Document G6kBbrxJaxpJpKegzbaEZVem4

/ OEATUENT or EHVIAOHWEWTAL HEALTH KETTEKIHO CAiGHATOAV (5111 (714700 University of Cincinnati Medical Center 3223 Eden Avenue Cincinnati, Ohio 45219 January 4, 1973 Mr. Royal A. Brown Technical Director National Paint and Coatings Association 5100 Rhode Island Avenue, N.W. Washington, D. C. 20005 Dear Mr. Brown: Enclosed is the copy of the preliminary literature survey on the "Potential Hazards of Ingesting Metal Containing Paints" carried out for the National Paint and Coating Association by this Department. As you can see, the effort necessary was larger than originally planned. I hope it serves its purpose well. If the report is to be reprinted or widely circulated, it will need to be core carefully edited and retyped. Please call'on me if you have any questions, or when you plan to come to Cincinnati to discuss the report. Sincerely yours, SBGtnp Ene. Stanley B. Gross, Ph.D. Associate Professor of Environmental Health (Toxicology) technical d:v:s!c;< 001513 N 4155 * -J .jMBfnUL;; CONFIDENTIAL FOR VOUR USE ONLY NOT FOR PUBLICATION LITERATURE SURVEY "Potential Hazards of Ingesting Metal Containing Paints" by The DeDortment of Environmental Health University of Cincinnati Medical School Cincinnati, Ohio for The National Point and Coatings Association Washington, D. C. December 1972 ;;***-i : .* : -* V * **V- V., i- + +- + p" Co c cl Pi a. pk /4 cj V. "h ~~ r *5 b Mi- N 4155.01 S-W 001512 Potential Hazards ofNlngesting \ Metal Containing Points < * A preliminary literature survey carried out for the National Paint and Coating Association ' Washington, D.' C. by ' The Department of Environmental Health . University of Cincinnati Stanley B. Gross. ?h.D. Project Director Raymond R. Suskind, M. D. Department Head December, 1972 WS5 m? w.. my. S-W 001514  K <* Potential Hazards of Ingesting Metal Containing Paints by Stanley B. Gross, Ph.D. NC I. Introduction Recent concerns over the hazards to children of * ingesting leaded paints has prompted a ban on the use of such paints on children's toys and appliances and for in terior use. The National Paint and Coatings Association (NPCA), concerned with potential dangers of other metallic constituents, as well as lead, has asked the University of Cincinnati's Department of Environmental Health to carry out a preliminary literature survey on the toxicological significance of,metal compounds used by the paint industry, with special concern for hazards by ingestion. Table 1 contains a. list of the specific compounds provided by NPCA which were evaluated. The percentages of these compounds used in paints are found in Section III and in the Summary (Section IV). The search was based on materials readily available within the files of the Kettering Library rather than a search of the new literature. Many more references were available in the Library than could be used for the present survey. -- ,7-, f. r- s tv.v V ` fr- irie&Z'. i "S-W 001515 Table 1. Compounds of specific interest provided by the National Paint and Coatings Association. i - * Antimony Oxide Nickel-Antimony Titanate. Barium Sulfate Barium Meta Borate Lithopone (30% Zinc Sulfide 70% Barium Sulfate) Cadmium Lithopone Cadmium Selenide Cadmium-Barium Soaps 'V. (Stabilizers) Chromium Oxide f Lead and Zinc Chromates Cobalt Naphthenate and other . ' . ' metallo-organic soaps Cobalt Nickel Titanate Copper Oxide " . 'V *. Copper Phthalocyanine .* 4- Copper Naphthenate and other r.. .'. J-;''-. metallo-organic soaps . BcSiC jjccC CsibOuBwC Basic Lead Silicate Lead Chromates Lead Oxides Lead Silico-Chromate .Lead Naphthenate and other ~ metallo-organic soaps Lead Metal Phenyl Mercuric Acetate, Phenyl . Mercuric Oleate and other metallo-organic compounds ' Mercury Cadmium Lithopone Nickel Titanate Cadmium Selenide Pigments - ' Strontium Chromate Tri-butyl tin oxide -f Other tin organo compounds o . Aluminum Silicate Aluminum Oxide and Hydroxide Aluminum Stearate Aluminum Metal Borates (Barium meta-boratc, sodium tetraborate, etc.) Boron tri-fluoride Calcium carbonate Calcium oxide Calcium Naphthenate and other metallo-organic soaps Lithium hydroxide Lithium Naphthenate Magnesium Silicate Magnesium Aluminum Silicate Magnesium Oxide Manganese Dioxide Manganese Naphthenate and other metallo-organic soaps Lead Molybdate. Zinc Molybdate Titanium Dioxide (commercial grades) Titanates (Nickel, Antimony, Tungsten) Zinc Oxide Zinc Stearate Lithopone (30% Zinc Sulfide - 70% Barium Sulfate) Zinc Naphthenate and other metallo-organic soaps Zinc Metal Zinconium Naphthenate and other metallo-organic soaps Zirconium Oxide 'O S-W 001516 - ? - This report is divided into a brief summary of body metals and their absorption from the gastrointestinal tract, a review of the specific compounds by elemental classes, a summary, and recommendations. II. Absorption of Metals Metals in the 3odv There is an extensive literature on the role of metals in biological systems. Bowen (5), Lee(37), and the numberous articles by Schroeder and Tipton appearing in the section on References provide an overview of body metalsj Browning (6), Gefafer (10), and Stokinger (22) provide recent overview of the toxicity of metals. The essential bulk metals of the body -- calcium, potassium, sodium and magnesium -- comprise 1.5, 0.2, 0.15 and C.05 of the body weight, respectively. The remainder of the body metals (the trace metals) make up less than one percent of the total body weight (12). Many trace metals are essential in only milligram and microgram quantities. These metals are important in neuromuscular function, in acid-base balance, in structure and as acti vators or constituents of many of the body's enzymes. According to Schroeder's publication in i960 (25) > trace metals found in man may be,divided into four groups: 1) metals considered to be essential for mammals, in that the requirements for growth have been established, deficiency : .-i. . i. m- '.it . - ..\Vv;- ** .7*.-**. : f- ' S-W 001517 -4 states discovered or essentially inferred as ccfactors for certain purified metalloenzymes -- manganese, cobalt, copper, zinc, and molybedenum; 2) metals ubiquitous in plant and animal tissues with suspected metabolic functions but with essentialities unproven -- rubidium, boron, bari um, strontium, vanadium, chromium (now considered essential), nickel and aluminum; 3) metals without known functions, believed to be contaminants -- silver and lead; and 4) metals usually not detected in infants but apparently ac quired and accumulated as environmental contaminants -- cadmium, tin, titanium and in some locations, bismuth, gold and gallium (rarely). Excesses of essential or nonessential metals are toxic by inhibiting the absorption of essential metals, by interfering with metallic enzyme activators, by replacing metals in metallo-enzymes or by direct action on nonmetallic biochemical systems. Absorption of Paint Metals There is a large literature dealing with gastro intestinal tract anatomy, physiology and biochemistry. The reader is referred to such texts as Kimber et al. (1) and Wilson (2) for general information on intestinal absorption and to Skoryna and Waldron-Edward (3) for a discussion of the intectin&l absorption of specific metals. j * r; '.'2! S-W 001518 -5- Figure 1 and Table 2, Pathways for Mineral Metabolism, taken from Altman and Dittner (31)> summarize the absorption and disposition of many metals (and nonmetals). This information is derived from the literature cited by Altman and Dittner and applies primarily to lab oratory animals under experimental conditions. These results are not always consistent with data for humans, such as those data of Tipton and Stewart (2U) who carried out balance studies for 22 elements on several individuals. Two of these subjects were followed for 3^7 days. Absorption of metals from the alimentary tract is potentially complex. It involves the grinding action of chewing,the mixing due to the physical action of peristalsis, the chemical interactions with saliva, acid gastric juices, alkaline bile, pancreatic and intestinal juices, the poten tial changes (metabolism) by microorganisms and the inter actions of metals with food digests (chelating agents). Other factors are the chemical form of an element, its concentration, its molecular size, its solubility in the different fluids of the intestinal tract and, ionization at the various pH levels. Specie, sex and age differences may also be important. S-W 001519 6 Fleure 1. Pathways of mineral metabolism. Diagram for . Table 2.~ Taken from Altman and Dittner (31)* ... . ' DIAGRAM FOR TABLE 54 :>v V ' v '7-"f:***',;: Ill Percent abaorptloa from oral administration haa lr ion else* bees ratber arbitrarily elaaulfled. alnce the ex* teat of absorption may depend oa the amount administered and on tbe pretence or abaeaee of food rttidoea is the dljeattet tract. 1*1 Some trace elesesta with no knows function alee included, /a/ Primarily sissclt, ekm. and ex tracellular ftatda. // Other than m the bUa. or by a rode not defluttaly eatablitbed. K-r *ir.&vL-. 1. e re. 7 Table 2. Pathways of mineral metabolism. Taken from Altman and Dittrier (31) ' ' * ) . Tba course, or courses, of various Ion* during metabolism can be located in the diagram fat left) by tracing the combination of letter* and numbers acrompanymf each ton (columns B and C below). Observations were made on s end* variety of mammalian species. Ions were administered In the form of simple soluble compounds or metallic d*s. unless otherwise specified, Underscorin' indiesles radioactive elemenu. or that data were obtained tt least in part from studies using radioactive isotopes. Different isotopes of the same clement may show different tissue predilections, but there te usually no difference in their absorption or route of excretion. "Plus" symbols iDdieate valence states to whieb data apply. Other Known Pathways (column C) are listed, so far as possible, in order of deereasiaf importance. ton (A) i Actinium 2 Aluminum 3 Americium 4 Antimony* s Arsenic*? 4 Barium 7 Beryllium Bus mu in'* 7 Csdmlum 10 Calcium 11 Cerium* u Ceaiura u Chromium*** 14 Cobait** 15 Cooocr** 14 Curium IT Dvsorostvm* it tfDium f 17 Europium* 20 Francium 21 G*dohntum* 22 Gallium 25 Ger.-nsnlum 24 Cold** 25 Hafnium* 24 Holmium* 2T Indium 28 Iridium 27 Iron** 50 Lanthanum* 51 Lead** 52 Lithium 32 34 V.arnesium 35 IslflflACOt** 54 Mercui f** 57 Nroovmiuss* 58 Neptunium 57 Nmel*f 40 Niobium* 41 Palladium 42 Platinum 43 Pluiontumr 44 Polonium Principal Oral Pathway*1 IB) CE CE CE BE. BDH2 BE. BDH2 BE. BDB4 CE CE CE BE. BDMfl) CE ADHZ CE BE. BDRZ BE. BDH3 Probably CE* . .................................................... .. CE Probably ADH2* " lit CE ADH2 CE i|,,,|rrrnr.r,,,,,Ji,| -------------- T1 CE CE CE CEBE. B0H4 AJDK2 - ", II - BE. B0B2 CE BE. BOHZ Probably CE* CE BE. BDH2 CE Probably CE* CE CE CE Other Known Pathways (Cl Cations* PDFKU.ZI PDH2. PDH1. PDFJU) P01U. PDFK(2. 1). FDH2 BDFKI2.5). BDH4 BOFKI2.5). BDH4 BDFK(l). BDH2 PDFKU.3.2). PDH2. PDH4 PDFKU). PDH4. PDH2 PDPK(2. 3.1). PDH4. PDH2 BDH4. BDHJ. BDH2. BDFJ(5) PDFKU. 1). PDH3. PDH2 ADH). ADH4. ADFJfSf PDH2. PDH4. PDFKU. 1) BDKJ. BDH4. BDFJU) B0K2. BDFJI2) PDFKU.)). PDH4. PDHZ PDH1. PDFKU) PDHJ. PDFKU. 2) PDH3, PDHZ. PDFKU. 2) PDFKU.3) PDHZ. PDH3, PDFKU.Z) PDH2. PDFKU. 2). PDH4 ADH4. ADFK(Z) PDFKf2). PDH2. PDH4 PDFKU. U. PDHZ. PDH4 PDHJ. PDFKU. 2) PDFKU. 1.2). PDH4, PDH2 PDH2. PDH4. PDFKU*2.1) PDH4. PDFJt2| PDH2. PDH3. PDFKU. 1) BDKZ. BDFKU.3.2) ASH4. ADFJO.Z) PDHJ. PDFK(U BDHJ. BDFJU.2.3) PDHJ. PDH4. PDFJU. 3) BDFKU.Z. Ji. BDHJ. BDH4 PDHZ. PDFK(Z. t), PDHJ PDFKU) B0H4. BDF3U) PDHZ. PDH4. PDFKU. 1.5) PDHZ. PDH4, PDFKU) PDHZ. PDH4. PDFKU. 3.1) PDFKU. Z). PDH4. PDK2 PDFXU. l.J). PDH4. PDH2 Reference 12)_______________________ _________________________ JO 40.71.73 It.) 02 31.34.40.73 14.40.54.51.73 1Z.34.47.73.IOZ 13.73 40.57.73 20.23.40.72.73.110 3.17.40.75.72.77.10J,110.111 Z3.Z4.40.44.74.10Z 34.3Z.71-74.70.73 Z3.Z5.50.104 5.17.17.40,54.73*118 17.40.44.73.110 84.102 24 24 24 74 24 2Z.53.73 71 34.40.77.93 47.7) 24 23.37 23 17.40.45.73.110.il! 13.23.24.34.40,73.75.102 1.7.23.34,35.40.57.82.73 30U3.tl.73 24 2.40.71.73.110 8.17.28.40.40.44.73 23.40,73 23.24.38.40.55 34 5.35.40.73.71.101.110 JJ.n. 34.10.102 23.40.47 23.40 11.27.34.44.87.102.107 27.44.73.74,102 /if lens may be assumed follow the same pathways when gtven perenurally, /a/ Beesuse sf Inadequate Inform* - tine- so pathways haw beea listed for beruelium. californium. einsteinium. fermlum. and mendclcvium. /*/ Usu ally (tven aa solsbl* ewmpiea. // As yu*|re {ram Um poetuao of the element ia the periodic table, or oe solubility ot aoslrol pH valueo. conttmuai *.T5 L.'Bm.'-a U\.T-sJ 3dflbir Si tV *' ; ;4f' >. . l.*v.V . tft-f'v' "y S-W 001521 o Table 2. Continued Ion Principal Oral Pathway** Othtr Knon Fathnayp Refermee i2___________(At . (Bl L ;________________ ___________ * UJ Cationa 41 Potassium 40 Pras eoo vm lutn* 47 Promethium 41 Protactinium 44 Radium 10 Radium D SI Rhodium St Rubidium s> Ruthenium 54 Samarium* SS Scanaium Si Saltntum 57 Silvtr SI Sodium 54 Strontium 10 Tantalum hi it Tellurium* 45 Terbium* 44 Thallium 15 Thorium 4i Thulium* 47 Tut** 41 Tin***"** 44 Titanium 70 Uranium* * * 71 Uranium*^ * 72 Ytterbium* 75 Yttrium 74 Zinc 75 ZirebMum ADH2 ' CE CE Probably CE* BE. BDFXO.2) Probably BE. BOK2* CE ADH2 CE CE Probably CE*. ADH2 CE ADH2 BE. BDFKU) CE BE. BDCH2 CE BE CE CE BE. BDKZ BE. BDK2 Probably CE* BE. BOH2 aeeaeeeoeaeeeeMOoeeeeeeoeee cr CE CE ADFJfl. 2), ADH1. ADH4 PDII2. PDFKU. 1). PDH) PDH2. PDFKU.l). PDH5 PDFKtl) BDH4. BDH2 PDH2. PDH4. POFK(l) PDFXI5.2.1). PDH2. PDH4 ADFJU. 2). ADH). ADH4 PDH2. PDH4, PDFKU. 1.2) PDH2. PDFKU. 11. PDK5 CDH2. CDFJO.5) ADCH1. ADFKU. J>. ADH4 PDH1. PDFKU.l). PDH2. CDGFK* ADFJU. 1.2). ADH). ADH4 BDH2. BOH4. BDH5 PDH2, PDH4. PDFKI2. 1.5) ' PDH2, PDH4. PDFKtJ.2.11 BDGH5. BDGH1. BDCFKI2) PDH2. PDH5. PDFKU. 2) BOH4. BDFKU. 1.2). BDH2 PDFKU.l). PDH4. PDK2. PDH) PDH2. PDH5. PDFKU) BDFJU.2). BDHt. BDB5 BDH4, BDFJU.5.2) CDFJU) BDFXU) BDFKU.2) PDH). PDFKU. 2) PDFKU.2), PDH2. PDH4 CDH4. CDFJU.U. CDH2 PDFKU.)) )l.l9.tC,7l,7i,105 24.)440 24.56.102 It 27.4S.7S.45.47.102 4.70 25 61.71 25.100.101 25.40 4 61.42.4) 40.47.45.110 14.40.41.4) 5.56.45,75.42.102.10) 25.24 .. 2) 36.45.102 24 40.54.45 56.15.45.10Z 24 40.45.110 2) 95 102 21.40.95.102 24 15.24 .52.56,46,14.102.109 53.40.60.77.95.102-10S.U0 13.>6.eo.102 Anions* 74 AstatiCe 77 Bicarbonate 7t Beratt 74 Bromata 10 Bromide 1 Cltlerata 12 Chloride 7 Chromata 14 Cyanide S 14 Fluorioe .17 Hypopbeepbtbo II loOato 14 Iodide 40 Molvbdate 41 Nitrate 42 Nitrite 45 Oamat* *4 45 Pcrchlorato 44 Permanganate 47 PerrhetiaW 41 Phoepnate 44 Sihcste too Sulfate Probably A' ADH1, ADE2. ADH) ADH2 ADH2 ADH2 ADH2 AOK2 BDH2 ADHZ ADH2 BDH2 ADH2 ADC (to todldo) ADH2 BOK2 AOH2 ADGtto nitrate) . . . ............... ............... .................. AOKZ ADH2 CE (radocod to SioOg) CE BE. BDK2 BE. BDKZ BE. BDH2 PDFKU). PDfil. PDHt ADH4. AD FI (all tlaauea) .......... ............................................................................................ ADC (to bromide) ADH). ADH4. ADFJU) ADH). ADH4. ADFJU. ),2) BDHt. BDCH2. BDCH4. BDCFK(Z) ADH1. ADC (to SCN-1 BDFJO.l). BDHt PDH2 ADFJU. 2), ADH) BDFJU.1.1) ADFXUI oeeeeeeeeeeeeeeeeeeeeeeeeooeeeeeeeeeeeooOOOOOO PDHi. PDHt. PDFKU, 2.1) . eoeeeeeeeeeeeeeeeeeeeeeeeteeeeeeeeoeoeeeeeeooe PDH2. PDFKU)*. PDH4 BOFJO.l.)). BDK). BDH4 BDFJU) BD1U. BDH4. BOO 57 9) 40.9) 41.95 14.95 40.9) 91.45 40,65.93.104 93 41.49.95 40.91.95 43 9) 9) 7.15J4J5.40.95.1K 43 4) 2) 43 41 41 23.43 14.4) 54.35,42.91.9) I4.24.SI ft/ 1mm may be aeavmed to (olio* dm him pathartya when given Mniutrtlll. 1*1 Vutlly |lm at enhible rem* pWa. 1*1 At )udgv4 Irem the pomton of Iho elemoni ia the periodic ublo. or on toiublUty at notnral pH valuta. 1*1 Kiln, hi Been*it* of inadenuaie information. no paUTvaya hava boos luted for cyanoie. terricyaaide. and perto* data. 1*1 At Jueged front aolubUlty at netnnl pH valuta. tenIlMittJ r- :V Toxicity and Hazard V The term "toxicity" as used in thife report, re fers to the innate ability of a material to induce harm once inside the body. "Hazard" refers to the ability of a toxic material to be absorbed into the body where it might effect its toxic action. A highly toxic material, for example, which cannot be absorbed appreciably from the gastrointestinal tract would not be a significant hazard. The mere presence of a toxic material at a low concentration inside the body also may not constitute a significant hazard. A toxic substance to be considered a hazard, should cause measurable adverse effects (such as irritation, growth impairment, disease, etc.) when used as intended and at levels approximating intended use. Usually safety factors are applied when setting standards. Table 3, taken from Spector (18), presents commonly used terms that are associated with acute ex posures by various routes. These terms are used in the body of this report in similar fashion. III. Compounds by Elemental Class This section considers the toxicity and hazards of the specific compounds by elemental classes. The ori ginal list suggested by NPCA is found in the Introduction. An expanded alphabetical listing of these compounds can be found in the Summary. - 10 Table 3. Combined tabulation of toxicity classes* taken from page 4 of Spector (18). ------------ ---- . * .*.r - v'-'V- C ** V t cv.; ^ :tv*7-r Various Route* of Administration Toxicity Commonly Rating Used Term LD50 Single Oral** Dose Rats Inhalation 4 hr Vapor Exposure Mortality 2/6-4/6 Rata EDj0 Skin Ka suite Probable Lethal Duse (or Man i Extremely 1 mg or less/kg <10 ppm toxic 5 mg or lesa/kg A taste, 1 grain 2 Highly toxic 1-50 mg 10-100 5-43 Ag 1 teaspoon 4 cc 3 Moderately 50-500 mg toxic 100-1000 44-340 mg 1 ounce 30 (m 4 Slightly toxic 0.5-5 g 1000-10,000 .35-2. (1 g/kg 1 pint 250 grn S Practically 5-15 g non>10x16 10.000-100,000 2. >2-22. 59 g/kg 1 quart 4 Relatively 15 g and mors >100.000 hamlesa 22. 6 or more g/kg >1 quart 1lodge, H. C., and Sterner, J. n.. American Industrial Hygiene Association Quar terly, 10:4.93. Dec 194 9 Standards for intravenous LD50 ^or raU ana rabbit* may be obtained approximately by dividing the oral toxicity standard* (or rat* by 10. r K^*V. Y'.\ '* <^r V?,- V. v.V%V. .V.' S-W 001524 - 11 Since many of the compounds belong to more than one elemental class, they appear listed at the beginning of each class to which they belong, along with the concen trations at which they are used in paints. References ^ to 26 were used "routinely" for all elements or compounds while the other references generally refer to specific compounds or classes of compounds. In each section are provided, when available, the following types of information: (a) overall toxicity, estimated from animal and human data obtained primarily from ACGIH (4), Browning (6), Christensen (7), Fairhall (8), Sax (16), Spector (18) and stokinger (22); (b) body burden data, taken primarily from the ICRP Committee II report (12) and (c) data on absorption and disposition (18, 2^, 25) pro viding an indicator of absorption and excretion rates and the amount of body pools which might assimilate the absorbed metals; (d) acute oral hazards, taken from Christensen (7) and Spector (18), based primarily on animal studies; (e) water supply criteria and standards which describes human chronic oral exposure, primarily taken from McKee and Wolf (13); (f) toxicity data on specific compounds obtained primarily from Christensen (7), Spector (18), Sax (16) and Stecher (1^); and (g) oral hazards in paints, which, based on the above information, suggests the degree of potential hazard in using these compounds in paints. tv;.: r . i s'; s S-W 001525 12 i In many eases there are insufficient data available on which to base safe levels of these compounds In paint formulations. Recommendations for studies to obtain this information are presented in Section V, Recommendations. f\ ( Aluminum 'Compounds Aluminum Metal 0 - 25^ Aluminum Hydroxide Magnesium Aluminum Silicate 0 - 5% 0 - 25 Aluminum Oxide 0- Aluminum Silicate 0 - 5056 Aluminum Stearate 0 - 10 There is a considerable literature on aluminum and its health effects. In addition to the ''routine" references (4-26), the 1957 review of Campbell et al. (27) of this Department is useful. Dr. John Sorenson, also of this Department, is currently updating the 1957 review. Aluminum is very abundant in the earth's crust and is widely used in metallurgy, in various chemical industries, and as a therapeutic agent. This element is considered to be nonessential to man and generally of low toxicity once inside the body. In the industrial setting, the cocide (AlgO^) is considered only as a nuisance dust. The Threshold Limit Value, TLV, is set at 30 mppcf (4). However, a benign pneumoconiosis #*. ... ;*: . Vv- h :;w.- : \-iiv . .* ' i u**' '.* kv. >H- * # S-W 001526 (aluminosis) due to very high levels of dust exposure has been reported. The etiology of the aluminosis is debated (6, 10). The body contains an estimated 100 mg of aluminum distributed relatively uniformly in most organs in concen trations of approximately 1 ppm, wet weight basis (12). The lungs contain approximately 24 ppm while the skin, ileum, trachea and blood contain 24, 28, 1.8, 2,0 and 0.16 ppm, respectively. The concentration of aluminum in the lungs increases with age in men (26). The human diet contains 10-150 mg of aluminum per day (26), almost all of which is excreted in the feces. Tipton and Stewart (24) found in two subjects on normal diets averaged over 247 days, daily oral intake of 17 mg each, a fecal excretion of 17 and 15 mg and urinary excretion of 0.87 and 0.72 mg. Large oral doses of aluminum compound are nec essary to kill or damage experimental animals -- lethal mg/kg doses (LD's) from 3730 to 4280/(18). The species and types of compounds used are important. Spector (18) reported an oral ID50 (lethal dose killing 50# of the animals) for AlCl^ in the rat as 3730 mg/kg AlCl^ while Evenshtein (28) reported a Btudy in which 750 mg AlCl^ administered to a rabbit caused death in two hours. Christensen (7) lists the oral LD50 for aluminum sulfate for the mouse at 770 mg/kg. There are no standards set for domestic water supplies because of the low level of toxicity of aluminum. Cooking with aluminum utensils can add 70-75 mg to the diet with no apparent harm. In one study (28), one man reported ingesting 264 mg/day for 70 days without ill effect. Rabbits, however, maintained on water with 1400 ppm aluminum developed decreased blood, bone and urine phosphate (13)* Specific Paint Compounds. Aluminum metal dust has been reported to produce contact dermatitis and bron chial asthma (14) and pulmonary fibrosis (16) in industrial use but is not generally regarded as an industrial poison. Aluminum hydroxide is used as a food additive (29) and as.-*'"an anti-acid with good safety. Aluminum oxide (Alumina) industrially has been associated with pulmonary fibrosis (Shaver's disease), the etiology of which is controversial. Toxicity data on the other compounds were not readily available in the literature. Oral Hazard in Paint. Based on the poor ab sorption from the gastrointestinal tract and on the rela tively low toxicity of aluminum compounds in man, the specific aluminum compounds under consideration by the paint industry should be safe at the concentrations specified Antimony Compounds Nickel - Antimony Titanate o - 15# Antimony Oxides 0 - 10# Antimony plays no known essential metabolic role In biological systems and has been known for its toxicity since Roman times (32). This toxicity has been demonstrated in its therapeutic uses as an emetic (potas sium antimony tartrate) and for the treatment of human parasitic diseases (schistosomiasis and leishmaniasis), in food poisoning from enameled cooking ware and in acci dental and industrial poisonings. Lethal doses by parental routes vary from 3*07 to A000 mg/kg. Industrial TLV for antimony and its compounds is set at 0.5 mg/m^. The TLV of the highly toxic hydride of antimony, stibine, is also 0.5 mg/tn^. Antimony probably exerts its toxic action by reacting with sulfhydryl-containing enzymes, thus inter fering with cellular metabolism. The body is estimated to contain about 90 mg of .. antimony with tissue levels of 0.05 to 4 ppm, wet weight basis (12). Little appears to be known about normal dietary levels of Sb. Woolrich (30) indicated less than 100 >xg Sb per day is contained in the diet. Gastrointestinal absorption is between 5 and 70#, most of which is excreted rapidly in either the urine or the feces (31) * v. m m m - ***<.'! V iV t ... . H ;; S-W 001529 Acute oral LD50 studies for Sb compounds in animals range from 100 to 20,000 mg/kg (7, 18). A f lethal dose of antimony potassium tartrate is estimated at 2 mg/kg for man. There is no permissible level established for domestic water use. Antimony added to the food of rabbits caused progressive increases in both Hb and RBC's and when fed to rats caused an increase in WBC's (6). Antimony fed at 5 ppm over a life time caused a decreased survival and longevity in rats (26). Specific Paint Compounds. Antimony oxides. The pentoxlde was reported to have low toxicity (ip LD50 in rats, 4 gm/kg). Rats tolerated well 4 mg daily, how ever, both rats and rabbits experienced reduced growth rates on dietary levels of 2% (13)- Toxicity information on the tetraoxide or on nickel antimony titanate was not readily available. Oral Hazard in Paint. Because various antimony compounds have been found to be highly toxic in man and animals, oral hazards of antimony compounds in paints should be adequately evaluated to determine if currently used concentrations in paint are safe. y. -* v 7' ay _ S-W 001530  Barium Compounds i--' Barium Metaborate i 0,- 15% Barium Soaps 0 - 356 Barium Sulfate (inlithopone) 0 - 35^ Cadmium-Barium Soaps 0 - 3# Lithopone 0 - 5056 There is a relatively large literature on barium available in the Department's library, including several recent reviews by Browning (6), Schroeder (33) > Miner (3^), and Rumyantsev (35) Barium is relatively abundant in nature. It is nonessential to man and soluble forms are considered highly toxic. Lethal dcses range from U-700 mg/kg depending on * ' ' ' the route of administration and species. The industrial TLV is 0.5 mg/nr as 3a. Barium stimulates smooth, striated and cardiac muscle and may produce violent peristalsis, arterial hypertension, muscle twitching and cardiac dys function. Barium sulfate, used extensively as an x-ray contrast medium, is relatively insoluble and apparently innocuous when ingested. Prolonged inhalation of Sa com pounds has been reported to cause a benign form of pneumo coniosis known as baritosis. Barium behaves similarly to Ca and Sr and is found notably in bone tissue and the aorta, where it is deposited irreversibly (33) 3a presumably can displace Ca to some extent in biological systems by mass action EZ*y-T:i-*77:W - 18 The body contains approximately 16 mg of 3a with most of the organs containing levels in ppb range except for bone which contains approximately 1.63 ppm (12). / Barium has been shown to accumulate in the lungs with age, apparently due to deposition from inhalation. The diet contains approximately 16 mg/day (26). Tipton and Ste wart's (2^) individuals' diets contained an average of 0.65 and 0.92 mg/day over 3^7 days. Excretion averaged C.69 and 0.88 mg in feces and 0.037 and 0.017 mg in the urine re spectively. .' Acute oral lethal doses in animals range from 7-9600 mg/kg. Five hundred to 600 ng of a barium compound in man has been reported as fatal (13)* The USPHS 1962 water standards for domestic water supplies limits 3a to 1 mg/1 based on the toxicity of barium (13). Specific Paint Compounds. 3aS0)| is used as a contrast medium for gastrointestinal x-rays. It is con sidered innocuous; however, this use is on a short term basis -- usually a single pass through the gastrointestinal tract. Data on humans, especially the young, on a chronic exposure basis are not apparently available. Lithopone has been considered "non-toxic"; however. Sax (16) indicates that hydrogen sulfide can be liberated from lithopone on decomposition by moisture, acid, or heat. S-W 001532 - 19 Oral Hazard In Paint. Barium chloride apparently is readily absorbed and is highly toxic to many species (18). Since insoluble barium compounds might form chlorides In the stomach all the barium compounds of concern (soluble or insoluble) used in paints should be adequately evaluated for chronic and short term exposures. Boron Compounds Boron Tri-fluoride 0 - 1% Borates (Barium metaborate 0 - 15# sodium metaborate, etc) The literature on the health effects of boron compounds is relatively limited. Browning (6) and Durocher (38) offer recent reviews of this subject. Although essential to higher plants, boron is not considered essential to man and has no known metabolic role. Boron and its compounds are considered by Sax (16) as not highly toxic to man. The most common health hazards have been accidental ingestion of household chemicals, such as boric acid or borax, and absorption- of boric acid from wounds or bums. The most highly toxic boron com pounds are the boranes used in high energy fuels. Lethal parenteral doses of boron compounds range from 20 to over - 2000 mg/kg depending on the species, route of administra tion, and the compound. Industrial TLV's are set at S-W 001533 3, 0.3* 0.1 and 0.01 mg/m^ for boron trifluorides, deca- r borane, diborane, and pentaborane, respectively. Boric acid may produce primary skin irritation and conjunctivitis locally. The ingestion of excessive doses of borates may cause nausea, cramps, convulsions, coma, and other symptoms of distress. Inhalation of the boranes may lead to chest tightness, cough, headache, dizziness, convulsions and unconsciousness. The body contains approximately 10 mg of boron. Most of the tissues contain sub-ppm quantities except bone which may contain nearly 3 ppm. The diets in Tipton and Stewart's studies (24) contained 1.2 and 11 mg/day wi*t*h- most of the boron being absorbed and excreted in the urine (0.95 and 4.7 mg). Lethal oral doses in animals ranged from 45 to 5140 mg/kg (7, 18). Fifteen to 20 gm of boric acid has been lethal to adults and 506 gm to children. Hats drinking water containing 0.25# boric acid experienced drinking water decreased growth rats; however, boron in publie/is not generally regarded as a hazard to human beings (13). Con centrations 'to 30 mg/1 of boron in drinking water have been reported as not harmful. Hoskins, however, has recommended a boron limit of 20 mg/1 in drinking water (13)* n- Specific Paint Compounds. Boron trifluorijeis highly hazardous by the inhalation route ' .............a (TVL, 1 mg/nr). It is highly irritating to mucous membranes. Oral hazard data were not readily available from the references used. Borates. Sodium borate is strongly alkaline and soluble in water. Its oral LD50 for the mouse is 2.0-3.0 gm/kg (38), which can be considered only slightly toxic. Intra venous administration of 0.3 gm/kg of sodium metaborate to the rabbit caused no notable toxic effects. Oral Hazard in Paint. Orally, the borates are probably relatively non-toxic on a short-term basis; however, inadequate data nr eavailable on long-term expo sures. Since boron once inside the body can be quite toxic, the oral hazards of these compounds in paint formu lations should be more adequately investigated to determine safe levels for paints. Cadmium Compounds Cadmium Barium Soaps , Cadmium Lithopone Mercury Cadmium Lithopone Cadmium Selenide Cadmium Selenide Pigments Cadmium Soaps 0 - 3# 0 - 15* 0 - 1556 0 t 15# 0 - 25* m `A1'-',;'.: . ~\. vXx- ! - f;. ' S-W 001535 There is an extensive and rapidly growing litera ture on health effects of cadmium and its role in the pollution of our environment. Recent survey articles by Browning (6) and Fasset (39) and extensive reviews by Athanassiadis (Uo) and Friberg (^1) are available. Cadmium is not widely distributed in nature and finds its way into the biosphere primarily as waste pro ducts of technology. Cadmium is considered to be highly toxic to man by any route of administration. Although Cd tends to be deposited irreversibly in the liver and kid neys (metallothionine) as a possible protective storage of the metal, cadmium in toxic levels interferes with the many -SH containing enzymes and many metal-containing enzymes. Ingestion of cadmium has caused nausea, sali vation, vomiting, diarrhea, and abdominal pain. Locally, it is irritating to mucous membranes, produces yellow dis coloration of the teeth, and contact dermatitis due to hypersensitization. Inhalation of cadmium fumes may be followed by respiratory irritation, dry throat, metallic taste, chest pain and dyspnea due to bronchitis, pneumonitis and pulmonary edema. Liver, kidneys and bone marrow may be damaged. Lethal doses in animals range from 2 to 230 mg/kg depending on the chemical form and species (7, 18). - 24 1 O Cadmium fumes at 9 mg/nr has caused death in man. The i^ TLV's for Cd*. are 0.1 and 0.2 mg/nr for the oxide fumes and soluble dusts, respectively. The body is estimated to contain approximately 30 mg of cadmium. Most tissues contain less than 1 ppm except for the kidney (32 ppm), the liver (2.4 ppm), and the pancreas (1.2 ppm). Under normal exposures, Cd accumu lates in the kidney with age. The diet contains approxi- * mately 25 jug/day, the major portion of which is absorbed and excreted in the urine (42 and 83#) (12, 24). Acute deaths in animals are seen with oral doses of 70-369 mg/kg. Food poisoning from Cd-plated containers ha^s been reported. One boy died two hours after Ingesting 8.7 gm of CdClp. Limits for domestic water supplies were ------------------------ * Standards set at the low levels of 0.05 mg/1 by the WHO European/1962 Standards and 0.01 mg/1 by the USPHS/I962 organizations because of the highly toxic nature of Cd (13)* Specific Paint Compounds. Most of these com pounds listed in Sax (16) and the Merck Index (14) were listed with cross reference to the high toxicity of cadmium and mercury compounds. Lithopone compounds would have added potential hazard due to the possible liberation of HgS gas (See Barium Compounds above). Cadmium selenide has a low toxicity because of the compound insolubility (14). Cadmium stearate has an oral LD50 of 1225 mg/kg in the rat, giving this a "moderate" toxicity rating. r t'S t? k K t.I" W. i`H.. v-v.-tr 4 S^W 001537 -xr- - 25 - % Oral Hazard In Paint. Because of the highly toxic nature of cadmium in man, cadmium salts should not be used in interior paints or on children's articles without extensive research showing its nonabsorbability from paint formulations, both from short-term and long-term exposures. Calcium Compounds. Calcium Carbonate 0 - 70% Calcium Napthenate 0-2% Calcium Oxide Calcium Soaps 0 - 15# 0-2% Calcium is the most abundant metal in the earth's crust and is essential to all forms of life. It is also the most abundant divalent metal in the body and is essen tial for many functions including the activation of many enzymes, neuromuscular irritability, and the structure of bone and teeth. There is a large literature on the roles of calcium in living systems. However, for the pur pose of this review, the "routine" references (4-26) pro vide the primary sources of toxicological information. Many calcium compounds are used therapeutically and are considered to be relatively non-toxic. Problems of dietary deficiency of calcium have been of more concern to the general population than the toxicity of calcium. On the other hand, industrial exposure to dusts containing :S i . :'i .. :: - r-.: ' i-"*' * v r. .r r: y- a r-v;: b'-v mm.if' * S-W 001539 - 26 calcium oxide (lime) and calcium arsenate have "been of concern -- the oxide because of its irritation to the ma skin, conjunctiva, cornea and mucous membranes of the respiratory tract and the arsenate because of the arsenic toxicity. The TLV's for these materials are 5 and 1 mg/m^ respectively. The body contains about 1050 gm of calcium most of which {99%) is found in the bones. Tipton and Stewart (2^) reported 9^0 and 2300 mg per day of calcium in the diet with only 1^0 and 230 mg being excreted in the urine, the rest appearing in the feces. The human body requires approximately 0.7 to 2.0 gm of calcium per day as a food element and amounts considerably in excess of these re quirements are consumed with the use of hard water with out overt adverse effects. Parenteral and oral lethal doses in animals range from 100 to 25,000 and 15 to 73^*0 mg/kg respectively depend ing on the compounds, species and routes of administration (7, 18). 3ecause of its low oral toxicity, the USPES drinking water standards of 1962 and the WHO European Standards of 1961 do not contain limits for calcium; how ever, the WHO International Standards of 1958 indicate 75 mg/1 as a permissible limit and 2000 mg/1 as an excess ive limit. -Jr ys-iuvH'ggr . *> , T S-W 00153 **' st. 27 Specific Paint Compounds. Calcium carbonate is used as a nutrient and/or dietary supplement \2S), anti acid and anti-diarrhea agent and is relatively non-toxic. Calcium Oxide is also used as a dietary supplement (29) but is relatively toxic as an industrial dust. In short i Rockhold term studies using calcium naphthenate/reported an oral LD50 greater than 6 gm/kg in rats (42). The soap, calcium stearyl-2-lactylate, is used as a food additive and is considered relatively non-toxic. Oral Hazard in Paints. Based on the fact that relatively high levels of calcium can be safely tolerated iri'rthe diet or as oral therapeutic agents in man, the rela tively low toxicity of the calcium compounds in question and the probable unabsorbability of these compounds from ingested paint chips, these compounds can probably be con sidered as only a slight oral hazard ln_palnt formulations. Chromium Compounds --- ---------------- Chromium Oxides 0 - 15# Lead Chromate 0 - 25# Lead Silico Chromate 0 - 25# Strontium Chromate 0 - 25# There is an extensive literature on the health aspects of chromium. Browning (6), Sullivan (47) and Smith (48) provide recent overviews for chromium. **"*--* r i -.;' f i. 't I : t v -V' sy'--..-'* iff}J. fill l v?*se: >^v- *. * $?M: VviDr .'`VjictV S-W 001540 - 28 * Chromium is an essential element involved with glucose and lipid metabolism (an insulin factor). The biologically active form of Cr is not known. Chromium metal itself is relatively inert. Di- and tri-valent chromium compounds are relatively non-toxic; however, the hexavalent forms (chromates and dichromates) are considered highly toxic. Most toxic hazards are from airborne chro-. mium in industrial settings. Cutaneous allergy is not uncommon from hexavalent compounds but are rare from trivalent chromium compounds. Contact with chromates or chromic acid can produce small, painless cutaneous ulcers as well as primary irritation or hypersensitivity. Allergic bronchial asthma has been associated with chromium tri oxide fumes. Bronchogenic carcinoma has occurred at an abnormally high rate among chromate workers. Industrial TLV's are 0.1 mg/m^ for chromic acid and chromates 0.05 mg/m^ for soluble chromic and chroiDus salts, and 1 mg/m^ for metallic chromium and insoluble salts. The body contains approximately 6 mg of Cr, the i banes containing 0.49, the lungs 0.2, the skin 0.33 and the uterus 0.24 ppm. Chromium accumulates in the lungs with age. The daily diet contains approximately 60ng (26) per day. In Tipton and Stewart's studies (24), 0.20 and 6.29 mg appeared in the diet with 55 and 41# excreted in the urine. Parenterally, lethal doses of various chromium (SSKj *%&: PI-,:. --- m `y-r- ;%.v % :* -* . ,-r` .: * . :v /. -:: --,r:j^?rvv-- 1 S-W 001541 ' ' t.r*' compounds vary from 0.11 to 6185 mg/kg while acute oral doses vary from 1870-3250/^7,^.8). Rabbits receiving 1.9 gm of KgCrgO^, died within two hours. Schroeder found the 5 ppm of Cr +3 in the diet of rats to be beneficial. Both the USPHS 1962 and the WHO European 1961 agencies set 0.05 mg/1 as a standard for hexavalent chromium in drinking water apparently be- cause of a concern for possible carcinogenicity (13). McKee and Wolf (13), however, question this restrictive ness because of a case of a family which had drunk . water containing 25 mg/1 of Cr +6 for years (1957 on) with no apparent adverse effects. Specific Paint Compounds. j' I* Chromium oxides. All of the hexavalent oxides are orally toxic, producing gastrointestinal irritation, vomiting and diarrhea, and in experimental animals, renal damage. Oral toxicity data on the other compounds were not readily available from the references used in this survey. Oral Hazard in Paints. Chromium compounds, especially the hexavalent forms of chromium, have the potential of toxic action at relatively low levels. It is not sufficiently clear from this brief survey what oral hazard would be provided by ingesting the specific compounds to be used in paint formulations. Experimental investigation will probably be necessary to establish acceptably safe levels. is.-'YSf t " -- r,. - ikr . . *.<r 'u* ` `JS-" ' Sv?.. fv^-V - \ - 30 - \ Cobalt Compounds Cobalt Naphthenate 0-1# Cobalt -Nickel Titanate 0-20% Cobalt Soaps 0 - 1% Cobalt is a relatively rare element, composing about 0.001# of the earth's crust. The toxicity litera ture on cobalt is relatively limited. The "routine" references (^-26) were used.- Stokinger (22) and Browning (6) deal with the.general toxicity of cobalt and Valberg (63) discusses the gastrointestinal absorption of cobalt. Cobalt is an essential trace element for man and animals, rt is an important constituent of vitamin a&d certain enzymes, and is associated with the production of erythro poietin, and red cell stimulating factor. Parenteral lethal doses of cobalt compounds in animals vary from 21 to 1^00 mg/kg (7, 18). Administration of cobalt salts produces polycythemia. In one case of human poisoning, liver and kidney damage was attributed to cobalt. Metallic cobalt dust and cobalt salts may produce allergic contact dermatitis and comeal irritation. Inha lation of cobalt dust has been associated with gastro intestinal irritation and possible bronchial asthma. The industrial TLV for cobalt metal dust or fume is 0.1 mg/m . The body contains an estimated 3 mg of cobalt with mo6t tissues containing 0.1 ppm or less. Cobalt is m ~ 3 '-3 M K i^-> t l..-v ' ***>i'. *& i&n. w&. r-V--: i--; . /-v- VI.V-.:'-;- S-W 00154B concentrated In bone, liver, kidney and cecum at 0.6, 0.3, 0.2 and 0.26 ppm, respectively. In the studies of Tipton and Stewart (24), the diets contained 300 and 500 jug per day with most of the cobalt being excreted in the feces (48 and 77%). Oral lethal doses of cobalt range from 0.5 to 1700 mg/kg (7, 18). Excessive oral intake causes nausea and vomiting. Five hundred mg/day for 30 days was lethal for calves and 50 mg/kg was lethal to chicks. Three to 4 mg/day given to children for the treatment of anemia was goitrogenic. The ingestion of 0.1 to 0.25 mg per day does not appear to have any adverse effects whereas single daily doses of 25 mg per day over a period of one week or longer increase the hemoglobin content of blood. McKee and Wolf (13), however, state that maximum safe concentration for cobalt in drinking water cannot be established or estimated on the basis of present knowledge. Specific ?air.t Compounds. Cobalt napthenate was found by Rockhold (42) to have an oral LD50 in rats of 3-9 gm/kg. Toxicity or solubility data on the other cobalt compounds we not readily available. Oral Hazard in Paints. Since relatively low levels of cobalt intake can be toxic to children, appropriate studies to establish safe levels of cobalt compounds in paint formulations should be carried out. s$ - ir Compounds t Copper Metal o-5<# in i o Copper Naphthenate Copper Oxides 0 - 25* Copper Phthalocyanine 0 - 5* Copper Soaps o - 5* Copper is an essential element to man in that it is required for the formation of erythrocytes and hemoglobin as well as being an essential part of several proteins: ceruloplasm, tyrosinase, cerebrocuprein, erythrocuprein, cytochrome oxidase, and other proteins. There is a large literature on copper essentiality, bio chemistry and toxicity. Scheinberg and Stemlieb (43) and Davenport (68) provided extensive reviews. For more recent reviews see Scheinberg (4$), Browning (7)j and Van Campen (46). The toxicity of copper compounds has been known for centuries. Soluble copper salts are strongly irritating to the skin and mucous membranes. Ingestion of excess quantities (copper sulfate) in man has caused vomiting, gastric pain, convulsions, and death (16). Nerve, kidney and liver damage has been recorded. Metal fume fever ("brass chills") results from the inhalation of copper dust or fumes (TLV for fumes, 0.1, and for dusts, 1.0 mg/m^) N hoggi r- z&m r. S-W 001545 The body contains approximately 100 mg of Cu, concentrated mainly in the liver, brain, kidney, heart amid stomach (12). The diet normally contains from 2 to 20 mg per day with most of it being excreted in the feces (24). Lethal oral doses in animals range from 22-940 mg/kg. Hemolytic anemia has been induced by the therapeu- * tic use of copper sulfate. Sixty to 100 mg in the diet due to heating tea in a copper pot has caused gastroenteritis (13). Three ounces of 1% copper sulfate also caused one case of enteritis. Ten to 30 mg per day in drinking water apparently causes no symptoms; however, because of bad taste problems, USPHS 1962 standards limit copper to 1 mg/ liter (13). Specific Paint Compounds. Copper metal is in soluble in water but soluble in acids and therefore may form absorbable compounds in the stomach. Copper naphthenate, orally administered to rats (42), had an LD50 greater than 6 gm/kg (low toxicity); however, Gefafer (10) describes the naprthenate .as an irritant. Copper oxides, used in fungicides, are irritants (10) and are soluble in acid. Copper soaps are generally insoluble in water or acid S-W 001547 are available, such as the National Academy of Sciences' "Airborne Lead in Perspective" (^9), Hammond's "Lead Poisoning: An Old Problem with a New Perspective" (50), and more recently Goyer and Chisolm's lead review (51). Lead poisoning is one of the most common of occupational diseases. The industrial TLV's (^) for lead as lead, lead arsenate or tetramethyl lead are 0.15 mg/cu. m. and for tetraethyl lead, 0.1 mg/cu. m. Inorganic lead poisoning may produce abdominal pain (colic), constipation, headache, weakness, muscular aches or cramps, loss of appetite, nausea, vomiting, anemia and other signs and symptoms. Lead palsy and lead encephalopathy resulting from industrial exposure is rare but not infrequent in children exposed to lead. Children poisoned by lead may and other sequelae. develop mental retardation as well as permanent paralysis/ Symptoms of organic lead poisoning are usually confined to the nervous system. Biochemically, lead interferes with several enzymes involved with the synthesis of hemoglobin which leads to increased urinary excretion of coproporphyrins and delta-aminolevulinic (ALA) acid and decreased blood AIA synthetase and AIA dehydratase. High levels of lead are also associated with hyperglycuria, hyperamino aciduria, hyperphosphaturia and hypophosphatemia. The action of lead on the kidney and on neuromuscular activity is not well understood. - 36 - The body is estimated to contain 80 to 120 mg of lead, most of which (over 90#) is stored in bone. Except for bone, most tissues contain 1 ppm or less of lead. The normal adult diet contains approximately 0.3 mg of lead per day, most of which is excreted in the feces. About 10# of the dietary lead is absorbed and excreted in the urine. Lead normally accumulates in bone and other calcified tissue (aorta) with age. Kehoe (52) found in young adults that supplementing normal diets with 0.3 mg of lead (total of 0.6 mg of dietary lead/day) caused ele vations in blood leads which remained at acceptable levels of 0.4 ppm or less. Supplementation with 1 mg (a total o'f 1.3 mg lead in the diet) caused blood lead levels of 0.4 to 0.6 ppm. Blood leads of 0.4 to 0.6 ppm are con sidered suspicious of excessive lead exposures. The acute toxicity of lead compounds varies considerably, ranging from 1.4 to 35,000 mg/kg depending on the species, route of administration, the compound and experimental conditions (7, 18). Lethal doses of lead acetate in the rabbit given Intravenously ranged from 50 to 300 mg/kg and in the dog from 9 to 300 mg/kg for differ ent investigators. This was also true for lead arsenate which ranged from 100 to 825 mg/kg administered orally to dogs. The individual values for these experiments are given below under Specific Paint Compounds. ' ' -- ^ T_ i- irvre1w. .* * S-W 001549 37 - 1 i Lead poisoning in human beings has been re ported to have been caused by drinking of water containing lead in concentrations varying from 0.042 mg/1 to 1.0 mg/1 or more. However, concentrations of 0.01 to 0.16 mg/1 have been apparently non-poisonous over long periods of time (13). For many years, the mandatory limit for lead in the USPHS drinking water standards was 0.1 mg/lj but in the 1962 Standardo, tho limit for lead was lowered to 0.05 mg/1. e In the WHO International Standard*and the WHO European ' Standards the limit for lead was set at 0.1 mg/1 (13). Specific Paint Compounds. There have been many studies on the toxicity of lead compounds. Tables 4 and 5 5S, "'r * are taken from Spector (18) and Christensen (7) and are presented to emphasize the wide variation of responses of animals, discussed above, to the various compounds and methods of administration. An oral LD50 for rats for lead ra.rhthg-;ate (not in the table's) was found by Rochold (42) to be 3 gm/kg. Three reports found in the literature involved the administration of lead in paint or paint materials to animals (53-55) White and Cotchin in 1948 (53) re ported the results of a study of the absorption of lead paint, lead carbonate and lead acetate given to calves. The authors refer to a similar study by Haltenhoff who r- - ;sm- *&?.** `>y s-w 001550 t .f - 38 - \ * Table fa. Toxicity data for lead compounds taken from Spector (18). References to the original literature are provided by Spector. Caapound Lad - Lead SWUat* Lea4 eulflde ~ lad Ittnitlvl la< tcrau Lead arsenate ... - Lead earbooaie Lead chloride Lad chraui Lad dlaadt Lead lactate Lead -***-<* Lead nitrate Lead eleate Lud MMUIOU bad arthepuapoia Lad sea U>< iredl Lead silicate Lead atearate Animat Route Dose Rabbit Rabbit Rat Guinea pig Guinea pig Pigeon or w ip ip ip or MLD* MLD* LD LDj, LD2S LD Dosage mr/Xg Value 400 10 >1000* too 200 too Guinea pif or Guinea pig IP Guinea pig tp * Dog or Rat Guinea pig Guinea pig Guinea pig ip or lp IP IUl Rabbit Rabbit Ip PC le MLD* LD, ld7* LD LDjo MLD LD*o LDjS MLD* MLD MLD 35.000 144 UP 2000-3000 1600 10.000 113 220 10 312-dtl 2I.I-4U Prog Rat Rat Rabbit Rabbit Rabbit Cat Dog Dot Dog rfaf Rat . . Rat Rabbit Rabbit Qicken Sieep e ip ip pe le ie pe or *c ir iv or or or or or or Guinea pig Guinea pig Guinea pig Guinea pig or ip lp or Cum pit ip Cunea pig Guinea ptg Guinea pig j Guinea pig ip lp er * Guinea pig Guinea pig Rat Guinea pig ip ip lp ip or Guinea ptg or Guinea pig Guinea pig Guinea pig Cuinea pig Rat Ceinea pig IP IP IP IP ip r Guinea pig Cuinea pig Guinea pig Guinea pig ip IP ip or LD LD ldm LD LD LD LD LD LD i.D LD 1400 1J0 iso 300 50 300-400 100 300 to 4 300 LD5o* LDso* LDso* MLD LDSO* LD 825 100 125 200 450 4M0l MLD* LD LD75 1000 124 250 MLD 1500-2000 LDts U>M 154 310 LDjj LDfc* 115 U0 LDa 1000-4000 !*> LD40 LDts LD LD '400 101 210 270 2000 LD 1000 LDlOO LDs 140 31 LDJJ LD 131 2M LDjo MLD 450 2000 LD40 LDso LD 1 318 1 120 | 134 XI LD | 20.000 Tf 3*. i -v-;.-.. . o--'v- v- r.0?& 1 Iv-^sr I:" 1 v S-W 001551 - 3 Table 5. Toxicity data for lead compounds taken from Christensen (7). References to the original literature are provided by Christensen. Compound Animal Route Dose Dosage Lead Guinea Pig Man ip ih LDca LC 100 3 0.43mg/m Lead Acetate Rat ip LD50 150 iv LD50 120 Lead Arsenate Rat or LD50 100 Lead Arsenate (basic) Man or LDca 1.4 Lead Carbonate Guinea Pig ip LDca 124 Lead Chloride Guinea Pig or LDca 2000 Lead Chromate (vi) Lead Compounds-Triethyl-Chloride Lead Compounds-Triethyl-Oleate Guinea Pig ip Rat ip Rat or LD50 LD50 LDca 400 11 50 Lead Dioxide Lead Fluoborate Guinea Pig ip Rat or LDca LDca 115 50 Lead (11) Cyanide Rat ip LDca 100 Lead (11) Fluoeillcace Rat or LDca 250 Lead Lactate Guinea Pig or LDca 1000 k ~ y.- -*: * W&pgferr i srsv.?*? 1 i: -v-r" V>'* I *':SS--S j ! :% :* ' w`.. ' ! S-W 001552 Table 5. Continued Lead Monoxide Lead Nitrate Lead Orthoarsenate Lead Orthophosphate Lead Oxide Lead Perchlorates Lead Silicate Lead Sulfate Lead Sulfide Lead Tetbaethyl Lead Tetrapropyl Lead Tetroxide Lead Titanates Lead Triethyl Lead Trinethyl Lead Triphenyl Zluoallicate Lead Tripropy1 Rat i-P LD50 400 Rat ip LDca 270 Cuinea Pig ip LD50 38 Guinea Pig ip LDca 131 Rat ip LD50 450 Mus ip LDca 275 Guinea Pig ip LDca 136 Guinea Pig iP LD50 300 Rat ip LD50 1600 Rat or LD50 35 Rat iP ' LD50 200 Guinea Pig iP LD50 220 Rat ip LD50 2000 Rat ip LD50 11.2 Rat ip LD50 25 ooH Rat or LD50 Rat iP LDca 20 '.v*' i i ! t ........ I i ! i i j ^ * 2SS#* p| r \ ,. !. } r 1 ; 1' V" i V- S-W 001553 used red lead paint flead oxide) with similar results. Calves were given single or repeated doses orally in gram quantities. The signs of poisoning and the concentrations of lead in the tissues were similar irrespective of the form of lead given. All animals died from their expo sures. Nervous symptoms varied but included seizures, blindness and kidney degeneration. Flakes of lead paint 4 could be detected in the stomachs days after administra tion. Concentrations of lead in the liver varied from 9.5 to 182 ppm and in the kidney from 0.5 to 300 pm. Gage and Litchfield (5^) studied the absorption of lead in rats given four polymer formulations in their diets: Polythene contemning lead carbonate pearlescent pigment, polypropy'ene containing a lead chromate-molybdate pigment. FVC stabilized with tribasic lead sulphate and rigid urethine foam catalysed with lead 2-ethylhexoate. Tb-se polymers were fed at the level cf 1% of the dietary formulations for 4 to 5 months. The lead contents of blood, bile, urine, liver, kidney and bone were measured. Control animals received no lead, and reference animals received 2, 6 and 20 ppm of lead as lead nitrate in their diet. Appreciable quantities of lead were absorbed from, the FVC containing lead sulfate (containing 230 ppm as lead in the diet). The absorption of lead from the other mm ' * "'-V. r- S-W 001554 - ug diets was not much different from that of the control diets. The authors concluded that lead was poorly absorbed from the rat intestine. A second otudy by Gage and Litchfield (55) in volved the absorption in rats of lead from paint films contained in the diet at a level of 1%. Two paint films were used: one containing middle orange chrome pigment and the other, lead raphthenate drier. The diets were fed up to 12 weeks. Control groups and reference groups using lead nitrate at 20, 50 and 100 ppm and lead napthenate at 100 ppm of the diet were also used. Blood, bone, kidney, liver, bile and urine lead determinations were made. The authors concluded that one-half of the lead in the chromate paint migrated (was absorbed) from the film under the experimental conditions. Oral Hazard in Paints. The hazards cf ingesting paint flakes containing lead has been the subject of con siderable study. The above mentioned references (^9-51) also provide review of this problem. The Deputy Commissioner of Food and Drugs, James D. Grant, recently declared a limit of 0.06% of the total weight of the contained solids or dried paint film for paints to be used in or around the household (56). This decision was made on the bases of several publications. V ;>-; S-W 001555 announcements and testimonies (57-61). A detailed account of the bases for the Commissioner's decision is outside the scope of this survey. However, it perhaps should be pointed out that a daily permissible intake of lead for children (6l) was based on the human lead balance studies of Kehoe (52), using a soluble lead compound, extrapolated to children and verified indirectly by studies on lead intoxicated children. ; Lithium Compounds Lithium Hydroxide 0 - 1% Lithium Naphthenate 0 - 2% Lithium is nonesser.tial to nan and is found in low levels in human tissues. The literature on the health effects of lithium compounds is relatively limited. Most of the information provided here comes from the "routine" references (b-2S), especially Browning (6) and Stokinger (22). Schow, in 1957 (62), reviewed the pharmacology ana biology of the lithium ion. The body contains approximately 0.5 mg of lithium distributed throughout most of the tissues in levels of approximately 0.01 ppm. Being one of the alkali metals, Li behaves chemically in the body much like Na and K. Lithium compounds are moderately to highly toxic depending on the species, route of administration and the compound used. Sodium antagonizes the action of Li. .hr- im... * i .. * ' r i;K`v IS.: 1 -*/' i-M ,r i ' -i W* S-W 001556 - Mi - . Ni The most prominent symptoms of acute lithium poisoning in animals, when given by mouth or intraven ously, include anorexia, nausea, vomiting, diarrhea, weight loss, dehydration and fall of body temperature. Effects on the central nervous system are manifested by muscular weakness, hyperirritability, stupor, and con vulsion; on the heart by EKG ch.'ingoo, auricular standstill or fibrillation; on the kidney by oliguria, a ri3e in blood protein nitrogen and degenerative changes in the tubular epithelium. Many of these symptoms have been seen in humans in years past when lithium compounds were used therapeutically for gout,mental diseases and as a salt substitute. Normal dietary levels of lithium were not readily available; however, lithium is readily absorbed from the gastrointestinal tract (greater than 70$) and excreted in the urine (31). Lethal oral coses of lithium compounds range from 0.025 to 200 mg/kg. Information on chronic oral exposures is lacking; however, the industrial TLV (U) for the highly toxic lithium hydride is set at 0.025.mg/cu. m. because it is intensely irritating and corrosive. No limits have been set for drinking water; however, Hibbard recommends, without references, that lithium should not exceed 5 mg/1 (13). : jgjr : r-.--' | i--. . ! fOs-'v ---vr--. i-- : gStfl * I : r-.vj*? : t&rf* y-w - agST.'.; i u Specific Paint Compounds. The hydroxide is is strongly alkaline and caustic in high concentrations. Information on the naphthenate was not readily available. : V r.v`u'i l S-W 001557 -5 - Oral Hazard in Paint. Because of the highly toxic nature of lithium compounds, studies should be carried out to confirm the safety of any levels of those materials in i- paints. i T -V" " s* Magnesium Compounds Magnesium Aluminum Silicate 0 - 20# Magnesium Oxide 0 - 1* Magnesium Silicate o - so# Magnesium is abundantly distributed in nature and is an essential element. There is a large literature on the biological role of Mg in living systems. Schroeder et al. (69), Browning (6) and Stokinger (22) provide re- v cent views of the essentiality and toxicity uT magnesium compounds. Magnesium i9 the second most abundant divalent cation in the body amounting to a total of about 25 gm, 70# of which is found in bone (980 ppm). Cartilage con tains 200-300 ppm while other tissues contain from 100 to 200 ppm (12). On normal diets containing ISO and 360 mg/day (24), one-third of the dietary intake appeared in the urine, the other two-thirds appearing in the feces. Aside from its structural functions in bone and teeth, magnesium is important in neuromuscular conduction of skeletal and cardiac muscle and to the activity of numerous enzymes involved with oxidative-phosphorylation, protein, lipid and carbohydrate metabolism. Magnesium deficiency produces symptoms of hyperirritability (tetany) sometimes f , ..; ,f 1 .'1" ; S-W 001558 - t6 - seen in patients on i.v. fluid therapy inadequate in magnesium. In cattle, magnesium deficiency produces "grass staggers". Magnesium compound toxicity varies from slightly to highly toxic depending on the species, route of admini stration, and the compound used (7, 18). When administered intravenously, magnesium salts can produce general an esthesia, narcosis and muscular paralysis which can be counteracted by intravenous calcium administration. In dustrial TLV (4) for magnesium is set at 10 mg/cu. m. for MgO fumes because of fume fever reactions. Oral ingestion of magnesium is considered rela tively non-toxic to man. Magnesium acetate, however, has an oral 1D50 of lS mg/kg (highly toxic) in the mouse. At high concentrations, magnesium salts have a laxative ef fect. Drinking water standards do not impose maximum allowable concentrations but do suggest limits under 150 mg/1 primarily for taste problems. Specific Paint Compounds. Magnesium Oxide is used as a dietary supplement for magnesium and therapeu tically an an antiacid and catharic and can be given in gram quantities safely. Long-term use of Mg compounds as laxatives can develop dependency (constipation) as the only apparent advarao offoet from their uuo (65). Magnesium silicate (talc) has been "generally recognized as safe" (FDA's GRAS list) as an anticaking agent in table t-*-;': 5.. rr ; - S-W 001559 salt up to 2% and In vanilla powder and in vanilla-vanil lin powder under food standards (29)- Information cn magnesium aluminum silicate was not readily found but this compound might be expected to behave similarly to magnesium silicate. Oral Hazard in Paints. Because of the low acute or chronic oral toxicity of magnesium compounds, the oral hazard due to magnesium in paints is probably quite low. Manganese Compounds Manganese Dioxide 0-2% Manganese Naphthenate 0 - 1# Manganese Soaps 0-1% Manganese iswidely disfibutec in nature and is an essential element for both pl.\nts and animals. There is a relatively large literature dealing with normal, deficiency and toxic states of mangant..-,e. Cctzias (66), Schroeder (67), Browning (6), Stokingtr (22), and Smith (48) provide recent reviews of manganese health literature. Manganese is involved with the .'unctions of numerous enzymes governing carbohydrate, 1.pid, protein metabolism and oxidative phosphorylation, including ar- genase, alkaline phosphatase, prolidase, can.f'sir.ase, cysteine desuifhydrase, thiaminase, deoxyribon'.vlease, glycyl-l-leucine dipeptidase and other enzymes C'7). i- .... * '. H WT-v'-.' .-'-.r-V-' S-W 001560 parenterally administered lethal doses of man ganese compounds vary from 0.12 to ^10 mg/kg (7, IS) depending on the species, route of administration and the compound. Organic manganese compounds tend to be con siderably more toxic than inorganic compounds. In chronic exposures of human beings, manganese is a nerve toxin, with polymorphic manifestations of psychic and neurological disorders. Manganese cam also cause a pneumonia-like condition known as "manganese pneumonitis" (5). Acute exposure to manganese fumes can cause metal fume fever. The industrial TLV for manganese is set at 5 mg/cu m. (4). The body contains about 20 mg of manganese with most of the tissues containing 0.1 to 0.2 ppm (12). The kidney, liver, and pancreas contain 0.18, 1.3 and 1.16 ppm, respectively. Tipton and Stewart's (2k) . subjects over a 2^7 day period averaged 2-3 and 5.5 mg/day in the-diet, 2.5 and 3.C mg in the feces, and 0.0k and 0.05 mg of manganese in the urine. Manganese is considered only slightly toxic orally. The oral LD50 of manganese acetate for the rat was 3*7 gm/kg (7) while dally oral doses of 0.5 to 6.0 gm/kg in the rabbit produced decreased growth and bone development (13). A small outbreak, of an encephalitis-like disease, with early symptoms of.lethargy and edema, was traced to manganese in the drinking water in a village outside of Tokyo; three persons died as 2. result of poisoning by well water contaminated by manganese derived from dry cell batteries buried nearby (13)* There are no limits set on the amounts of manganese -_n domestic water supplies. i . -,. .*. ^1 1~-- .V r* -a. Vl'tv .* ;-V' a#- r ; ;. \ ~ :: V : " ' ' - S-W 001561 * io - The normal dietary intake is far higher than the amount that would be tolerated esthetically in drinking water (13). Specific Paint Compounds. No toxicological information on the specific compounds of interest was readily available. Oral Hazard in Paints. Because manganese com pounds are poorly absorbed and the amounts of such compounds used in paints are relatively small (2% or less), their use in paint probably provides low toxic hazard. Mercury Compounds Phenyl Mercuric Acetate Mercury Cadmium Lithopone o - 0.5* 0 1 Kffl! Phenyl Mercuric Oleate o - o.= Mercury Soaps, other 0 - 0.5* Mercury is a nonesscntial element for humans and its toxicological history dates back to the earliest of medical writers. There is an extensive health litera ture on mercury which recently has grown at an explosive rate in response to the concerns of mercury contamination in the environment. Bidstrup (69)> Stahl (70), Friberg et al. (71), Friberg et al. (72) and Goldwater and Clark son (73) represent Just a few of the recent reviews on mercury toxicity. Mercury is considered highly tcocic to man. The - -SFV "T" ` ` - '* - A*a.< i.-v ** -- , i?*,.." - - '*' S-W 001562 - 50 - signs and symptoms are numerous and depend on the compound and the rate and the route of exposure. Acute severe ex posures may produce abdominal pain, vomiting, diarrhea, gingivitis, pneumonitis, renal damage, circulatory fail ure, and respiratory failure. Chronic excessive exposures may result in one or more of the three classical signs of gingivitis, tremor and emotional instability (10). Lethal doses in animals range from 16 to 500 mg/kg. Three to thirty gm of mercury have been fatal to man. The indus trial TLV.for alkyl mercurial compounds is 0.01 mg/cu. m. and for other mercury compounds, 0.05 ng/cu. m. (A). The diet normally contains about 5 micrograms daily of mej ~ury, most of which is- absorbed and excreted in the urine (26). The drinking water standards of the USPHS and the WHO do not include limits for mercury but the maximum permissible concentration of mercury or mer curic ions in drinking water in the USSR has teen set at 0.005 mg/1. According to one investigator, adults may safely drink water containing about L-12 mg of mercury (inorganic) per day and a fatal dose of such water would te 75 to 300 mg/day (13) Specific Paint Compounds. Oral LD50s for phenyl mercuric acetate were reported as 40 mg/kg for the rat and 70 mg/kg for the mouae. Qunntitativo toxicity data on the other mercury compounds were not readily found. * *" - iT*** % * r*-*3~;*- V1. .< to *** k.\ S-W 001563 Oral Hazard in Paints. The amount of mercury to be used in paints is relatively small. However, due to the highly toxic nature of mercury compounds, the possi bility of chronic exposures (months), and the possible increased susceptibility of young children, studies should be made to ensure safe levels of mercury used in paints. * >77.- , . i.-. .** .. -* Molybdenum Compounds i Lead Molybdate 0 - 15% Zinc Molybdate 0 - 2=% Molybdenum is essential for certain plants and animals. Toxicity data on humans is limited. Fairhall (75) provides a summary of industrial exposures. More recent reviews include those of Browning (6) and Stokinger (22). Molybdenum compounds are moderately toxic in animals. Lethal doses for molybdenum compounds in animals ranged from 100 to 500 mg/kg (7, IS, 22). Available in formation concerning exposure to molybdenum compounds in industry is insufficient to define a health hazard (10); however, based on animal studies, the TLVs are set at 5 tng/cu. m. for soluble molybdenum compounds and 10 mg/cu. m. for insoluble compounds (4). The body contains an estimated 5 mg.of Mo with most of the tissues containing C.l ppm or less. Bone, liver, adrenal and kidney contain 1.5, 1.1, 0.6 and 0.4 ppm, respectively (12). The diets reported by Tipton and Stewart (24), contained 0.21 and .46 mg/day half of which was ex--"' :* i ** - --v-.. m . . --.* -77-,:-- : f'iv-f"*: 7.-' creted.in the feces and half in the urine. There are no limits set on the amount of molyb denum in drinking water; however, molybdenum levels in feeds and domestic animals have been of concern (13)* Five mg/day given to rats in their water caused increased mortality (13). Specific Paint Compounds. No quantitative toxic ity data on these compounds were readily found. Oral Hazard in Paints. Insufficient information is available to estimate oral hazards for humans. Adequate studies will need to be performed to establish safe levels of these molybdenum compounds in paints. Nickel Compounds Cobalt Nickel Titanate 0 - 20# Nickel Antimony Titanate 0 - 1=# Nickel Titanate 0-15# There is a considerable literature on the health effects of nickel. Recent reviews include those of Sullivan (76), Schroeder (77) and Smith (48), as well as Browning (6) and stokinger (22). Nickel is considered nonessential to man. Most of its toxicological concerns in man have centered on the industrial use of nickel car bonyl. The TLV for nickel carbonyl is 0.007 mg/cu. m., for other nickel compounds, 1.0 mg/cu. m. Nickel carbonyl ! '-.barf". f ' . *-- -- T* T S-W 001565 - 33 - has been associated with an increased incidence of cancer of the lung and ethmoid sinuses in men exposed to dust in nickel refining. Nickel salts are considered to be highly toxic following access to the blood stream (22). Acute lethal doses in animals range from 5 to 1620 mg/kg (7, 18). Systemic poisoning by nickel salts in humans, however, is unknown (6). Allergic contact dermatitis is not in frequent with skin exposures. The body contains about 10 mg of nickel with most tissues containing approximately 0.1 ppm (12). Bone, skin, tongue, lung and adrenal contain 2.0, 0.44, 0.24, 0.27, and 0.28 ppm, respectively. The diet contains about 450 micrograms of nickel per day. In Tipton and Stewart's study (24), the diets contained 0.39 ana 0.8l mg, the feces C.22 and O.35 mg and the urine 0.11 mg each. Orally, chronic administration of 2 mg of nickel per day in the drinking water of rats caused no ham; how ever, 10 to 20 mg/kg proved fatal to dogs (13)* The USPHS Drinking Water Standards do not place a limit on nickel; however, it is reported that in Russia, the maximum per missible concentration is 1.0 mg/1 (13). Specific Paint Compounds. Quantitative toxicolog ical data for these compounds were not readily found in the literature. s-w 001566 Oral Hazard In Paint. Nickel and titanium (see Titanium Compounds, below) compounds tend to have low ti.-.vixity with oral administration and probably offer low 'nnsari risks in paints at the levels used. Antimony and cobalt (see individual sections above) offer considerable poten tial hazard and these compounds should be evaluated experimentally to determine safe levels for paints. Strontium Compounds Strontium Chromate 0 - 2596 Except for rudiractive strontium, strontium com- pounds are considered relatively non-toxic to man, similar to calcium compound'. (6, 10, 16, and 22). Since chromates are toxic, strontium chromate is discussed under Chromium Compounds, above Tin Compounds Organic (specific compounds) Tributy' Tin Oxide 0-196 Tin Or;,ono Compounds 0 - i '.he full toxicity of tin is observed almost cxclucive.y from its organic compounds - the alkyl deriv atives (i). Tin itself when taken by mouth is practically innocuru/, but its dust or fume when inhaled can cause a jymptomless pneumoconiosis. The TLV for inorganic tin (oxccpt tin hydrido and tin cxido) is 2 mg/cu. m. (^). The alkyl derivatives are highly toxic and one of them. ; v.. i" >:!. f;.' * -r2-' m vT-".>v TKT S-W 001567 diethyl tin, has proved lethal to human beings with symptoms of cerebral edema and gastrointestinal disturbance (6). Certain organo tin compounds, especially the tri-butyl series, are potent skin irritants. The TLV for organic tin compounds is 0.1 mg/cu. m. (4). * Numerous articles on the toxicity of tributyl tin oxide and other alkyl tin .compounds (78-81) and other organo tin compounds are available in the Kettering Library. * Elsea and Paynter (7&f'found the acute oral LD50 for tri- butyl tin oxide to b4 1^8 mg/kg (moderately toxic) for rats. f The oxide fed' to^rats in the diet at levels of 32, 100 and ..f' ' 320 ppm/frkppressed growth. Stoner et al. (79) and os.m6s and Ston. e/ r^SO) studied a series of tetra-, tri-, di- and monoalkyl tin compounds in rats, rabbits, guinea pigs, and fowls in both acute and chronic experiments. In rabbits, triethyl tin, the most active compound, produced muscular weakness, tremors and death. Other species and compounds showed vari i ations of this pattern. The outstanding sign of chronic poisoning was muscular weakness. Oral Hazard in Paint. Since organo tin compounds are moderately to highly toxic in animals and man, the use of these compounds in paints should be adequately studied to determine the levels which can be used safely. ec ... v* - : t . v- ---v' - : S-W 001568 - 56 - Titanium Compounds Titanium Dioxide 0 - 30% Titanates: Antimony 0 - 1556 Nickel 0 - 15# Tungsten 0 - 13% ,Cobalt Nickel 0 - 20% Titanium is widely distributed in the earth's crust where it is the eighth element in abundance. It is not essential for plants or animals nor is it regarded as toxic to animals or humans. The lack of toxicity of titanium and its compounds by contact with skin and tissues has been amply demonstrated by its use in the therapy of skin disorders and as a surgical prosthesis (6). The body contains an estimated 15 mg of titanium with most of the tissues containing approximately 0.1 ppm or less. Lung contains about 2.8 ppm and the bone 1, the zhyroid 0.49 and the skin 0.61 ppm. Titanium accumulates in the lung with age, apparently due to polluted air. Tipton and Stewart's studies (24) indicated 0.75 and 2.0 ng/day in the normal diet with 0.46 and 0.82 mg/day and 0.49 and 0.47 mg/day appearing in the feces and urine, respectively. Oral administration of large amounts of titanium salts nixed with the diet is stated by Ereaux not only to have no toxic effect but actually to have an im provement on health (6). There are no water drinking limits set for titanium (13). [ 77-. i : ; r- . -tV-"V->* : *.. . . jSSjs^ i ' T-..-. t l /- S-W 001569 - 57 Specific Paint Compounds. Antimony, cobalt, nickel, and tungsten are discussed in other sections of this survey. Titanium dioxide is used as a food additive' (29) and is considered to be chemically inert in the body (82, 83, 6, 22). The TLV for titanium dioxide is set at 10 mg/cu. m. Oral Hazard in Paint. Antimony, cobalt, nickel * and tungsten possess significant toxicities of their own and should be considered on individual bases (see corre sponding sections in this survey for these metals). Titan ium dioxide is apparently inert and should pose no oral hazard in paint formulations. Tungsten Compounds Tungsten Titanate 0 - != The literature on the health effects cf tungsten is limited. Stokinger (22) and Browning (5) provide re cent reviews on tungsten; however, the literature cited is not very recent. Tungsten is nonessential to humans. Data on the body burden (12), dietary levels (26, 2^) or on the absorp tion of tungsten (31)were not readily found. Data on the toxicity of tungsten compounds was aloo limited (7j 18). The following, taken from the "Documentation of Threshold Limit Values" (^), represents i./-. ( . S-W 001570 similar data presented in 3rownir.g and . stokir.ger. The LD50 of sodium tungstate was between 140 to l6o mg/kg when injected subcutaneously into adult rats, making this compound moderately toxic. On oral administration to rats, the toxicity of this compound was greater than that of tungsten oxide while amnunium -;aratungstate was the least toxic of the three" 3oth podium tungstate and the oxide proved leth?.1- to rats on a diet containing 0.5% as V. ine ammonium salt was not lethal at this level but resulted in weight loss (4-50#). A similar weight loss was pro duced by dietary levels of O.IJb of the oxide and the sodium salt. Tungsten powder when fed to weanling rats of both sexes at levels of 2, 5 and 10% of the diet resulted in a 1556 reduction in body weight gain among the females but not the males. long industrial experience has indicated no pneumoconiosis among workers exposed solely to V or its insoluble compounds. Dust chamber exposures of animals to V, tungsten dioxide and tungsten carbide produced only minor pulmonary changes. The TLV for soluble tungsten compounds is 1 m^cu. m. and for insoluble compounds, 5 mg/cu. m. Calcium, magnesium and iron salts of tungsten are insoluble; hence they are not likely to occur in natural waters or to remain in solution in waste waters . >v ; '-'v T S-W 001571 from industry. Therefore, there are no limits set for tungsten in domestic water supplies (13). Specific Paint Compounds. Toxicological data on tungsten titanate wp.z. not readily found. Oral Hazau in Paint. Since tungsten compounds can be signifies.,-cly toxic, adequate investigation should be made to establish the safety of using tungsten titanate in paint uz the 15% level used in paints. Zinc Chromate Lithopone Zinc Metal 0 - 25% 0 - 50% 0 - So% Zinc Molybdate 0 - 20% Zinc Napthenate 0 - 1% Zinc Oxide 0 - 25% Zinc Soaps (other than stearate) 0 - 1% Zinc Stearate 0 - 5% Zinc Sulfide (in Lithopone) 0 - -5% Zinc is widely distributed in nature and is an tial element to humans. There is a large literature on the biological importance of zinc, primarily dealing with zinc deficiency, metabolism and its role in metallo- enzymes and less so on the toxic effects of zinc compounds, - So Browning (6) and Stokinger (22) provide recent reviews of * the literature on zinc toxicity. Zinc salts in high enough concentration are astringent and corrosive to the skin and irritating to the gastrointestinal tract (22). When ingested they act as emetics. Zn ion, however, is ordinarily too poorly absorbed to induce acute systemic intoxication. After large doses have been ingested, fatal collapse may occur as a result of serious damage to the buccal and enteric mucous membranes. In industrial exposures, zinc chloride fumes have been found to cause damage to the mucous membranes of the nasopharynx and respiratory tract. The TLV of the chloride fume is set at 1 mg/cu. m. The TLV for zinc oxide is set at 5 mg/cu. m. due to its ability to induce metal fume fever (zinc chills, brass founder's augue, etc.). The human body content of Zn is estimated to be about 230 mg. Most of the tissues contain from 3 to 30 ppm with high concentrations being found in bone, kidney, liver, muscle and prostate (12). Tipton and Stewart (2M) found normal diets to average 11 and 18 mg/day with most of this.. ` excreted in the feces (lM and 16 mg/day) and about 10# excreted in the urine (1.3 and 1.2 mg/day). Acute oral lethal dooen for Zn compounds listed in Spector (18) and Christensen (7) range from Mo.5 to 2M60 mg/kg depending on the species end compound. There *. t' *--. i-iv... -i. S-W 001573 have been numerous cases of food poisoning from the use of galvanized containers. Six hundred and seventy-five to 2280 mg/1 has been reported to have an emetic effect. Ingestion of 6 gm of zinc chloride has been fatal in man. The USPHS 1962 limit for zinc in drinking water is set at 5 mg/l based on the cad taste (13)* Community water supplies have been reported with 11.2, 17, 18.5 and 26.6 mg^'-iii/l with no ill effects. Pigs drinking .''S'* water /itfitaining 100C mg/l developed lameness and mal nutrition . Rats, however, receiving 1000 mg/l showed no /' effect. In these latter studies, rats receiving 5000 mg 2n/l had slight toxic effects and rats receiving 10,000 mg/l experiences decreased growth rates and early death. Specific Paint Compounds, lithooone, liberates hydrogen sulfide upon decomposition by moisture or acids (14, 16). Zinc oxide is used as a trace mineral food supplement (29) and in skin ointments. It is considered relatively non-toxic orally. Freshly forced ZnO fumes can be toxic to workers in industry (k). Zinc Nanhthenate was reported by Rockhold (^2) to have an oral LD50 greater than 6 gm/kg in rats, which makes it of low acute toxicity for rats. Zinc stearate, like zinc oxide, is used as a dietary and nutritional supplement but is toxic, producing pulmonary fibrosis, when inhaled. Zinc metal is considered by Sax (16) as not inherently toxic. i * :v S-W 001574 Oral Hazard in Pair.t. Most of the zinc compounds of interest do not appear to offer much of an oral hazard at the concentrations used in paints. Some of these com pounds such as the chromate and possibly the molybdate, may be toxic because of the accompanying anion and there fore should be -adequately evaluated to determine safe / levels. Although zinc metal is relatively inert biologi- cally, tfc-e use of it at an So# level in paint may lead to the formation of the zinc chloride in the stomach which cculd produce toxic effects. Zirconium Compounds Zirconium Naphthenate Zirconium Oxide 0-2# 0 - 1# Zirconium Soaps 0 - 2# Zirconium is not essential to man. Browning (6), Stokinger (22) and Schroeder and 3alassa. (34) pro vide recent reviews of zirconium toxicity. Zirconium is relatively non-toxic to animals and there is no well authenticated evidence of toxic effects from industrial exposure (6). However, there have been reports of pulmonary granulomas in zirconium workers and granulomatous skin lesions from its use in deodorant sticks (16). The TLV for zirconium compounds is 5 mg/cu. m. (4). - 63 - The body contains about 6 mg of zirconium. In Tipton and Stewart's (24) study, normal diets contained 0.43 and 0.55 mg/day with 0.12 and 0.059 rag appearing in the feces and 0.08 and 0.18 mg appearing in the urine, providing for an average positive balance of 0.23 and 0.31 mg/day over the 347 day period. Retained zirconium is thought to accumulate in bone (6). There are no limits for zirconium in drinking water (13)* The toxicity of Zr salts is very low by the oral routej. the LD50 dose of the nitrate, chloride, sulfate, and acetate of Zr and sodium zirconyl sulfate for rats ranged from 2.5 to-10 g/kg (22). Intraperitoneally, the same Zr compounds were considerably more toxic acutely, (LD50's from 0.175 to 4.1 g/kg). Hydrated Zr carbonate is physically inert in rats in oral doses up to 10 g/kg. Zr gluconate, however, was moderately toxic (LD50, 247 mg of ZR/kg) acutely by intraperitcneal administration in razs. Animal studies reported by Rothstein (in 13) in dicated neither acute or chronic injury in response to Zr compounds given orally for as long as two years. Even 20% Zr oxide in the diet was not harmful. Specific Paint Compounds. Zirconium oxide is relatively non-toxic orally. Toxicological data on the other Zr compounds was not readily found. *" Z i-r..-* i : m?: 1. ; iv... S-W 001576 Oral Hazard In Paint. Zirconium compounds have low toxicity orally and probably represent little oral hazard when used in paints at levels of up to 2%. IV. Summary This study was intended to provide a preliminary survey of the literature pertaining to the potential hazards of ingesting paints containing metals. Over 100 specific compounds containing 25 different elements were reviewed for possible inclusion in this report. As was expected, very little experim\ ental data were available on the ingestion of paints containing metals, e.g., only three-articles were found on leaded paints. Relative to the toxicity of specific compounds per se, again there were few data which could be used to predict ingestion hazards for acute or chronic exposures in children or adults. Each section on the different compounds in part III contains a summary of hazards for that elemental class. As an overall summary, aluminum, calcium, magnesium, man- ' ' ganese, strontium, titanium and zirconium compounds are generally of low oral toxicity. Except when toxic components (such as antimony in antimony titanate) are contained in the formulation, these compounds should be of low oral hazard. Compounds of antimony, barium, cadmium, lead, lithium, and mercury are generally highly toxic and should be limited to low levels in paints. Compounds of boron, cobalt, chromium, copper, molybdenum, tungsten and zinc vary from slightly to highly toxic depending on the chemical form and therefore need to be evaluated on individual bases. Table 6 presents a listing of most of the specific ^compounds, their ranges of concentrations used in paints, and crude estimates of oral hazards in paints based on the findings of this survey. The concern of the paint industry for potential hazards of the ingestion of paints involves both acute and chronic exposures of children to specific paint formu lations. Most of the known toxicity of the compounds considered in this report is based on animal experiments (acute and chronic) and on human experiences (mostly acute intoxication) of exposures to compounds which might not be related closely enough chemically to the compounds of interest. Therefore, any conclusions based on this study should be adequately verified by animal and human experi ments with flakes from commercially formulated and applied paints (see recommendations below). ' rr-t.-y. sar,*-. l v: v* 2-X *r t 1 .. . ./ v- v;;--*----S-W 001578 - CO - Table 6. Preliminary Estimates of Oral Hazard for Specific Compounds in Paints. . fu. |t' * r I '' >--. Table Le.cer.d: The ranges indicate the percentages v * of the compounds (*&s-str e.. Cry JML.rf}- *s*i lr- oa^. ;s. Tnc predicted oral hazards are only crude estimates based on toxicity data derived from this search of the literature. r Hazard ratings are 0, 1, 2 and 5 - or no, slight, moderate and high relative hazard, respectively. A dash in the hazard column indicates insufficient data available to make an estimate. An asterisk indicates that the estimate is based loosely on information about the general class cf the cocpound. Note; Many compounds have several oxides depend ing on the valence states. The designation of "soao" refers to salts of oleic, laurlc, palmitic, stearic and erucic acids, r Lf?-yT^ ' //' .i CoaDCJund Oral Hazard j SKf Aluminum E^-foxide 0- 5 0 Aluminuj* Metal Aluminum Oxide 0- 5 0- 5 o ' i ;V i r> 0 Aluminum Silicate Aluminum Stearate Antimony Oxide 0- 5 0 - 10 0 -.-10 . 0* . . 0* 0-1 ;* *' ... *. i; Barium Meta Borate 0 - 15 2* P-- ;vw 3arium Soaps 0- 3 2* Barium Sulfate 0 - 30 0 Barium Sulfide (Lithopone) Boron Trifluoride Cadmium Barium Soaps 0 - 50 0- 1 0- 3 0 r1 2-3 3* f' * 4-*- -- i t -'i. Cadmium Lithopone 0 - 15 3* Cadmium Selenide 0 - 15 1* Cadmium Selenide Pigments Cadmium Soaps Cadmium Stearate Calcium Carbonate Calcium Kaphthenates Calcium Oxide m 0 - 25 0- 3 0- 3 0 - 70 0- 2 0 - 15 1*. 2-3* 2-3* 0 \ 0/ 0 ,v , ry : fj/f' ' ! '\ i -. i i- , \:. S-W 001579 Table 6. Continued 67 Calcium Soaps Chroaium Oxide Cobalt Naphthenate Cobalt Nickel Titanate Cobalt Soaps Copper Metal Copper Naphthenate Copper Oxide Copper Phtha1ocyanine Copper Soaps Lead Carbonate Basic Lead Chromates Lecd--Ghr oastco--VI-- Lead Metal Lead Molybdate Lead Naphthenate Lead Oxides Lead Silicate Basic Lead Silico-Chromates Lead Soaps Lithopone . Lithium Hydroxide Lithium Naphthenate Magnesium Aluminum Silicate Magnesium Oxides Magnesium Silicate Manganese Dioxide Manganese Naphthenate Manganese Soaps Mercury Soaps Nickel Antimony Titanate Nickel Titanate Phenyl Mercuric Acetate Phenyl Mercuric Oleate 0- 2 0 - 15 0- 1 0 20 0 - 1 0- 1 05 0 25 0- 5 0- 1 0 - 60 0 - 25 0 - 25 0 - 25 0 - 15 0- 3 0 - 50 0 - 15 0 - 25 0 -^ 3 _0 - 50 0- 1 ' 0- 2 0 - 20 0- 1 0 50 0- 2 0- 2 0-1 0 - 0.5 0 - 15 0 - 15 0 0.5 0 - 0.5 0 1-3 0-1 2* 2* 2* 0-1 2* 03* 3* * 3* 3* 3* 3* 3*' 3* 3* o-l . 2-3* 2-3* 0* 0 0 1-2 0-1 1-2 2-3 2* 2* 3* 3* .... ^ !' ::Th~:-; i i 1 - 1 ; ' - '.; 1 '* : .* * *, r-~\ ;</ .vTA.-t VS", T &y.". ^-***~; -i ;iS? m- -i S-W 001580 Table 6, Continued - 6d - Sodium Tetraborate Strontium Chromate Titanium Dioxide (commercial grades) Tributyl Tin Oxide Tin Organo-Compounds Tungsten Titanates Zinc Chromates Zinc Metal Zinc Molybdate Zinc Kaphthenate Zinc Oxide Zinc Soaps Zinc Stearate Zinc Sulfide (Lithopone) Zirconium Naphthenate Zirconium Oxide Zirconium Soaps 0-15 0 - 25 0-50 0-15 0-25 0-20 0-25 0-1 0-2 0-1 0- 2 00 0 11 1 vno VJl H 0 1 H 0 CO 1 o <A * w 1 O 2* - 0-1 <r~^~* 3* 3* 2* - 2* 2* 0-1 0-1 0-1 0 0 0 H 1 O fIm 8 im rm , V- ' i; ! '.vl? .. ' V/ ' - -V- :/-'V VV-.-vs-tV*-';** .'Ui vr-m- S-W 001581 69 V. Rec ommen datlon s Recommendation 1. The purpose of this survey was to examine super- ficially the literature on the potential hazards of in gesting paints containing metallic constituents-^ The survey did not yield much information on which to base standards for permissible levels of metals in paints. In this author's view, an exhaustive literature search on each of the specific compounds or elemental classes of compounds would not be especially productive either. However, before undertaking laboratory experiments to generate the required data, more detailed, but not ex haustive, literature searching should be carried out in order to give direction to the initial experiments. Auto mated literature searching techniques such as those pro vided by Medlars or Medline of the National Library of Medicine or by Chemical Abstracts could be used. Utilizing the additional literature contained in the Kettering Library files would also provide considerably deeper coverage. Recommendation 2. Man is his own best model and any conclusions based on animal data should be, if at all possible, con firmed by human studies such as those cited for lead. Before human studies are undertaken, extensive studies using animals will need to be conducted in order to v- . V rf.-. i.VV-r 7 i > S-W 001582 - 70 - fet: characterize the degree of toxic hazard, both acute and vi chronic; to determine the mechanisms of toxicity and rr--w. early indicators of toxic effects; and to determine the degree of absorption, the distribution patterns and the rates of excretion. Only when safety seems assured should small quantities of the paint flake materials be given to children or adults to make certain that the types of metabolism and the degree of absorption are similar to test animals i- . It is beyond the scope of this study to detail the types of experiments which should be carried cut. However, te in addition to the studies involving the health hazards of lead exposures (^9"6l;, the reader is referred to such documents as those of Lehman (85), Fitzhugh (86), Irwin - . (87), and the National Academy of Science (88) for back f ground in toxicological testing. A* f Recommendation 3Studies used for predicting the hazards due to aetal-contaihing paints should involve the use of the metal-contcining paint formulations themselves. Toxi cological information on pure compounds or related metal compounds should not be considered a sufficient substitute for actual paint flake ingestion studies. Paint fillers, binders, modifiers, etc., may increase the absorption of the metals concerned, or as is most likely, they may reduce the toxic hazards by reducing the solubility of the metals in intestinal juices. s-w 001583 Recommendation Since there is a large number of compounds and varieties of paint formulations, it is desirable to develop in vitro testing techniques for screening purposes. Cramp- ton (89) and others describe a number of in vitro methods such as closed loops, inverted sacs, etc., which could be used. Solubility studies using synthetic intestinal juices have been discussed with members of the National Paint and Coatings Association on previous occasions. Any in vitro studies should be validated for their ability to predict in vivo behavior. *r / S-W 001554 72 - VI. References 1. Kimber, D. C., Gray, C. E., Stackpole, C. E., Leavel. K. A., Miller, F. M. (1966) "Anatomy and Physiology1* 15th ed. The Macmillan Company, New York. 2. Wilson, T. H. (1962) "intestial Absorption" W. B. Saunders Co., Philadelphia. 3. Skoryna, S. C., and Waldron-Edward, D. (1971) "Intestinal Absorption of Metal Ions, Trace Elements and Radionuclides1' Pergamon Press, New York. h. American Conference of Governmental Industrial Hygienists (1971) "Documentation of Threshold Limit Values for Substances in Workroom Air" Secretary-treasurer, ACGIHV P. 0. Box 1937, Cincinnati, Ohio ^5201. 5. Bowen, H. T., (1966) "Trace Elements in Biochemistry" ' Academic Press, London, New York. 6. Browning, Ethel (1969) "Toxicity of Industrial Metals" Appleton-Century-Crofts, New York. 7. Christensen, H. F. (1971) "Toxic Substances. Annual List" National Institute of Occupational Safety and ` Health, U. S. Dept, of H.E.W., Rockville, Md. 20832 8. Elkins, Hervey B. (1959) "The Chemistry of Industrial Toxicology" John Wiley and Sons Inc., New York. 9. Fairhall, L. T. (19^9) "Industrial Toxicology" Williams and Wilkins Co., Baltimore. 10. Gefafer, W. M. (1966) "Occupational Diseases" Public Health Service Publication No. 1097, U. S. Govt. Printing Office, Washington, D. C. 11. Gleason, M. N., Gosselin, R. E., Hodge, C. H., Smith, R. P. "Clinical Toxicology of Commercial Products" Williams and Wilkins Co., Baltimore. 12. International Commission on Radiological Protection (1959) "Report of Committee IL Permissible Dose for Internal Radiation" Pergamon Press, New York. i , Ur.:. * sr:--* rY-1: g;: ~~ 7''- ...f S-W 001535 V'*:. 73 - 13. McKee,. J. E., and Wolf, H. V. (1963) "Water Quality Criteria" State Water Quality Control Board Pub. No 3-A. Sacramento, California. 14. Stecher, Paul G. (1968) "The Merck Index" (8th Ed.) Merck and Co., Inc., Pahway, New Jersey. 15. Patty, F. A. (1963) "Industrial Hygiene and Toxicology" Vol. II. Interscience Publishers, Division of John Wiley and Sons, New York. 16. Sax, Newton Irving (1963) "Dangerous Properties of Industrial Materials" Reinhold, New York. 17. Schroeder, H. A. (1970) "Metallic Micronutrients and Intermediary Metabolism (Report #3). Final progress report" U. S. Army Medical Research and Development Command, Washington D. C. 18. Spector, W. S. (1956) "Handbook of Toxicology" Vol. I. National Research Council, Saunders, Philadelphia. 19* Lange, Norbert A. (1956) "Handbook of Chemistry" 10th ed. Me Graw-Hill 3ook Co., New York. 20. Kodgman. Charles (1949) "Handbook of Chemistry and Physics" Chemical Rubber Pub. Co., Cleveland, Ohio. 21. Stewart, C. P., and Stolman, A. (i960) "Toxicology Mechanisms and Analytical Methods" Academic Press, New York. 22. Stokihger, H. E. (1963) ChaDter XXVI. The metals (Excluding lead) pp. 787-119^ in Patty (15). 23. Tipton, I. H. et al. (1965) Trace elements in human tissue. .Part III. Subjects from Africa, the Near and Far East, and Europe. Health Physics 11:403-451. 24. Tipton, I. H. and Stewart, P. L. (1969) Patterns of elementary excretions in long-term balance studies. Health Phys. 16:455. Note: Only the data from subjects C&D were used in the body of this survey. 25. Schroeder, H. A. (i960) Possible relationship between trace metals and chronic diseases. Chapter 6, pp. 59 in Seven, M. J. "Metal Binding in Medicine" J. 3. Lippincott, Philadelphia. ic*:. I i .* \ :... ` .- t $-W 001586 - 74 - 26. Schroeder, H. A. (1965) The biological trace elements or peripatetics through the periodic table. J. Chron. Dis. 18:217-228. 27* Campbell, A. B., Cass, J. S., Cholak, J., Kehoe, R. (1957) Aluminum in the Environment of Man. A.M.A. Archives of Industrial Health 15(No.4-6) :359-448. 28. Evenshtein, A. M. (1967) Toxicity of aluminum and its inorganic compounds. Hyg. & Sanitation 32:244-249. 29. Furia, T. E. (1968) "Handbook of Food Additives" Chemical Rubber Co., Cleveland, Ohio. 30. Woolrich, Paul F. (1972) The occurrence of trace metals in the environment. Presented at the Industrial Hygiene Conference, May 14-19, 1972, San Francisco, California 31. Altman, P. L., and Bittner, D. S. (1946) "3iology Data Book" Federation of American Societies for Experimental Biology. 32. Fairhall, L. T. (1947) "The Toxicology of Antimony". U. S. Public Health Service Publication Supplement No. 195. 33* Schroeder E. A. (1970) "Barium Air Quality Monograph #70-12". American Petroleum Institute, 1801 K Street, N.W., Washington, D. C., 20006. 34. Miner, Sydney (1969) "Preliminary Air Pollution Survey of 3arium and its Compounds. A literature review". U. S. National Air Pollution Control Administration. Publication No. APT O-69-28, Raleigh, N. C. 35* Rumyantsev, G. I. (1967) 3arium compounds, pp. 118-25 in Izrael'son Z. I. ed. "Toxicology of Rare Metals" Jerusalem, Israel Program from Scientific Translations, Jerusalem. 36. Barnes, Abigail A. (no date) Annatated Bibliography of Barium. Laboratory of Industrial Medicine. Eastman Kodak Company, Rochester, N.Y. 37- Lee, Douglas H. K. (1972) "Metallic Contaminants and Human Health" Academic Press, New York. . i1 s * ** ! S-W 001587 75 - 38. Durocher, N. S. (1969) "Preliminary Air Pollution Survey of Boron and its Compounds. A Literature Review". U. S. National Air Pollution Control Administration, Raleigh, N. C. Publication No. APT 0-69-31. 39. Fassett, David W. (1972) cadmium, Chapter 4, pp. 98117, in Lee (37). 40. Athanassiadis, Y. C. (1969) "Air Pollution Aspects of Cadmium and its Compounds". Report by Litton Systems, Inc. Bethesda, Maryland for the National Air Pollution Control Administration, Consumer Protection and Environmental Health Service, Dept, of Health Education and Welfare. Contract No. (PH-22-6S-25) APTD. 41. Friberg, L, Piscator, M. and Nordberg, G. (1971) "Cadmium in the Environment". Chemical Rubber Company, Cleveland, 0. 42. Rockhold, W. T. (1955) Toxicity of naphthenic acids and their metal salts. Arch. Ind. Health 12:477-82 43. Scheinberg, Herbert, I.and Stemlieb, Irvin (i960) Copper metabolism. Pharmacol. Rev. 12:355*381. 45. Scheinberg, H. (1969) The essentiability and toxicity of copper in man. pp. 79*82 in "Trace Substances in Environmental Health1' Proceedings of University of Missouri. 3rd Annual Conference, Columbia, Missouri, June 24-26, 1969. 46. Van Campen, D. R. (1971) Absorption of copper from the gastrointestinal tract, pp. 211-28, in Skcryna, S. C. and Waldron-Edward (3). 47. Sullivan, Ralph J. (1969) "preliminary Air Pollution Survey of Chromium and its Compounds". U. S. Dept, of HEW Public Health Service, Consumer Protection and Environmental Health Service, National Air Pollu tion Control Adm., Raleigh, N. C. Prepared under contract No. F.H. 22-68-25. 48. Smith, R. G. (1972) Chapter 6. Five, of potential significance, pp. 13S*lo2 in Lee (37). j JTRU V t r':V.vr.` I ! fc#; VT&S: l ! r ir* fhl r j: ,I 3U t& i. i&. b-T S-W 001588 - 76 - 49. National Academy of Sciences(1972) Lead. Airborne Lead in Perspective", Committee on Biologic Effects of Atmospheric Pollutants, National Research Council, Washington, C. D. 50. Hammond, P. B. (1969) Lead poisoning, an old problem with a new dimension. Chapter 4, pp. 115-. 155. in Blood, Frank, R. "Essays in Toxicology". Academic Press, New York. 51. Goyer, Robert and Chisolm, Julian (1572) Lead, Chapter 3> PP* 57-95> in Lee (37). 52. Kehoe, Robert (1961) "The Metabolism of Lead in Man in Health and Disease. The Harben Lectures i960". Reprints from the Journal of Royal Institute of Public Health and Hygiene. 53. White, E. G. and Cotchin, E. (1968) Natural and experimental cases of poisoning of calves by flaking lead paint. Vet. J. 104: 75-91* 54. Gage, J. C. and Litchfield, M. H. (1968) The migration of lead from polymers in the rat gastro-intestinal tract. Fd. Cosmet. Toxicol. 6:329-338. 55- Gage, J. C. and Litchfield, M. H. (1969) The migration of lead from paint films in the rat gaszro-intestinal tract. J. Oil Col. Chem. Assoc. 52: 236-243. 56. Federal Register, (1972) Part 191 - Hazardous substances; Definitions and Procedural and Interpretative Regulations. Classification of Certain Lead-Containing paints and Other Similar Surface-Coating Materials as Banned Hazardous Substances. Volume 37, number 49, oo. 52195272. 57. Statement by Dr. Merlin K. DuVal, Ass't Secretary for Health and Scientific Affairs, Department of HEW, before the Subcommittee on Health, Committee on Labor and Public Welfare. United States Senate. March 10, 1972. 58. Levine, R. M., Technical Director, Dutch Boy Paints. Testimony before Senate Sub-committee on Lead Based Paint Poisoning. Legislations S. 3080 March 8, 1972. r:--v r--~- i I X&z ; 1 -- ; S-W 001589 - 77 59* Statement by Robert A. Roland, Executive Vice President, National Paint and Coatings Association. Before the Sub-committee on Health of the Senate Labor and public Welfare Committee on Amendments to the Lead-Based Paint Poisoning Prevention Act. (S. 3080) March 9, 1972. 60. American Academy of Pediatrics. "News Release, March 30, 1971. A. A. P. Recommends Reducing Lead Contents of Paints" Department of Public Information 1801 Hinman Ave., Evanston, 111. 61. King, Barry (1971) Maximum daily intake of lead without excessive body lead-burden in children. Am. J. Dis. in Children 122:337-40. * 62. Schow, M. (1957) Biology and pharmacology of the lithium ion. Pharmacol. Rev. 9:17-49. 63. Valberg, L. S. (1971) Cobalt Absorption, pp. 257-64 in Skoryna, S. C. and Waldron-Edward (3). 64. Schroeder, H. A. (1970) "Manganese. Air Quality MonograDh #70-17" American petroleum Institute. 1801 K Street, N. W. Washington, D. C. 20006. 65. Goodman, L. S., Gilman. A. (1970) "The Pharmacological Bases of Therapeutics" ^th ed. Macmillan. New York. 66. Cotzias, George C. (1958) Manganese in health and disease . Physiol. Rev. 37:503-532. 67. Schroeder, H., Nason, A. and Tipton, I. (1969) Essential metals in man. Magnesium. J. of Chron. Dis. 21:815-841. 68. Davenport, Sara J. (1953) "Review of Literature on Health Hazards of Metals I. Copper" Bureau of 2<lines Information Circular 7666 United States Department of the Interior. 69. Bidstrup, Lesley, P. S. (1964) "Toxicity of Mercury and its Compounds" Elsevier, Amsterdam. 70. Stahl, Quade R. (1969) "Preliminary Air Pollution Survey of Mercury and its Compounds" Publication No. APTD 69-40 National Air Pollution Control Administra tion. - ...-i :- ..V' . :.V | I j :.v-; ; ; ! ; i- i : r 'I':'-' ft ? = V I r'Xi& !<!** S-W 001590 - 78 71. Friberg, Lars et al. (1971) "Mercury in the Environment. A Toxicological and Epidemiological Appraisal" APTD-0838 Karolinska Institute, Stockholm, Sweden. 72. Friberg. Lars (Chairman) et al., (1971) "Methyl Mercury in Fish" Expert Group, S-104-01, National Institute of Public Health, Stockholm 60, Sweden. 73. Goldwater, Leonard and Clarkson, Thomas (1972) Mercury. Chapter 2. pp. 17-56. in Lee (37). 74. Fairhall, L. T. et al. (19^5) "The Toxicity of Molybdenum" Public Health Bulletin No. 293 United States Government Printing Office, Washington. 75. Sullivan, Ralph J. (1969) "Preliminary Air Pollution Survey of Nickel and its Compounds" publication No. APTD 69-41. National Air pollution Control Administration. 76. Schroeder,.Henry (1970) "Nickel. Air Quality Monograph #70-14" American Petroleum Institute 1801 K Street N.W., Washington D. C. 77. Elsea, John and Paynter, Orville (1958) Toxicological Studies on bis (tri-n-bulyltin) oxide. A.M.A. Arch, of Indust. Health 18:214-217. 78. Stoner, H. B. et al (1955) Studies on the toxicity of alkyl tin compounds. Brit. J. Pharmacol. 10:16-25. 79. Bams, J. M. and Stoner, H. B. (1958) Toxic properties of some dialkyl and trialkyl tin salts. Brit. J. of Indust. Med. Ip:15-22. 80. Barns, J. M. and Stoner, B. H. (1959) The toxicology of tin compounds. Pharmacol. Rev. 11:211-231. 81. Schroeder, Henry A. et al. (1963) Abnormal trace metals in man. .Titanium. J. of Chron. Dis. 16:55-69. 82. American Industrial Hygiene Association (1959) Titanium dioxide, pp.256-7 A.I.K.A. Hygienic Guide Series. 83. Mikac-Devic, Dusanka, (1970) Methodology of zinc determinations and the role of zinc in biochemical processes. Adv. Clin. Chem. 13:271-586. 84. Schroeder, Henry, Balassa, Joseph (1966) Abnormal trace metals in man. Zirconium. J. Chron. Dis. 19:573-586. i-sr' * f m 71,'->*-<* $0 r..J:*' --T* T-vr-2- ? T M" f rfe S-W 001591