Document 03Ddb9DXx1exgJmR0zn8mmwn

SUMMARY o f p r e l i m i n a r y t o x i c o l o g i c i n v e s t i g a t i o n OF THE LEAD ALKYLS The toxicologic behavior of tetraraethyl lead and certain of the other lead alkyls was investigated at The Kettering Laboratory some years ago. Although these studies were limited in scope the information obtained has been reviewed and constitutes the subje of this report. For the most part, rabbits were employed as the experimental animals in these investigations, which consisted primarily of at ter-' to obtain information as to the lethal dosages of tetramethyl lead, dimethyl-diethyl lead, trimethyl-ethyl lead, triethyl-methyl leal and a mixture containing tetraethyl lead and the other alkyls in definite proportion. In order to point up possible differences in the toxic responses induced by tetramethyl lead and tetraethyl ic comparisons with the latter material have been made so far as i.-* n were available. Certain of the chemical properties of these materia are listed in Table 1. SUMMARY OF INVESTIGATION AND RESULTS The investigation of tetramethyl lead included observations of the toxic manifestations resulting from its administration to rabbit intravenously, subcutaneously, orally, upon the intact skin, and by inhalation; determination of the approximate lethal dosages by each 0 0 0 3 4 10 -2- route of administration, as compared to tetraethyl lead; analytical determinations of the distribution of lead in the blood and,body tissues,, at various intervals after the administration of the com pound ; and, demonstration of the pertinent gross pathologic changes produced in the body tissues. Similar observations were made with the other alkyls except that the intravenous and subcutaneous rout'-: of administration were omitted. The data relative to the lethal aosages, as summariset in Ta suggest that there are certain differences in the toxicologic bohav of tetraethyl lead and tetramethyl lead, which can be accounted for in part (but not entirely) by differences in their chemical compos. tion. It will be noted that, when the two compounds are iuorcduce. directly into the blood stream of rabbits, aeaths occur at. a lower dosage of tetraethyl lead than of tetramethyl lead. The gross path ologic lesions (multiple infarction in the lungs) of tne animals injected intravenously with tetraethyl lead indicate that the early deaths were the result of the immiscibiiity of the com pouno with bConversely, when these two materials (TEL and f?-!L) were administers subcutaneously (as a 20 per cent solution ir. almond oil), tebrameta lead appeared the more toxic, a reversal of the relationship noted after intravenous administration. The results obtained, following the oral administration of tat ethyl lead and tetramethyl lead, reveal another striking difference which deserves comment. Tetramethyl lead administered orally, was lethal at one-half the lethal intravenous oose, e.g., it was twice He 0003411 -3- toxic, via the oral route. On the other hand TfiL was founa to be less lethal, when administered orally, than intravenously, a phenom enon which may be explained in part on the basis of its immiscibility' ^ith blood, as noted above.* Observations made following the application of the several com pounds upon the intact skin of rabbits demonstrated highly divergent, results. Whereas the lethal effect of the application of tetraethyl lead upon the skin of the rabbit was evident and uniform at a suitable dosage (750 mg./pb per kilogram), no fatalities were produced by tetramethyl lead under comparable or even much more severe conoitions, i.e., contact of the skin of the rabbit with as much as 7000 mg./Fb per up kilogram ,for periousyto 3 hours. This discrepancy can be explained, in part, at least, by the high volatility of tetramethyl lead, where! / the quantity on the skin decreases progressively following its applica tion. Support for this opinion is provided by the fact that 500 mg./Fb per kilogram (as TML) applied under a glass cell cemented to tnc skin produced illness which was followed by slow recovery. It would seem that this dose (500 mg./Pb per liter for 1 hour) is not far from the lethal range when the liquid is confined to prevent its becoming volatilized. The inhalation for 1 hour of pure tetramethyl lead, in air, under * This is not the entire explanation, for the earlier observations, on tetraethyl lead demonstrated its appreciably greater toxicity when administered intravenously, than when given orally, even under 'conditions (in emulsion) which eliminated pulmonary infarction. It was evident that trie absorption of tetraethyl lead from trie alimentary ..tract was comparatively slow ana incomplete. K-e 00C3412 i -if- conditions in which 4.5 mg./Pb per liter (as TML) were delivered into the respiratory chamber (after this concentration had been achieved) produced deaths, whereas the concentration of 2.3 mg./Pb per liter, delivered similarly, was not lethal. Exactly comparable experiments with tetraethyl lead are not available, and strictly parallel experiments will have to be carrie out in order to make satisfactory comparison. The available information, which is neither sufficiently precise nor sufficiently definitive of the minimum lethal concentration, in relation to specific periods of exposure, indicates that the concentration of tetraethyl lead which is lethal, following 1 hour of exposure, is lower than that of tetramethyl lead. When deaths occurred from 12 hours to 7 days after the administra tion of tetramethyl lead by any route, analyses of the tissues demon strated quantities of lead of the same general order of magnitude, and distributed in the tissues in much the saTMe manner, as those found previously, following the administration of tetraethyl lead. Liver, kidneys, bone and brain consistently showed the highest concentrations of lead. When deaths occurred within the first 24 hours, the levels of lead concentration in the blood and blood-containing organs (heart, spleen, kidneys) were elevated well above normal values. The most consistent features of the illness wnict followed the absorption of tetramethyl lead were weakness, diarrhea, weight loss, irritability, tremors ano convulsions. Patnologic findings iiiciuoed ^congestion of lungs, liver, brain and kidneys, in most inotances, regardless of the route of administratinn. 00034 3 -5- It can be seen from Table 2 that, following the oral administra tion of the individual lead alkyls and of the mixture of all of them, the lethal dosages were of the same approximate order of magnitude (in mg.of Pb per kilogram) as that of tetrsmethyl lead. Comparison of the lethal dosages of the several compounds applied upon the intact skin, suggests that there is a close resemolar.ee between trimetn*! ethyl lead ana tetramethyl lead, in that respect, in all likelihood because of their similar volatility. The percutaneous ubsor .t-ion f aimethyl-diethyl l e a d , triethyl-meohy.1 lead ana the mixt.o.j * of _ alkyls produceu ueaths only when the uo sages an] lieu npc-n tie s in increased two to three times higher cnan that of tetraethyl 1e a n . The triethyl-methyl derivative, as well as the mixed alky:5 , were of lethal, following 1 hour/exposure to air containing approximately 4 ' "f i </ Pb per liter. T* 1-ethyl-etnyl lean was .Lethal at ap] roximafcvjiy 01 c 1f of that concentration (2.0 mg. /pb per liter)., /'hen aeaths resulted from trie administration of these oompotnus. ! 1\ i :>. the tissues demonstrated the presence of lead in qu.Vib.i Lt a in manner of distribution generally co-parable to those found. 1:> . iug the administration of tetramethyl lead. 7 be g r o s s pathological changes induced by the absorption of the various methyl-ethyl ;eri',,i t. -res, ana the mixture thereof, -were of generally similar tvpe. A much more detailed analytical investigation of the tissues of at.}-a ' subjected to various experimental conditions with respect to co^cou.ru dosage and iiiterval of time after trie administration of the .jo-pourc in a specific m a n n e r , would be required to disclose any cLgnii icur.t r 0003414 -6- consistent differences in the extent end the pattern of distribution of the organic lead compounds and their metabolic (degradation) products, These matters will require further investigation if justi fication is afforded for such further investigation by the technologic. cr commercial utilization of these co^pounos. From The Kettering Laboratory in the Department of Preventive Medicine Lt . d Industrial Health, College of Meciicine, University of Cincinnati. Cincinnati3 Ohio, Experimental Work by: Willard F, Machle, 1 9 3 5 ,193o,1937 fieport- by: Albert a , Brust, M,D, Date: June 1^, .1959 Robert , Kehoe, M,.. D Director 0003415 | Compound Tetraethyl lead Taole 1 Formula (C2H5 )4sPb Density 1.00 t Per Cent p-25C | Le&ci 64.0 0.5 Tetramethyl lead (CH3 )4 ^Pb 1.99 77.5 30.0 Trimetbyl-ethyl lead i ]Dimethyl-diethyl lead (CHa )3 ^ pp (C8HB K * (GH3 )2=>pb (C2H 5)e^ Triethyl-methyl lead (CH3 ) ^ p b (g2h s )3^ jAlkyl Mixture* l.*W 73.7 10.0 o e c*~\ 1.79 70.2 1.71 67.0 1.0 1.795 o7.0 6.2 *This mixture contained the following .mounts of tne leau alxyls (expressed in moles per cent): tetraethyl 5.4; tetrametnyl 7.5; trimethyl-ethyl 24.0 ; dimethyl-diethyl 35.5 and triethyl-methyl 27. ( 0003416 Compound * Tetraethyl lead 20$ in almond oil pure compound I.ethal DosagtS of the Le.vi Alkyls Following Their Administration to Rabbits I.V. (mg.Pb7kg.) Not LeHal Lethal Subcut. Oral (mg.Pb/kg.) (mg.Pb/kg.) Not Not Lethal Lethal Lethal Lethal, Cutaneo Applicat (mg.Pb/k Not Lethal 15 17 250 (1) 20(4) 20 40 500(3) Tetramethyl lead 20$ in almond oil pure compound 30 40 50 30 (1) 70 10 20 7000 500(3) 5 Trimethyl-ethyl lead - - - - 10 15 2100(1 Fir Dimethyl-diethyllead - - - - 7 10 1200 Triethyl-methyl lead - - - - 15 20 700(1h -) Alkyl Mixture ` - - - - 20 25 1700 (1) Not carried to lethal level. (2) Comparable information not obtained. (3) Contained in glass cell cemented to skinj duration of exposure 1 hour. (4) Deaths accompanied by embolism, not necessarily associated with, or independ . (5) Animal became ill but survived.