Document N2y3DRJM4GnOOK8KJ5M57XbVQ

Corporate Medical Department A Memo From T. R. Torkelson (517) 636-5197 11 . n'u /II <: 'jo run '.Oil {.(/. v.o/ i y<// (/>111 i /11 < ; i > . 11 Oil 0 >,. I'om .i City, OK J ihoi;ia Cc: 74(,tn . T. Senwc-11 i :> t 'II. iappears to bo lliu latest manuscript n ( m': 1 a bo I j i v/tji t on Vf iM . V T. R. Torkclson CHEMICALS Research JUN27 1978 VVC 000003155 RESOLUTION OF DOSE-RESPONSE TOXICITY DATA FOR CHEMICALS REQUIRING METABOLIC ACTIVATION: EXAMPLE - VINYL CHLORIDE 1 P. J Gehring G. Watanabe^ and C. N. Park- Abbreviated Title: Dosci-rGSpon^G: Vinyl Chloride Manuscript # B600-176-77 Toxicology Hedcarch Laboratory 1801 j;u hiding Health and Env i. romcteriLal Research Dow Chemical, U.S.A. Midland, Michigan 48640 2 Physical Research Laboratory Math Applications, Bldg. 1707 Dow Chemical U.S.A. Midland, Michigan 48640 This study was funded by the companies supporting the vinyl <: h l o r'l d p ro j c. <; i ;; hi: I n y adnri n l s t c rod by l h<" Ma n u fa a tu ring Chn.m l s /, s, A s sac in l ion , Ua shiny t: >n , l>. C. VVC 000003156 Presented at the 17th Annual Meeting of the Society of Toxicology, March 12-16, 1978, San Francisco, Calif. Accepted for publication in Toxicology In Applied Pharmacology, 1978. Resolution of dose-response toxicity data for chemicals requiring metabolic activation: Example - vinyl chloride. Gehring, P. J. Watanabe, P. G. and Park, C. N. (1977). Toxicol. Appl. Pharmacol. ___, ____-___. The toxicity of many chemicals results from biotrans formation products formed from the chemical rather than from the chemical per se. In such cases, the incremental response may become diminishingly smaller with increasing dose or exposure because activation of the chemical to the toxic form follows <ij <[/ i / < - fi i M i cIm- I i :,-M< Tii t. ('ti ra l.h<*c than u i;|m ren1:1 rs L-oraer kinetics. To illuMral.fr Lh iconcept, rats wi;r'j exposed to concent ration?; ranging from 1.4 to 4G00 ppm vinyl chloride for 6 hours and the total amount metabolized determined. The amount metabolized followed apparent Michaelis-Menten kinetics. For rats, the logarithmic probability incidence of angiosarcoma versus the amount of vinyl chloride metabolized rather than the exposure concentration of vinyl chloride is linear. Assuming no threshold inspite of evidence to the contrary, extrapolation of the data below the range of doses causing experimentally obscrvabl e responses predicted nn incidence of 0.03ft hepatic angiosarcoma in rats exposed to 4.6 ppm vinyl chloride. Theoretical extention of the extrapolation to humans after adjusting for metabolic and body mass differences was under taken. The theoretical extrapolation for man exposed daily for 8 hours to 1 ppm suggests an incidence of 1.5 per 100,000,000. This theoretical incidence, although a likely vvc 000003157 -11- overestimate because of a less than predicted incidence in men exposed to 200 ppm and greater as well as evidence for a threshold in rats, is less than that expected to occur spontane ously. The concepts evolved from this analysis reveals why pharmacokinetics must be considered in designing toxicology experiments as well as in interpretation of the resulting data. 000003158 vve 1- - There exists a great deal of uncertainty in predicting the potential response of exposure to chemicals at concentra tions below those producing an experimentally discernible response. This is particularly true when the response to the chemical in question is oncogenesis. Statistical projections recommended for assessing the risk of exposure to doses of oncogenic chemicals lower than those producing an observable response include those ha .sod on logarithm, pr oba b i I i l y curves ( pr. ob i l. curves), Log i.i c curve:; or linear curves (one-hit curves), (FDA Advisory Committee on Protocols for Safety Evaluation, 1971). One of the most commonly used statistical projections for risk assessment has been that promoted by Mantel and Bryan (.1961) in which a logarithm probability projection with a slope of one is utilized. A flaw innate to all of these methods is that the dose-response information used to make the projection is based on the dose of chemical administered to the animal rather than the quantity of the administered dose giving rise to the response; the latter may either increase or decrease disproportionately as the administered dose is increased. The use of high doses to reveal the chronic toxicity incurred with exposure to a chemical is a common, scientifically vve 000003159 2- defensible practice if judgment and scientific rationale are used in designing the experiments and in assessing the resulting data. However, such doses overwhelm frequently the enzymatic processes for activation of the chemical to the toxic form or for deactivation of the toxic form to an innocuous form. In this paper, it is demonstrated how the dose-dependent activation of vinyl chloride to an oncogenic product must be considered in resolving the dose-response of rats exposed via inhalation to vinyl chloride. VVC 00000 3160 \: gy-Tgiy u Material. 14 i j Vinyl chloride ( C-labeled) v-ac synthesized from (1,2- C) 1,2-dichloroethane (New England Nuclear, Lots #819-221 and 819-292 , 5.0 and 4.8 mCi/mmole, respectively) directly prior to use (Wagner et al., 1975). Ncn-labeled VC (Matheson Gas Products) of 99.9% purity was mixed v/ith the 14c~material to obtain the desired specific activity. Animals Male, Sprague-Dawley rata (Sparcan Research Laboratory) weighing 200-250 g were used throughout the study. Food and water were provided ad libitum except during the exposure. Exposures were conducted between 9:00 a.m. and 3:00 p.n. (EST) Groups of 3-6 rats were exposed to various concentrations of 14C-VC for 6 hours. Exposure and Procedure. The rats were exposed by inhalation under dynamic conditions in a 30 glass inhalation chamber. The mean analytical concentrations of VC measures by gas chromatography were 1.40.3 (SD) , 9.310.2, 24.7rl.4, 51c2, 109 123 , 25012 , 511111 , 1020113, and 46001311 porn. Details of this exposure and the method of analytical de term-x.-teens have been retorted previously (Watanabe o_t a_i. , ''1575a; . Immediately following WC 000003161 the 6-hour exposure to various concentrations of ^C-VC (1.4-4600 ppm) the rats were killed by a blow to the head, and the carcass was analyzed for total radioactivity (Watanabe, e_t a_l., 197 6b) . Previous studies have shown that only a small percentage of radioactivity (<12%) is excreted a 14 metabolites other than C-VC during 72 hrs .following a 6 hr inhalation exposure (Watanabe et al., 1976a). The large 14 proportion or the 121 is comprised of CO^ excretion 72 hrs <x i r i . ['in ' , m.x, voj. y I i. L L I 1: urine is excreted during the exposure ireriod. Thus, the non-volatile radio activity determined immediately after exposure in the tissue and carcass is a good estimate of the total amount of metabolized VC. VVC 000003162 -- 'J -- :rry Q Consistent with the results of previous studies (Watanabe el <i 1 . , i mid IV/tb), i;r- vo.bool o:::i ' '/v by rats don;} not incre-me proportionately with i rv rf-a a i nr; concentrations r * { V(' j a Mr/ i a ha I I ('['ild" 1 ) . Tl i' 11` a i i i 11 - . 11 i t v o f the a (noun t of VC metabolized during 6 hours of exposure to various concentrations of VC appeared to be in accordance with Michac?! is-Monton kinetics as described bv the ocuation: Va V K -r S (1) In this equation, v and V , are the velocitv and maximum m velocity respectively for the bio trans forma t.ion of VC expressed as pg equivalents VC metabolized per 6 hours. S and K are the concentration of VC beinc inhaled and the m Michaelis constant expressed as eg VC/- air, respectively. To ascertain whether Michaeiis-Menten kinetics were applicable, the data in Table 1 were analyzed in accordance with the ) i ;i< .< r Id,o 1 1 /.'igu V bo V : : a,,.: f or::, i I i on of the M Lchav 1 i n-Mefiton (nr.i.i L i o.i (Coye'., i'.'VO/, v (2) VVC 000003163 --o-- It can be seen from the plot (Fig, l) that the data appear to lie along a straight line then verifvincr, at least visually, the Michae1is-Menton model. V and K can be estimated by the ordinate intercoot and the slope of the line or they can be estimated directly by fitting the nonlinear Michaelis-Menten model. Both procedures yield similar parameter estimates. The estimates derived bv fitting the model directly are 855811117 (SD) ;:g VC metabolized and 8601159 (SD) ug VC/i air for and respectively. Once a means is obtained to calculate the amount of VC metabolized by rats as a function of exposure, it is then possible to relate the untoward effects associated with \1C exposure to the amount biotransformed rather than the exposure concentration of VC per se incurred bv rats exposed to VC. Multoni and Lefemine (1975) reported the incidence of hepatic angiosarcoma in rats exposed to different concentrations of VC, 4 hours/dny, 5 duys/wcok for 12 months and subsequently held for observation untiL dutch (Table 2). Before attempting to relate `cheat- data to t lie <imou:ih or VC b io Lrany Lonnud in accordance with the Michaelis-Menten equation using the previously determined values of V and K , the value for V ^m m must be adjusted for the shorter exposure duration used bv VVC 000003164 -7- Hi'-nl is accomp 1 i :,|r '! Py mi j 1 I. ! 1 - I y i 11 g V I )/(,. Thun, the: amount of VC biotransformed daily by rats exposed to the various concentrations used in the experiment of Maltoni and Lefemine can be calculated from the ecuation: v 5706 ( UQ VC, A V-, v- ) S(^) S60 (^-) S (^) x. (3) The resulting values for v are given in Table 2. a-Figure 2 depicts a logarithm probability plot (orobit plot) of the incidence of hepatic angiosarcoma observed in rats by Maltoni and Lefemine (1975} versus the amount of VC biotransformed for 4 hours of exposure, v, or the exposure concentration, S. The incidence of hepatic angiosarcoma in rats is linear with respecr no log v but not log S. The line drawn for log v versus tumor incidence (Figure 2) was doter- m in*" i by 11i ri'i .i t > i wi, i t r ' i r ; ; i on i ri i I /:: i p mg ran, and the u'lu-.i t i'Jii r<_ i u t. tha mcid^aise of hepatic a ng i.oua rc:t;!ia to log v was: nrcbit response = -1.625 ^ 1.543 loq v (4) VVC 000003165 -8- Using the foregoing equation, a projection below the levels of exposure producing an experimentally discernible response has been made (dashed line). Assuming no threshold for the induction of angiosarcoma in rats exposed to VC, the exposure concentration producing one angiosarcoma in 10,000 rats can be calculated. The probit percent representing an incidence of 0.01% is 1.28. Substitution of this value into the equation (4) yields: Log v = 1.8827 v = 76.33 gg VC metabolized/4 hours Using equation 3, the concentration of exposure to VC needed to give this value for v is 11.66 ug/9. or 4.6 ppm (approximate 95% confidence limits obtained by substituting the upper and lower 95% confidence limits for v in equation 3 and solving for S are 0.03-3.7 ppm). Hence, exposure of rats to 4.6 ppm VC for 4 hours daily, 5 days/week for 1 year can be expected to produce one angiosarcoma per 10,000 rats if the dose-response curve remains valid at exposures less than those producing a discernible experimental response. VVC 000003166 -9- DISCUSSION For many chemicals, toxicity may not be a function of exposure to the chemical per se, but rather to a biotrans formation product of the chemical. Frequently, production of a toxic metabolite is dependent upon' enzymatically mediated reactions which are classically described by Michaelis-Mentcn kinetics. Since enzymatically mediated reactions are concentration-dependent and saturable, toxicity resulting from exposures to chemicals requiring activation to a toxic form cannot be related directly to the magnitude of exposure or dose. In such a case, it is necessary to determine the amount of the chemical undergoing biotrans formation as a function of dose or exposure before a meaning ful dose-response relationship can be established. There is considerable evidence that vinyl chloride requires bioactivation to produce tumors. Metabolic activation is required to induce mutations in bacteria exposed to VC (Bar tsch e t a 1 . , 19 7 5 ; Me lav lei J o 19 7'',,. Vei V' l } < * b 1 rrl : ;.g n i r*t al. , 19 7 5 ; Ranr.ug i ' C to hep. 11. i r ri.-icro- !..i i 1 i < : u 1 < in r .it . (\L> r . i r i a \j>j ( 1. . i 1 . , 19 7 7) nape <-d to 1VC also requires bioactivation. Covalent binding of elcctro- phile:; to [>;.'A hu:; been aecu: i a t ed with tumor i genes i . vve 000003167 -10- For vinyl chloride-induced hepatic angiosarcoma in rats, a logarithmic probability plot (probit plot) of the incidence versus the amount of vinyl chloride metabolized, v, over a rang-,- of expose res from 50 to ] 0,000 ppm VC gives a classical :, i ; i i ; j ' I i 11< , !'!'/ - < 'fh < < lo pen:; < r< I i I i ons h i p j not a straight Line when plotted as a function ot the exposure cone-lit r.i jun, (rig. '/.),) . Those rr-sult.u support further the cone ! !: or; id. a VC r :11 i r < r, b j o L r .1 no 1 o 1 ;;ia t i on to an active re! I t 1 < I o 1 1" o / i ;' j 1' '. : :. . S' 1 j r t.' ,r mo r <:, ..1 mere- r. van or nib 1 r r evaluation of the dose-response data for vinyl chloride induced tumorigenesis requires knowledge of the amount of VC activated as a function of exposure. After arbitrarily excluding data acquired from rats exposed to concentrations of VC exceeding 500 ppm in the experiment of Maltoni and Lefemine (1975), Schneiderraan et al_ (1975) extrapolated the remaining data to predict an incidence of 0.01% hepatic angiosarcoma in rats exposed to 1 ppm VC. This number is reasonably close to our prediction of 4.6 ppm VC for the same incidence. If Schneiderman et al_ had used all of the data, a dose-response curve with an unrealistically shallow slope v/ould have resulted and the predicted level c,iun:r:'j 0.01 , o'-o.O.ie n nq i o:;u r coma v/ou'ld have been much smaller, on the order of 0.00001 ppm. vve 000003168 -11- Thc concepts developed herein allow use of all of the data [ / r ' ' .< I; t < < I h / fv I I 1 O l, ; ill') J ,' ) * ! H I M 1 {l / 1 'i e i , j,; , | j- 11 < ' I .1 d r /:r1 r j n pon:.e curve on . i c: i < vi I. i t i e, i 1 1 / d <_ I t 11:. i 11} e bu i . As sum i i ig that the resulting dose-response curve can be projected beyond the range of the experimentally discernible responses, the r / po:. 11 r < f ' >u< :< r 11 r i t i oi i ri'ifu i r'1'! to produce -in i no i donee o (: 0.01'i hepatic angi osaroorna in rats is 4 . 6 ppm. Aside from interpreting toxicity data for chemicals requiring activation to a toxic form, there are some practical implica tions of the concepts presented herein for designing experi ments to assess the toxicity, including carcinogenicity, of such chemicals. For these chemicals, increasing the concen tration above the apparent will produce diminishinglv smaller increments in the response; no increase in the response is to be expected when the exposure concentration is 2 or 3 times K . Since total dose is a function of in exposure time as well as concentration, it is important to determine the effect of exposure time cn the response. j shown in Equation 3, the only parameter influence^ by As exposure time is V , which is increased linearly with time. in 1 Therefore, after the concentration to which the animals are exposed becomes 2 to 3 times Km , the amount metabolized, v, . i 1 ! iiirr'M.v lin'-irly with mcnMidn'i <.-xpo:;u r>. tine*. For VVC 000003169 -12- this reason, the gradation of incidence of angiosarcoma in rats exposed to high concentrations of VC will become a function of exposure time rather than concentration. This reasoning makes it imperative that the duration of exposure its well ns exposure- concentration be considered in evaluating the ri'-'uj ] t: ; or op i d r-ri } o 1 og 1 cn 1 stud i or; of people; exposed to 11 i - ,11 < ' / / i1' f i I t i I i ' < 11'. < < i `/o i f i t 11 < '//ink n v i i ' / m/ii< n I. , nr ile.r. I.h'- 'f ;j 7n L , M i oh a c; ! i:. -lien t.< m Ly pe pharmaco kinetic parameters are resolved prior to designing the experiment, the results may be robbed of much of their value for characterizing the dose-response function for the untoward effects observed. Thus, the current approach using the maximum tolerated dose as defined presently and fractions thereof, may be scientifi cally unsound if the objective is to assess the potential toxicity of exposure to much lower doses or exposures. For some chemicals detoxification of the chemical per se or reactive metabolites formed from the chemical may also be dose-dependent and saturable leading to a build-up of toxic materials. in such cases, the incremental responses to increasing doses or exposures will become dispropor1 j i / fi. t ' 1 y ] > r< r r . t * L < r h "i n r-ir. 11 J < * m (';<< C* *h r i ng and R1 au , ] ') 7 7 ) . VVC 000003170 -13- In the foregoing analysis of the dose-response data for the induction of angiosarcoma in the rat, no threshold for the response was assumed. As indicated, extrapolation below the range of doses resulting in an observable response may over estimate the response in rats because there is evidence that detoxification of reactive metabolites of VC may occur more <: f f i 1 i, L 1 y imL:; f o corKs-n t. m t ion:; of VC bo lev/ SO ppm (vM! <! n.ihe *_ til tOVOr:). Tnde-.-d, I'urlitK'r analysis of the data reported by Multoni and Lefemine (197a) also provides an indication of a practical threshold. In a subsequent p/ > , 'ii t /i I. j on (/[ data, i L. V/aS revealed I haL t'.ne latency for the development of hepatic angiosarcoma was respectively 64, 70, 78, 81, 79 and 135 weeks for rats exposed to 10,000, 6,000, 2,500, 500, 250 and 50 ppm VC (Maltoni, 1975). These results indicate that at some low levels of exposure the time required for induction may exceed considerably the life expectancy for rats. This is consistent with the work of others suggesting that multiples of a lifetime may be required for expression of cancer in response to low doses of a carcinogen (Druckrey, 1967 and Albert and Altshuler, 1973). Thus, extrapola tion of the data obtained for rats below the range of exposures causing a discernible response may be expected to overestimate the projected i ncidunco. VVC 000003171 -14 The ultimate objective of a toxicological study is to develop data which can be used to assess the potential risk for man. It is worthwhile to utilize the concepts presented herein to achieve this objective realising fully that such extrapolation is fraught with uncertainties. The basic assumptions made are: 1) Induction of angiosarcoma is related to the amount of reactive metabolite of VC per unit of mass. 2) Exposure of rats for 12 months approximates exposure of workers for their working life. 3) There is no threshold for the induction of angiosarcoma in either rats or man which likely overestimates the assumption of risk as discussed above. 4) The efficiency of the metabolic processes involved in the conversion of VC to the reactive form is propor tional to the body surface area. Since data for the biotransformation of VC by man are not available, the most logical basis for translation of the animal data to man would seem to be on the basis of body surface area. VVC 000003172 -15- The last assumption deserves comment. There are considerable data in the literature showing that metabolism in general and other physiological parameters as well are relatable directly to the surface area of the body (sec Sehmi.dt-Nie Isen, 1970 } and Pinkol, 1958). For this reason, administration of biolo gical ly active chemicals to various species frequently gives . 111 ` ' i 11 i I < - r 11 i ` 11 , > ,/r e 11 t 1,' (!(,:,> is -1(11111 r i i fit ` ) ('if in proportion to the surface area of the body, that is dose per S'; u > r1 iw i ' r o I body s i j t 1 . c :< ( Pi n V. < i , i 9 5!') This re 3 a fion- ship is gaining recognition in estimating the risk incurred by man from exposure tc chemicals in the environment (Committee on Safe Drinking Water, National Research Council, 1977). In utilizing this relationship it must, however, be recognized that the original relationship was developed for biologically active agents. Since metabolism and other phvsioloqical processes involved in dotoxification are more active in smaller animals, the dose of a biologically active chemical per unit of mass required to produce a given effect increases as the body mass decreases, while the dose per unit surface area remains rolacively constant. However, for a chemical ; equ i. r i raj <ic t. i vn t: ion 1; o the b i.o locji. an I 1 y active toxic form, the total amount transformed will be roughlv proportional to the body surface area. Since toxicity is a function of *. -.a coseentrarron of the active form in tissue, this total o * ` r i' r r .o' ' b" norm i / ; for m.-.s:; to . i: v ! ! : i ! r : ,;, i. . VVC 0000031*3 -I6 Using aforementioned rationale, the maximum velocity, V , for a 70 kg man can be estimated bv calculation usinq the V value 3m obtained for a 0.250 kq rat. The Vm of man for VC will be : V (man) rn V 1.85 sq m . (rat)( m 0.045 sq m or V (man m (8998 iiy/6 hr) mm> - 331829 pg/6 hr '///,'/< I he v t j J 11' :. \ .cir.fi 0.0-15 sq m aro- the body surfae'* areas of a 70 kg man and a 0.250 kg rat, respectively (Pinkel, 1958). For an 8 hour exposure, the value is 469105 ug/8 hr. In order to use this number to theoreti cally estimate the response in man using data collected in rats, the for man must be adjusted to a mass equivalent to that of rats since toxicity is a function of concentration in tissue. To do t.hi.s the- number is divided by 70 kg/0.25 kg or AHh. T! l` : r f S! 1 1 l i 1 if J V f.or man on .1 huiss ( . (. {u i v a 1 uni bus i s m to that of rats is 1675 ug/3 hr. Using this value, the amount of VC transformed to a reactive form by man on a mass equiva lent basis to rat is given by the equation: V g/8 hr 1675 l:ct/3 hr . S uq/f, 860 sg/s + S ug/i (5) vve 0003174 -17- Using this equation, the amount of VC transformed by man on a mass equivalent basis to rats was calculated as a function of exposure concentration ar.d the expected incidence of angio sarcoma estimated from equation 4 (Table 3). For men exposed to greater than 200 ppm VC, the incidence of angiosarcoma has been reported to be 0.02% (Fox and Collier, 1977). Hence, the theoretical calculated incidence using data from rats exceeds that currently detected by approximately 50 fold. This may indicate that people are less sensitive than rats to the induction of angiosarcoma or it may indicate that a practical' threshold for the induction of anglesarccr.a had been attained. Consistent with (hi:, lot f "i [n \ [j \ l i. y in t ha I. Von < i m< i.;s < -c: a i va ! v n1. basis to rats for men exposed to 200 ppm is G25. This number i. <' 1 o v/ lh.it for r 11 s c ;: .< ,'d to 70 ppm. As indicated previously, anylosactxnua observed in rats exposed to 50 ppm occurred only in a rat that lived 135 weeks (Maltoni 1975). Further, this rat did not die as a result of the angiosarcoma but was killed. Thus, as indicated previously, projection of the data collected in rats below the range of exposures producing an ob.cervabie response mav overestimate the incidence. 0000^ V'/C -18- Inspite of the likelihood of overestimating the incidence of angiosarcoma in rats or man, the incidence predicted for people exposed to 1 ppm, the current OSHA (Occupational Safety and Health Act) standard, is very small (1.5 per 100 million)'. This value which is likely an overestimate is h' ! ow t he ex pee ted i no i donee o f upon l.antour; an gi osar coma repo r t i i tv > he do I o >. '> (:. i sr n in I. ho U . b , annual I. y (Ma kk , et al, 1976) . In summary, it has been demonstrated that the incidence of VC induced angiosarcoma in rats is relatable not to the < ' ,i i' a (11 f . i I j ' ,n nl i x) < / a i f - bill t a I i \< i \ < > I 1 a 1 < i hk a 1111 oh VC bi o trans lormtatl. bio trans tormu Lion ol VC by rats is a dosedependent process characterized by Michaelis-Menten type kinetics. The concepts evolved from this analysis reveals why pharmacokinetics must be considered in designing toxicology experiments as well as in interpretation of the resulting data. Having characterized the dose-response for et induction angiosarcoma in rats as a function of the amount r of VC biotransformed, a theoretical estimate of the incidence expected to occur in exposed men was undertaken using the data collected in rats. For daily 8 hr exposures to 1 ppm, l h" p r ('d i o t '.-d i no i < i< no* is 1.5 in 100,000,000 which is less than chat expected to occur spontaneously. This predicted VVC 000003176 -19incidence is likely an over-estimate of that which will occur as a result of exposure to .1 ppm because there is some evidence for at least a practical threshold in both rats and man. There are no illusions that this estimate by extraoolation of data outside the range of doses causing experi mentally observable responses and subsequently to man is without flaws. However, the rationale used represents a new approach which utilizes more logic than methods employed currently for such extrapolation.0000031 000003177 vvc 20- REFERENCES Albert, R. E. and Altschuler, B. (1973). Considerations relating to the formutation of limits for unavailable peculation exposures to env i. r onim-e ta 1 carcinogens . i' i'I i o i. i' I j ' i' < i rr i r.'; : i < . i s , l' r < >< ' i i ir j'. of t. y j <- 1 2 f h Annual Hanford HioJoriy Nyrnp' i urn at Richland, Wa sh i ng ton , 231-253. Bartsch, H., Malavielle, C., and Montesano, R. (1975). Human rat and mouse liver mediated mutagenicity of vinyl ehloridf i :i f-il rori'-l 1 a \ vsh i ran r i urn strains. Tnt^ A. r.ui'-'-t , It, 1/7 4 d. Cf -if .'ii i I I 1" on h i I minting Wm < r (19 7 7). hum; i o y I'cnort: Drink i ng V/at.or and Health, Advisory Center on Toxicology, Assembly of Life Sciences, Washington, D.C. r Druckjtey, H. (1967) . Quantitative aspects in chemical carcinogenesis. In Potential Carcinogenic Hazards From Drugs. Evaluation of Risks, R. Trubant, Ed., UICC Monograph Series, Vol. 7, Springer-Verlag, Berlin, 60-7a . Food and Drug Administration Advisory Committee on Protocols for Safety Evaluation (1971) Panel on Carcinogenesis Report on Cancer Testing in Safety Evaluation of Food Ad'l i I i 7'::, .ind R< 1 i ': j d- s , To;-:. And. Rh-> rcnco 1 . , 2 0: 4 1 9 03 . 0000031^9 v\rc -21- Fox, A. J. and Collier, P. F. (1977). Mortality experience of workers exposed to vinyl chloride monomer in the manufacture of polyvinyl chloride in Great Britain, Drib. J.__Ind. Med., 3 4 : 1-10. Gehring, P. J. and Blau, G. (1977). Mechanisms of carcino genesis: Dose-Response. J. Environ. Path. Toxicol., in press. Makk, L., Delmore, F., Creech, J. L., Ogden, L. L., Fadell, E. H., Songster, C. L., Clanton, J., Johnson, M. N. and Christopherson, 17. H. (1976). Clinical and morphologic effects of hepatic angiosarcoma in vinyl chloride workers. Cancer, 37:149-163. Malavielle, C., Bartsch, H., Barbin, A., Camus, A. M., and Montesano, R. (1975). Mutagenicity of vinyl chloride chloroethyleneoxide, chloroacetaldehyde and chloroethanol. Biochem. Biophys. Res. Comm., 63, 363-370. Maltoni, C. (1975). The value of predictive experimental environmental carcinogenesis. An example: vinyl chloride. Ambio, 4:13-23. Maltoni, C. and Lefcmino, 0. (1975). Carcinogenicity assays of vinyl chloride: Current results. Ann. N.Y, Acad. Sci., 246, 195-224. VVC 000003179 -22- Mantel, N. and Bryan, W. R. {19GD. "Safety" testing of carcinogenic agents. J. Nat. Cancer Inst., 27, 455-470. Pinkel, D. (1958). The use of body surface area as a criterion of drug dosage in cancer chemotherapy. Res . , 18 : 853-856 . Cancer Rannug, U., Johansson, A., Ramel, C. and Wachtmeister, C. A. (1974). The mutagenicity of vinyl chloride after metabolic activation, Arabio , 3, 194-197. Schmidt-Nielsen, K. (1970). Energy metabolism body size, and problems of scaling. Fed. Proc., 29:1524-1532. Schneidcrman, M. A., Mantel, N. and Brown, C. C. (1975). From mouse to man - or how to get from the laboratory to Park Avenue and 59th Street. Ann. N.Y. Acad. Sci., 246, 237-243. Segel, I. H. (1976). Biochemical Calculations, 2nd Ed., pp. 236-237, John Wiley and Sons, Inc., New York. Wagner, E. R., Mueldcr, W. V.1., Watannbe, P. G., Hefner, R. E., Jr., Braun, W. H., and Gehring, P. J. (1975). Gas chromatographic method for the preparation of "'C-iabeled vinyl chloride, J. Labeled Compounds, 11, 535-542. vve 000003180 -23- Watanabe, P. G., McGowan, G. R., Madrid, E. O., and Gearing, P. J. {1970a) . Fate of ^C-vinyl. chloride* following inhalation exposure in ral:n 3_7 , <19-59. Toxicol . Appl . Pharmacol . , Watrunabo, P. G., McGowan, G. P.., and Gchri.ny, P. J. (1976b). Fate of ^^C-vinvl chloride after single oral administra- tiori in rair;, Toxicol. Arad., Pharmacol . , 96, 339-352. Watanabe, P. G., Hefner, R. E., Jr., and Gehring, P. J. (1976c). Vinyl chloride induced depression of hepatic nonprotein sulfhydrvl content and effects on bromosulphthalein (BSP) clearance in rats, Toxicology, S_, 1-8. Watanabe, P. G., Zerapel, J. H., Pegg, D. G., and Gehring, P. J. (1977) . Hepatic macromolecular binding following exposure to vinyl chloride. in press. Toxicol. Appl. Pharmacol., vve 0003181 -24 LEGENDS Figure.- ]. . M(."tabo.l. i.sm of viriy] chloride.* analyzed In accordance with the VJooi F-Auqustiriuon-Hof.stee linearized form of i h': /-I i r: h. i e I i - Mf n t fn i ju a I j or \ . Value:; of v a rid v/S were taken from Table: J . The line was fit by 1 i w -o r r '-') r er;r; i on a rm 1 yi . The co r rcl.a ti on coefficient, K, was 0.88. Figure 2. (a) Metabolism of vinyl chloride expressed as 'log v (i-2----------------------------------) versus percent -incidence or hepatic angiosarcoma (probability scale). (b) Exposure concentration expressed as log S (pom) versus the percent incidence of heoatic angio sarcoma. The probit equivalents of the nercent incidence are shown on the right hand ordinant. The solid line is the best'fit for experimentally observed responses while the dashed line represents extrapolation below those doses producing an observable response assuming no threshold. V vc 00000312 -25FIGURE 1 CO > o co o r itn VVC 000003X83 26 FIGURE 2 YVC 000003184 Log S ^r i--t ! -27- TABLE 1 Parameters for Describing the Metabolism of Inhaled Vinyl Chloride (VC) Using Michaelis-Menten Kinetics Exposure Concentration S (ocm VC) 9 25 51 109 250 511 1020 4 600 S (yq VC/Z air) 3 3.6 23.0 64.0 130.6 279.0 640.0 1308 . 2 2611.2 11776.0 yq VC metabolized13 v" 6 hr 30 + 3C 242+26 557+42 1181+93 2406+173 3826+345 62631355 4257+765 9255+1467 v/S 8.33 10.52 8.70 9.04 8.62 5.93 4.79 1.63 0.79 3 1 ocm VC = 2.56 ug VC/Z air b Determined from the total radioactivity in the carcass C Mean standard deviation VVc 0003185 -28- u ae 0) -H o X ox u cc^ QJ 01 C- Q M m CN fN U'a o n ?c\ I--I 04 04 X -H X o ai u -.h QJ 'O rH m u 4-J o lO rH C ^ CT' MOC < X CJ G H --1 r; i 1 r, >i }, > ri 04 co 04 ro CO o^ \n -r ro O ro CO CO .0 f i - r - 1.0 ro cn (, . . 1 ** ' ' ' i r i ' j f 4 4( c; o '/) O c: r 1 St o rH c X< id 5-4 o X H CX CN <D rd U a. u C CD XI 0 P3 CJ < <4-1 H 0) 0 'CJ QJ N rH rH 0 XI H f--1 ro o co in CO rd X >- 04 o co r--\ CO ro X x -4> in o ^3* r- CD - - - * H c- o lo >n m co OJ CJ > X QJ N rH <--I O .a rj X GJ e CJ > IT1 VD o r- m II VO -'U Cj) Ii H 1 O XJ x xi C <u E VD U > tr x ax xu xa CO co m m co r: j ; 'll i 1 '(J 4-* X ai rj CQ E c LO o rH H rH 4J 0 rd X f--1 o OJ 4-1 u0 us o CJ <5 .--. i - <H fd C3 o O O O CO oH <4 Jt, VO VO ro o vr CO 04 ^r VD 04 i--1 u- -- > X> 1-0 LO VO r--4 t-04 r--1 cr --- CO C 0 ,_, rH CJ a 4J > 5-i rz O O o CD O o ;0 F. - o O o o in LO O', i J CJ rj i.O i.O c J o * r . 'j t, -- rj /. f > '` ; c: . (J 5^ > H <TJ O' ji c>C -- VO in 04 1 u > f f 4. c r< C4 r J 5< ;J U> > -t Ui . ! \ O -- CJ'1 a. LO >: -- o to x+ 3U o > 5-1 .-- XX CO o. -- Ut' VO Oo VM o- CJ1 o. o VO in CO o a1 4- o> o u u o u D- .-- m iCT\ r-4 '---' 0 G ' rH E 0 MO a X T3 C <d H c o X I--l a V' 5 o 5i u XI VVC 000003186 P a oo pP d dJ 0 tO O C. X U-l Wo 0) do c xr--j O x to 0 r- C 0OE a. O 0d /"H u d d o 0 Cl *H p xr--1 0 rH 0 U cr C r; o i-i < 0 O' m\p O 0 x X *H E-1 o CP Occ r- w H V dx 0 >: p d Cl to 0 p CO H c ca a < X0 0 CJ a. to x JJ wd Oa <n 0 tf e o Cn C fc. H H d5 "rD- X 0o0 E c. P to U ri o o 0 I.., , (') !> i . t . I 4 1 O <) ffl u U li 3 E- oa 0 X d -p p d O, a > r; d i 'U 0 > c, d eo rK u 4-) 10 (u ou d 3X oo0 v-. P <4-1 CO ur^ oX 0 in o p Cl, 0, c >, to o i--1 d E 01 < 3 cn OE i--t 3 o dGo o rH -P d 4-1 to 000 u u H o CP 0 x 0 N *H f--1 0 X r~\ d p 0 CO E u > cr p > 000003181 \/\ft O i1 V. <". 3< to jj o c: i D u 29- J vo ol i--i o OJ --# i-H. .o i--t X X r--( o C" n. ro --i CO CO rst >^r \D cn cn in .. CM r-t o o ) CP T CP G .r- m rO r. fi <l , i ri VO r- L/1 T" 03 CM f-i '3' . CD CJ C4 *3" CO 'C* C 1 '/J 111 , | C1 C l in r- t r 1 t~Nj O o in >~l C tn CJ I--i d c dO E H P Pu Oo VJ-i a. X ou d rv E > to -n 0 4J d VJ 4J O 0P X Xd p d r-- EP CP > C o H CP p pc d H p r--1 E c 330 O CO rH r~~i to d dd> a H >3 p X cr 00 p0 p "d dd E to to d c o0 >--I d Cl pV dO 3 r-j jj C' CJ 0: P i > i d 0 r-t CP P3 o -rH 0 --1 P d cn t u3 to t--i H cn rO --1 H d 0X d E-* X 0 H (0 JJ 0d .C P Vj cr> O C cm r^ > .-t p C 0 3 C7 0 10 X 3 CO to d3 X 30 C CO TJ r-4 0Ed P0 . d 0 I-L< <-A J-i d \ 30 CP U XJ 0 r-4 a d Xd \5 td rt '* i m E .c 3 ti o 10 00 JJ 1! ,Q X > X 0X 0 E cn op tx, d E X C. X O 0 u00 Gl p CO dX 0 X -U >~. * r--1 p P M cX 0o 3 cr 0 0 cn 0 X> 3 iH cn P o 0 a to p0 X 0 4J 0 '" X P m c0 o H 44 p d dJ 30 CP c 0 *rH E P Vi H 0 XP o0 'C f.\ to fi d O jf p-t d <x 0 0U P dd to 30 U r-t CP dc ud to p do ? 0 0o CO a O d3 a CO V 0c Pp *H X0 00 O, 0 a T> 0 r-l tJ ) Oo 0 . P X0 0 O 00 xx b* p u Chloroe thylene Vinvl chloride ca.'I onz-rh^n': i-R * ! \)f > J. i r;ui Doso-rcsponGO INDEX TERMS VVC 000QQ3188 22936 RULES AND REGULATIONS . i "/ !'J ( [4910-13] [Airspa.ce Docket No. 78-WT-5J PART 71--DESIGNATION OF FEDERAL AIRWAYS, AREA LOW ROUTES, CONTROLLED AIRSPACE, AND RE PORTING POINTS PART 73--SPECIAL USE AIRSPACE Designation of Temporary Restricted Area AGENCY: Federal Aviation Adminis tration <FAA), DOT. ACTION: Final rule. SUMMARY: These amendments des ignate a temporary restricted area identified as R-2309 In the vicinity of Bill Williams River Valley, Ariz.. to contain high explosive detonations. These amendments provide for the safe and efficient use of the navigable airspace by prohibiting unauthorized flight operations of nonparticipating aircraft within the designated areas during the designated period. EFFECTIVE DATE: July 13, 1978. Period of designation is August 27, 1978, through September 2. 1978. FOR FURTHER INFORMATION CONTACT: Mr. Richard Huff, Airspace Regula tions Branch (AAT-230), Airspace and Air Traffic Rules Division, Air Traffic Service, Federal Aviation Ad ministration, 800 Independence Avenue SW., Washington, D.C. 20591; telephone: 202-426-3715. SUPPLEMENTARY INFORMATION: History On April 20, 1978, the FAA proposed to amend Parts 71 and 73 of the Feder al Aviation Regulations (14 CFR Parts 71 and 73) to designate a temporary restricted area identified as R-2309 in the vicinity of BIJ2 Williams River Valley, Ariz., to contain high explosive detonations and to include this re stricted area in the continental control area for the duration of its time of designation (43 FR 18741). Interested persons were invited to participate in the rule making proceeding by submit ting written comments on the proposal to the FAA. We received two responses to the NPRM in which the commenters posed no objections to the proposal. Sections 71.151 and 73.23 were republished in the Federal Reg ister on January 3, 1978, (43 FR 344 and 664). The Rule These amendments to Parts 71 and 73 of the Federal Aviation Regulations designate a temporary restricted area in the vicinity of Bill Williams River Valley, Ariz., to protect nonparticipat- ing aircrSit from a large scale airblast associated with a high explosive field test program called Misers Bluff which involves the detonation of high explosives. In addition, the airspace at and above 14.500 feet MSL during the designated period (continuously from 0001 August 27. 1978, through 2400 hours, local time September 2. 1978) is Included in the continental control area. These amendments adopt the airspace actions proposed in the NPRM (43 FR 16741). fn accordance with established FAA policies, the using agency has provided the FAA with a statement that the require ments of the National Environmental Policy Act have been met. Drafting Information The principal authors of this docu ment are Mr. Richard Huff, Afr Traf fic Service, and Mr. Richard W. Danforth, Office of the Chief Counsel. Adoption of the Amendment Accordingly, pursuant to the author ity delegated to me by the Administra tor, Subpart D of Part 71 and Subpart B of Part 73 of the Federal Aviation Regulations (14 CFR Parts 71 and 73) as republished (43 FR 344 and 664) are amended, effective 0901 G.m.t., July 13,1978, as follows: In 71.151, the following temporary restricted area Is added for the dura tion of its time of designation from 001 hours, August 27, 1978, through 2400 hours, local time, September 2, 1978: R-2309 Misers Bluff. Ariz. In 73.23, the following temporary re stricted area is added: R-2309 Misers Bluff, Ariz. Boundaries. A circular area with a 10-nautical mile radius centered at lat. 34*15.5' N., long. 113*52.5' W. Designated altitudes. Within a 3,000-foot radius centered at lat. 34*15.5' N., long. 113'52.5' W., surface to FL 320; within the circular area that lies between the 3.000foot radius and the lO-n&utlc&l mile radius centered at lat. 34*15.5' N.. long. 113*52.5' W., 100 feet above the surface to FL 320. Time of designation. Continuous, 0001 August 27 through 2400 hours, local time, September 2, 1978. Controlling agency. Federal Aviation Ad ministration, Albuquerque ARTCC. Using agency. Defense Nuclear Agency Field Command. Kirtland Air Force Base, N. Mex. (Secs. 307(a), 313(a), Federal Aviation Act of 1958 <49 U.S.C. 1348(a) and 1354(a)); sec. 6(e), Department of Transportation Act (49 U.8.C. 1655(0): and 14 CFR 11.69.) Nor*.--The FAA has determined that this document does not contain a major proposal requiring preparation of an Economic Impact Statement under Executive Order 11821, as amended by Executive Order 11949, and OMB Circular A-107. Issued in Washington, D.C., on May 23. 1978. William E. Broadwater. Chief, Airspace and Air Traffic Rules Division. [FR Doc. 78-14896 Filed 5-26-78: 8:45 ami 16355-01] TiHe 16--Commercial Practices CHAPTER II--CONSUMER PRODUCT SAFETY COMMISSION SUBCHAPTER C--FE0ERAL HAZARDOUS SUBSTANCES ACT REGULATIONS PART 1500--HAZARDOUS SUB STANCES AND ARTICLES; ADMIN ISTRATION AND ENFORCEMENT REGULATIONS Self-Pressurized Household Sub stances Containing Vinyl Chloride Monomer; Classification as Banned Hazardous Substance AGENCY: Consumer Product Safety Commission. ACTION: Confirmation of final order. SUMMARY: The Commission an nounces that no objections have been filed within the statutory period to Its final order of March 24, 1978 classify ing any household substance in a selfpressurized container containing vinyl chloride monomer, manufactured or imported on or after October 7, 1974, as a "banned hazardous substance.'* In this document the Commission, there fore, confirms the final order. DATES: The effective date of the rule declaring any household substance In a self-pressurized container containing vinyl chloride monomer to be a banned hazardous substance la June 22, 1978. The rule is applicable to products which have been manufac tured or Imported on or after October 7,1974. FOR FURTHER INFORMATION CONTACT: Charles Jacobson, Consumer Prod uct Safety Commission, Directorate for Compliance and Enforcement, Division of Regulatory Management, Washington, D.C. 20207. 301-4926400. SUPPLEMENTARY INFORMATION: On March 24. 1978 the Commission published in the Federal Register, 43 FR 12308, a final regulation1 pursuant to section 2(q)(l)(B) of the Federal Hazardous Substances Act (FHSA), 15 U.S.C. 1261(qXl)(B), declaring any 'Editorial note: The final regulation re vised 16 CFR 1500.17(a)(10). FEOERAl REGISTER, VOL. 43, NO. 104--TUESDAY, MAY 30, 1978 VVC 000003X89 RULES AND REGULATIONS 22937 self-pressurized products intended or suitable for household use, manufac tured or imported on or after October 7, 1974, that contain vinyl chloride monomer (VCM) as an ingredient or in the propellant to be "banned hazard ous substances." The final regulation was a reissuance of an earlier fully ret roactive ban (39 FR 30112) that had been set aside for failure to hold a hearing on objections to the retroac tive effect of the regulation. (For a complete background discussion on the original ban, see the preamble to the March 24. 1978 notice.) In the March 24, 1978 document the Commission affirmed its determina tion made in the original ban that selfpressurized household products con taining vinyl chloride monomer are toxic hazardous substances within the meaning of the FHSA because of vinyl chloride monomer, which, when in haled, has the capacity to produce substantial illness, specifically cancer. Because no safe level of human expo sure to vinyl chloride monomer has been established, the Commission fur ther affirmed its earlier finding that adequate cautionary labeling could not be written under the FHSA for self-pressurized household products containing VCM and concluded that the degree and nature of the hazard presented by the use of these products is such that the public health and safety can be adequately served only by keeping the products out of inter state commerce. In taking the banning action, the Commission noted that ample scientific evidence in the form of long-term animal bioassays and human epidemiological studies is avail able to demonstrate the carcinogen icity of vinyl chloride monomer by in halation and to demonstrate that human exposure to the substance can result in angiosarcoma of the liver, a rare form of liver cancer. The March 24, 1978 banning regula tion also provided, as is required for the issuance of regulations pursuant to section 2(q)(l)(B) of the FHSA, that the procedures for rulemaking under section 701(e) of the Federal Food, Drug and Cosmetic Act would govern and that adversely affected persons could file objections and re quests for a public hearing within 30 days of the publication of the Commis sion's final order. The last day for the filing of objec tions with the Commission was April 24, 1978. Since no objections have been filed within the statutary period, the Commission in this document con firms its final order of March 24, 1978, declaring as banned hazardous sub stances any self-pressurized household products containing vinyl chloride monomer as an ingredient or in the propellant, manufactured or imported on or after October 7, 1974. (Secs. 2(f)(1), (A), (B). (g), (q)(l)(B), 3(a), 74 Stat. 372, 374, as amended 80 Stat, 1304-05, 83 Stat. 187-189, 90 Stat. 503 <15 U.S.C. 1261. 1262); sec. 701 <e>, <f). <g), 52 Stat. 1055-56. as amended 70 Stat. 919, 72 Stat. 948 (21 U.S.C. 371 (e), ((>, (g)); sec. 30(a), 86 Stat. 1231 (15 U.S.C. 2079(a)).) Dated: May 23,1978. Sadye F. Dunn, Acting Secretary, Consumer Product Safety Commission. (FR Doc. 78-14883 Filed 5-26-78; 8:45 ami [4810-22] Title 19--Customs Duties CHAPTER 1--UNITED STATES CUS TOMS SERVICE, DEPARTMENT OF THE TREASURY [T.D. 78-1501 PART 153--ANTIDUMPING Carbon Steel Plate From Japan AGENCY: U.S. Treasury Department. ACTION: Finding of dumping; final rule. SUMMARY: This notice is to inform the public that separate investigations conducted under the Antidumping Act, 1921, as amended, by the U.S. Treasury Department and the Inter national Trade Commission, respec tively, have resulted in determinations that carbon steel plate from Japan is being sold at less than fair value and that those sales are injuring an indus try in the United States. On this basis, a finding of dumping is being issued and, generally, all unappraised entries of this merchandise will be liable for the possible assessment of special dumping duties. EFFECTIVE DATE: May 30, 1978. FOR FURTHER INFORMATION CONTACT: Stephen Nyschot, U.S. Customs Service, Office of Operations, Duty Assessment Division, Technical Branch, 1301 Constitution Avenue NW,, Washington. D.C. 20229 202566-5492. SUPPLEMENTARY INFORMATION: Section 201(a) of the Antidumping Act, 1921, as amended (19 U.S.C. 160(a)), gives the Secretary of the Treasury responsibility for determin ing whether imported merchandise is being sold at less than fair value, Pur suant to this authority the Secretary of the Treasury has determined that carbon steel piate from Japan is being sold at less than fair value within the meaning of section 201(a) of the Anti dumping Act, 1921, as amended (19 U.S.C. 160(a)). (Published in the Fed eral Register of January 13, 1978 (43 FR 2032).) An "Amended Determina tion of Sales at Less Than Fair Value" was published in the Federal Register of March 27, 1978 (43 FR 12780). Section 201(a) of the Antidumping Act, 1921, as amended (19 U.S.C. 160(a)), gives the United States Inter national Trade Commission responsi bility for determining whether by reason of such sales at less than fair value a domestic industry is being or is likely to be injured. The United States International Trade Commission has determined, and on April 18. 1978, it notified the Secretary of the Treasury that a domestic industry is being in jured by reason of less than fair value imports of carbon steel plate from Japan. (Published in the Federal Reg ister of April 24, 1978 (43 FR 17410)). On behalf of the Secretary of the Treasury. I hereby make public these determinations, which constitute a finding of dumping with respect to carbon steel plate from Japan, For purposes of this notice, the term "carbon steel plate" means hot-rolled carbon steel plate, 0.1875 <ie) inches or more in thickness, over 8 inches in width, not in coils, not pickled, not coated or plated with metal, not clad, and not cut, pressed, or stamped to non-rectangular shape. Section 153.46 of the Customs Regu lations (19 CFR 153.46) is amended by adding the following to the list of find ings of dumping currently in effect: 153.46 List of current findings. Merchandise, country and T.D. Carbon steel plate, Japan. 78-150. (Secs. 201, 407, 42 Stat. 11, as amended, 18 (19 U.S.C. 160, 173).) Robert H. Mundheim, General Counsel. May 23, 1978. [FR Doc. 78-15014 Filed 5-26-78; 8:45 ami [4110-031 Title 21--Food and Drugs CHAPTER I--FOOD AND DRUG AD MINISTRATION, DEPARTMENT OF HEALTH, EDUCATION, AND WEL FARE SUBCHAPTER B--FOOD FOR HUMAN CONSUMPTION [Docket No. 77N-01771 SODIUM THIOSULFATE; AFFIRMA TION OF GRAS STATUS AS A DIRECT AND AN INDIRECT HUMAN FOOD INGREDIENT AGENCY: Food and Drug Administra tion. ACTION: Final rule. SUMMARY: This rule affirms that sodium thiosulfate is generally recog- FEDERAL REGISTER, VOL 43, NO. 104--TUESDAY, MAY 30, 1978 VVC 000003190