Document 50GVMdZJJoqR3EyjXzpaaRmB8

PROCEEDINGS OF THE SYMPOSIUM ON INDUSTRIAL SOLVENTS February 13- 14, 1974 C a r n e g i e - M e l l o n Institute of R e s e a r c h Pittsburgh, Pennsylvania Industrial Health Foundation 5231 Centre Avenue P i ttsburgh, Penns y lva nia 1974 I PETROLEUM HYDROCARBON SOLVENTS *R o b e r t A. S c a l a , P h . D. T h e n a m e m o s t c l o s e l y a s s o c i a t e d with t h e toxicology of p e t r o l e u m h y d r o c a r b o n s i s t h a t of H o r a c e W. G e r a r d e . D r . G e r a r d e w a s killed prematurely in a plane c r a s h in Turkey about two o r three weeks ago. I n f a c t , a m e m o r i a l s e r v i c e will be held f o r h i m on S a t u r d a y of this week. I have known D r . G e r a r d e s i n c e I e n t e r e d t h e f i e l d of toxicology and o u r c a r e e r s a t E s s o o v e r l a p p e d f o r about a y e a r . Out of r e s p e c t f o r his m e m o r y and his contribution to what is known about the toxicology of p e t r o l e u m h y d r o c a r b o n s , in m y own s m a l l w a y , I would like t o dedicate this particular paper. It is impossible in the time that I have available to me to discuss a l l that i s known a b o u t t h e toxicology of p e t r o l e u m h y d r o c a r b o n s . I t i s like talking about t h e t o x i c o l o g y of c h e m i c a l s o r t h e toxicology of p l a s t i c s . So in the next 3 0 m i n u t e s o r s o 1 would like to d e s c r i b e a p r o g r a m which is r.ow in its s i x t h year a t t h e B u s h y Run L a b o r a t o r i e s of Mellon I n s t i t u t e , Carnegie-Mellon University sponsored by the petroleum industry. This work will be published by D r . Carpenter and his colleagues there. The d a t a which a r e e m e r g i n g , I think, will be of interest t o all of u s . T h e work was sponsored and is continuing to be sponsored by the petroleum industry at large. Now the f i r s t q u e s t i o n i s raised: "Why bother to have a n industrywide p r o g r a m ? I' T h e f i r s t s l i d e is a r e p r e s e n t a t i o n of what we believe to be the justifications f o r industry-wide support, at least in our industry, f o r toxicological s t u d i e s . F i r s t of a l l , f e w materials are novel in the petroleum industry. In the petroleum industry a r e quite limited resources in the d i s c i p l i n e of toxicology. T h e r e a r e n ' t v e r y m a n y toxicologists. V e r y few of the c o m p a n i e s , have t h e i r own toxicology l a b o r a t o r y . T h e i n c r e a s i n g and unending d e m a n d s f o r r e s e a r c h o n t h e e v a l u a t i o n of s a f e t y a r e so e x t e n s i v e t h a t n o one company c a n afford t o do everything that has to be done. F i n a l l y , the influence of, what I politely call "non-scientific e l e m e n t s " on t h e scope and d e s i g n of t h e r e s e a r c h p r o g r a m s i s b e s t m e t on t h e b r o a d e s t p o s s i b l e b a s e . T h e r e is a l w a y s a question of credibility and we feel that by having a broadly funded, broadl y o p e r a t e d , b r o a d l y s c r u t i n i z e d p r o g r a m , we c a n m e e t c e r t a i n of t h e i r objections. *Senior Research Associate, Esso Research & Engineering Company, Linden, New J e r s e y 26 T h e h i s t o r y of the p r o g r a m i s a s follows: I n t h e S p r i n g of 1968, the Subcommittee on Toxicology of the American Petroleum Institute (that's the trade association which I will be referring to as API) began putting together a research program on solvents for several reasons. F i r s t of a l l , t h e r e r e a l l y w e r e no good toxicity d a t a on p e t r o l e u m solv e n t s s i n c e the t i m e B. C. - - t h a t ' s b e f o r e c h r o m o t o g r a p h y . T h e work of L e h m a n n , F l u r y , and Z e r n i k , and s e v e r a l o t h e r p i o n e e r i n v e s t i g a t o r s was all concentrated, f o r the m o s t p a r t f r o m 1928 to 1932. T h e r e had been additional scattered publications in the literature, but we felt that there was no sound data base. Along with this, the Threshold Limit Values (TLV's) for petroleum compounds were perhaps set on something o t h e r than a s t r o n g d a t a b a s e ; m a n y of t h e m by a n a l o g y , m a n y of t h e m based on quite limited work. The Committee did the best it could with what it had to work with. T h e idea that p e t r o l e u m products a r e safe b e c a u s e they have had a long h i s t o r y of safe u s e i s what we c a l l 'Ianecdotal". That i s , the plant n u r s e d e c l a r e s , "We have n e v e r had anybody injured!'. O r someone s a y s , "We have been using this solvent f o r 30 years in our plant and we have had no problems. In most people's opinion, that is no l o n g e r a s a t i s f a c t o r y m e a s u r e of the s a f e t y of a material. There are newer concepts in setting threshold limt values. It's no l o n g e r a m a t t e r of w h e t h e r the w o r k e r c a n be e x p o s e d eight h o u r s a day, five days a week , for an indefinite work time without falling dead, or being injured in s o m e way that is immediately apparent. T h e newer concepts involve nuisance, odor, discomfort, perhaps even biochemical changes. These are things that Dr. Stokinger and his TLV committee a r e w r e s t l i n g with e a c h t i m e they m e e t . We all know t h a t t h r e s h o l d limit values a r e being incorporated into legislation and into various operating codes,and the A P I would like to see those numbers, if they are going to be incorporated, established on the soundest possible basis. We anticipated in 1968 that we would have occupational health and safety legislation, which, in fact, we do. Finally, the industry is trying to take a responsible position. (Slide 2) D r . Golz, t h e f o r m e r M e d i c a l D i r e c t o r of t h e A m e r i c a n P e t r o l e u m I n s t i t u t e , e x p r e s s e d i n 1968 t h e e s s e n c e of why we a r e doing what we a r e doing. "In the a b s e n c e of soundly based toxicological and e x p o s u r e d a t a , industry i s f a c e d with the likelihood of being r e g u l a t e d by unne c e s sa r i ly r e st r i ctive st a n d a r ds a r bit r a r i ly e s tabl ishe d without sou nd scientific foundation. It is believed that the petroleum industry can p l a y a role i n the e s t a b l i s h m e n t of the s t a n d a r d s by which it w i l l be r e g u l a t e d if it i s willing t o u n d e r t a k e p r o m p t l y a n o r g a n i z e d Long-range p r o g r a m of toxicological i n v e s t i g a t i o n of i t s p r o d u c t s . I ' T h a t g e n t l e m e n , is really why I am standing here today. T o give you the f i r s t f r u i t s of that c o m m i t m e n t . I t is a continuing c o m m i t m e n t . I t h a s been an expensive one. 27 (Slide 3) I want t o now acknowledge the a s s o c i a t e s t h a t I have had in this program. T h i s is the A P I ' s Committee on Toxicology a t the time this program was first established. I merely wish to acknowledge formally t h e i r continued s u p p o r t and p a r t i c i p a t i o n . (Slide 4) F o r p u r p o s e s of o r g a n i z a t i o n of o u r p r o g r a m , we have s e t up a c e r t a i n n u m b e r of r e s e a r c h p a n e l s . This is s i m p l y to show you how we have subdivided o u r t a s k s to look into things. T h e first p a n e l i s the one which has been c o n c e r n e d with the work I will t a l k about f o r the m o s t of the r e s t of m y t i m e . (Slide 5 ) T h o s e of you who have s t u d e n t s know that it is a l w a y s good t o s t a r t them o u t in a n e x p e r i m e n t with a s t a t e m e n t of o b j e c t i v e s . Why a r e w e doing t h i s r e s e a r c h ? So the objective of t h i s e x p e r i m e n t a l p r o g r a m i s to define t h e t o x i c i t y of p e t r o l e u m products. W e a l s o have as a n objective,recognition of o u r r e s p o n s i b i l i t y to c a r r y o u t a p r o p e r p r o g r a m - - t h a t the i n d u s t r y does have r e s p o n s i b i l i t y f o r t h e s a f e t y of its products. The emphasis, initially, in this program, was on materials under review by the T L V Committee. L a t e r on, we selected materi a l s o n the b a s i s of c o m m e r i c k a l usage, availability of d a t a , and o c c u p a tional health needs, Two other things need to be pointed out. W e excluded benzene and m o t o r fuels f r o m this p r o g r a m as we have s e p a r a t e r e s e a r c h studies on those two products, Early we established what we believe to be satisfactory interaction with the TLV Committee and that interaction has continued. They see all the data a s soon as we s e e it. The approach to t h i s p r o g r a m was s e v e r a l - f o l d . F i r s t of a l l , we wanted to identify m a t e r i a l s of i n t e r e s t f o r s t u d y , then we wanted to c h a r a c t e r i z e t h e -c h e m i c a l composition of the p r o d u c t s s e l e c t e d . W e f e l t we would c h a r a c t e r i z e toxicity, which is different f r o m determing hazard. We a r e going to c h a r a c t e r i z e t o x i c i t y through a study of acute and s u b a c u t e effects in animals, and limited study in man. Finally, we hope to develop techniques f o r c o r r e l a t i o n , p r e d i c t i o n of potential e f f e c t s , a n d / or safe exposure levels. O u r initial q u e s t i o n w a s what d e t e r m i n e s the toxicity of a p e t r o leum hydrocarbon? A r e there any physical characteristics or other p r o p e r t i e s that might be c l u e s to the toxicity of the m a t e r i a l ? W e thought boiling range and a r o m a t i c s content would be c r i t i c a l d e t e r m i n a n t s of toxicity. T h e r e was s o m e precedent f o r this i n the l i t e r a t u r e To relate these items in o r d e r to allow u s to do meaningful experiments and avoid repetitious experiments a s well as identify toxicologically important compositional matters needs a matrix approach. (Slide 6) Our m a t r i x was simply a graph to relate total aromatics content in p e r cent and boiling r a n g e i n d e g r e e s F. We could put as a point on that m a t r i x e a c h solvent we wanted to study. W e could t h e r e - 28 f o r e identify c i r t i c a l a r e a s of zones, and also avoid doing what we would consider to be repetitious experiments. (Slide 7) T h e s e a r e the basic a n i m a l e x p e r i m e n t s which we a r e doing on t h e s e s o l v e n t s and include the a c u t e LC50. We u s e r a t s and we expose t h e m f o r f o u r h o u r s . We then did a s i m p l e a c u t e inhalation study using cats and dogs. These were also four hour exposures. The final acute test simulated a massive over- exposure. Rats were exposed at a significant level above the LCso f o r a s h o r t period. Finally we c a r r i e d out a conventional subacute inhalation study f o r six hours a day, five days a week, for 13 weeks using rats and dogs at graded levels. We a l s o did a challenge acute e x p o s u r e o n a c e r t a i n n u m b e r of these animals after they had been through this 13-week exposure regimen These animals, plus some animals which had never been exposed before were.given a brief, high level exposure to determine whether o r not t h e r e was a n y hardening o r any increased sensitivity. We m e a s u r e d the t i m e to d e a t h , b e c a u s e we gave t h e m a v e r y high d o s e . If the a n i m a l s which had been exposed for 13 weeks died e a r l i e r , their exposure had r e n d e r e d t h e m m o r e s e n s i t i v e . If they d i e d l a t e r , t h e i r e x p o s u r e had rendered them less sensitive. O u t of 14 m a t e r i a l s which we have s t u d i e d , we have s e e n one i n s t a n c e of h a r d e n i n g , t h a t i s lowered s e n s i t i v i t y , as the r e s u l t of p r i o r exposures and no instances of increased sensitivity. Finally, we did respiratory tract irritation tests, an excellent p r e d i c t o r of r e s p i r a t o r y i r r i t a t i o n in m a n . (Slide 8) The human protocol included two experiments. One was o d o r p e r c e p t i o n a n d t h e o t h e r was s e n s o r y i r r i t a t i o n . T h e n u m b e r s of subjects a r e small, f e w e r than 10. W e didn't realize a t the t i m e how important these experiments were. I think it will become apparent as I w o r k m y way t h r o u g h s o m e of the data. (Slide 9) T h e s e a r e the r e s u l t s of t h e e x p e r i m e n t s which w e r e c a r r i e d o u t in t h e f i r s t year of the study. We s t u d i e d t h r e e s o l v e n t s , V M & P Naphtha, Stoddard Solvent and Rubber Solvent. These are common s o l v e n t s in t h e i n d u s t r y and they h a v e r e l a t i v e l y low a r o m a t i c s content. T h e term " hygienic standard" is employed by o u r contractor, Mellon I n s t i t u t e of C a r n e g i e - M e l l o n U n i v e r s i t y is t h e i r i n t e r p r e t a t i o n of t h e i r findings. I n c i d e n t a l l y , this w a s a " hands off" e x p e r i m e n t . W e gave the contractor guidance, and counsel, but the data and the interpretations are t h e i r s . "Hygienic standard" is their evaluation of an acceptable industrial exposure level. These data are the property of the people carrying out the experiments. Manuscripts have been prepared 29 and a r e in the p r o c e s s of being submitted to the journal Toxicology and Applied Pharmacology. The hygiene standards have been expressed as parts per million and milligrams p e r liter. The chamber measurements a r e based on m i l l i g r a m s p e r l i t e r of m a t e r i a l which was c o n v e r t e d by m e a n s of a n average molecular weight to parts per million. The parts per million figures given in the data tables a r e derived figures. The milligrams per liter figure is a laboratory measured figure. F o r V M 81 P n a p h t h a , the hygienic s t a n d a r d w a s b a s e d o n the human studies. There was a human sensory response at a lower level than in the animal studies. F o r Stoddard Solvent, it was the animals that were the more.sensitive. F o r Rubber Solvent, the 800 parts per million figure is based on the human response, (Slide 10) Now we get into the 1970 s t u d 5 T h e f i r s t thing to be explained i s the terms t h a t we used. Mixed xylene is one which is common to you, just like the three names on the previous slide. 60 Solvent, 70 Solvent, 140 F l a s h Aliphatic a r e what we call trivial names. These a r e names which we have used within the program to identify these solvents. First of all, b e c a u s e we don't know who supplied t h e m , t h e r e f o r e , w e don't know t h e a c t u a l t r a d e n a m e for t h o s e s p e c i f i c m a t erials. Secondly, because there is no generally accepted trade name within the entire industy. The numbers generally bear some relationship either to flash point, as in the latter case, o r to the kauri-butanol number. The .Mixed X y l e n e s t a n d a r d i s 230 p a r t s p e r m i l l i o n , one m i l l i - .g r a m p e r l i t e r , b a s e d on t h e human work. The 6 0 Solvent figure i s 45 milligrams per liter (90 parts p e r million) and that is based on a n i m a l work. T h a t o n e h a s t h e biggest q u e s t i o n m a r k of any of o u r work. The 70 S o l v e n t s t a n d a r d is 100 ppm (0. 54 m g / l ) based o n both human and a n i m a l w o r k . T h e s t a n d a r d f o r 140 F l a s h Aliphatic is 37 p p m (0. 23 mg/l) and it is based on the m a x i m u m obtainable concentration. This illustrates the third criterion for selecting the hygienic standard. 140 Flash Aliphatic solvent has such low vapor p r e s s u r e that it was not possible to achieve a vapor concentration high enough to cause any effects in either the animals o r in man. The standard is therefore, t h e maximum o b t a i n a b l e c o n c e n t r a t i o n . T h i s s t a n d a r d s i m p l y r e f l e c t s the maximum obtainable vapor concentration. One could generate a m o r e concentrated t e s t atmosphere, even as a vapor, but it is no longer 140 F l a s h Aliphatic Solvent. Again, the ground rule was to achieve a8 high a vapor concentration as possible, and still have the vapor composition the same as the liquid composition. Any higher termperature. in effect, d i s t i l l e d off t h e l i g h t ends of the solvent. 30 . . ..,... I . . Y..,I (Slide 11) 80 T h i n n e r a n d 50 T h i n n e r a r e t r i v i a l n a m e s , and the hygienic s t a n d a r d s a r e 150 p p m (. 6 5 m g / l ) and 430 ppm ( 1 . 7 m g / l ) , respectively. The human studies on deodorized kerosene have been c o m p l e t e d and the maximum o b t a i n a b l e concentration (. 11 m i l l i g r a m s p e r l i t e r , 16 p a r t s p e r m i l l i o n ) s e e m e d t o be the limiting f a c t o r . The standards are in brackets because they a r e still teaative. (Slide 12) For toluene concentrate the tentative f i g u r e is 1. 9 m g / l , (488 ppm), a g a i n based o n h u m a n studies. Toluene c o n c e n t r a t e i s a l m o s t 5070 toluene and the s t a n d a r d i s a t s o m e v a r i a n c e w i t h t h e T L V for toluene. T h e s t a n d a r d f o r 40 T h i n n e r is 2 2 m g / l , (36 ppm). T h e s e are tentative values because the final r e p o r t has not been issued. The high aromatic solvent work i s still in progress. (Slide 13) Another element began to emerge as a possible responsible factor for toxicity besides boiling range and aromatics content and that i s the "naphthene" content. Naphthenes are cycloparaffins. I am not talking about naphthalene, the condensed ring a r o m a t i c , but "naphthenes" which are, saturated ring structures To challenge this prop o s i t i o n a naphthene e x p e r i m e n t w a s d e v i s e d using High Naphthenic Solvent, Naphthenic Aromatic Solvent, and Nonane, which is purely paraffinic. The three solvents have the same boiling range and varying naphthene content: 0 , 4070, 7070. A s r e f e r e n c e m a t e r i a l s , S t o d d a r d Solvent and 70 Solvent w e r e used. This may be viewed as extending the matrix. into three dimensions. (Slide 14) On this slide are noted the various m a t e r i a l s which w e r e studied. T h e t e x t u r e of the s t r i p e u n d e r n e a t h j u s t i d e n t i f i e s t h e y e a r of the study. T h e l e n g t h of t h e s t r i p e , however, is c r i t i c a l , and covers the boiling range for the material. As examples, item D which is Mixed Xylene, and item M, which is the Toluene C o n c e n t r a t e , are fairly narrow bands because they are relatively narrow boiling materials and have r e l a t i v e l y f e w i s o m e r s p r e s e n t . Stoddard S o l v e n t is a m u c h m o r e c o m p l e x m i x t u r e , c o v e r i n g a far l a r g e r n u m b e r of h y d r o c a r b o n s o v e r a b r o a d e r boiling r a n g e . Is t h e r e s o m e way to c o v e r t h a t c h a r t with a series of bands o r z o n e s which will indicate, b a s e d o n a r o m a t i c s content and boiling range, what the TLV should be? (Slide 15) T h i s is the result. M a t e r i a l s to the left of the line, a p p e a r to have hygienic standards of g r e a t e r than 200 p a r t s p e r million, ( g r e a t e r t h a n 1 m i l l i g r a m p e r l i t e r ) . M a t e r i a l s t o the r i g h t of the zig zag line appear to be below 200 parts p e r million (below 1 m i l l i g r a m p e r liter). Low boiling s o l v e n t s r e g a r d l e s s of t h e i r a r o m a t i c s content have relatively high hygienic standards. At a given aromatics content in the bottom third an increase in boiling range results in a decreased hygienic s t a n d a r d . T h e z i g z a g l i n e is s i m p l y a q u e s t i o n of v o l a t i l i t y and 31 . . . . I . . .....,I...-...-.. not a toxicological i s s u e . A low hygienic s t a n d a r d s u c h a s for 1.10 F l a s h Aliphatic and Deodorized Kerosene, is based on the maximum obtainable concentration. So the bottom right i s a zone in which volatility i s a limiting factor, not toxicity o r irritancy to humans. The upper right is an area where high boiling materials o r high aromatics are both operating to k e e p t h e hygienic s t a n d a r d on the low s i d e of t h i s g r o u p of s o l vents. So to a d e g r e e , based on p r e s e n t knowlege, boiling r a n g e and aromatics content do seem to determine the final hygienic standard, even if they don't really determine toxicity. T h e issue is still open because we have not fully resolved the naphthene question, the third dimension on the slide. But we have some tentative conclusions to be shared with you. F o r low boiling materials, aromatics content doesn't s e e m to make a difference, and the materials have relatively high hygienic standards. T h e r e does not seem to be a tremendous need for exposure control based on t h e s e s t u d i e s . F o r high boiling m a t e r i a l s of low a r o m a t i c s c o n t e n t , the volatility seems to be the limiting factor, and therefore, the hygienic s t a n d a r d s will be low, but they will be low b e c a u s e of v o l a t i l i t y , not because of toxicity. And for m a t e r i a l s which are either high boiling or with significant aromatics, (the top right h a d area) lower hygienic standa r d s and g r e a t e r control, seem to be indicated. (Slide 16) This is another experiment being done for API by Dr. C h a r l e s Hine of Hine l a b o r a t o r i e s and invalves m u t a g e n i c i t y t e s t i n g . Mutagenicity is not confined to females; it is also potentially a problem in m a l e s , so dominant lethal tests w e r e performed. T h e r e is no s t a t i s tically significant difference between controls and test animals in t e r m s of dominant l e t h a l e f f e c t , which i s one of t h e c u r r e n t measures of m u t a g e n icity. Additional work related to genetic effects is planned for three of the s o l v e n t s : R u b b e r Solvent, 6 0 Solvent, and the High A r o m a t i c Solvent, in a c y t o g e n e t i c t e s t . T h a t ' s a q u i c k o v e r - v i e w of o u r ongoing program. 32 JUSTIFICATION FOR INDUSTRY -WIDE SUPPORT O F TOXICOLOGICAL RESEARCH Slide 1 * Few materials are novel * Resources in this discipline are limited * Increasing and unending demands for research on evaluation of s a f e t y a r e so e x t e n s i v e t h a t no one c o m p a n y c a n a f f o r d to undertake the bur den * Influence of nonscientific e l e m e n t s on s c o p e and d e s i g n of r e s e a r c h p r o g r a m s is b e s t m e t on broadest possible base. Slide 2 I n t h e a b s e n c e of soundly b a s e d toxicological and e x p o s u r e d a t a , i n d u s t r y i s f a c e d with t h e likelihood of being r e g u l a t e d by unnecessarily restrictive standards arbitrarily established without sound scientific foundation. I t is believed that the p e t r o l e u m industry c a n p l a y a r o l e i n t h e e s t a b l i s h m e n t of the s t a n d a r d s by which it will be r e g u l a t e d if i t is willing t o u n d e r t a k e p r o m p t l y a n o r g a n i z e d , l o n g - r a n g e p r o g r a m of toxicological i n v e s t i g a t i o n of i t s p r o d u c t s . H. H. Colz A p r i l 16, 1968 33 -A P I SUBCOMMITTEE ON TOXICOLOGY S- l_ i_ d- e ~ 3 -E.R. A v e r i l l Mobil -R. W. C a l l Union -I.T. F r i t z Consultant -J.M. M c N e r n e y A P I Staff -C . F . R e i n h a r d t Dupont -W.E. R i n e h a r t E t h y l -R.A. Scala Esso R e s e a r c h -H. W. Spies A m e r i c a n -J.J. T h o r p e Exxon -A.S. Todd Sun -A P I SUBCOMMITTEE ON TOXICOLOGY *Slide 4 -P a n e l s Matrix studies Rinehart, Spies -M e t a b o l i s m Todd, R e i n h a r d t -H u m a n S e n s o r y R e s p o n s e Averill, Spies -Mutagenicity C a l l -Histopathology T h o r p e * Liaison -National C l e a r i n g h o u s e f o r poison c o n t r o l c e n t e r s Spies Ansi 2 - 6 6 C o m m i t t e e on prevention and c o n t r o l of -h a z a r d s t o c h i l d r e n A v e r i l l 34 OBJECTIVE AND IMPLEMENTATION -A P I HYDROCARBON TOXICITY PROJECT * -Objective Define toxicity of petroleum h y d r o c a r b o n s * -E m p h a s i s Initially, m a t e r i a l s under review by T L V Committee L a t e r , m a t e r i a l s selected on b a s i s of c o m m e r i c i a l usage, availability of data, occupational health needs * -Approach Identify m a t e r i a l s of i n t e r e s t f o r study Characterize chemical composition C h a r a c t e r i z e t o x i c i t y through study of a c u t e and subacute effects in animals, limited study in man Develop techniques for correlation and prediction of potential effects and/or safe exposure levels. Slide 6 -100 -90 ' -80 -70 v) $ I2 6o 50 s -C -40 30 -20 -10 100 I I 150 PETROLEUM HYDROCARBON TOXICITY MATRIX 1II I I I 1 III I 200 250 300 350 III 400 450 500 1 - d -.I - - I 550 35 -BASIC P R O T O C O L HYDROCARBON TOXICITY P R O J E C T ANIMAL STUDIES Slide 7 Test Speicies/Number Duration Purpo8e Acute LCs0 Acute Inhalation 15 Rats/ Level -4 C a t s - 1 level Dogs Several levels 4 hours 4 hours Define acute toxicity Species comparability Massive Acute 5 R a t s at 5xLC50 5-15 min. D e t e r m i n e e f f e c t s of acute overexposure Subacute Inhalation 2 5 R a t s and 4dogs 6 hours/D. per level 5 D. /WK. 1 3 WKS. E f f e c t s of r e p e a t e d exposures at graded concentrations Challenge A cute 10 Rats /Level 6 hours Measure changes in susceptibility Respiratory Irritation 6 Mice/Level 1 minute Simulate human r e sponse * Histopathology and statistical analysis done in all tests -BASIC P R O T O C O L HYDROCARBON TOXICITY P R O J E C T HUMAN STUDIES Slide 8 -Test Odor Sensation Duration 5-10 seconds Purpose Determine Concentration at which odor is detected (not identified) Sensory Irritation 15 minutes Determine concentration at which eye,nose, and throat irritation is detected 36 -A P I HYDROCARBON TOXICITY P R O J E C T 1969 STUDY Slide 9 Material VM & P Naphtha Stoddard Solvent Rubber Solvent Boiling Range 'F 250 - 300 300 - 380 -170 230 Aromatics Hygienic Standard 70 PPm mg/l 10 400 2.0 20 200 1.2 <5 800 3.2 Basis H A H BASIS: H = Human S e n s o r y R e s p o n s e ; A = Animal Pathology -API HYDROCARBON TOXICITY P R O J E C T 1970 STUDY Slide 10 Material Mixed Xylene 60 Solvent 70 Solvent Boiling Range -"F 280 290 -260 320 320 - 410 Aromatics Hygienic Standard 70 PPm mg /1 100 230 1.0 50 90 0.44 65 100 0.54 -B a s i s H A H,A 140' Flash Aliphatic -360 410 (5 37 0.23 MC BASIS: H = Human Sensory Response A = Animal Pathology MC = Maximum Attainable Vapor Concentration 37 -A P I HYDROCARBON TOXICITY P R O J E C T 1971 STUDY Slide 11 Material 80 Thinner 50 T h i n n e r Boiling Range "F 210 - 290 210 - 220 Aromatics Hygienic Standard 70 PPm 70 150 mg/l .65 30 430 1.7 Basis H H,A Deodorized Kerosine 410 - 520 c 5 (16) (. 11) MC BASIS: H = Human S e n s o r y Response A = Animal Pathology MC = Maximum Attainable Vapor Concentration Data in Brackets are tentative and subject to change. -A P I HYDROCARBON TOXICITY P R O J E C T 1972 STUDY Slide 12 Material 40 Thinner Boiling Range -"F 370 450 Aromatics Hygienic Standard Basis 70 PPm mg/l 20 (36) (0622) MC Toluene Concentrate -200 230 45 ( 48 0) ( 1 . 9 ) H - -High A r o m a t i c Solvent 365 400 N. A. N. A. N. A. BASIS: H = Human Sensory Response MC = Maximum Attainable Vapor Concentration N.A. = Not Available Data in brackets a r e tentative and subject to change l 38 c -API HYDROCARBON TOXICITY PROJECT 1973 MATERIALS Slide 13 Material Selected Paraffin Naphthene Aromatics 70, Approx. High Naphthenic Solvent 28 71 . 1 Naphthenic Aromatic Solvent Nonane 22 100 41 -- 37 -- Boiling Range "F,E s t . 300 - 400 300 - 400 300 Ref erence Stoddard 70 Solvent 40 41 16 16 -19 300 375 -68 320 410 Slide 14 PETROLEUM HYDROCARBON TOXICITY MATRIX I 100 60 40 cl II I I I I I I I 1 D m .rsrm0 rm MATER1A L S 1969 mtm-8 A. VM 6 P NAPHTHA 8. STOOOARO SOLVENT C. RUBBER SOLVENT - - - 3H F M -E - 1____1 L 1970 0 . MIXED XYLENE E. 60 SOLVENT F. 70 SOLVENT G. 1 4 6 FLASH ALIPH. 1971 %IIIIII H. 80 THINNER 1. 50 THINNER I 1. DEOWR. KEROSINE Q 1972 20 LO I 100 A c -0 1 1 1 0 1 1 I,mt1*lO II I I 150 200 250 300 G I t=- 3 350 400 L. 40 THINNER M. TOLUENE CONC. 0. HIGH AROM. SOLVENT T & I 450 500 550 BOILING POINT IN OF I 39 I -100 -90 * - 80 E 70- -v1 2 60 ff 50-2 c 40 J -3is 3 Q 20 100 II > 1 mg/l C -11111-1 II 150 200 II / .,1)*8*11 II I I I MATERIALS -L --A. .~. V.M... i%P. N...A.P. H..T.H..A.. 8. STODDARD SOLVENT C. RUBBER SOLVENT -1970 D. MIXED XYLENE E. 60 SOLVENT F. 70 SOLVENT G. 140' FLASH AUPH. 1971 H. 80 THINNER 1. 50 THINNER J . DEODOR. KEROSINE 1972 R.nrrnlm..ll.m L. 40 THINNER M. TOLUENE CONC. 0. HIGH AROM. SOLVENT - - - - 1I II I 250 300 350 400 450 500 550 BOILING POINT IN O F -MUTAGENICITY TESTS HINE LABORATORIES Slide 16 -T e s t Dominant Lethal (nonviable Mutations) - -S p e c i e s / D o s e R a t s and M i c e 1 ML/KG -C r i t e r i a Evaluated F e r t i l i t y ((70Pregnant) Conclusions * Mutagenic Index Total Implants x 100) No Mutagenic activity Any effect on fertility would be marginal Marginal effect on fertility possible 40