to 57 ppm. So far as can be determined the lowest measured concentration of benzene vapor associated with a fatal case of benzene intoxication (due to aplastic anemia) was the 60 ppm reported by Hardy and Elkins in 1948,(2') in a plant where repeated air analyses were made, and a num- ber of other workers showed some blood abnormalities. Blaney(22) found little evidence o f benzene intoxication in a group of 90 workers regularly exposed to benzene for about 1 3 years. Concentrations were generally low, but urinary phenol measurements indicated some exposures ot the order of 25 ppm.c?') A followup several years later showed no evidence ot persisting blood dyscrasias. No cases oi leukemia are known to have Occurred i n this Group of workers. Pagnotto et a/(") found workers in rubber spreading opcraiions involving naphtha with a relat l v ~ hlig~h benrcne conic`nt cbxposed to Ilcnzcnb i n conrcntralions whlch wprp tor the most part t)etwcrn 6 and 25 lwrn. A number 01I~looil~tuclic~sshowed J fcw at)norin.lll1 ~ h s t onlv [ n o \rere wiou5 to warrdnt S ~ C C I J I c-onsitItBrJtlon. In one case the pc)s.sit)ility o t It*uAemla \v.ij ralq.(t, L)'t on I ) f * l n grcirnoved from hi\ 101) and xiven iron therji)\, 38 the worker recovered. Because of several job changes h i s benzene exposure could not be reliably estimated. The other worker was in a group studied intensively over a period of several years by Pagnotto.(z5)He had a red count below four million, a hemoglobin below twelve grams and suffered from nose bleeds. His benzene exposure, as estimated from several urinary phenol determina- tions, was to about 40 ppm. After his exposure to benzene was terminated, his blood picture gradudly returned t o normal. The 38 workers in this plant were followed up for ' 15 years after the use of naphtha containing benzene was discontinued. None showed any signs of permanent blood abnormalities. There were three deaths, none being from leukemia. It was concluded that 25 ppm of benzene vapor is safe for most workers, but that since the margin of safety is small, a TLV of 10 ppm was recommendedJZ1Elkinsi'bl in a summary of the findings i n the rubber spreading industry, came to a similar conclusion. These conclusions were consistent with those of Fu~hsW)i n 1969,who found variations in the blood pic- tures of three workers but did not consider that the changes were proved to result from their benzene expo- sures of 19,28and 43 ppm, respectively. He also stated that he could find no data in the literature on proved benzene poisoning in concentrations below 16 ppm, nor could he find any Soviet report which cited reasons for decreasing the Russian MAC to 6 ppm. Two investigators have studied the effects on rats o i exposures at relatively low levels o f benzene vapor extend- ed periods. Deichmann er aF28) found that after 5 to 8 weeks of 5 hourlday, 5 dayslweek exposure at 41 and 47 ppm, rats developed a moderate degree of leukopenia, but that none resulted from 15 to 31 ppm. Nau et aW9) found a decrease in the white blood cell counts of rats following 756 hours of exposure at SO ppm of benzene on a schedule of 8 hourslday, 5 dayslweek. Reduced amounts of DNA in the white cells, a depression in myelocytic activity, and a n increase in the relative numbers of red cell precursors i n the bone marrow were also observed. There have been numerous reviews of the literature or benzene intoxication. Noteworthy are those of the Na- tional Academy o f Sciences i n 197600) and the NlOSH criteria document on benzene. published in 1974.01, AS a result of this extremely thorough review, NIOSH recommended a workplace time weighted average standard o i 10 ppm, with a ceiling of 25 ppm. In 1976,however, NIOSH issued a revised recommenda- tion for an occupational exposure standard for benzene.(") The key to this recommendation i s the statement in the introduction that "Because it i s not at present posslble to establish d safe c.uposure level tor a carcinogen, rhe NlOSH recommendalion i s to rrstrict esposurc to very lo\v ler*els rvhich c-an still h! rehblv measured in rhct workplace." A number o l rcferrnces an' given. primartlv l o support the charactcrization o i t)cnzcne d s a carcinogen (leukctnogen). Thus most relate l o leukcirnia C d w S associated wtth hejvv benzene t!xposurw. eilhcr measured or intcrrcd from asso- (`idtion with nulncirous c ` J w s 01 plastic .inpmid or othtv tilood dyscrasias. Others arc c'pldtvnlotogtc studicts on CJn- cer in which no vvdencv ot thc ricgrcc*.or w e n iact, 01 benzene c-xposiirc is c . i t c * d . Thus in at Iwst two ot thcw ;),ipc`rs,t'' ``1 the word "t)cwzcnc" clocs not Jppvar. In thew a n d othcv papcrs the incitlcnce o f varto11b tvpc`s 01 cancer. g -- - -* a- -. ** including leukemia, was found to be higher than in.the general population among certain groups of rubber workers. Monson and Nakanot's) found 55 cases of leukemia, vs. 43 expected, among rubber workers. It was noted that benzene has been used extensively in the rubber industry, but is no longer employed, although i t i s a contaminant of extensively used naphtha solvents. The degree of exposure to benzene in the rubber industry during the first half of the 1940-1950 decade may well have been excessive. Wilson(20) has not& deaths and blood abnormalities among workers in the rubber industry during the war years who were exposed, on the average, to concentrations of benzene vapor o f 100 ppm. Neither Monson-Nakano or other authors of similar papers quoted in the NIOSH update mention whether or not aplastic anemia or other blood dyscrasias, apart from leukemia, occurred in the groups of workers that were studied. Nevertheless OSHA, i n 1977, issued an Emergency Temporary Standard (ETS)(S)establishing a TWA limit of 1 ppm for benzene vapor. (Enforcement of this standard was voided by the courts). Much of the evidence substantiating this action was the same as that quoted i n the NIOSH update. However, one additional paper was cited by Infante et a/:'7) in which nine leukemia deaths were reported from two rubber film casting plants where benzene vapor con- centrations allegedly ranged from 0 to 15 ppm. This report was critically examined in OSHA hearings on a permanent standard, with essentially the same provisions as the ETS, which were held during the summer of 1977. The data on benzene exposure in the two plants in question, especially during the first part of the ten year employment period , (7940 to 1950) covered by the study, were found to be incomplete, unreliable and contradictory. Even in 1976 a NIOSH report of one of the plants involved, or its succes- sor, showed concentrations in excess of 15 ppm at several locations.('*) A study by Harris e l al(39) in 1973 and 1974 revealed similar findings, although the overall average of all sample results was slightly above 1 ppm. During the period 1940 to 1945 or so, when many of the involved workers were employed, the permissible concentration for benzene exposure (ASA standard) was 100 ppm. In corn- mon with the papers cited by the NIOSH update, no infor- mation on other blood abnormalities was given i n the In- fante report. Epidemiologic studies of workers exposed to measured low concentrations of benzene vapor have yielded negative or inconclusive results. Thorpe(*) after studying the occurrence of leukemia in a population of 38,000 workers in a variety of European petroleum and petrochemical operations, some of whom were exposed at levels of benzene that occasionally reached 20 ppm, over a period o f ten years, found that deaths from leukemia "were not abnormal" for the countries involved (18 VS. 23.23 expected). Retrospective studies of employees o f a large chemical company, exposed ior many years to benzcnc, mostly at low levels, rrvcaled no excess mortality.~J'~AJ2c~ohort of 594 workmen were divided into four oxposurr groups: very low exposurcs, less than 2 pprn as lime weighted average (TWA); low c'xposurt.5. 2-9 ppm; moderate cxoosurrs, 9-24 ppm: and high exposures, above 25 ppin. In many dreds there w a s c~xposureto other chemic,lls as w d l J S to Iwnzenc. The (Juration ot exposure wd5 dm diiwlcd inlo tour groups, with lllh workers h;lving in i'xcess o r 20 years. Of 102 deaths, two were due to anemia, two to leukemia, and one had leukemia as a complication. Of these five. cases, only one, an autopsy-confirmed pernicious anemia, involved a previous exposure to benzene of significance, 5520 ppm months. The other anemia death, diagnosed as being of the aplastic type, was of a worker with 453 ppm months of benzene exposure. Two of the leukemia cases involved exposures of 545 and-305 ppm months, respectively, while the third was of a worker with only 18 ppm months benzene exposure. To put these exposure data in perspective, three of the deceased workers had had exposures to benzene equiva- lent to 40 years' employment in concentrations slightly above or below 1 ppm; the exposure of the fourth, if spread over 30 years, would have been at a concentration of 0.05 ppm. The predicted deaths from anemia and leukemia were 0.2 and 1 respectively. The fact that, apart from the pernicious anemia death, there appeared to have been no dose response relationship, apparently led to the conclusion of the authors that "nomorrality findings directly aftriburable to benzene exposure were observed". The NIOSH update mentions the consistent observa- tions of chromosomal aberrations associated with benzene exposure, but further comments that the implications oi these findings with respect to benzene leukemia are still not clear. The possbility of a chromosomal instability acting as a stimulus for a latent leukemogenic virus has been speculated upon.(4') This question was discussed at some length at the International Workshop on the Toxicology ai Benzene, held in Paris in November 1976. Tough(") hac previously reported that marked aberrations were founc only in plants where concentrations of benzene vapor were believed to be between 25 and 250 ppm, and that nc significant changes were observed at 12 ppm. Forni,('F however, stated that there had been a few positive, as we1 as negative, reports at levels between 5 and 25 ppm. Thr consensus of opinion was that the significance of the find ing of increased chromosome aberrations for the -occur rence of benzene leukemia was still not clear. Maugeri an( PoIIiniW) reported that among Italian shoe workers 'a/moS a l l the cases of haernopathy due to benzol which lead I . ..death show features of rerminal leukemia,. and (the /eL kernias) were always preceded by aplastic conditions". Opinions of the workshop participants relative to th appropriate TLV for benzene were varied. The final recorr mendation was to retain 10 pprn as a permissible T W t which must not be exceeded, but it was also specified th; benzene should not be employed when substitute mat rials were available. DeGowin's report('71 of a case of leukemia following a apparent benzene-induced aplastic anemia contains a di: cussion which implies that there is evidence that aplast, anemia per se may lead to leukemia, and that delave cases of this disease are not Confined to aplastic anem, due to benzene. It i\ the opinion of thc Committee that the characteriz tion of bcnzrne as a leukemogen, by NIOSH, is, in essens valid, although benzene may be what lruhaut has d~ scribrri ,IS "secondav cJrcinog:L'n''.") A n A2 notaiic should bc ~ l ~ l ) l ~tocbdcnzcnc in the TLV listings. On the othw hand, the Cornmtltw does not rlcret. \VI the NIOSH rc-tommcndJtion 01 1 ppln JS dn O C C U p J I i O r exposure standard, insofar as the TLV can be defined as such a standard. There is little evidence that exposure to -. benzene at concentrations below 25 ppm causes blood dyscrasias of any kind. Setting the TLV at 10 ppm, as a timeweighted average, provides an added margin of safety. Ifthe standard i s to be set at the lowest practicable detectable limit, it i s the opinion of some members of the Committee that a value lower than 1 ppm should be selected. In the absence of interfering substances benzene vapor can be measured*ith reasonable accuracy in concentrations at least as low as 0.1 ppm; in the presence o f certain interferences, it may be difficult t o achieve the prescribed accuracy and reliability even at concentrations somewhat above 1 ppm. Because the effects the TLV i s designed to prevent are chronic in nature, a ceiling designation i s not appropriate and a STEL of 25 ppm is recommended. Other recommendations: ANSI (1969)IO ppm; Czechoslovakia (1969)16 ppm; USSR (1972)1.6 ppm; DDR (1973) 16 ppm; Sweden (1975)10 ppm; BRD (1974)0 pprn (treats as carcinogen). References: 1. Merck Index, 9th ed., p. 138, Merck & Co., Inc., Rahway, NJ (1976). 2. Gerarde, H.W.: Toxicology & Biochemistry of Aromatic Hydrocarbons, Elsevier Publishing Co., NY (1960). 3. Elkins, H.B.: Chemisfry of lndustrial Toxicology, p. 103, Wiley & Sons, N Y (1959). 4. Vigliani, EL. Saita, G.: New Eng. I. Med. 277:872 (1%4). 5. Legge, T.M.: 1. lnd. Hyg. 7:539 (1920). 6. Greenburg, L:U.S. Public Health Reports $13357 (1926). 7. Bowditch, M., Elkins, H:. 1. lnd. Hyg. & Tox. 27:321 (1939). 8. Hunter, F.T.: lbid., p. 331. 9. Mallory T.B. et al: lbid., p. 355. 10. Greenburg, L et al: lbid., p. 395. 11. Helmer, Lj.: Acta Med. Scand. 778354 (1944). 12 Pvihhti, M.: Arch. Gewerbepath. u. Gewerbehyg. 15147 (1956). 13. Koslova, T.A., Volkova, A.P.: Gig. Sank 2529 (1960). Cited by NIOSH in ref. 31. 14. Juzwiak, 1.: Med. Przemylowa 20.67 (1969). hid. 15. Aksoy, M. et ak Brit. 1. lnd. Med. 2956 (1972). 16. Aksovy, M. et al: Blood e 8 3 7 (1974). 17. Ikeda, M.: Poisoning Due to Benzene and its Substitutes in Japan,lnternafional Workshop on the Toxicologyof Benzene, Paris (1976). 18. Winslow. C.E.A.: 1. lnd. Hyg. 969 (1927). &. . . . ' .' 19. Heimann, H., Ford,CB.: NY lnd. Hyg. Bull.. p. 224 (November 1940). 20. Wilson, R.H.: 1. Lab. Clin. Med. 27:1517 (1942). 21. Hardy, H.L., Elkins, H6.:. 1. h d . Hyg. & To%.30.1% (1948). P, Blaney, L: Ind. Med. & Surg. 19227 (1950). 23. Walkley, J.E. et a t Am. lnd. Hyg. Assbc. 1. 22362 (1961). 24. Pagnotto, 1.0. et al: /bid., p. 417. 25. Pagnotto, LO. et al: Benzene Exposurein the Rubber Coating Industry; a Followup. Presented at the American Industrial Hygiene Conference, New Orleans (May 1977). 26. Elkins, H.B.: Significance of Benzene Exposure Among Workers in Rubber SpreadingOperations. Presentedat the lnternational Workshop on the Toxicology of Benzene, Paris (1976). 27. Fuchs, A.: in Documentation of the MAC in Czechoslovakia, Prague (1%9). 28. Deichmann, W.B. et al: TOX.Appl. Pharm. 52oI (1963). 29. Nau, CA. et al: Arch. Env. Health 72382 (1966). 30. National Academy of Sciences: Health Effects of Benzene; a review (1976). 3l. NIOSH: Criteria for a Recommended Standard for Occupational Exposure to Benzene (1974). 32 NIOSH: Revised Recommendation for an Occupational Exposure Standard for Benzene (August 1976). 33. McMichael, AI. et al: I. Occup. Med. 16458 (1974). 34. Andjelkovic, D. et ah lbid. 18387 (1976). 35. Monson, R.R., Nakano, K.K.: Am. I. Epidem. 703284 (1976). 36. OSHA: Emergency Temporary Standard for Occupational Exposure to Benzene. Federal Register 42:22516 (May 3,1977). 37. Infante, PF.. et ah Leukemia Among Workers Exposed to Benzene. A manuscript (1977). 38. Young, R. et a/: Walk Through Survey of Goodyear Tire & Rubber Co., St. Mary's, OH. A manuscript (1977). 39. Harris, R.L jr.: Testimony before OSHA hearings on the proposed standards for occupational exposure to benzene, Washington, DC (August 1977). 40. Thorpe, 1.1.: 1. Occup. Med. 16375 (1974). 41. Ott, M.G. et al: Morfality Among Individuals Occupationally xposed to Benzene. A manuscript (1975). 42. Fishbeck, W.A.: Testimony before OSHA hearingson the proposed standards for occupational exposure to benzene, Washington, DC (August 1977). 43. Todaro. C1.. Huebner, R.I.: Proc. Naf. Acad. Sci. 691009 (1972). Cited by NIOSH in ref. 31. 44. Tough, I.M. et al: Eur. 1. Cancer 649 (1970). 45. Forni, A.: Report in the Proceedings of lnternational Workshop on the Toxicology of Benzene, Paris (1976). 46. Maugeri, S., Pollini, C.: Benzene Haemopaty; Cellular Damage and Chromosome Changes; Personal Researches, lbid. 47. DeCowin, R.L.: I.A.M.A. 785748 (1%3). 48. Truhaut, R.: Proceedings of the XI lnfcrnatronal Cancer Congress, Florence, Italy (1974). 40