Document zo8yXRRY2JRN8M6no7OKZdQY3

MM *4Ml | IIH-tIMMi G. Wen two. ,,h Noventer 26, 1974 New Safety Measures for Handling Halogen-Containing Monomers TO : Distribution Distribution: V. G. Bryant R. A. Evans E; W. Folk R. G. Garmon P. H. Hobson J. R. Kirby R. S. Knorr J. C. Masson G. Palethorpe S. A. Roberts R. 6. Thompson Because of the probable toxicity of monomers such as VCI2 and VBr, it is iterative that personnel exposure to these monomers be kept to an absolute minimum. With the active assistance of all of the polymer technicians, Roger Evans and I are attempting to make immediate changes in our methods of operation. To determine whether these changes are effective, we must monitor air-borne halogen levels during every polymer preparation (Pfaudler, CP, PCP) for the next several weeks. In order to arrange for this monitoring, I must now ask that anyone planning to make a polymer containing VBr or VC1? give me at least 24 hours* notice, describing the monomer levels and apparatus to be used. > In general, the new procedures will mean that more time must be alloted to make a polymer run. In addition, a substantial amount of technician time will be . required to modify existing apparatus and procedures. The changes being made will require large doses of patience and cooperation from each of us, but they should ensure both our continued health and our continued operation. For the present we'll operate on verbal instructions for changes in procedure. This will be followed by written OI's within two or three weeks. AG4/74-109/OO G. Wentworth RSV 0010459 p RSV 0010460 AB0103IX01 -36TOXICOLOGY Goals The goal of the toxicology section is to obtain a complete de scription of the spectrum of biologic effects of materials important to Monsanto. The section will seek to achieve this goal by expanding the quality and quantity of toxicity data on materials of interest to Monsanto. Quality pertains to more than excellence of toxicity data. It relates to the nature of the process by which those data are developed, encompassing variety of - tests and depth of testing. Quantity refers solely to the number of products or intermediates judged to have been tested to an acceptable level. Over the years, animal teats which had been used in special cir cumstances have been incorporated into routine safety evaluations. Thus, words such as carcinogenicity, mutagenicity and teratogen icity have come into everyday use. Since tests for these effects are time-consuming and expensive, attempts are being made to de velop short-term screening tests, such as microbial mutagenicity which can be used as an indicator of carcinogenicity to provide rapid estimates of potential long-term hazards. Finally, concern over environmental effects of chemicals has led to studies of \ their effects on fish and wildlife and to the determination .of biodegradability and bioaccumulation of materials. These three factors have contributed to the increased variety of procedures included in the quality of toxicity testing. The depth of toxicity testing depends on the nature of the. material and its intended uses. It would include determination of (1) the effect(s) produced in animals, (2) the amounts required to produce the effect (s) and, (3) the amounts which can be tolerated without observable effects. While close, intensive scrutiny will increase the probability of detecting adverse effects, it is neither neces sary nor possible to give every material the same detailed*exami nation. Consequently, it is necessary to make judgements in the selection of materials for study and the tests which are to be conducted on them. We estimate that approximately 10% of the products and intermedi ates which Monsanto handles have been tested to an acceptable level. Initiation of needed in-depth toxicity tests on a halfdozen, or even a score, of materials would reduce the backlog of a few thousand substances by only a fraction of a percent per year. Thus, it will be necessary to increase contacts with other researchers throughout the world to determine which materials they have studied, are investigating, and plan to test. Using that information to guide our programs, we can provide greater assurance that adequate toxicity data will be available on com pounds of major interest to Monsanto. Ultimately, it must be recognized that priorities and judgements will dictate which chemicals are studied and the depth of this testing. RSV 0010461 -37- Functions The FUNCTIONS of the toxicology section are to use toxicity data to help Monsanto: 1. Keep products on the market for uses judged to be safe, 2. Market new and existing products, 3. Stop development of products fudged to present unusual health or environmental hazards, 4. Restrict sales, if necessary, of selected products to specified uses, and 5. Guide its research projects. Toxicity data is used to ACHIEVE these functions by: 1. Estimating "safe" and "unsafe" uses and handling Conditions, 2. Providing Industrial Hygiene with a basis for establishing permissible personnel exposure levels, 3. Providing Physicians with diagnostic clues for monitoring exposed individuals, and 4. Providing Process Environment with guidance on environmental effects of chemicals. This will be ACCOMPLISHED by: . 1. Searching the literature for, 2. Developing, 3. Evaluating, and, 4. Disseminating toxicity data as it pertains to health and environmental hazards of chemicals. RESOURCES available f6r these purposes include: 1. Monsanto's Environmental Health Laboratory, (Mid 1978) 2. Professional staff in DMEH, a* 3. Professional staff elsewhere in Monsanto, 4.. Consulting laboratories, 5. "ad hoc" task forces (acrylonitrile, butadiene, chloro benzenes ,, epichlorohydrin, vinyl bromide, vinyl chloride, vinylidene chloride are current examples) , RSV 0010462 38- 6. CUT, 7 . Trade associations, 8. Government agencies tNational Cancer Institute, National Institute for Environmental Health Sciences, Environ mental Protection Agency, Food and Drug Administration, etc.) 9. International agencies (International Agency for Research on Cancer, a unit of the World Health Organization), and 10. Professional societies. Predictions In developing a plan to meet these goals and fulfill our function, certain events that will affect the operations are postulated. These include: 1. The amount and variety of toxicity data needed to maintain existing products or to market new products will increase. A. Toxic substances legislation and/or regulatory \ quirements of other agencies will increasingly dictate what is to be done. As resources are spent on what is dictated to us, toxicity testing will have to expand if we are also to do studies we believe are needed to protect Monsanto's interests. B. Allegations of adverse human or environmental effects will lead to incorporation of additional toxicity tests, aimed at answering specific questions,into safety evaluations. C. Worldwide concern over health hazards of chemicals will increase. This will be reflected in special test re quirements which specific countries will adopt. 2. Emphasis will shift to subtle, chronic effects of chemicals such as behavioral changes and alterations in physiological parameters without clinical signs of impairment. 3. Teratologic, reproductive, and mutagenic effects of chemicals will command more attention as increased numbers of women enter the chemical workforce, and as chemicals aare identified in the general environment. 4. Studies on the biological transformation of foreign, compounds will become more important. These will be needed to under stand how chemicals behave in man and in the environment. 5. Concern over the effects of pesticides on wildlife and non target organisms will spread to encompass unintended adverse effects to the environment from all chemicals. RSV 0010463 i -39- 6. The search for short-term tests as screening procedures to evaluate potential harmful effects of chemicals will in tensify^ Premature publicity given to the findings of these tests before their significance has been evaluated will pose threats to many materials* 7. Epidemiological studies in man and ecological surveys of the environment will be required to justify continued use of some materials. 8. The Environmental Health Laboratory and its Aquatic Toxicity satellite will be operating and the former will have been enlarged at least once. 9. Laboratory accreditation will be a reality and there may be some form of individual certification. 10. Government agencies will routinely audit laboratory prac tices and raw data from all chronic studies. 11. It is probable that less hazardous products will replace current ones without regard to considerations of economics or efficacy. 12. The increasing amount of toxicity testing and government activity will make it more difficult to keep abreast of regulations, literature, and programs of government agencies, trade associations, regional groupings, and special "ad hoc" committees. 13. Although successes may go unnoticed, failures will be high lighted. While all events cannot be foreseen, attacks on more prominent, profitable products can be minimized. Program Since all studies cannot be done on all products simultaneously, priorities for study must be established. Thus, an integral part of the program requires decisions to be made in the selection of materials and the tests to be performed on them. Priorities can be assigned on the basis of commercial importance, concerns of customers, business or public groups regarding inherent or alleged toxicity, and the availability of toxicity data. An advisory committee, consisting of representatives from the operating companies and DMEH can develop these priorities. Literature Surveillance Prior to development of new research data on any chemical, a thor' ough evaluation of existing information is made to determine its extent and current validity. This includes: 1. A survey of in-house data (Appendix 1, Page 47, Shows a s,ample) 2. Assimilation of other Monsanto data (biodegradation, fish toxicity, tissue residues, etc.) into DMEH files RSV 0010464 -40- 3. A review of .published literature covering experimental and clinical experience with the product and related chemicals. (Appendix 2 Page 48 Library of Medicine Toxline Computer Printout) 4. Contacting other agencies conducting toxicity'testing to determine if they have unpublished data or if they are Studying compounds of interest to us. (Appendix 3/ Page 53) 5. Development of a procedure for continuous surveillance of literature to keep knowledge current and up-to-date. Toxicity Testing 1. Acute toxicity and irritation data will be developed on all Monsanto products. This is the minimum information needed for precautionary labeling and freight classifica tion and it provides a basis for preparing Toxicity and Handling Statements. (Appendix 4, Page 59) 2. Acute toxicity and irritation data will be developed on all intermediates and by-products handled in Monsanto if such information is not otherwise available. 3. Status of toxicity data on all agricultural products will t be reviewed to determine whether it is adequate to meet current standards. This will require additional testing on older products if they are to continue to be marketed. 4. There is very little toxicity data on most rubber chem icals. Testing programs will be developed to define working conditions under which they can be made and used safely. 5. Toxicity data needed, for commercialization of new materials will be developed during the incubation period between con cept and commercialization of a new product. a 6. As new uses of existing products arise/ available tox icity data will be reviewed to determine its adequacy for the new use and for continuation of existing uses. If needed/ additional testing will be initiated. 7. New products which are variations of existing products will trigger a review of the toxicity data on the related products. A testing program will be developed to cover * needed toxicity tests on the new product and obvious gaps in our knowledge on the related products. 8. Annually, broad screening studies will be started on six selected existing products in addition to the on-going pro grams on new products, insofar as possible, these screening tests will be standardized in order to obtain data that will allow comparisons of results obtained on different materials at different times and in various laboratories. These studies are designed to identify target organs or oth>er specific .... effects and to establish no-effect levels. A selected sefcl'es RSV 0010465 -41- of test protocols is shown in Appendix 5, Page 60. ,These screening tests can identify specific-adverse effects. Turther testing may show them to be dose-related or may provide a rational basis for defining safe conditions of use. Portions of these protocols are directed toward worker exposure which requires information on effects of inhalation, contact hazards, and systemic effects, others are more directly related to consumer exposure which requires information on acute and chronic effects and demonstration of a no-effect exposure level. Restriction to six products is based on availability of in-house staff to formulate protocols, monitor studies, and evaluate results, and prepare information for dissemina tion through data sheets, white papers, scientific publications, internal guidelines, and other means. In addition, there are limited numbers of commercial labora tories with acceptable capabilities. The number of products to be studied will be increased by development of the En vironmental Health Laboratory (EHL) (which will approach maximum productivity about 1980), by establishing working relationships with more laboratories and aiding them to up grade their quality control and reputation, by initiating cooperative studies on common products or intermediates with other companies, and by participation in the Chemical Industry Institute of Toxicology (CUT) . Our current long-term toxicity testing program ftppen. 6,Pg.63) has resulted from the preceding activities. The table shows the year in which testing of a material was started. Since most of these products are undergoing multiple tests, and since some of the tests span 2-3 years, the annual addition of new materials will lead to an expanding overall workload. The actual level at which this will plateau will be determined by available resources of laboratory space and, more im portantly, qualified scientists to conduct the tests and evaluate the significance of the findings. Coordination of Programs The EHL will become the focal point around which our toxicol ogy program will revolve. As it becomes functional, it will undertake portions of the testing program now being conducted at consulting laboratories. While the^laboratory will be capable o.f conducting a wise range of studies, it will enable a greater emphasis on inhalation toxicity, metabolism studies-, and in vitro procedures. In addition, the staff of .the laboratory will increase the depth and breadth of our exper tise in the various areas of toxicology. RSV 0010466 The increasing emphasis on employee exposure and air pollution in general has led to a serious shortage of in halation facilities. The new laboratory will enable us to provide for a large measure of Monsanto's needs in this area. Metabolism studies will be needed to answer questions about biochemical transformations which chemicals undergo in man and the environment. Knowledge of these transformations is needed to understand how chemicals behave in the biosphere and why they do or do not produce effects in the environment. Non-mammalian test systems, microbes and tissue cultures, are being employed with greater frequency. Extrapolations of findings from such studies are used to indict chemicals. It will be necessary to evaluate the technical implications of using non-mammalian systems and to assess their relevance in estimating potential health or environmental threats. The new laboratory will provide space for expansion of the limited program started this year in "N" building to perform and to weigh the significance of such tests. An expanded aquatic toxicity testing facility is needed to^ centralize research in this area and to provide for better integration of environmental and mammalian test programs. A separate acquatic laboratory possibly at St. Peters has been proposed as a satellite of OMEH (Appendix 7). At present, Monsanto's aquatic toxicity testing is concentrated primarily in "N" building. Those facilities are overtaxed by demands of the Detergents and Phosphates Division alone. This re quires other business groups to do virtually all of their testing at outside laboratories. Staff toxicologists, separate from those assigned to the laboratory, also will be needed to coordinate activities. These will involve contacts with consulting laboratories, liaison with other groups conducting toxicity testing, inter facing with regulatory agencies, and editing available data into forms suitable for use, including publication. Dissemination of Data Every criticism or allegation of harm cannot be anticipated. Questions can be raised before satisfactory answers have been developed on a material, and questions may arise re garding materials believed to have been studied adequately. This will require diversion of time and talents to investi gate those questions. In addition, any testing program can give ambiguous or spurious results requiring further testing. Nevertheless, the following approaches will be undertaken. 1. Toxicity and Handling Statements (Appendix 4 ) will be prepared on all products. Toxicity data will need to be developed on some products, and previously pre pared statements may need revision. At the rate of RSV 0010467 -43- 40-50 per month, it will take approximately 10 years to prepare statements for the estimated 4,000 - 6,000 products Monsanto has. 2. Available toxicity data will be used to prepare internal guidelines for employee exposures. When data are deemed adequate, they will be collected, evaluated and forwarded to the American Conference of Governmental Industrial Hygienists with a request that they establish a Threshold Limit Value (TLV) for the material. TLVs established by that group can influence legal exposure limits for workplace atmospheres adopted by the Occupational Safety and Health Administration. (Appendix 8, Page 65). 3. A summary of Monsanto and literature information will be prepared on each product and intermediate for ready ref erence. This will include environmental and toxicity data. 4. As toxicity data is developed on important products, de tailed white papers will be prepared. These will contain a summary of toxicity data and will include judgements as to the overall risks associated with use of materials. 5. Publication of toxicity and environmental data in the open literature will be accelerated. This will give public and professional recognition to the scientific .staff and Monsanto, will provide peer review of our data, and may forestall unwarranted criticism of products. 6. If products are judged to present unusual health or environ mental hazards, the appropriate Monsanto unit will be alerted as soon as possible and, if necessary, appropriate regulatory agencies. If the risks are judged to outweigh benefits, the product can be eliminated at an early stage of development. Alternatively, it may be necessary to restrict sales to specified uses; i.e., those in which the benefits are judged to outweigh the risks. The indicated restriction on sales may lead to elimination of the product 7. Toxicity data, particularly the results of short-term test ing, can be used to guide selection of prospective products from a series of .potential candidates. Alternatively, accumulated toxicity data can be employed to choose com pounds which will have a greater probability of safety for specific uses. Needed Resources The proposed manning table for the EHL and the sequence in which it is to be staffed are shown in Appendix--9) . As the laboratory becomes operational, additional technicians and/or animal care takers may be heeded to fully exploit its potential. RSV 0010468 -44 By 1980, the section will have undergone a major expansion and the EHL will be in full operation. That will be an opportune time to review current programs and to plan expansion of the% laboratory. The expansion can be directed toward those areas of toxicology in which facilities are limited or which are deemed critical to Monsanto's interest. The planned expansion will cost $10 to $12p00,000. It will increase laboratory and animal holding space by 80%, and require an additional staff of about 50 people. (Appendix 10 ) The distribution between scientists, technicians, and animal caretakers will be determined by the nature of the planned programs. If the emphasis is on metabolic and special studies, a greater proportion of scientists will be added. If the shift is to carcinogenic and reproductive studies requiring large numbers of animals, technicians and animal care takers will be needed. A separate aquatic facility will cost approximately $1,000,000. This preliminary estimate will be refined when definitive design begins. About 12 persons will be required to staff the in stallation. (Appendix 11 ) The exact number will be influenced by the scope of the operation and the availability of round-theclock security. It is anticipated that funds for this laboratory will be sought in 1978. An estimated six additional staff toxicologists will be needed for functions described earlier. These additions should come within the next three years. I It may appear illogical to request permission to hire additional toxicologists when we are unable to fill existing vacancies. However, we need authorized positions against which to recruit, . and we could effectively use additional toxicologists at present. Monsanto's decision to build a toxicity laboratory has aroused interest in several areas. This should improve our ability to attract qualified people. During the next few years, we will be able to offer opportunities to both laboratory and non-laboratory scientists. RSV 0010469 Environmental Ijealth Laboratory Expansion' Aquatic Toxicity Facility Assimilate present biodegradation, tissue residue, fish toxicity data in DMEH Agricultural 'Products Complete data required for reregistration . Develop employee exposure guidelines Rubber chemicals Develop employee exposure guidelines Other Business groups Define program requirements a Acute toxicity, irritation data, toxicity and handling statements TOXICOLOGY PLANS 1976 77 78 79 80 8l 82 83 84 85 L OPERATION <r START-UP y FUL ] p^Nj^QWflTRlinT ; ( STAI q?=UP > FULL OPERATION COPNLSATNRUCTHr star;?- fui L OPERATION -------> -> > i 1 All I Products ij | i 1 1 tn > RSV 0 0 1 0 4 7 0 * RSV 0010471 ersonnel ectlon Manager taff Toxicologist lerical Manager Scientist (PhD) Scientist (BS/MS) Clerical Technician Animal Caretaker Equipment Cleaner vquatic Toxicity Laboratory Manager Scientist (PhD) Scientist (BS/MS) Clerical Technician Pish Caretaker Totals Capital ($1,000 TOXICOLOGY RESOURCES mL XL 78 79 80 81 82 83 84 +85 1 4 1 6 1 1 111 1 1 1 8 10 10 10 10 10 10 10 1.5 1.5 1.5 2 22 2 2 2 2 1111111 11 4 10 11 11 11 11 15 20 20 1 4 1 9 2 11 3 11 3 11 3 11 3 174 22 5 22 e; l 10 15 15 15 15 23 30 30 4 7 7 7 7 13 18 18 i 2 2 2 2 2 4 4 "T V 1 111 1 1 1 22222 2 111 1 1 11 1 1 1 1 1 5 2 5 2 5 2 5 2 o5 \a 7.5 19.5 48.5 64 68 75 75 102 125 125 1,000 2& 12,000 20 20 30 35 35 I -47- Appendix 1 (Printout from Microfiche reader) .UBL^UDJM_______$2.Ng, SYWOWYWS; A*o-tis-isoliiTfffr*n riti AIN CATALYST tiewcACiiBTi cp oh9'~ ALPHA.ALPHA PAlnC A200IIS08UTYAONITRJlE U.N : NCXllNUNXCM IfPiaiOL PMhulAs ca*Hi2-m MATO 1-QuPOnT A\iH CATALYST < Y-73-0278 t QgAL_LO-SO H - ? RATS (NC/Kfi) zm * Y-73-0278 * XRHAL yp-SQ n*f rabbit nC.'KCi * ,--73-0278 Y iRRt', M*P RABBIT *' >t. HAa iflAXs i IU .- 73-0278 5k JN i RR l_T m.F RABBIT HI . ftHA . .in. . a i >SQlO 0 .a y0 NON- IfiRI TAi iNu MgN-lAfil Th: INC, *8T- 73-00'jH * iNTET5RRTAi|on 90-0AV SUBACUTE ORAL TO*I Cl TV !H 0005 LEUELS TESTED; 50.tSO.jOO >nG iCOG PPh MO EFFEtl L6UEL: 5TPWT MICROSCOPIC Ll'fR CHANGES AT iso PPn ANQ nBCi"E *1T - 73"OOSI I" !"MteRPR67A? i Qn 001 90 DAY SUBACUTE ORAL TOXICITY IN RA75 LEUCLS TESTED: 0.SO.ISO ANO 300 PPM MO gPUTT Cr.'EL~ 300 PW- '- CP. QH.H* ... / 'i v I "X: RSV 0010472 V -48- "f /rtf.It. I /u*.. HITROAttlJLIfcK (QBTLO) Apfien^lx^ (page 1 of 5) SI - PUS1A3/76/1033 All - Gallo HA ; Bacbnann ; Golherg L TI - nitocliondrial effects of 2,6-dichloro-4-nitroenilino ann its metabolites. 50 -- Toxicol. Appl. Pharmacol. 35(1): 51-61; 1976* (18 references) JC - TXAPA AB - PESTA'3- The effects of 2,6-dichloro-4- nitroaniline (DCHA) and its primary aamnalian metabolites 3,5-dichloro-4- aainophenol (DCAP) and 2,6-dichloro-p- phenylenediamine -(DCPD) vcsrc* studied oa Isolated rat liver mitochondria in vitro and ex vivo, dcna and DCAP inhibited electron transport and uncoupled oxidative phosphorylation in vitro at 10 nun while DCPD produced only slight uncoupling at 0.2 mfl. Ex vivo studios at 1000 ag/kg p.o. or 500 ng/kg p.o. revealed a slight increase in respiratory rate and an increased sedimentation coefficient of isolated mitochondria. Orine analysis indicated tvo pathways of DCHA metabolism in the rat, but interconversion of DCPD to DCAP could not be demonstrated. (Author abstract by permission) SI - CA/082/149997F AU - Vasilenko hfl ; Zvezdai VI ; Kovalenko II ** TI - Inactivation of the blood respiratory pigment under^jthe effect of aroaatic niro and amino* compounds from the benzene series SO - Sovrem. Probl. Biokhi*. Dykhaniya Klin., Hater. Vses. Konf*, 2nd; VOL 1,, 1972, P411-13 LA - Buss JC - 29LJA AB - CBAC COPYRIGHT: CHEH ABS when administered orally to rats at 0.1-0.2 LD50 for 30 days, aniline, a^hloroaniline (I), nitrobenzene, o-nitroaniline, p-nitroaniline, o-chloro-p-nitroaniline, p-chloro-o-nitroaniline, p-nitrochlorohenzene, m-nitrfctoluene, dinitrotoluene, or trinitrotoluene (XI) caused transformation of Hb into nethemoglobin, nitrosylheaoglobis, and sulfheaoglobin. An increase in the levels of aetheaoglobins and salfheaoglohins was acconpanied by a decrease in oxyhemoglobin, but the total level of Hb remained unchanged. (62-53-3 Aniline)(108-42-9 a-Chloroaniliae) (98-95-3 nitrobenzene) (88-74-4 o-Hitroaniline) (100-01-6 p-Uitroaniline) (121-87-9 o-Chloro-p-nitroaailine)(89-63-4 .p-Chloro-^>-nitroaniline) (100-00-5 p-Hitrochorobenzene) (99-08-t a-Nitrotoluene) (25321-14-6 Dinitrotoluene) (llfl-96--7 Trinitrotoluene) Bff - 62-53-3, 108-42-9, 98-9S-3, 88-74-4, 100-01_=6, 121-87-9, 89-63-4, 100-00-5, 99-08-1, 25321-14-6, 118-96-7 SI. A0 A0 TI SO JC - CA/082/0477169 -* Catronovo FP Jr ; Callahah BJ ; Potsaid AS ; Pendergrass UP - Heel HS a - Hew technetiua-99a skeletal-imaging radiopharmaceutical. 1-Hydrozyethylidene-1, 1-disodiuaphospbonate-technetium-99m complex (technetiua-99a-ttDSPl} - Badiopharm. Label. Compounds, Proc. Symp.: VOL 1,, 1973, P79-92 - 280.01 RSV 0010473 -49BITKOABlLliJC (OW'i'UO) l-AGl. Appendix 2 (page 2 of 5) AB - CBAC COPYRIGHT: CDEtl ABS the synthesis of 1-hydroxyothylidene-l, 1-disodiuu phosphonate rteC(Otl) v (0) (OH) un< 2 99Tca (8BDSPA is described. (7414-03-7 1-hydroxyethylidene-1,1-diso<lium phosphor* ate) (14133-76-7 Technetium 99) the coupd. has a ain. lethal dose in mice of 0.2 g/kg. a scanning dose of 0-5 mg is rccoaaendeti for hunans. the coupd. was used in approx- 1000 persons for bone scanning without adverse effects, is easily synthesized, and has good cheis. stability. BH - 7414-83-7, 14133-76-7 SI - CA/Q82/026764V AD - Vasilenko Ufl ; Zvezdai VI ; Kolodub FA TX - Toxic actios of aononitroaniline isoners 50 - Gig- Sanit.; ISS 8, 1974, P103-4 LA - Russ JC - GISAA AB - CBAC COPYRIGHT: CHEM ABS when administered orally to rats, the LD50 values of o--nitroaniline, a--nitroaniline, and p--nitroaniline were 3.52, 0.9, and 1.41 g/kg, resp. (88-74-4 o-Nitroaailine) (99-09-2 a-itroaailine) (100-01-6 p-Sitroaniline) when administered at 1/2 LD50, the a-, but esp. p-iseaer caused significant increases in the levels of HetHb and SfHB is the blood, o--isoaer shoved hepatotropic properties, all isomers 'h./ a skin--resorptive effect, exposure of rats to the p--isoaer at 5 mg/a3 for 5 hr daily during 4 souths caused a decrease inthe Hb level and erythrocyte count in the blood, the hemotoxic effect of the o-isoaer was less pronounced. EH - 88-74-4, 99-09-2, 100-01-6 51 - CA/080/120157A AD -- Loiseau G ; Hillischer B ; Berthe G ; Donadieu AH ; Lobier P AO - Barguet JP TX - Phosphorylated biguanide. Benfosforain (JA7 852)* I- Hy-poglyceaic and antidiabetic properties 50 -- Arzneia.-Borsch.; VOL 23, ISS 11, 1973, P1571-6 LA - Pr JC - ARZHA AB - CBAC COPYRIGHT: CHZfi ABS the hypoglyceaic activity of benfosforain JIT 852, PbCB2NHC (:NB) NHC (:KH) HHP (0) (Oil) Oh) Oha (I) , which vas more narked in diabetic rats than in normal ones, was comparable to that of phenformin and 2--3 times as strong as that of metformin. (51287-66-2 Benfosformin) (114-86-3 Phenformin) (657-24-9 Hetforain) benfosforain hypoglyceaic antidiabetic BH - 51287-66-2, 114-86-3, 657-24-9 51 - CA/080/103 873T AD -- Loiseau G ; Hillischer B ; Berthe G : Donadieu AB ; Lohier P AO - Barguet JP T1 -- Phosphorylated biguanide. Benfosforain (JA7 852) II. General pharmacological properties SO - Arzneim.-Porsch.; VOL 23, ISS 11, 1973, P1576-B3 LA - Pr JC - ARZHA RSV 0010474 I -50PAGt 3 Hll'liOMJILllil' (Of.ll!OJ # Appendix 2 (page 3 of 5) AD CBAC COPYRIGHT; CHEH AUS the hypoylycetic and anLidiabetic benfosforniu JAV 852, PhCll2 HHC{: KH) KBC{:UU) KHP (0) (OKa) OH (1) bad a high safety Kargin and was less toxic: than phenforain (11} , esp. on i.v. adninistration in mice and rats* (51267-66-2 Benfosforain) benfosfornin hypoglyceaic antidiabetic RN 51287-66-2, 834-20-6 SI AD TI SO JC Afi _ B1 - HEEP/73/00668 - EASL FL ; CURTIS Jfl ; BEHHSTEIN 11U ; SB ALLEY U E JR - Ocular effects in dogs and pigs treated with dichloran (2, 6-dicJxloro-4-nitroaniline) * - FOOD COSHET TOXICOL; 9 (6). 1971 819-028 - FCTXA - KEEP COPYRIGHT: BIOL ABS. Beagle dogs and miniature swine were fed dichloran (2,6-dichloro-4-nitroaniline) , a fungicide, at levels of 0*75, 6.0, 24, 48 or 192 ag/kg/day in the diet for periods of 50-306 days* Corneal opacities appeared in the eyes of dogs given the 24- or 48-ag levels in 53-104 days in aniaals exposed to sunlight* Dogs unexposed to the light or with one eyelid sutured in the closed position failed to develop lesions in the unexposed eye or eyes* Slit-lawp examinations revealedk that the corneal changes were located in the anterior corneal strowa just below the epithelium. Lens danage was confined to the central anterior cortical areas, giving a circular plague appearance* These lesions were not reversible when the conpound was withdrawn frow the diet* Paraffin sections of the daaaged * corneas of dogs showed, when stained with hematoxylin and eosin, snail yellow globules associated with the superficial corneal stronal-cell nuclei* Frozen sections stained with Oil Red 0 and toludine blue revealed the globules as light-to-dark orange droplets* These droplets were sore numerous in the group given 48 ng/kg/day but could also'be observed in the groups given 6*0 and 0*75 mg/kg/day* The eyes of swine were unaffected by the feeding of dichloran at the dietary levels that were fed to dogs* ' Heinz bodies were present in the red blood cells of both dogs and swine given dichloran* other toxic nanifestations were not present in either species, except in the group, of dogs given 192 g/kg/day. - 99-30-$ si ID ^ XI SO LA JC IB Cl/77/148145 Svstatieva BH Data on the toxicity of acetoacetic acid p-chloro-0 -nitroaniline-4-carbamoylanilide Gig. Primen*, Toksikol. Pestits. Klin* Otr; F351-6 Buss D8BJ1T VOL Bo* 9^, 1971, CBAC COPT RIGHT: CHEH IBS acetoacetic acid P"Chloro*K)--aniline-4-carbamoylanilide (I) (sic) (10 mg/kg, orally) decreased blood catalase, riboflavin, and SH group conca.; and increased SH coacn* in the protein fraction of the liver of mice and rats* (036894801 Acetoacetic acid P~chloro-o-nxtrouniline-4-carbaaoylaailido) (009001052 Catalase) (00Q0H3U85 Riboflavin) whoa givon to rats as 96 dosec RSV 0010475 rt 51HITItOAh'ILISC (OiilJiO). PdKL Appendix 2 (page 4 of 5) of 500 fcg/kg, I caused an increase in hippuric acid secretion and in hepatic protein SU content without-affecting blood constituents or the liver noaprotein fraction. (0004yb692 Hippuric acid) BN - 83-08-5, 495--69--2, 9001-05-2, 36894-80-1 SI - CA/77/1WW2 A0 - Bvstatieva All T1 - Toxicity of acetoacetic acid nitrocsrbamoylanilide derivatives based on experiaental tests SO - Gig. Pri/sen., Toksikol. Pestits. Klin. Otr; VOL No. 9,, 1971, P356-60 LA - Buss JC - D8MHT AB - CBAC COPYRIGHT: CHKH ABS acetoacetic acid tt-nitro-p-aniline-4-carbaaoylaniIide, acetoacetic acid o-nitroaniline-4-carbaaoylanilide, and acetoacetic acid p-chloro-o-nitroaniline-4-carbaaoylanilide (in 96 doses of 500 ng/Xg, during 120 days) caused changes in nice respiratory enzynes, indicative of their toxicity, and induced temporary changes in heaoglobin concns. I also caused leukopenia. * (036894787 Acetoacetic acid "; n-nitro-p-chloroaniline-4-carbaBoylanilide) (036894798 Acetoace*'* r acid o-nitroaniline-4-carbanoylanilide) (036894801 Acetoacetic acid p-chloro-o-nitroaniline-4-carbanoylanilide) HU - 36894-78-7, 36894-79-8, 36894-60-1 /O SX A0 T1 so JC AB `SB - CA/77/096794 - Jenter s ; Better KJ - Inhibition of aicrosoaal drug metabolism by SKF 525-A 2-diethylaninoethyl 2,2-dipbenylvalerate - Biochen. Pharnacol.s VOL 21, ISS 14, 1972f P1921-7 - BCPCA - CBAC COPYRIGHT: CHBB ABS inhibition of aouse liver uicrosoaal - o-deaethylatioa of p-nitroanisole and N--deaethylation of H-ttonoaethyl-p-nitroaniline (I) by * 2-diethylaainoethy1 2,2-diphenylvalerate-BCl. (SAP 525-A) (II) was changed froa noncoapetitive to coapetitive by benzene recrystn. of II. - (000100174 p-Hitroanisole) (000100152 H--Bonoaethyl-p--nitroaniline) (000062680 2--Siethylaainoethyl - 2,2-diphesylvalerate hydrochloride)(000071432 Benzene) benzene - produced no chea. alteration of the IX nol. that could he - detected. - .*: . *:; -* - 62t68tQ. -71-42-T2, .tOO-15-2, 100-l7-4 SI - CA/77/070274 . " AO Dohre V * - Hev di (2-chloroethyl') aainophosphoric acid derivatives with - antituaoral activity >t- * SO. - Paraacia (Bucharest) s-rVOL .20, XSS--0, 1972, P229-34 LA -- Boa . -------, - -. - ... JC - PHHBA .-r-- :AB - CBAC COPYHIGHT: CHfik ABS XOB XXX ' Ha-O-benzoyl bis (2-chloroethyl) aainophosphate . (C1CH2CB2) 2SP(0) (ONa)OBz to a lesser degree 103 XXIX * di-Ha , . and (^$V 001047b )!1 TUOAMLXf S (Oli7l!0) Appendix 2 (page 5 of 5) bis (2-chlorooLhyl) auinophosiphatc (ClCU^CIl^) 2llfc (0).(0U) 2 inhibited tie growth oi various exptl- tutors in rata and mice. (014451377 IQD XIX) (C3576J112 IUU XXXI) the growth of Jensen tunor in rats was completely inhibited by 40 ng IGI XXX/Jcg/J/ty and 50 mg IOC XXXI/itg/tfay administered for 14 days- the LD50 values lor 100 ZXX and I0!> XXXI administered i.v. to mice were 417 and bOQ ing/g, resp. the comnds- had little effect on hematopoiesis in alee. 14451-37--7, 35763-11-2 EHD OP OFPLIHK PBIHT * * * * * RSV 0010477 Monsanto mom (name * location! -53Dept. of Medicine & Environmental Health Appendix. 3 * (page 1 of 6) DATES SUBJCCT: ncrcAtNCC: TO July 7, 1976 Distribution cc: George Roush, Jr'., M.D, J. T. Garrett G. J. Levinskaa D. L. Eby P. O. DeGanao E. Tillman, M.D. J. H. Spraul, M.D. F. R. Johannsan P. L. Wright J. Laveglia M. Stevens The attached listing shows currant or planned long-term studies of materials of direct interest to Monsanto. The most complete reference for worldwide information (World Health Org.IARC) is published at about six to nine month intervals and ve will plan to issue updates to our listing accordingly. However, other lines of coimamt cation, as Indicated by the attached references, will result In published and unpublished Information which will be summarized on a quarterly basis. Reports and technical papers will be distributed as obtained. Additional Information concerning these studies is, in msny cases, available. This includes specific location and names of principal investigators. Let us know if you wish to know more details* s so Ate. RSV 0010^78 -54 Appendix 3 (page 2 of 6) CHEMICALS OF INTEREST TO MONSANTO UNDER TEST FOR CARCINOGENICITY (JULY 19761 MATERIAL Acetaldehyde SPONSOR TNO Acetone NCI Aceeophenetldin JAP. NCI Acetyl Salicylic Acid JAP. JAP. Acrolein TNO NCI Acrylonitrile MCA Europ. Acrylic/Methacrylic Acid duPont R& H Allyl Chloride Ammonium Chloride MCA NCI NCI Aniline NCI Arsenic NCI Benzene Benzyl Salicylate API NCI Butadiene IISRP -Butyrolactone France Cadmium Caffeine ('ale turn Chromate Carbon Disulfide NCI JAP. JAP. UK NCI NCI Australia Nr i TYPE TESTING* label., i. tr. (H) Skin & Ingest.(M) p.o.-diet (R) (M) p.o.-diet (M) p.o.-water (R) p.o.-diet (M) Inhal. (H> Infaal. (H) Inhal. & Ingest. IT f* Inhal. Gav. (RfM) p.o.-water (M) Ingest. (R,M) i.m.-inj. (R) Inhal. i.p.-(M) s.c.,3k.,i.g.;m) p.o.-diet l.a.-lnj. (V) i.Chor.inj. p.o.-diet (R) p.o.-water vR) p.o.-water (R) i.p.-(M) i.m.-tnj. (R) Inhal. ffi) ^ ... '^ STATUS** (see P REF Partially compl. (5) (publ. in pert, see p. 5.) <l) Just started Complete (5) (5) Just started In progress (5) (5) Histology In progress In progress (5> (5) Six aos. report due 8/76 (2) Maltonl-status unknown (3) In progress In progress (3) (3) To be started Report due (2) (1) Completed (5) Completed la progress Completed Report Issued Histology in progress (1) (5) (4) (5) (3) (5) Completed Corrrpleted In progress Tr* progress In progress In progress . Completed ' n progress RSV 0010479 (5) (5) (5) <5> (5) (5) (5) (5) MATERIAL Carbon Monoxide Chlorine Chlorobiphenyl Chloroform Chloroprene Chromic Oxide Cobaltoue Oxide -- SPONSOR NCI NCI NCI IARC NCI NCI p-Dichlorobenzene Dichloroethyl ether Dlcyclopentadiene JAP. Neth. NCI NCI TYPE TESTING* Gav. (R,M) Appendix 3 (pas 3 of 6) STATUS** In progress (see P. REF, (1) p.o.-diet (R) In progress i.p.-(M) In progress p.o.-<R) Should be complete i.m.-inj, (R) Completed l.trach. a.c. & i.p.inj.(H) Completed p.o.-diet. (M) - In progress p.o. i.p. (R) In progress <M) In progress i.m.-inj. (R) Completed * (1) (5) (3) (5) <5) (5) (5) (5) (5) 1-Dope Epichlorohydrln Ethylene Ethylene Dichloride EthyLene Oxide Formaldehyde Hexane Hexachlorobutadlone Maleic Anhydride Mercury Methyl 1'arachion MOCA . ' (4,4 *-r.iochylene 2-chloroaniltne) \ NCI NCI MCA CUT MCA NCI NCI CUT CUT NCI CUT Dow CUT NCI NiU UK . NCI i.p. (H) Inhal. & p.o.-(R) it u Inhal. (R) Inhal. (M a r) i.p. (M) i.g. (R,M) Inhal. (H) Ingest. a In progress In progress To complement NCI study Begun 3/76 Begun 2/76 (Maltoni) In progress In progress To be funded To be funded histology in progress To he funded Report about to issue To he funded (5) (5) (2) * (7) (2) (5) (5) <6> (6) (5) (6) (7.) (fr) i.ra.-inj. (R) . a.c. (R) p.o.-diet <H) p.o.-diet (R,M) %`onipleted In progress In progress In progress (5) 13) (5). (1) RSV 0010480 _ MATERIAL SPONSOR Morpholine NCI Nltrllotrlacetic Acid NCI B-Nicrostyrens NCI Parathlon France NCI Pentacblorophenol Daw Petrochemicals API (Petroleum Hydrocarbons) Phenol Phthallc Aohydrifis Phthallffilde Pivalolactons Polychlorinated biphenyls * Resorcinol Sodium Benaoat* Sorbic Acid Styrene Styrene Oxide Tetrachloroechylane Titanium- Dioxide CUT NCI NCI NCI NCI NCI NCI Israel NCI NCI NCI NCI JAP. UK NCI MCA France NCI France NCI NCI NCI NCI NCI Appendlx 3 56- (page 4 of 6) 0 TYPE TESTING* p.o.-diet (R) STATUS** % In progress (see P. REF. (5) p.o.-diet (M,R) Report la prep. (5) p.o.-diet (M,R) Histology 1& progress (5) p.o.-diet (R,M) p.o.-diet (R,M) In progress Awaiting pathology (5) (5) Ingest. (R) In progress (7) Mortality Tumor Registry Solvent Hixt. Metabolism Studies Skin Carcinogen. Report due In progress To be started In progress la progress (4) (4) (4) (4) (4) Inhal. (H) p.o.-water (R) p.o.-water (M) To be funded To be planned To be planned In progress (6) (3) (5) (5) p.o.-diet (M,R) Pathology in progress (5) p.o.-diet In progress (5) o.g.- (R,M) In progress (5) p.o.-water (R) p.o.-diet <W,R) In progress Completed (publ. in part) (3) (5) p.o.-diet (R) Subcut. Inj. (R) Skin (Rabb.) Hlstopathy in progress * Completed (5) (1) (5) p.o.-diet (R) In progress <5> p.o.-diet (M,R) Gav. CR.M) 3 Generation Studies p.o. & i.g. (M,R) Ixflial. (R) Compl. in press Histology completed In progress 18 mo.Inhal. report <5JC In progress In progress <5> (2) <5? (5; p.o. & i.g. (M) In progress (5) . i.p. (M) Inhal. <R) i.g. <M,R> In progress Histology in progress In progress (5) (5) <5) p.o.-diet (M,R) i.trach. (H) In progress Completed <5> (5) RSV 0010481 57- Appendix 3 [page 5 of 6) MATERIAL Toluene Toluene Sulfonamides Trichloroethylene Trlphenylphosphate Urea Vegadex Vinyl Bromide Vinylidina Chloride SPONSOR cin JAP. CAN. m:a NCI NCI NCI NCI NCI NCI NCI France NCI NCI MCA TYPE TESTING* Inhel. & Ingest. p.o.-diet (R) p.o.-diet (R) Inhel. (MVR) i.g. (M,R) tk.,a.c.,l.g.(M) i.p. (M) p.O.-dlet (M,R) p.o.-diet (MR) k. & s.c. (M) i.g. 00 p.o. (Mf2) p.o. -water (R) Inhal. (R) Inhel. Ingest. (R) STATUS** (see P REF. Begun 3/76 (7) Histology la progress In progress C5) (5) Be?,am 12/75 Paper in prep. Just started (2) (5) (5) In progress (5) Blatopathology completed (5) In progress (5) In progress In progress In progress In progress 4 In progress Cotspl. (18 mos.) ~ Pathology incompl. Almost completed (5) (S) (3) (5) (5) (2), (2) *Tvp<a Testing Abbreviations: M " Mouse R - Rat H Hamster inj. - injection l.p. intraperitoneal **Statuat i.v, - intravenous l.a. * intramuscular i.g. - gavage p.o. " oral sk. skin i, trach intratracheal Where current status Is knotra, dates are given* When completion is indicated, no reports are known to have been published except where shown. Status updates will be distributed when information available. RaCttraasan 1. National Cancer Institute. List of Chemicals being tested under Bloassay Program.(6/76) 2. Personal comsunleatlon. 3. SPI listing of studies. 4. API list of Studies underway (1975) 5. IARC (World Health Org,) March 1976 Information Bull. 6" Survey of Chemicals tested for Carcinogenicity." 6 CUT Brochure May 1976 RSV 0010482 Appendix 3 (page 6 of 6) PUBLISHED STUDIES; Acetaldehyde: Faron, V. J. & Kruyase, A. a.) Acute aubehronie and chronic inhalation toxicity studies, (p. 63) b.) Acute aubehronie and chronle atudles on acetaldehyde instilled lntratrachaally. Cp, 82.) In: Experimental Lung Cancer studies in Syrian goldau hamsters. Central Inst, for Nutrition & Food Res. TJJD, Zaiat, (1973) Polychlorinated 3iphenyla: Sorbic Acid: Aroclor 1254 J. Nat'l. Cane, Inst. 53. 547 (1974) Aroclor 1260 J. Nat'l. Cane. last. 54, (1975) BIBRA Report No. 1973/9 BIBRA Report No. 1975/8 9 * RSV 0010483 Monsanto -59- MONSANTO COMPANY D&AffTMBfT Of MEBW1NC A ENVIRONMENTAt HEALTH Appendix 4 TOXICITY INFOPMA TION TOXICITY INFORMATION ON: SANTICIZER* 409 Plasticizer TOXICITY When SANTICIZER 409 was administered to rats, the acute oral LDm was found to be greater than 50.0 grams/kilogram. All rabbits receiving a continuous 24-hour dermal application of SANTICIZER 409 survived the highest dosage tested (10.0 grams/kilogram). Thus, SANTICIZER 409 is considered to be practically non-toxic by ingestion in single doses and by single dermal applications. When 0.1 ml. of undiluted SANTICIZER 409 was placed into the conjunctival sac of the rabbit eye, a slight degree of irritation resulted. The average maximum score, recorded 1 hour after treatment, was 7.3 on a scale of 110.0. All eyes had regained a normal appearance 72 hours after they were dosed. No irritation resulted after SANTICIZER 409 was held in continuous 24-hour contact with intact rabbit skin. In a 4-day static fish toxicity study using flngerling rainbow trout and bluegill, the SANTICIZER 409 96-hour LDm was calculated to be 100 parts per million and 125 parts per million, respectively. On this basis, SANTICIZER 409 is considered to possess a relatively low order of toxicity to* both freshwater fish species. HANDLING PRECAUTIONS SANTICIZER 409 appears to possess no acute toxicologic properties which would require special handling other than the good hygienic practices employed with any industrial chemical. 9 5/7/76 Y-57-35 BT-74-55 49 * The above information it based upon studies conducted for Monsanto Company. It ii*beiieved to bo eorract, and it i* supplied to others upon tha condition that tha parson* recarving it shall make thair own determination of its suitability for thair purpose#. No warranty is prewad or impliad regarding tha accuracy of this Information or tha rosulti to ba obtained from its usa^ Inquiries regarding thte information ere to be referred to the Department of Medicine A Environmental Health. 800 N- Lindbergh. St LoutsJiAo. 63t60. (31*) 694-1000. RSV 0010484 -60TESTS USED TO EVALUATE SAFETY OF A PRODUCT Appendlx 5 (pa^e l or 3) Introduction - The methodology used to test a chemical or drug for various pharmacologic .and pathologic effects has developed gradually. Some of the tests are general in their scope and others are very specific. It is recognized that all exposure results in some absorption into the body. Safety can be man aged by keeping exposure small when compared to the toxic dose. An underlying assumption in animal testing is that the response of the animal is a reliable guide to at least the qualitative response to be expected In man exposed to the chemical. Where a cause-effect relationship can be established readily, such as tissue injury or death resulting from one or n few doses of a chemical over a short period of time, animal test data pro vide a reasonably good basis for predicting effects in man following short exposures. When there is a considerable time lapse between dosing and the observed effect, or vrhen the effect is observed only after prolonged, repetitive treatment with a chemical, the interpretation of animal test data presents vary ing degrees of difficulty'. These chronic effects, carcinogenicity, reproductive impairment, mutagenicity, may result from quanti tative or qualitative differences in absorption or metabolism and the nature of the response may be affected by degenerative changes resulting from aging of the animals. Consequently, their causeeffect relationship is not always clearly established. This necessitates detailed observations on large numbers of animals and the integration of data from several experiments to develop an understanding of how a chemical could, or could not, produce the observed effect. Specific comments on individual tests in the screening protocol follow. Adverse findings in any one test could necessitate further studies to determine their potential sig nificance as human health or environmental hazards. Experimental Toxicological Testing Acute Toxicity and Irritation Testing --These tests are sufficiently specific, standardized, and widely used that the results are usually well accepted. --They serve as basis for labeling and safe handling procedures, --The fish acute toxicity tests are not as well standardized but they are a useful predictor of dangerous water concentrations, % --Mutagenic potential can be detected by* bacterially screening. The interpreta tions of such results is difficult, as are all mutagenic test systems. RSV 0010485 Biodegradation Appendix 5 (page 2 of --This testing will determine whether bacteria can metabolize the chemical* Such data gives good Indication that the product will not accumulate In the en vironment# Metabolism --These studies are not standardized but a great deal of information is obtained quite inexpensively. --The possibility of accumulation is evaluated and possible accumulation in one or\gan or another can *be detected# --Species differences are great and extrap olation to man must be made very cautiously# Sub-Acute Toxicity --These studies are of paramount importance because, together with cancer# mutagenicity# and teratology, they represent subjects at the forefront of public health concern today# --Such testing will establish the target organ, at least for the test animal# --It will establish the safety factor between the highest no effect and lowest effect level. --It will also evaluate absorption from the GI tract and the hazard of inhalation# Beproductive Effects --The significance of the dominant lethal test has not been established# It is a means of evaluating a concern of public health effects, --Rabbit teratology studies are better standar dized and can be useful# but'studies are often equivocal rather than discriminating# Chronic Toxicity * --Methodology for cancer testing has not been standardized but does involve lifetime testing using more animals# --Negative studies are most useful# but because of many factors, statistical findings are difficult to interpret. RSV 0010486 Appendix 5 (Pe 3 of 3) These tests should be-performed on ell products unless there Is a specific reason for not doing them--such as Availability of comparable data from other sources. Most of these will be performed on rodent species, although larger animals could be used with certain materials or in special circumstances. $500 $250 $150 Acute toxicity and Irritation tests (Hat oral LD*>o (Rabbit dermal LD50 (Rabbit skin irritation ( Rabbit eye irritation (Rat inhalation (vapor, dust, aerosol) Pish acute toxicity Mutagenicity in microorganisms B1 od e grada t ion $2000 Semi-continuous activated sludge (SCAS) Metabolism and target organ response nnn *zu,uuu Distribution, storage, excretion Detection of specific urinary metabolite Subacute toxicity Oral $25,000 Dermal Inhalation (Cost will depend on route of exposure and duration) Reproduction effects $5,000 Teratology $8,000 Mutogenicity Chronic toxicity, $75,000 Oral to $250,000 Dermal Inhalation carcinogenicity screen (Cost will depend on and duration) route of exposure RSV 0010487 PRODUCTS CURRENTLY ON LONG-TERM TESTS CANDIDATES POR STUDY Co.__________ 1974 :_________________ 1973_________________ 1976 MAP ,' AVADEX AVADEX BM Monochlorotoluene RANDOX Rice herbicide ROUNDUP metabolite VEGADEX Aniline, 2,6-diethyl- N-isopropyl- Chloroacetyl chloride Chloropropenes, di-, tri-, tetra- Monochlorotoluene Chioropropanea, trl-, tetra-, penta- * Eplchlorohydrln MACHETE Root worm Insecticide Soybean herbicide MCP - - CYCLESAFE MIC SANTOFLEX 13 ' SANTOFLEX 77 #* ,u KP&P * . * Acrylonitrile * Styrene * Vinyl chloride * Vinylidene chloride MT ` Na ie Ca salts. Builder M SANTOSOL 200 TCC Tolyl xylyl sulfone 30 to < O Dimethyl *-* acetamide O <x> CD Benzyl chloride Capacitor fluid - MCS 1238 DEQUEST 2000 Monochlorobenzene Phthallmide 0 SANTICIZER 154 SANTICIZER 160 SANTOGARD PVI Synthetic fatty acid Butadiene Hexamethylenediamine Sodium methalj.vl sulfone * Vinyl bromide Benzylated C9 aromatics * Dichlorobenzene, 0-, p#* Maleic anhydride NITROL Pentachlorophenol SANTOSOL 100 SANTOSOL 340 ** Phenol Glutarlc acid 1 - NED - Hypocholesteremlc agent - -- ft-- *** Chemlc Industry Institute of Toxicology ' International Institute flvnthetlo Rubber Produce* * Appendix 6 o1 \ CJ I l Monsanto -64- -FROM IfTAMC A LOCATION! Dept, of Medicine & tnvironmcnt.il Health re: suajcct: August 27# 1976 Aquatic Toxicity Test Facilities cc RCrCHtNCE: TO George Roush, Jr. Appendix 7 G.J. Levinskas," A2SG Initially, the proposed Biological Research Laboratory was to contain facilities for aquatic toxicity tests. The subsequent decision to locate the laboratory near Washington University's Medical School resulted in increased costs and raised questions about providing water suitable for aquatic tests; In order to maintain momentum, it was decided to proceed without the aquatic areas. Since then, I have queried others regarding their opinions and/or experiences at attempting to dechlorinate a municipal water supply. From their replies, I conclude that dechlorination can provide water of sufficient quality for many fish studies. There is , concern about the quality of water for testing certain types of materials and for tests with invertebrate species. I recommend that aquatic toxicity test facilities be established at St. Peters, That location: a) has well water suitable for all types of aquatic studies, ,,0 b) provides space for outdoor fish ponds to study seasonal effects on aquatic species, c) provides space for "pilot plant" biodegradation studies (septic tanks, small-scale sewage treat ment plants), d) permits economies in construction and operation,and e) alleviates crowding in the Research Center. Brief citations in support of'these advantages follow. Well water from St. Peters currently is used in N building for aquatic studies. Outdoor ponds would not be practical in St. Louis. Scaled down versions of septic tanks or sewage treat ment plants would permit field studies of blodegradablllty under various climatic conditions. This would.be a one-story building with less frequent air changes, and a large part of the air could be recirculated. If the aquatic toxicity, facility includes biodegradation studies now being performed at Creve Coeur, this would permit conversion of the latter space to other uses. This could require purchase of additional analytical instruments. Finally, it is recommeded that the aquatic toxicity test facility be a part of DMEH. W' George J. Levinskas RSV 0010469 -65` $m(j* inau( k location) Ot'iif. of McJirino Ht Environmental Health :OATf June 4, 1976 cc suBiECT: NTA: Recommended Exposure Guidelines Appendix 8 (pw: or 2) G.J. Levinckas, A2SG J.T. Garrett - A2SG S.A. Roberto - A25C E>; W. Eley - A2SC t, BCFCMMCE: SAR tO GR, 6/1/76 TO G. Roush, Jr.,M.D A2SA o Suggested exposure guidelines for air levels of NTA are: aj 1.0 mg/m| for an 8-hour TWA, and b) 2.0 mg/nP for a 15-minute excursion. Excursions should be limited to no more than 2 per 8-hour day. Concurrent analyses of urine for NTA would be desirable. They would afford an estimate of the proportion of the inhaled amount which appears in the urine. If the suggested TWA is not exceeded, urinary output of NTA should' be no more than 10 mg in 24 hours. t A .judgement that around 0.1 mg/kg/day is "safe11 underlies this recommendation. That judgement is based upon the following conside rations. A lifetime feeding study with the sodium salt of NTA shows that*2000 ppm is a "no-effect" level in rats. Using A.J. Lehman's conversion factor, that translates into a dosage of 100 mgAg. Application of a safety factor of 1000 provides an estimated safe dosage' of 0.1 mg/kg/day. Similar studies with mice resulted in a "no-effect" level of 2500 ppm. This calculates out to a dosage of 375 mgAs which leads to an estimated safe dosage of 0.375 mgAg. The adequacy of a 1000-fold safety factor for a potential car cinogen can be debated. However, urinary tract tumors in the rat are rare in the absence of concretions. The reports we have received do not indicate whether or not chelates of NTA had formed and deposited in the urinary tracts of the test animals. If there were chelates, the safe level would be any level below which deposits occurred. In addition, it is not likely that there will be complete absorption of. the entire amount inhaled. Thus, the safety factor may be greater than indicated by the calculations discussed above. A man breathes 10m3 of air during an 8-hour wording day. At a RSV 0010490 G. Roush, Jr., H.D. June 4, 1976 Page - 2 - ,, "00TM (PM a Of 2) concentration of 1.0 mg/m3, if he inhaled and retained all of the NTA, he would receive a total dose of 10 mg. ^ For the hypothetical 70-kg man, this would be a dosage of 0.14 tng/kg. In order to control the total dose to the man, It will be necessary to avoid NTA Intake by other routes. Thus, food or beverages should not be brought Into or consumed in the work area, and all employees should wash their hands thoroughly before eating or drinking and at the end of the work shift. /bkp RSV 0010491 Appendix 9 (pag 1 of 4) * * RSV 0010492 PROPOSED MANNING TABLE ENVIRONMENTAL HEALTH LABORATORY -68- Appendix* 9 (page 2 of k) Environmental Health Laboratory Staffing aa of End of 1977 Lab Manager (FhDl....................................................1 Secretary..................................... 1 Operations Manager (BS/MS).......................1 Data Processing Supervisor (BS/MS)..l ^Toxicologist (PhD),....................................1 [Senior technician....................................... 1 ____ Clinical chemist (PhD)................ ,....1 Inhalation Toxicologist (PhD)................1 [Chemist (BS/MS)............................................ 1 Biochemist (PhD)................................................. 1 (Biochemist (BS/MS).............................:. .1 Total 11 Critical specialist. Early hiring needed. RSV 0010493 -69- Environmental Health Laboratory Staffing an of End of 1978 Appendix 9 (page 3 of it) Have Lab Manager (PhD). ......................... ........................ 1 Secretary ................................................................... 1 Operations Manager (BS/MS). ........................ [Secretary......................................................... Equipment cleaner...................................... Support technician .................................. Shift mechanic ... ............................. 1 Data Processing Supervisor (BS/MS). . . 1 Toxicologist (PhD)................................................ Toxicologist (PhD) ........................ . . Toxicologist (BS/MS) ............................. Senior technician....................................... IShimal caretaker....................................... 1 1 Pathologist (DVM/PhD) ... ......................... [Clinical chemist (PhD) ...... Toxicologist (BS/MS) ............................. Senior technician .................................. [Technician..................................................... 1 Inhalation Toxicologist (PhD) ............... [Inhalation toxicologist (PhD). . Analytical chemist (PhD) .................... Chemist (BS/MS) ....................................... Technician ..................................................... Jflnimal caretaker................... .... . . . 1 1 Biochemist (PhD)............................................... . DCheraist (PhDj....................................... BDChemist (BS/MS) :hnician ................................................. . Grand Total 1 1 U Hire Total 1 1 1 2 1 k H H O J !-!=} H H W W r l( n H H H H r l H H H W H r l r lH O I H 2 2 3' 5 1 1 1 1 1 1 1 1 1 1 1 1 27 38 RSV 0010494 -70 Appendix 9 (page 4 of 4) Environmental Health Laboratory Staffing as of End of 1979 Have Lab Manage r (PhD^..........................................................1 .Secretary . .................................... . . . 1 Secretary ......... ................... Operations Manager (BS/MS) ........................ 1 [Secretary.......................................................... 1 Equipment cleaner . ............................... 2 Support technician ............................. 1 [Shift mechanic. . ..........................................4 Data Processing Supervisor (BS/MS) . . 1 Toxicologist (PhD) ............................................ 1 Toxicologist (PhD)........................................2 Toxicologist (BS/MS)...................................2 Senior technician .................................. 1 [Animal caretaker........................................ 3 Pathologist (DVM/PhD).............................................1 [Pathologist (DVlVPhD)...............................- Clinical chemist (PhD).............................. 1 Toxicologist (BS/MS)............................. 1 Senior technican * .1 [Technician ....... ...... . . . 1 Inhalation Toxicologist (PhD)......................... 1 [Inhalation toxicologist (PhD) . . 1 Analytical chemist (PhD)..........................1 Chemist (BS/MS) .............................................2 Technician................................. 1 Qplm&l caretaker......................................... 1 Biochemist (PhD) ................................................. 1 [Biochemist (PhD). 1 [Biochemist (BS/MS)........................................ 2 [Technician.......................................................1 Grand Total 3d HHHHHW H4 Hire ' Total 1 1. 11 1 2 1 r3 '1 25 i 1 1 1 12 1, 23 1 1 1 2 12 12 1 X 2 1 *2 12 50 RSV 0010495 -71- Appendlx 10 environmental Health Laboratory Tentative Manning Table - Proposed Expansion Assistant Laboratory Manager (PhD)........................... 1 Pathologist (PhD/DTM)..................................................... 1 Histologist (BS/MS) ......................................................... 1 Biochemist (PhD) ............................... ............................... 2 Biochemist (BS/MS) ............................................................ 2 Microbiologist (PhD)......................................................... 1 Inhalation Toxicologist (PhD) .................................. 1 Inhalation Toxicologist(BS/MS) ................ 2 Toxicologist (PhD)(Carcinogenicity)...................... 1 Toxic ologlst (PhD).............................................................. 2 Toxicologist (BS/MS) ....................................................... 6 Secretary.................................................... 1 Stenographer .......................................................................... 1 Shift mechanic.............. ...................................................... 3 Equipment cleaner.......... .......................................................2 Senior technician ............................................................... 2 Technician................................................................................ 10 Senior animal caretaker ......................................... 1 Animal caretaker.............................................................. .10 Total b 50 4 RSV 0010496 -72- Appendix 11 > Aquatic Toxicity Laboratory Proposed Manning Table Senior Aquatic Toxicologist (PhD) .................... 1 JSecretary............................................... 1 ^Aquatic Toxicologist (PhD) ............................. 1 [Aquatic toxicologist (BS/MS).....................1 Senior technician..................................... 1 Technician .......................................................... 3 [Fish caretaker................................................ 2 ^Biochemist (PhD) .............. [Senior technician..................... 1 1 Total 12 RSV 00X0497 PROCESSERVIRONMENTOl \ RSV 0010498 -7 3- 6 PROCESS ENVIRONMENTAL The Process Environmental Section's function is to develop, in concert with operating companies, health related surveillance of the environmental effects of plant effluents and emissions and of the appearance of Monsanto1s products in the environment resulting from transportation and use. We must develop in-house experts as needed to provide effective liaison among the operating units and staff- departments. Considerable effort is needed to follow and hopefully influence legislative developments as well as to be up-to-date on regulations, permits, and trends in en forcement agencies. Predictions 1. Government regulation will increasingly zero in on specific toxic pollutants - carcinogens leading the parade. Politically sensitive areas such as auto transportation controls and urban run-off will not be tackled serious ly. Chemical targets are easy to attack, cause limited direct voter antagonism. Both government and environmentalists PR programs can effectively exploit public's fear of the unknown. 2. It will be increasingly necessary to explain the facts of risks and benefits to public at large and to employees. 3. Approval for new facilities and for. major expansions and . modifications will require more detailed and broader scope Environmental Effects Assessment - and thus longer lead times. 4. More specific chemical compounds will be "discovered" in places. Analytical techniques will be more precise. Monitor ing and sampling by governments will be more intensive. 5. Monitoring and enforcement for chemicals will shift from sanitary engineering parameters toward trace quantity analysis and biological effects determination. 6. Industry's- responsibilities will be increased by pressures transferred from municipalities. * Publicly owned sewage treatment plants can solve their problems by more stringent pre-treatment re quirements for industrial users. Public water treatment plants can prohibit chemicals in intake water instead of removing them by treatment. Boiled down to issue of using private capital vs. RSV 0010499 o {} -74- public funds, decisions will be based on best politics rather than best technical solution. 7. Cost-benefit arguments will be more effective fof specific cases than on broad national and industry scope. How many local jobs will be affected? How will local economic input-output numbers change? Impact on local tax revenues. 8. New approaches to our technical-economic decisions will be needed. Trade-off situations will occur. If we need to add a pollutant to environment, we must subtract a somewhat greater amount elsewhere. If we are allowed .1 mg/1 of a certain chemical in plant effluent, what is the best product/process mix? Questions and Responses * 1. Regulation will emphasize specific toxic pollutants. Which ones will have priority? Factors in setting priorities will be: a. Existing regulation, and regulatory trends. b. Known or indicated harm to environment. c. Economic significance to Monsanto. d. Extent to which measurement or detection is feas ible. It is expected that priorities will change as new in formation is developed and control policies are altered. For 1977-78 period, high priority will be on substances presently established for regulation under water and air laws. Arsenic Mercury Cadmium Cyanide Polycyclic Organic Matter Polychlorinated Biphenyls a Longer term, the suspect carcinogens from established hazardous chemical lists wi.ll gain top priority. Among the many on suspect lists, these will' be of RSV 0010500 -75- most economic significance: Benzene Maleic Anhydride Refractory Organo-Chlorine Compounds 2. Risk/benefit educational programs will be needed. DMEH must anticipate probable areas of concern. Factors to consider are: a. Follow on apprehensions from OSHA workplace con trols , i.e. when exposure to a substance is stringently controlled in-plant, families and communities will worry about external risks. b. Publicized chemical "incidents" will focus public apprehension. c. Our own clinical or toxicological findings will suggest need for information programs. Typical substances of near-future concern: J Vinyl chloride monomer Benzene Arsenic Dioxins Nitrosamines DMEH will be responsible to identify areas where public awareness will be important and to provide assessment of health and environmental risks. Degree of risk will generally be proportional to amounts of substances present or potentially released to environment. Action should be through Public Affairs group, line or ganization community programs or well-placed technical or general media publications. DMEH will support such actions with data and suggested strategies. Information should be developed on benefits and economic impacts vs. risk. DMEH will provide technical informa tion on comparative health and environmental factors for substitute or competitive products or substances. 3. Major new projects will need Environmental Assessment. It will take time for agencies to decide if full Environ mental Impact Statement is required - and more time to complete procedures and hearings if it is. Could stretch start-up date -one to two years. . By evaluation 'of regulatory trends'and actual site en vironmental situation, we should determine what baseline RSV 0010501 -76- data will be needed and obtain it as early as possible. Such actions can include: Determining existing levels of pollutant in soil, air and water. Assaying present biota and vegetation conditions. Projecting ecological changes which would result from proposed projects - both harmful and beneficial. More specific chemical compounds will be discovered in the environment. We need to anticipate the significance of such dis coveries and obtain more complete data where warranted DMEH will initiate monitoring in specific cases where there is reason to anticipate the presence of Monsanto substances. However, the tremendous efforts and expenditures for worldwide government-sponsored monitoring and analyysis cannot be duplicated by private sector. DMEH will follow results of such monitoring closely and will concentrate on determining the environmental fate and sources of introduction of those discoveries which are significant to Monsanto. Priority lists for environmental presence and fate de terminations will be started in 1977. Initial basis will be screening of data from 117 city drinking water supply analysis by EPA and also the expected ranking of aquatic bio-accumulative substances by EPA research laboratories. When significant findings emerge, the actions required will be: To confirm, perhaps duplicate the data. Evaluate the health and.ecological risks. Determine the sources of introduction of the substance to the environment. Initiate suggestions for elimination and also ,, for practicable regulations and control. RSV 0010502 -77- 5. Regulations will shift from sanitary engineering param- . eters to trace analyses and biological effects. It will be necessary for DMEH to establish field biological aquatic monitoring expertise and to broaden laboratory aquatic toxicological capabilities. DMEH has established protocols for aquatic toxicity testing of specific substances under laboratory con ditions. These will be translated to on-sitef mixed effluent conditions to assist operating plants where EPA is beginning to require such tests. Field evaluations of receiving waters biological con ditions will be conducted to determine the overall effects of our effluents. The Toxicology section will propose laboratory facili ties for aquatic toxicity testing. It is planned that these will include capabilities for testing and evalu ation of mixed effluent streams to back up the field work of the Environmental section. It is probable that regulations will require reduction ^ in toxicity of plant effluents in addition to BOD re ductions currently imposed. Effluent toxicity testing should include ability to determine characteristics of components as well as mixed effluents. From this the process and treatment changes necessary for toxicity reduction can be determined. r Although beyond the current scope of DMEH responsibilities, waste treatment pilot-plant facilities may be required to correct the toxicity conditions determined by the aquatic laboratory work. It is expected that CRD and Operating Companies will con tinue to stay at leading edge of state-of-the-art chemical analysis. DMEH does not plan to build analytical expertise in environmental functions. 6. Industry's load will be increased by pressures from municipal ities . Pre-treatment requirements from publicly-owned treatment plants will require point-source removal of specific toxics. The composition of wastesdestined for public plants must be characterized. Bio-degradability and aquatic toxicity of composite wastes must then be deter mined. Selective testing and plans for elimination of damaging effluents must be done before the risk of opera tional upsets is incurred. RSV 0010503 These requirements * will be supported by the Environ mental Section aquatic monitoring and toxicity testing described in Section 5. The intrinsic features of the public treatment works and the technical ability of its staff will be elements not encountered in our plants which have their own treatment. DMEH will provide consultation and initiate suggestions to the line organizations dealing with the public works. Drinking water plants will require removal of specific toxics from our direct discharges. The organic compounds with high persistence and low bio-degradability are likely to be pinpointed despite satisfactory overall BOD re moval. Suspect carcinogens from the list of 77 hazardous chemicals which are now being studied by EPA Effluent Standards group will have priority. Such requirements will be based on the capability of the municipal plants to handle the toxic chemicals in their systems. We will need to provide more chemical, toxi cological and treatability data on our substances. The aim will be to arrive at cooperative technical solutions. Otherwise, we face refusal to accept and be obligated for complete removal in our plants. DMEH will identify potential chemical problems in the drinking water situations and provide sufficient lead time for the development of solutions or avoidance. The capabilities described in sections 4 and 5 will be utilized Monitoring and identification Toxicity testing Pilot-plant treatment studies Cost-benefit arguments will be critical to gain local or state approval for expansions or modifications and to continue pub lic acceptance of our presence in the face of probable fears and alarms. DMEH needs to describe health effects and epidemiological data in understandable terms. Process Environment Section will prepare yearly priority listing of those chemicals for which we are likely to need to establish a health effects position. At present, no specific new area is identified. The health effects information, together with economic advantages of jobs, tax revenues, etc., plus evidence of our operational and waste disposal safeguards should be presented to the public in a manner that will provide understanding of the advantages as well as disadvantages of our presence, and of our proposed new projects. RSV 0010504 79- 8. New approaches to our technical-economic decisions will be needed. Capital, energy and operating costs for environmental controls have increased to the point that they are significant factors in business decisions on products and processes. Governmental cost-benefit analyses, in the few cases where they are required, tend to understate costs and inflate societal benefits. DMEH should contribute projections of possibilities and probabilities of environmental requirements to be factored into business decisions. These should be based upon our developing specific chemical and toxicological findings and on our presumption of the course of future regulation. In 1977-78, our direct participation in MCA projects on hydrocarbons-photochemical oxidants standards and regulations will be a major effort. This is typical in that health effects per se cannot be made a major issue. The extreme cost of proposed solutions, with questionable technical basis, would yield minimal health benefits. DMEH will continue to represent the Company in construc tive action on regulatory and legislative issues. Development of specifics on costs, technical feasi bility and economic consequences continues to be on an ad hoc basis with participation of operating company and CED personnel. A more unified system would be de sirable as the need for presenting integrated socio economic positions increases. Resources Required This function will continue to be predominantly advisory and con sultative. The technical resources for the most part exist in other parts of the corporation - although expanded effort will be required. CED - Technology for pollution treatment, removal and process monitoring $ CRD andOperating Companies - Technology for chemical analysis, treatability and biodegradation and de composition. * We expect to continue to utilize outside contractors for environ mental assessment and monitoring on a project-by-project basis. r RSV 00X0505 *W -80- Expanded use of MRC - Dayton capabilities will have first priority* It is not planned to build up complete capability in,environment ally-related functions with* a view to selling it outside, as Carbide has done with its subsidiary. Aquatic Environmental Sciences, or Dow with Hydroscience. If such enterprises .were contemplated, it is assumed they would be under MRC or EnviroChera. We do need to establish expertise in aquatic biological monitor ing and general aquatic bio-assay techniques. The utilization would be: 1. To obtain source, fate and effects of our substances as they are discovered in the environment. 2. To provide guidance to operating plants in aquatic effluent monitoring until such becomes routine. Although legislative, regulatory and industry association con tacts are of a generally continuing maintenance type of activity, it is expected that special projects and task force missions will increase. Where possible, we plan to continue to "borrow" participants from CED, operating companies, etc., but antici pate the need for increased full-time DME5 managerial attention. It is proposed to add one technical specialist in aquatic mon itoring and survey procedures in 1977. When DMEH aquatic toxicological testing laboratory facilities are available (1978?), one full-time laboratory professional should be assigned to process environmental studies to augment the field survey pro grams . In 1978, the need for the addition of one environmental engineer ing specialist is expected for assignment to major, complex projects both with the corporation and with industry-wide study projects. Most contract studies will be for specific productprocess areas and should be costed directly to the operating units. Since we expect to preferentially use MRC, there is little advantage in pass-through cost allocation as is done for Toxicology contracts. The DMEH supported contract costs will increase only incrementally. 9 0 RSV 0010306 PROCESS ENVIRONMENTAL PLANS PROCESS ENVIRONMENTAL RESOURCES 32 1 CO at co o m 1-^ oU1) CO CO Ot in oCO CO at 1-^ CO 09 co o at H N CD co o at 0 oH CD CO at H o 00 co o at tn m m ~ O 6 H at r- co o at iH H oo oCO r*- CO at H r* rat to at H * Ci tn O o tH ' m O % .* c o. fi .. a un z . Q) Z *w O aMs . uo . cu 04 r-t <9 M (Q M. 0> M o <0 eft. O .O .Q H < * 4<-01 * ^ H .a CJ RSV 0010506