Document NO9Je95vQoZqGz4DNpgdKBrD

A Method for Calculating the Acceptable Daily Intakes (ADI's) for Man of Volatile Extraction Solvents Using Established Threshold Limit Values (TLV's) For Inhaled Vapors by T. R. Torkelson, Sc.D. Senior Research Toxicologist Howard C. Spencer, Ph.D. Research Scientist Biochemical Research Laboratory The Dow Chemical Company Midland, Michigan 486^0 U.S.A. March 6, 1970 00 136614 CONFIDENTIAL I 1- - Acceptable Daily Intakes (ADI's) for man in terms of mg/kg oodyweight have been established by the Join'- FAC/WHO Expert Committee on Food Additives for many of the well-known additives in conmon use. Similarly, Maximum Acceptable Daily Intakes in terms of mg/kg body-weight for pesticide residues have been establishes uy the Joint Meeting of the FAO Working Party and the WHO Expert Committee on Pesticide Residues. In general, long-term (two year) dietary feeding studies in laboratory animals furnish the basis of judgement In establishing an ADI. Relying solely on data obtained or laboratory animals, it is common practice to apply a 100-fold "safety" factor. In cases where data are available from experience with human subjects I tor from controlled numan studies, which supplement and confirm the observations on animals, a smaller (10-foid) safety factormay be justified. Pozzanl et al" have shown a relationship between single dose inhalation data and single dose oral data for certain compounds; however, similar studies comparing repeated inhalation data and repeated oral data are not available. This is because meaningful, jlonc-ierm die-ary or water feeding data wLth volatile compounds are not obtainable due '-o the .loss of the test compound from doe food or water during the study, and because of decreased palatabilicy due .o taste and odor. Incubated doses or doses contained in capsules and fed orally are not representative cf a dietary residue and place unduly high acute toxicity stress on the animal at the time of dosing or when the capsule dissolves in the ali mentary tract. Due in part to these technical difficulties, no chronic (2 year) dietary feeding studies have been carried ou,. with the common extraction solvents: ethylene d ich.i or idc:, CH2Cl-CHpCl; methylene chloride, CHgClg.; and sriohloroetnylene, CHC1=CC1?. In order to surmount these technical, difficulties, alternative method is suggested. he fn'l owing Industrial experience has shown that certain levels of comm* ab used solvents can be Inhaied safely by workmen who are expose7 or 8 hours daily for their working lifetime. These acceptor e, safe concentrations have taken various names tuch as Hygienic Standards, Maximum Allowable Concentrations, Maximum Acceptable Concentrations and MAK's. Perhaps the oldest, and best documented are chose used in the United States which are caned Threshold bimit Va.ues (TTV's)," Threshold imlt Vaiuei (TIP's) are re viewed and issued annually by a committee of the American Conference of Governmental Hygienists (ACGIH),2 A TLV is defined by ,,he ACGIH as follows: Threshold limit values refer to airborne concentrations of substances and represent conditions under which it is believed that nearly all workers may be repeatedly ex posed day after day /itnout adverse effect. Because of wide variation in individual susceptibility, however, a small percentage of workers may experience discomfort from some substances at concentrations at or below the threshold limit, a smaller percentage may be affected more seriously by aggravation of a pre-existing condi tion or by development of an occupational 1LIncss.^ ' D0 1.36M 6 CONFIDENT X At -3- Aceording to Stokinger and Woodward^: These threshold limit values represen. a maxima ! average concentration of a substance in workroom air tha1 nr. vides no hazard to health or well-being of the worker during his working lifetime. Tested under practical conditions over a period of years, these values nave considerable validity. Mist have safety factors In corporated which are often of appreciable magni .ud-'. Some of these arise because the values are baseu >n considerations other than health--sucn as freedom from irritation; oc.iers, because of engineering adapt an l I: y, n;a:' provide large factors of safety to health. Use experience has borne out the fact that if the average exposure of the workmen does not exceed the TUV .here is lit tie likelihood of injury. The oasis for selection of tne T'i1s are diverse and include such criteria as objectionable odor, eye irritation, anesthesia, as well as systemic injury. Documentation bn support the safe use of specific TPMs are publisned by the ACGTH.^ For the three volatile extraction solvents discussed In this paper, references 5 througn 9 are particularly pertinent. Threshold Limit Values have been established as Legal safety requirement:, for obtaining U.S. Federal Supply Contracts.-1'-' The American National Standards Institute Incorporated (ANSI) nas published consensus standards for safe repeated exposure -o these extraction solvents Z37.21-1969; 137.93-] 969; ,9- 1967. 11 * 1"0* 13 This committee composed of representatives of 1.36617 ^NFTDFNTTA! Labor, Government, Universities, Industry, Military and other groups has adopted maximum average figures identical to the TLV's recommended by the ACGIH for these extraction solvents. Obviously if the TLV is based on odor, discomfort, or respiratory irritation, the TLV bears little relationship to an ingested dose; but for ethylene dlchloride and trichloroethylene the criteria used in establishing the TLV's for inhaled vapors are based primarily on systemic toxicity. For methylene chloride the TLV has been selected to prevent anesthetic changes; since organic injury has been shown not to occur from repeated exposure of animals co 10 times the TLV, an additional 10-foid safety factor results.^ Consequently, for these volatile extraction solvents, it is valid to use the Threshold Limit Values (TLV's) in terms of mg/m^ of air as a basis for calculating the Acceptable Daily Intakes (ADI's) in terms of mg/kg body-weight. Similar calculations have been used to establish drinking water standards by Stokinger and Woodward. The following is duplicated from their publication: TABLE 3 Limih for Orla nit Subslarutt in Water Calculated From Threshold Limits for Air* Organic Compound Ai etone Acrylonitrile Ally! -kohol Aniline Benrene Caibon tetiachlw idc Forma Idehj do Meth) I bromide Methylchhn-ofornt Phenol Pyridine Absorption Factor IphiJition o.s 0 7s 0 75 0.5 0.35 0.3 0.75 0.8 01 0.1 10 0.1 logevtiun 1.0 0.8.1 0.8 1.0 04 05 0.8 08 0.5 0.5 1.0 0.5 Limit for Water 0em 6.000 240 55 47 340 480 140 30 240 2.700 95 30 ThreihoM Limit for Air mg/rn m l,000` 20 5 5 25 25 10 5 10 500 5 10 CONFIDENT I At -5- In the conversion of the amount of volatile solvent In the f^rm of vapor absorbed by the lungs into an equivalent amount of s - vent ingested, certain factors and assumptions are required. 1. The volume of air that a human breathes is related to the amount of solvent sorbed by the lungs. On ,,he basis of the 14 generally accepted work of Silverman et a.L, It is assume; that moderately active workmen will inhale about 10 cubic meters (m^) of air per 8 hour workday. This is the same factor used by Stokinger and Woodward. 2. Less than 100$ of the solvent in the air breathed in uy humans is sorbed through the lungs. Stokinger and Woodward^ . 15 suggest 75$ but McCollister et ai, in a study using monkeys, found that an average of only 30$ of the total amount of in haled carbon tetrachloride was absorbed. Carbon Letrachioride is less water soluble, less sorbed, and probably less retained than the solvents under consideration here. The smaller the lung retention factor used in calculating the daily retained dose, the smaller the calculated daily serbed dose, and therefore, the greater the safety factor in converting to daily ingested dose. In the absence of other data, the most conservative position is assumed. Therefore, the lowest probable retention factor for these solvents, based on carbon .etrachloride at is used in ail calculations instead of the less conservative 75$ suggested by Stokinger and Woodward.^ Using these factors and assumptions, the calculation of the Acceptable Daily Intake (ADI) in terms of mg/kg body-weight, for these volatile solvents may be made as follows: 13661^ 6- - TLVfmg/m^alr) x 'lO(m^alr) x 0.3(30$ retention = ADl(r,g/kg a- dy-v;:.) 60(kg,avg.body wt.) x 10(added safety fact ;r) Thus, the Acceptable Daily Intakes (ADI's) fox' .hcse three v d: tiie extraction solvents may be calculated: ETHYLENE DICH^QRIDE 200*x 10 x 0.3 60 x xO 1.0 mg/kg body-v;e.ir.ht METHYLENE CHLORIDE 17^0*x 10 x 0.3 60 x 10 8.7 mg/kg body-weigh: TRICHLOROETHYLENE 535*X-----1--0----X----0---.-3d _- n2. {-y mg//l,cg .b. odj y-we xghc o0 x 10 Conclusions Considerable difficulty has been encountered in obtaining meaning ful long-term feeding data on laboratory animals using volatile solvents. It is recommended that the Threshold ilmit Values (TLV's), established on the basis of vapor toxicity da' a on an'mals and confirmed through human tests and experience, be employed : calculate the Acceptable Daily Intakes (ADT's) for man. These ADI's can chen be used in the accepted manner to establish residue tolerances for these volatile extraction soiveni s hi t' oi. Threshold Limit Values (TLV) as published by the American Conference of Governmental Industrial Hygienists (ACHTH' (1?o9'# DO 136620 OONFTDFNTT At. REFERENCES Pozzani, U. C., Well, C. S., and Carpenter, C. : The Toxicological Basis of Threshold Limit. Values: 3. 'Me Experimental. Inhalation of Vapor Mixtures b;/ Rais, w* o NUpon the Relationship between Single Dose Inha i a' ion and Single Dose Oral Data. American Indus rial Hygiene Asr.n L; Journal, 2D, 364, 1959. : American "'onference of Governnenba i Indus-rial Uygicnls-s: Threshold Limit Values of Air-borne , ntaninents I'or , 06`M American 1,inference of Governmental Iiv iusfr la : Uygien*.: . Denver, Lsoraao, May l9o9. StokLnger, H. E., and Woodward, L. L. : T; xieologic MeMucu for Establishing Drinking Water Standards. Journal of The American Water Works Association, 50, 5'I5, 1958. 'Committee on Threshold aim it Values: Documentation of Thresnold Limit Values. Rev. Ed. American conference >f Governmental Industrial Hygienists, 1 ML Dr` ad way , Cincinnati, Ohio 45202. (19661 Heppei, L. A., Meal, P. A., Perrin, V, ' ., Orr, K. .., ant Porterfield, V. T. : Toxicology of D ! chi M'ome thane (fk. thy 1 me Chloride). I. Studies on Effects of Daily Inna'lat i jn. The -Journal of Industrial Hygiene and T x.: : 0j.ogy, 2L, R, i')4A. Heppe i., L. A., and Neal, P, A.: Toxicology of D1 oh. premie; iiane (Methylene Chloride). IT. Its Effects Upon Running Activity in dne Mate Rat. The Journal of Industria1 Hygiene and Toxicology, 26, 17, 1944. Spencer, II. 0., Rowe, V. K., Adams, E. I'., McCo Mister, D. D., and Irish, D. D. : Vapor Toxicity of E`.hyLene Dl.ch.ioride Determined by Experiments on Tabrratory Animals. A.M.A. Archives of Industrial Hygiene and Occupational Medicine, 4, 482, I95'M Adams, E. M., Spencer, H. C., Rowe, V. K., McCol11ster, D. D., and Irish, D. D.: Vapor Toxicity of Trichloroethylene Determined by Experiments on Laboratory Animals. A.M.A. Archives of Industrial Hygiene and Occupational Medicine, 4, 469, 195-1 . von OettIngen, W. F. : The Haiogenated A ipaatk, '.hefini-y Cyclic, Aromatic, and A Mi phatic-Aromai 1 c Hydrocarbons In cluding the Haiogenated Insecticides, the'r Toxic* y and Potential Dangers. U. S. Dept, of Uea'th, Euucat! m, ana Welfare, rublic HeaLth Service Publication No. i'- ( vt5'1. CnOoNFj'T3D6F6N2T1TmAl, - 8- - 10. U. S. Dept, of Labor: Safety and Health Standards for Federal Supply Contracts. Title 4i, Chapter 50, Federal Register, 34, 7916, May 1969. 11. American National Standards Institute: Acceptable Concen trations of Ethylene Dichloride. Z37.2l-19o9. American National Standards Institute Incorporated, New York. 12. American National Standards Institute: Acceptable Concen trations of Methylene Dichloride (Dichioroniethane), - 1969. American National Standard Institute Incorporated, New York. 13. American National Standards Institute: Aceeptab'e f-ncentrations of Trichloroethylene. USAS Z37.19-1967. American National Standards Institute, Incorporated, New York. 14. Silverman, L., L,ee, G., Plntkln, T,, Sawyers, L . A., and Yancey, A. R.: Air Flow Measurements on Human Subjects V.'ith and Without Respiratory Resistance at Several VtTit Rales, A.M.A. Archives of Industrial Hvgiene and Occupation;-*i Medicine, 3, 46l, 195'.' . 15. McCollister, D. D., Beamer, W. H., Atchison, G. -J., and Spencer, H. C.: The Absorption, Distribution and Elimination of Radioactive Carbon Tetrachloride by Monkeys upon Exposure to Low Vapor Concentrations. The Journal of Pharmacology and Experimental Therapeutics, 102, 112, 1951. onoonfidSNTTtot