Document gwZ1mO5gOwrZeYo20Rw0jK6a

f-'T.-"'''- '".'"r'f L J l' . x ..----- * S-8 . STATUS REPORT ON THE CHEMISTRY AND TOXICOLOGY OF POLYCHLORINATED BIPHENYLS (PCB) OR AROCLORS AS OF JUNE 1, 1970 'Bureau of Foods, Pesticides and Product Safety Food and Drug Administration Public Health Service Department of Health, Education and Welfare Washington, D.C. FDA status reports are Intended for internal use only and their distribution and availability are therefore limited. They should not be cited as a publication in the scientific literature. Tho status report docs not constitute a statement of FDA policy, but la solely meant as a summary evaluation of the problem area covered to date. Status reports may Include interim progress and Incomplete developments of unfinished research, which are specifically protected HONS 206308 I. Introduction In 1966- a Swedish scientist, Soren Jensen, revealed that the poly chlorinated biphenyls (PCB) were dispersed widely in the environment, to the extent that he identified PCB in pike (in different parts of Sweden), in othir fish and in an eagle (1). Further analyses for PCB were made in eagle feathers preserved in a museum, some of tliese dating back to 1BB0, but PCB was found in feathers which were collected in 1944. Within the same year of Jensen's observation, Widmark, a colleague . of Jcnscn'3, reported to an international commission studying pesticide analysis that a compound similar to DDT in identification and analysis, which contained chlorine, created a problem in isolation and identification of residues of DDT (2). Since that time TCB hjs been found in fish, sea birds, pine needles, rainwater (not detected as yet in airborne particulates), human body fat and mother's milk (3). As indicated in the following section of this report on chemistry and surveillance (Section II), TCB is manufactured in USA by Monsanto Chemical Company (tradename AroclorW) and in Europe and Japan by other manufacturers. Their industrial uses, as described later, are of a wide variety. Riscbrough and Brodine (3) state that PCB's are recommended for mixing with chlorinated insecticides to suppress their vaporization and extend their "kill life." USDA advises us that as part of an inert ingredient PCB is in some pesticide formulations, especially such insecticides as DDVP, lindane and toxaphene. The addition is apparently for the purpose indicated above. This may be one sourca of environmental pollution by thin extremely persistent fatsoluble compound. In this latter property it is like DDT in that is Is not soluble in water. The scries of Aroclors are marketed under various numbers and consist of mixtures of chlorinated biphenyls and terphenyls. The 1200 series re lates ta the biphenyls, the 3400 series to the terphenyls and the 4400 series to a mixture of bi- and terphenyls. The physical properties of the compounds are related to the chlorine content with viscosity Increasing In direct proportion to the chlorine content from very fluid liquids to viscous products and solids (see Table 3 in Section 11). Initially the concern about this synthetic chemical In terms of human health was limited to occupational exposure, at least prior to 1966. Since then, because of this series of compounds being to widely distributed In the environment and perhaps being as ubiquitous as DDT, their potential hazards to marine, avian, and mammalian species, including man, are being explored. In an investigation on the peregrin falcon (fast disappearing bird of prey), Risubrough et al (1968) showed the presence of some un known compounds, along with DDT and DDE, in the eggs of a falcon nest which did not hatch. These hitherto unidentified compounds were later found to be polychlorinated biphenyls (4). In the North American peregrine . MONS 206309 Page 2 - Status Report on the Chemistry and Toxicology of PCB or Aroclors falcon PCB uas found at level of 1.980 ppm and in a white tailed eas-le in Sweden at level of 17,000 ppm (3). Apparently the greater the distance away from indThuisstriisal ilcluenstterarstetdhe inmoTreabtlhees l1evaendl o2 f CPoCrB td=e"cre^asreisTMfor < and the eggs of sea birds. flICon TABLE 1 DDT and PCB in Peregrine Falcons Total DDTX (ppm) ?CB (ppm) Immature Bird (California) breast muscle (wet) liver (wet) brain (wet) brain lipid carcass (wet) carcass lipid 14.4 ' 7.7 2.8 36.0 20.2 300.0 9.4 4.5 1.5 19.3 19.8 160.0 Adult Bird (California) breast muscle (wet) liver (wet) brain (wet) brain lipid carcass (wet) carcass lipid 127.0 77.0 49.5 595.0 85.0 2600.0 98.0 57.0 34.6 415.0 65.0 1980.0 Ratio of DDT to TCB 1.5 1.7 1.9 1.8 1.9 1.9 1.3 1.4 1.4 1.4 1.3 1.3 Immature Bird (Arctic) breast muscle (wet) breast muscle (dry) liver (wet) brain (wet) body fat carcass (wet) carcass (lipid) 2.3 7.8 1.0 0.43 56.3 9.3 63.7 0.16 0.54 0.10 0.037 3.2 0.80 5.5 14.0 14.0 10.0 12.0 16.0 12.0 12.0 Second Year Bird (Arctic) breast muscle (wet) breast muscle (dry) brain (vet) carcass (vet) carcass lipid 99.0 296.0 85.0 70.0 5000.0 28.0 84.0 21.0 19.7 1420.0 3.5 3.5 4.7 3.5 3.5 x - Includes p,p'-DDT, p,p'-DDEt p,p'-DDD, p,p' -DDMU, o,p1 -DDT and o,p'-DD From Riscbrough et al. reference 4 HONS 206310 Page 3 - Status Report on the Chemistry and Toxicology of PCB or Aroclors '~ TABLE 2 ; PCB Content of Eggs of Sea Birds Species Brnnat's Camorant Pelagic Camorant Hurre Pigeon Guillemot Casslns Auklet Western Gull v *. .Si Black-crowned ijight heron Carplan Tern Forsters Tern Least Petrel Locality . No. of Samples .- Farallon Islands 17 San Mateo County, California 2 Farallon Islands Farallon Islands 6 1 San Mateo County, California 1 Farallon Islands 2 Farallon Islands 1 San Mateo County, California 1 San Francisco County, California -1 San FrancIifsco Bay It 1 1 2 San Dief*go Bay 5 2 Boy a, California it 2 1 *where more than one sample, value is average Average PCB Level* (vg) 11' 62 558 20 62 15 118 118 480 330 24 805 1010 114 3.1 471 From Rlsebrough and Bodine, Environment 12,, No 1 16-27 (1970) Ref 3 Various speculations, alluded to later in this report, have been ad vanced as to the origin of thete environmental pollutants but apparently these compounds, like DDT, are carried by global air currents from the Arctic circle to the southern hemisphere (3). Mora studies are needed to identify the routes of entry of PCB into the environment. Since wide scale distribution of PCB is now recognized, the primary question relates to transmission of these compounds to man through the environment and the possible human health impact from such exposure. For occupational situations the American Conference of Governmental Industrial Hygienists (ACGIH) have set a "threshold limit value" for PCB (containing 42 percent chlorine) of one mg/ro^ of air which happens to be the same as "threshold" for DDT (5). For more heavily chlorinated biphenyls the ACGIH threshold limit is decreased. . HONS 206311 Page 4 - Status Report on the Chemistry and Toxicology of PCB or Aroclos One important observation is that the more lightly chlorinated PCB's are somewhat less persistent and accordingly more readily metabolized and excreted, whereas the highly chlorinated compounds are more persistent and by inference, no doubt, less easily degraded in the body. There is little Uiiown about the metabolites of PCB. (6) ' Sax (5) in his description of dangerous properties of industrial materials includes PCB as a toxic agent affecting human skin and liver at high concentrations, lie describes the lesion produced in the liver as an acute yellow atrophy. Carbon tetrachloride exposure potentiates the toxicity of PCB. It would appear that in rats the acute toxicity of polychlorbiphcnyls (LDjq values) decreases with increase in chlorine content (Table 3). However, in the rabbit, on skin testing, there is a trend toward increased toxicity with an increase in chlorine content up to 542 where there is a decrease in toxicity (Table 3). With respect to hepatotoxic action of chlorinated diphenyls, Risebrough and Brodinc (3) and Sax (5) claim that the higher the chlorine content of the diphenyl compound, the more toxic it is likely to be. Oxides of chlorinated diphenyls arc more toxic.than .the unoxidized materials. Like the skin lesion produced by 2,4,5-T and 2,4-0 and the dioxins, the clinical observations in occupational exposure are that of chloracne. From systemic intoxication the usual symptoms are nausea, vomiting, weight loss, jaundice, edema and abdominal pain. If there is extensive liver pathology, the highly exposed individual may become comatose and die. Risebrough and Brodine (3) have the view that PCB in the environment may not attain those concentrations where severe injury or death from short term exposure would occur. However, they feel that the greatest hazard in continuous low level exposure to PCB may be the chronic effects cither from this compound or combinations of and interaction with other environ mental toxicants. They further indicate there may be a danger in de stroying other forms of life which are part of the food chain (3). Another aspect of this pollution problem Is the necessity of viewing not just the impact on local ecosystems but the global system. If future planning based on exploiting sea resources to feed the increasing population 16 maximized, then this problem of accumulation of PCB as well as other contaminants in marine organisms and other species closely related becomes a critical matter for resolution. Considering this problem in terms of exposure to PCB of many forms of life and of human populations of varying age and states of health demands a re-evaluation of "threshold limit values" regarding safety in terms of inhalation and ingestion. Subsequent reference to the toxicology of PCB in Section 111 of this report also emphasizes the effect of PCB on liver enzymes which, in turn, may relate to hormonal controls and the influence of physiological pro cesses, including reproduction. The fact that PCB has been identified in human fat and in human milk in a series of tests at a level of 0,06 ppm of the whole milk suggests the need for assessment of the hazard of these compounds to mammalian systems is clearly indicated. HONS 206312 page 4 - Status Report on the Chemistry and Toxicology of PCB or Aroclos One important observation is that the more lightly chlorinated PCB's are somewhat .less persistent and accordingly more readily metabolized and excreted, whereas the highly chlorinated compounds arc more persistent and by inference, no doubt, less easily degraded in the body. There is little known about the metabolites of PCB. (6) . Sax (5) in his description of dangerous properties of Industrial materials includes PCB as a toxic agent affecting human skin and liver at high c. ~entraiionr.. He describes the lesion produced in the liver as an acute yellow atrophy. Carbon tetrachloride exposure potentiates the toxicity of PCB. It would appear that in rats the acute toxicity of polychlorbiphcnyls (LDjq values) decreases with increase in chlorine content (Table 3). However, in the rabbit, on shin testing, there is a trend toward increased toxicity with an increase in chlorine content up to 54J! where there is a decrease in toxicity (Table 3). With rospoct to hepatotoxic action of chlorinated diphenyln, Risebrough and Hrodine (3) and Sax (5) claim that the higher the chlorine content of the diphenyl compound, the more toxic it is likely to be. Oxides of chlorinated diphenyls are more toxic.than .the unoxidized materials. Like the skin lesion produced by 2,4,5-T and 2,4-D and the dioxins, the clinical observations in occupational exposure are that of chloracne. From systemic Intoxication the usual symptoms are nausea, vomiting, weight loss, jaundice, edema and abdominal pain. If 'there is extensive liver pathology, the highly exposed individual may become comatose and die. Risebrough and Srodine (3) have the view that PCB in the environment may not attain those concentrations where severe injury or death from short term exposure would occur. However, they feel that the greatest hazard .in continuous low level exposure to PCB may be the chronic effects cither from this compound or combinations of and interaction with other environ mental toxicants. They further indicate there may be a danger in de stroying other forms of life which arc part of the food chain. (3). Another aspect of this pollution problem is the necessity of viewing not just the impact on local ecosystems but the global system. If future planning based on exploiting sea resources to feed the increasing population is maximized, then this problem of accumulation of PCB as well as other contaminants in marine organisms and other species closely related becomes a critical matter for resolution. Considering this problem in terms of exposure to PCB of many forms of life and of human populations of varying age and states of health demands a ro-evaluation of "threshold limit values" regarding safety in terms of inhalation and ingestion. Subsequent reference to the toxicology of ?CB in Section 111 of this report also emphasizes the effect of PCB on liver enzymes which, in turn, may relate to hormonal controls and the influence of physiological pro cesses, including reproduction. The fact that PCB has been identified in human fat and in human milk in a series of tests at a level of 0.06 ppm of the whole milk suggests the need for assessment of the hazard of these compounds to mammalian systems is clearly indicated. HONS 206313 Page 5- Status Report on the Chemistry and Toxicology of PCS or Aroclors Since speculations have been made as to sources of environmental residues of PCU, more definitive information is required to trace the paths by which these compounds move through the environment. There is an important difference between DDT and PCD as environmental contaminants in that the former has been intentionally introduced into the environment while the latter escapes into the environment by accident. 11. Chemistry and Surveillance Polychlorinated biphenyls (PCB) are industrial chemicals with a variety of uses. These compounds arc quite stable and have important applica tions as plasticisers in plastics, as modifiers in many paints and other products, lubricants, electrical insulators, and fire retardants. We understand that they are also used in printing inks, textile dyes, heat transfer fluids, and many other products. In the United States PCB are manufactured by the Monsanto Chemical Company with the tradename Aroclor(R). A series of Aroclors comprised of chlorinated biphenyls, chlorinated terphenyls, and mixtures of these are produced. Each Aroclor is a mixture of a number of individual chlori nated biphenyl or terphcnyl components. Chlorine content of individual Aroclors varies from about 10-70X by weight and the physical prupeitics vary with chlorine content. Those with low percentage of chlorine arc very fluid liquids; as percent chlorine Increases the products become more viscous or become solids, (See Table 3) There, is a food additive regulation permitting the use of polychlori nated terphenyls in adhesives for food packaging, No regulation has issued for polychlorinated biphenyls. We do not know the exact route by which PCB enters food products. Resi dues of PCB hove been found primarily in wildlife. European and U.S. Investigators have reported residues in fish, fish-eating birds, and some wild animals. The first literature reports of PCB residues were in .1967 by European workers. Residue findings although widespread appear to be associated to some extent with industrial locations. Literature in the early 1950's reported increased effectiveness of some chlorinated pesticides when formulated with PCB. There has been some speculation that PCB may be entering the environment via this route; however, wc are aware of no substantiation of this. In addition to waste from manu facturing plants using PCB, it has been suggested that these chemicals may enter the environment via leaching of plasticizer from plastic objects In waste disposal areas and thus enter streams or may enter the atmosphere from the burning of plastics at waste incineration plants. MQNS 20631** iiatui; St'."ort on the Clicaisli,. and To.sicelory nn.,1 n f .. . .. . _ ; _ . . TABLE 3 I* " 1` ^1 physical Properties of the , .. *..* . ` ` r Chlorinated Compounds . ' '. - - f' ** Aroclor 1221 . Aioclor 1232 . * Coloflett Practically mobile oil ,l coloilcn mobile oil S3 Met. (APHA) SO Max, (APHA) 0.014 . 0.014 ketlicioul or Expansion... .cc/k/*C rruily Cffvily.......................... for giUon -- n Fiance - AST M 0-20 (Mod.) r 0.C3071 (15'`<0O 1.1820.192 (25*/IS.S'C) MS 0.00373 (2S*-I00'C) 1.270-1.220 (2SVIS.S*C) I0.SS I7S*-3?0* 290*-32S* lion- Ion -- % -- AS7M 0-6 Mod. -- 1.0 10 1J \* --1.0 to 1.5 - /rtdnt -- Cleveland Open Cup. .......... *c *F L Point -- Clevctand Open Cup.. *F tm Poinl - AST M 0-92.............. ...........*C r* *f Sofltfiinj rinl - ASTU -21....... .......... *C . # ' *F 141**150* 286*-302* 176*349' CiyaUU at 1*0 Ciyilals at 34*f - 152* 154* 305--310* 233* . 460' -35J* . -32* -- Afoelor 1242 Practically colcrlcn mobile oil S3 Max. (APIU) 0.010 0.0006S (2S*-6S*C). 1331-1.392 (25'/la.S'C) 11.50 12S'.366' 3.0 to 3.C 0.0 to 0.4 176MJ0* 34l*-356* None* -1* 2* * -- -- ` Aioclor I7 CoIjiIcsj to liCbt JCtlOW. Iften, c Ira r. mobile oil 50 Me*. (APHA) 0.010 0.03070 (25'OS'C) I.49S-I.4I5 (CS\ I5.5"C) 12.04 340*375* 3.0 to 4.0 0.0 to 0.3 193* 196' 379*014* Hone -7* 19.4* --' --- Airdoi K LijM ydi Vi-.CIUJ !> fO Mai. (APltAt 0.010 0.003:5 (2S'-0V uik-i/ tfS'.-JS . 12 W 365*. 35 1.1 tol 0.0 to 0 None (tone 10* 50* --- rutiMlivc Index -- D-line -- 20*C............... 1.G17-U16 1.670-1.672 _I.C27-I.C29 1.G30-1.C3I 1 .C 39- Vi: rosily -- Siyboil Universal 210T (9L9*C) Set (AST (4 DM) ' ` 130'F (M.4*C) 30-31 35-37 31-32 ` 39-41 34-35 < 49-56 . 36-37 73-10 44 41 ' 2C0-3 100*F P7.CC) 36-41 4-1-51 ( 32-92 165-240 1103 *MaM - % laa tl I* IiN4*M4(7||T /){JT Ot'.'i) LDivj-ratn (iipprojo.)' 3900* 7]7|70* 8650* 11,000* n, B*i 1-1* M ----------- - ;*abb 31;r,-di"Ac ->2000 > T?60* > 79'i* > 79*i* > V.l ------------- <-31 ''i**----vc. 1:i;.-t) OF>P I-----1 ---- -O',-xPVCVO-5-----<--Ii Sr, ojV-- * . r Ar' i nl 1 // 1 n (iOTlI ''V HONS 206315 SSSM20* ` 39S*-425* . 435M5Q* . 230**320* >14 mnt. Hr. 215*-300* *1 4 nun. If;. 7E0*-33:* at 5 n;m. Ilj. O.DtoO.S 0.0 la 0.1 ' (tone Hone 31* ` tv 0.5 1o 0.6 0.0 lo 0.1 None None . 3S*-3S* 99* 0.1 lo 0.2 0.0 lo 0.06 None None -- ' ' 0.2 lo 6.3 0.0 lo 0.02 0.2 0.01 None 247* * 477* None >350* >662* -- ... 46* 115* 0.03 1M.&7t(o.'y1-.7 % mi l None None -- -- .. -- , " ,. *' V . 1.047-1X4S 72-76 ?:*oo-v>oo - 1.6501 '1.C517 6*100 . 6(I0W0*6,50< >1*0. 150*1# 170* . (bold rU . * 902* lo 338* (hold r-U CO* 10 66* 140* lo 151 * -- 1.G6U.667 --m * 0*150 ` 46*.l'o 52* ' 115*10 126* -- mm --' .-- 96* lo 105.5' 206' to 222* 1.600 1.CCS --. -- -- 0.2 lo 0.3 -- Hone None -- -- CG' lo 72* 149*to 1C? --` --_ -- -- 5 #f )OOr * IV.f.OKi. 11,300** >32<jO** 10,900** > ?.rjU)(llIH ^330.0?.*____ sioln. In corn oil- "m V roooo *w id,OOO** 10,600** >1260** .< 33GO**_. <2000** oln, in ci:>rn oil . 19,200// > 79 W 6, ;-;i o.7/ > oooo.;, <L3\0d HONS 206316 Pace 7 - Status Report on the Chemistry and Toxicology of PCB or Aioclors Arociors at relatively high concentrations (about 2000 ppm) have been shown by FDA and others to produce hydropericardium in chicks (chick edema.effect). We do not know whether the effect is from Arociors or impurities, FCB residues are detected by the FDA multi-pesticide residue analytical methods if the amount present in relation to the amount of pesticide precent is groat enough. Their presence in samples analyzed for pesti cides complicates tfie analysis for chlorinated pesticides. Mrs. Judith Arutrur, Division of Pesticide Chemistry and Toxicology, has developed a .jethod for separating PCB from chlorinated pesticides. Separation permits measurement of either the pesticide or PCB residue without cross interference- The separation method, information on the behavior of PCB in FDA's multiresidue analytical methods, and background on the problem have been made available to all FDA District laboratories through Laboratory Information Bulletins. District laboratories have been given guidelines on the determination and reporting of PCB residues. They have been asked to report to Washington any findings of FCB. Special emphasis has been placed on fish since this appears to be the most likely product to contain residues of both PCB and the DDT group. District laboratories have reported residues of PCB in Creat Lakes and certain other fish, fishmeal for animal food, crabmoat, and milk from one location in West Virginia. The identity of PC.3 in the tnilk sample whs verified by mass spectrometry. Dr. Francis Biros, Division of Pesticide Chemistry and Toxicology, has used mass spectrometry to confirm the finding of PCB iu a few samples of human adipose tissue. To our knowledge there has been no evidence of PCB residues in any field or orchard crop analyzed by FDA laboratories. Present rnd future plans include: discussion was held on the analytical aspects of PCB and PCB-pcsticide combination residues at the FDA Pesticide Analytical Workshop in March; accumulation of data on PCB occurrence through analyses by District laboratories; improvement of the measurement of PCB residues at low levels; investigation of the analytical character istics of other organohalogcns which may be similar to PCD in use and behavior. Chlorinated naphthalenes and chlorinated paraffins are being studied. HONS 206317 Page 5 - Status Report on the Chemistry and Toxicology of PCB or Aroclors III. Toxicology , The toxicological information on commercially used Aroclora is rather limited and incomplete. Early studies were done on compounds of undefined specifications or on mixtures. However, the following summary brings the data on toxicity, up to date. a. Early rtudies Smyth and Smyth (7) found that a chlorinated biphenyl was nontoxic when administered orally to guinea pigs and rabbits in doses of 4 gm/l-.g. Drinker of. &]L (1937) (8) found that 0.05 gm of a chlorinated biphenyl fed to rats over a period of 6 days caused liver injury to rats. Miller (1944) (9) found that 2 doses of an Aroclor fed to guinea pigs one week apart was fatal in 11 to 29 days and marked liver changes were present. The toxicity to rats of chlorobiphcnyl by inhalation was also investigated by Drinker 01.(1937) (8) and some hepatotoxic action was found. In 1953 the American Conference of Government Hygienists (10) set 1.0 to 0.5 tug of polychlorinated biphenyl compounds/fP of air as the threshold limits. In Food Additive Petition 8B-230G, two short-term studies were reported in support of the use of Aroclor 5460 as a plasticizer component of adhesive formulations. This aroclor is a chlorinated terphenyl with less than 0.05% biphenyls. In a 90 day study in rats with dosage levels of 100, 300, and 1,000 ppm, the "no effect" level was 100 ppm with only a alight increase of liver to body weight ratio of males in the 300 ppm group. A similar 18 week study in chickens demonstrated a "no effect" level at 500 ppm. A specific study (as outlined in J.A.O.A.C. _44, 142, (1961) for the "chick edema factor" was conducted with 12 chicks at dosage levels of 50, 200, and 400 ppm. Ko significant increase in edema was noted. b. Mora recent studies (1) The findings of Street e a_l (1969) (11) that feeding of a number of PCB materials to rats for 15 days resulted in induction of liver microsomal enzymes, and the degree of induction increased with Increasing chlorine content. Those PCB containing over 60% chlorine were more potent inducers than DDT. Street also reported that when a series of polychlorinated biphenyls were incorporated at 50 ppm together with 1 ppm dicldrin into the diets of rats for 15 days, those biphenyls containing 60% chlorine or more reduced the dieldrin storate in adipose tissue to the levels found in untreated control animals. (2) Consulting laboratories for Monsanto Company (12) found the oral LD50 in rats for Aroclor 1254 and 1260 to be in the neighborhood of 10 gm/kg. Monsanto is also conducting a 2-year chronic oral HONS. 206318 page 9 - Status Report on the Chemistry and Toxicology of PCB or Aroclors toxicity study of Aroclor 1254 and 1260 in beagle dogs and a three generation reproduction study in rats of Aroclor 1242, 1254 and 1260. The 90-day interim results of the dog study revealed no significant findings for body weights, food consumption, mortality, hematology, blood chemistry, or urine analysis. Data were recently obtained from Dr. Emmet Kelly, Medical Director of the Monsanto Chemical Company, St. Louis, Mo., by telephone on three polychlor biphenyls (13). These data were obtained with the promise from Dr. Kelly tlr.t he would send the interim report as soon as he obtained it. These were 90-day results; on a two-year experiment. Come rats were sacrificed and microscopic examinations of tissues were done on the sacrificed animals. Rats were fed diets containing 1, 10, or 100 ppm for the 90-day period. Dogs were fed diets containing 1, 10, or 100 ppm for the 90-day period. Reproduction studies in rats are in progress at dosage levels of 1, 10, and 100 ppm. Aroclor 1242 - Liver enlargement occurred in rats at 100 ppm. No microscopic change was seen. Dogs showed tto gross effect at any dosage. In the first mating of the reproduction study 100 ppm retarded growth of pups. Aroclor 1254 - Liver enlargement occurred in rats at 100 ppm but no microscopic change was scon in the tissues. The dosage of 100 ppm decreased growth in the dogs. In the first mating of the reproduction study 100 ppm caused death of many of the pups. Aroclor 1260 - Liver enlargement occurred in rats at 100 ppm but no microscopic change was noted In the tissues. Dogs on 100 ppm refused to cat the diet and two died. No effect was noted at the dosages of 1 and 10 ppm. Reproduction in rats appears normal at all dosage levels. Tha status after 9 months of study is covered in the attached Table 4. (3) In studies of the toxicological interaction between dieldrin, DDT aad 11 different Aroclors in flies, Lichtenstein e al (1969) (14) found that the Aroclors significantly increased the toxic effects of the pesticides. HONS 206319 TABLE 4 SUMMARY--INTERIM STATUS OF CHRONIC TOXICITY STUDIES page 10 - S ta tu s R eport on C h e m istry and T o x o c ity o f pcb o r A ro c io rs I!. i ; year chronic--rats t 1, 10, 100 ppa In diet tatus-- 9 months tatus--6months sacriice Including microathology Aroclor 1242 no effect clinically No effect clinically Aroclor 1254 Lowered weight gain at 100 ppm Increased liver ut in males at 100 ppa Negative path ology--all levels : year chronic--dogs ;t 1. 10, 100 ppm in diet i tatus--10 months No effect clinically Lowered wt gains* all females at 1, 10 & 100 ppm Levered wt gains males at 100 ppm itatus--6 months Including >lood & urine chem. Negative Negative * See report for details relative to "Mortality" ** See report for details relative to "Mortality" and "Blood Chemistry" Aroclor 1260 No effect (see below) Increased liver wt in males at 10 & 100 ppm. Negative path-- thology--all levels Lowered wt gains** females at 10 and 100 ppm Lowered wt galas at 100 ppm Negative** Monsanto Comapny, Interim Reports, Chronic Toxicity Studies on Aroclor 1242, 1254 and 1260 HONS 206320 ( I ... Page 11 - Status Report on Chemistry and Toxicity of PCB or Aroclors (4) A report by Risebrough t jal (1968) (4) states that poly chlorinated biphenyls are inducers of hepatic enzymes and together with other chlorinated compounds may be responsible for aberration in calcium metabolism observed in certain species of birds. (5) The polychlorinated biphenyls have also been reported to produce hydropericardium in chicks (chick edema) (15, 16). (6) In a petition for the use of Aroclor 5460 as a plasticizer component of adhesives (FAP SB-2306) there is a report of a feeding study in rats. Rats were fed diets containing 100, 300, or 1,000 ppm for 90 days. Growth repression occurred at the 1,000 ppm. Liver to body weight ratios were increased at levels of 300 and 1,000 ppm. Likewise, young adults (12 weeks old) white leghorn chickens were fed diets containing 500, 1,000, or 2,000 ppm Aroclor 4560 for 18 weeks. The dosages of 1,000 and 2,000 increased mortality. Average body weights of the male birds at oil dosage levels were slightly leas than the control.'.-. In a chick edema study 21-day old white leghorn chicks were fed 50, 200, and 400 ppm Aroclor 5460 for 21 days. There was a slight but not a significant average increase in pericardial edema fluid at all dosage levels. c. Studies in FDA laboratories (1) The single oral dose LD^q of Aroclor 1254 in female rats was 4 gm/kg and it was considerably higher for males'. The oral LD^g of Aroclor 1260 was 10 gm/kg. (2) In a preliminary study, rats fed diets containing Aroclor 1254 or 1260 were sacrificed after 7 weeks of feeding. At a dietary level of 2,000 ppm none survived. At a dietary level of 1,000 ppm one of six fed Aroclor 1254 and none of the six fed Aroclor 1260 survived. All rats fed 500 ppm survived. Liver enlargement appeared In the survivors at all dosages fed. \' (3) In behavioral and physiological studies using single doses of Aroclor 1260 In mice (1 and 10 mg/kg, p.o.) it was found that: (1) anti convulsant properties were exhibited with respect to maximum electroshock seizure (i.c. increased ratio of tonic flexion/tonic extension and in creased duration of clonus), (2) the Aroclor exerted little effect on open-field exploration and (3) Aroclor administration prolonged the latency of mice to enter a shock-stress chamber. All of these effects are in direct contrast to those noted when DDT was given. HONS 206321 page 12 - Status Report on Chemistry and Toxicity of PCB or Aroclors (A) A 30-, 60- and 90-day feeding study is underway in rats of Aroclors 125A and 1260 at levels of 0, 2D, 75, 150, 300 and 500 ppm. After each interval, body weight, liver weights, and the microsomal enzyme oliesterace, p-glucuronfdase, and nitroreductase will be measured. (5) In a study at FDA, Flick et aj^ (Poultry Science AA, 1A60, 1965) (17) reported a study in white leghorn cockerels. The clicks vicre fed diets containing 200 or A00 ppm chlorinated bipheny1s for 3 weeks. Both dosages produced toxic effects which parulalxy simulated those seen with the chick edema factor. Edema formation in the peri cardial sac and in the abdominal and subcutaneous areas was pronounced only at the 400 ppm level. Other gross effects were in decreasing order of incidence as follows: cream colored pancreas, enlarged hemorrhagic kidneys, enlarged adrenals, small spleens, dermatitis and defenthering. Kocraan txt al (Nature 221, 112B, 1969) (18) reported pericardiAl edema in Japanese quail at a dosage level of 1,000 ppm. No lower dosage was used. clor. (6) Other teratological data Results of various studies follow, keyed to the specific Aro- Aroclor 1242 (19) No. of Chicks FDA test (1963) for chick edema factor (A0AC bioassay method) Diet Level (ppm) Heart Fluid (ml) or Incidence of hydropcrlcardlua Early Death Remarks 10 100 6 * 349 2/9 1/12 1 Enlarged Heart Group Score 2-1- 4 Group Score 3+ ' (toxic) Aroclor 1242 was distilled in a spinning band column; 28 fractions were more toxic than the early fractions. Some of the results of chick bioassay on these follow: HONS 206322 pjIgO 1^3 -- Status Report on Chemistry and Toxicity of PCB or Aroclors oippl* . No. of Chicks Diet Hydropericardium Level (ppm) Incidence Group Score Remarks Fraction 1 Fraction 21 Fraction 25 Fraction 28 Residue Fraction 25 Fraction 28 Fraction 28 6 6 6 6. 6 10 7 10 100 100 100 100 100 50 10 50 0 0 1 early death 0 r0 no edema no edema 2 2+ Toxic 3 5+ 6 early deaths 5 5+ Toixt ic 0 0 2 early deaths no edema 0 0 ho edema 7/7 15+ 3 early deaths 5 hemorrhages Aroclor 1242 was injected into fertile eggs, 0.01 ml of 10% solution in dioxanc: o/20 hatched, with short upper beak in most of the embryos that failed to hatch, edema, weight retardation. Aroclor 3266 was used in a chick edema list 91963) with following results: No. of chicks Level in Diet ppm Heart Fluid (ml) or Incidence of Hydro pericardium Early Results Remarks 12 200 12 400 0.25 (1/12) 7.21 (3/12) 5 4/12 hemorrhage 3 6/12 " d. Proposed Investigations: (1) When the levels (see (4) above) producing ensyme induction are determined, then a study of mortality and enzyme induction afLer feeding combinations of Aroclors and various classes of pesticides will be made. The study is prompted by the fact that although the toxi cological data available at the present tine is spotty the indications are that the toxicity of pesticides may be increased in the presence of the Aroclors. This interaction becomes increasingly important as the Aroclors become more widespread as contaminants in the global ecosystem. HONS 206323 Page 14 - Status Report on Chemistry and Toxicity of FCB or Aroclors --. (2) A brief report in the literature (1) indicates that there is no substantial metabolism of Aroclors by living organisms, but that tliey can be stored in mammalian tissues. Investigations into the storage of Aroclors in animals are necessary, particularly since the toxicological hazard of these compounds to mammals has not been adequately evaluated. r` . Studies should include administration of Aroclors to rats for short periods (30, 60., 90 days) and to pregnant rats so that transmission to the fetus could be determined. For information please contact: Mr. J. W. Cook, Acting Director Office of Pesticide Chemistry and Toxicology HONS 20632* Page 15 - Status Report on Chemistry and Toxicity of PCB or Aroclors '- REFEIULNCES I- Jcn:;cn, So ran (1966) Report of a Hew Chemical Hazard - New Scicntis32, 612 c 2. Widmark, C. (1967) Possible interference by chlorinated biphenyls in pesticide residues - Report of 1UFAC Commission on the Development, Improvv-r'ont and Standardization of the Methods of Pesticide Residue Analysis, Jour of Assoc of Off Analytical Chemists i>0^ 1069 3. Riscbiough R. and Brodine, V. (19/0) More letters in the wind, Environment 12 No, 1, 16"*27 A. Riscbroufth, R.W,, Reichc., F,, Peakall, D.B., Herman, S.G. and Kiroch, M.N. (1963) Polychlorinated biphenyls in the Global Ecosystem, Nature 220 1098 5. Sax, N. Irving (1963) Dangerous Properties of Industrial Materials, 2nd Ed., Reinhold Publishing Co. New York 196g p. 551 6. Jensen, S. et al (1969) DDT in Marine Animals from Swedish Haters, Nature 224 247 7. Smyth, U.F. and H. F. Smith, Jr., J. Ind. Hyg., 13 07 (1931) 8. Drinker, C.K., K.F. Warren and G. A. Bennett, J. Ind. Hyg. Toxicol. 19 283 (1937) 9. Milier, J.W., Pub. Health Rep. 59, 1085 (1944) 10. Amcr. Conf. Govt. Ind. Hygienists, Los Angeles, Arch. Ind. Hyg. Occ. Med .8, 296 (1953) 11. Street, J.C., F. M. Urry, D. J. Wagstaff and A. D. Blan, Confidential Reprint of Paper presented at Am. Chem. Soc. 158th Meeting (1969) 12. <3. Confidential Report sent to Dr. A. R. Glasgow, Div. of Pesticide Chemistry and Toxicology, FDA (1969) Personal conmunication to Dr. Fitzhugh, January 1970 (FDA) 14. Lichtenstein, E. P., K. R. Schulz, T. W. Fuhremann and T. T. Liang, J. Economic Entomology 62(4), 761 (1969) 15. McCune, E. L. ct al, J, Poultry Science 41, 295 (1962) HONS 206325 p3Ee 16 - Status Report on Chemistry and Toxicity of PCB or Aroclors 16, ilusng, A., D, Firestone and A. D. Campbell, JAOAC 50, 16 (1967) 17. Flick, D.F., Poultry Science 44, 1460 (1965) 18. Koehntnn, J.A. et al, Nature 221, 112B (1969) 19, Firestone, D. (FDA) - Memo of Feb 25, 1970, Status of PCB * -o HONS 206326