Document ppxywX0mze8VEjaDaJz0YKXXw

'fCfr ' to/ <2r a '4 A a., trr *a es. of he .iy oa ha. .re. ose me L"w31* si- -.31 file ::on :rn- J% the arsch afl * or one tm icb rlor ad* -hit red r it 5 to V PROPOSED RULE MAKING 19383 MS.5 PwritwMH rf igrwun. Each trade agreement entered into by an airline hereunder shall provide: ( > Hiat it shall become effective on a specified day. an or before January 1, 191*-. * * 3. Amend 1225.9 to read aa follows-. the Administrator of die Environmental Protection Agency (35 F.R. 15623). and the authority delegated by the Adminis trator to the Deputy Assistant Adminis trator for Pesticides Programs (36 F-R. 9038), it is proposed that Part 180 be amended by adding the following new section to Subpart B: 180.36 Toxicology guideline* for eval 225.4 Limitation on tolnl value of trade agreements. uating pesticide chemical safety of re-idlie tolerance*. The total value of trade agreements (a) The following guidelines summa entered into by any single airline in ac rize in detail for the petitioner the cordance with the provisions of this part Agency's toxicological data requirements shall be limited, in the aggregate, to the for pesticide petitions. To determine the following: safety of a pestlcidal chemical to whose (a) For the airlines idoatifled in toxic effects man or animals are exposed 1 225.1 <)(3>, $200,000; when that chemical is added directly or (b) For the airlines identified in 225.1 indirectly to food, the Agency will con (a) (4) which have gross transport oper sider all relevant factors, including: ating revenues of less than 92 million in (1) Available toxicological data re the year prior to the effective date of the flecting experimental studies in animals agreement in question, 320,000 each year; and controlled studies in man. (c> For the airlines identified in <2> Epidemiological data on effects ! 225.1(4* (4) which have gross transport from general exposures to the pesticide. operatins revenues of $2 million or more (3) Estimated average dally intake of in the year prior to the effective date of the pesticide by those whose diet nor the agreement in question, 350,000 each mally includes foods containing such year. pesticides. <d> For the airlines identified in (4) Adequacy of the safety factor with 1225.ie> (3i, $100,000 each year: reference to severity of toxicity obtained (e> For the airlines identified in by dividing the quantity of the substance I 225.1* a) (1): that produces no effect in the most sen (1) 350.000 plus 34,000 per station sitive laboratory animal tested by the operated on January 1, 1972L for agree quantity of the substance expected in the ments becoming effective during 1972. diet of man on a mg./kg. dally, body <2> 54.000 per subsidy-eligible station weight basis. operated on January 1. 1973. in Class 1 b) The toxicological Investigation of Rate VI statical classifications C. D, and a substance proposed for pesticide use E, for agreements becoming effective may be conducted as outlined In the fol during 1973- lowing sections. Where strong or alarm (3> 5-t-OOO per subsidy-eligible station ing biological effects in the test animals operated on January 1, 1974. in Class are observed, it may be necessary to do Rate VI station classifications D and E. animal studies m addition to those lor agreements becoming effective during specifically prescribed before any usage 1974. of the substance will be permitted. Safety <4> 54.000 per subsidy-eligible station evaluation studies must be done under operated on January 1. 1975, in Class VI the guidance of qualified scientists who station classification E. for agreements by training and experience can plan and becoming effective an and after January employ reasonable experimental proce 1, 1975. dures to adequately explore unforeseen ^|PB Dwc.73-U9e4FUadt-19-T2;;31 ami toxicological manifestations. Nothing in this guideline shall be^ construed as re lieving the investigator of this respon- - sibillty. ENVIRONMENTAL PROTECTION (c) The toxicological data require ments for pesticidal chemicals are de AGENCY pendent upon the proposed use patterns for the specific chemical, The toxicity (40 cm Pent 1801 and impact upon other organisms in the environment must also be considered in PESTICIDE CHEMICAL SAFETY the evaluation of the chemical. As proto Propwad Toxicology Guidelines cols for such evaluations become avail able, they should be included in the test A. T> ittaklf petitioners have raised bimiom about the kinds of data and ether Information which will satisfy the toxicology requirements of the pesticide Procedural and interpretative regula tors. Accordingly, it has been concluded tost guidelines for studies to meet such [toibcMents should be officially pubtohed to eliminate this uncertainty. Thrn 9nri. pursuant to provisions of toe Federal Food, Drug, and Cosmetic Act (see. 701(a), 52 Btat 1055: 21 XJjS.C. ing programs. (d> Limited use of a specific chemical may modify the data requirements. In specified instances, a temporary toler ance is granted to permit experimental pesticide field trials on a limited scale In accordance with a temporary permit. In these Instances, for nonnegliglble resi dues, a progress report on the lifespan feeding studies at approximately l.year and-the reproduction studies through the first generation will suffice. (e) The pesticide used for toxicologi 171'a) > end the authority transferred to cal testing should be the same chemically characterized technical product used and produced commercially. Test diets should be analyzed at intervals to check for sta bility of test substances. (f) If plant residue studies show that a significant portion of the residue is a metabolite or degradation product of the parent compound, then acute toxicity (and in some instances subacute toxicity studies) for such a product will be re quired. (g) Protocols should be designed so that the data can be evaluated statisti cally. Guideunxs a. Toxicological data for all tolerances: 1. Acute toxicity--a. Oral administration. Oral LD,, In at least two species of labora tory animals. A full and complete descrip tion of effects observed should be reported. b. Neurotoxicity. Neurotoxicity test for Cholinesterase Inhibitors. 1. Species--Chickens. Although phospho rus compounds have been shown to produce locomotor ataxia in some animals other than chickens, the observations m hens of this species axe usually more clear cut. 11. Procedure. Single oral dose at LD,, level: to be administered to bens over 9 months of age and the birds observed for 21 days. !f no response, re-dose and observe an other 31 days. Include negative and posi tive controls (TOCP, 500 mg. kg. orally). c. Observations. The absence of clinical neurotoxic effects in birds surviving two LDj, doses of the compound at an Interval of 3 weeks will be accepted as evidence that the compound probably has no neurotoxic potential. Selected nervous tissue of any birds showing doubtful responses should be examined, as well as positive controls. 2. Subacute toxicity. Oral exposure (direct dosing or In the diet). 0, Number of species. At lesst two specie*, one a nonrodent. b. Number of animals. At least 13 of each sex at each dosage level for rodents. For nonrodents. four of each sex per level. c. Duration--Ninety days. For the non rodent (usually dogs), the study can be ex tended to 6 months and hlstopathologlcal examination made at the end of that period Instead of 3 months. (See B.3.e. under Non rodent studies (long-term)). d. Dosage. At least three dosage levels plus a control group. One dosage level should manifest severe pharmacological effects and one level should be "no-effect". e. Observations. Growth, food consump tion, general appearance, signs of local and systemic toxicity, mortality, hematology, urinalysis, organ function tests (SAP, blood sugar, urea, etc.), organ weights, and gross and microsooplc pathology. TImues exa mined should be those described In the WHO Technical Report Series NO- 423 (1989) 1 Eyes should he examined both ante and post mortem. All animats dying before ter mination should be examined grossly and microscopically. 1. Rodents. All tissues from a representa tive number of rodents from the highest dosage level and the controls should be examined histopsthologlcally, as well as major organs from each of the lower dosage levels. All gross lesions should be examined. 11. Nonrodents. All tissues from every nonrodent at all levels should be examined. 1 Atropine or PAM may be used to Insure survival of sufficient hens. `Guidelines for a uniform reporting of pathological examinations are being pre pared and will be made available when com pleted. i HMftAL tfOISTM, VOL 37. NO. 113--WfONfSOAL SIFftMlH 26, 1473 AST 00003444 % 19384 PROPOSED RULE MAKING f, Cholinesterase inhibition, If the teat compound la an organophoephet* or car* bamate pesticide, measurement of choline* sterase Inhibition of plasma and red cells at appropriate intervals and of brain at ter mination is required. 3. Negligible residue tolerance*. The com pletion of the acute and subacute toxicity studies are required for negligible residue tolerances for pesticide chemicals. The "negligible residue" concept defined in 40 CFK 180.1(1) as adding to the diet an amount of pesticide chemical which will be less than l /2000 the amount demonstrated to have no effect from at least two 90-day feeding studies cannot be construed literally in all cases. A negligible level should refer to a residue that la toxlcologlcally insignificant and usually about 0.1 p.p.m. or less on raw agricultural commodities for human consumption. B. Toxicological data for nonnegllgible tolerances: 1. See A. (Toxicological data for all tolerances.) 2. Carcinogenicity studies (long-term)-- s. Specie*. Usually two rodenta. b. Selection of animat*. Weanling randombred animals. At the option of the experi menter, these animals may be derived from a normal stock colony and maintained on the test diet for their lifespan or they may be the F,. progeny from a reproduction study in which the parents have been treated with the pesticide. c. Dotage. At least three dosage levels plus a control; the highest dosage should elicit any specific pharmacological action the test compound might have. One dose level should show no observable differences from control animals. d. Duration. Two years for rats and ham sters. 16 months for mice. e. Number of animal*. The groups should be large enough to assure an adequate num ber of survivors at the end of the study. De pending upon the strain of rodent, from 35--60 animals of each sex per doee level is suggested. f. Observation*. 1. Growth, food consump tion, general appearance, signs of local and systemic toxicity, terminal organ weights, and gross and hlstopathological examination of both rodent species1 11. In one species (usually the rat), clinical laboratory tests should be performed at 3, 6. 13, 18. and 24 months. These should include routine hematological measurements, quali tative urinalysis, cholinesterase activity at Intervals on plasma and red cells and terminally in the brain to determine "no effect" level (In the case of carbamate and organophosphate pesticides), alkaline phos phatase determination (other serum enzymes If indicated such as SOOT), and organic blood constituent analysis (Ca. Cl, Ns, K If Indicated). 3. Nonrodent studies (long-term)--a. Spe cie*. Dogs, monkeys, snd swine. b. Route. Orally. c. Duration--Six month*. This may be ac complished by extending the 90-day subacute study until biochemical studies are com pleted. d. Dosage level*. Three test plus a control. e. Number of animal*. Four of each sex at each level. f. Observation*. See under BJff. 1, and U- 4. Reproduction *tudy (long-term)--a. Species. One mammalian species, usually one of the same rodent species used In tbs chronic toxicity test. 1 Blstopathologlcal examination should be done on all survivors at the highest dosage level and controls and on major organs In 10 males and 10 females at the lower levels Changes In organs at the highest dosage level should be looked for In the lower feeding levels. All gross lesions at all levels should be examined. b. Dosage level*. Two dosage level* and a control. These levels may be derived from the 90-day study and should be (1) the lowest dose that caused s minimum effect and (3) one lower doee. e. Three success*-- feneration*. On* Utt per generation Is s .ent, provided the first litter in any generation Is healthy. d. Observation*. Fertility Index, viability index, survival to day four, weaning Index, lactation Index, body weights, and external abnormalities. 5. Teratogenicity studies--a. specie*. Bat. mouse, hamster, rabbit, or monkey. If the rat Is used tor the reproduction study (B-6.). a different species should be used for this study. b. Number of animal*. Twenty pregnant female rodents per level, 10 pregnant female nonrodents per level. c. Dose level*. Three levels plus a control, with levels selected so that a "uo-effeet" lead will be ascertained even though an effect k found at the highest level. d. Route of administration. Orally. e. Period of dosing. Daily through the sen sitive period of orgsnogenesls. For example, days 6 through 15 for rats, days 6 through 10 for hamsters. f. Method of birth. Except for monkeys, deliver fetuses by Caesarian section 1 day prior to term. _ g. Observations. Number snd position of resorption sites, number of corpora lutes and Implantation sites, fetal weights, external malformations, and skeletal anomalies after clearing and staining with Alizarin red. 6. Metabolism studies. Metabolism studies are required. These may be radiotracer studies. One or two species should be studied, depending upon the use snd the nature of the residue on the raw agricultural com modities. -7. Mutagenicity studies. If data from other toxicological testa indicate a mutagenic potential, then specific tests should be ""**. A survey of available methods indicates they are In an early developmental stage when ap plied to mammals. More data have been de veloped from the dominant lethal test, and this might bs asked for if Indicated. 8. Special studies, a. When appropriate, additional studies baaed upon similar chemi cal structure between the test compound snd those (nltrophenolica, dioxins, etc.) known to produce specific toxic effects may be In order. b. Proof of safety to livestock may be re quired if the tolerance requested Is for non negllgible residues In livestock feed or from dermal application. c. Studies may be required to demonstrate reversibility of effects found after subacute feeding. Any omission of data or Information suggested by the guidelines or substitu tion of other types of data or informa tion should be accompanied by an ex planation of why the material was omitted or how such substituted data adequately fulfill the requirements to demonstrate the safety of the requested clearance. B. Due to the addition of certain sec tions to Subpart B and to provide for future such additions, it is proposed that the center heading immediately preced ing 5 180.29 be revised to read "Miscella neous Provisions." Interested persons may. within 30 days after publication hereof in the federal Register, file with the Objections Clerk, Environmental Protection Agency. Room 3125, South Agriculture Building, 12th Street and Independence Avenue 8W, Washington. DC. 20460, written camwnito tmetmabty in quintupiicate) re garding Oils proposal. Commats may bn armmiiMieii by a memorandum or brief In sopped thereof. Date*: September 6.19721 WlttJW M TTstw.w XbiMr A sailant Admidsdmtar tor Pesticide* Program*, fFB Dac-n--15CTS FUcd 9-iS-7X^:47 ms) TUBAL COMMUNICATIONS COMMISSION C 47 CTR Port 1 J (Socket No. 19518) PUBIC INTEREST GROUPS AS CONSB.TANTS TO BROADCASTERS Prepend Reimbursement for legiti mate and Prodent Expenses; Order Fvteeding Time for FiEng Com meitor and Reply Commonts Be tke matter of reimbursement far legitimnr and prudent expenses of a public itouM group for a consultancy to a tenadoster in certain instances. 1. The notice of inquiry sad proposed rule mdrtng in the above-entitled procewlinL was adopted June 1. 1972, and published in the Federal Racism on June 9.072, 37 PR. 11592. Dates spec ified ter filing comments and reply common tie September 11 and Octo ber 1. HD, respectively. 2. Os September 8, 1972, request* tax extensim of time for filing comments and reply comments were filed by Storor Broadcasting Co. (Storer) and by ** Efforts hr Soul in Television (BEST). The fonmr requested an extension to and indkliag September 14. 1972 and the latter to and including October 3, 1972. BUST supports its request by stat ing it is pescntly laboring under extraor dinarily heavy workloads, and also that the pres of end of summer schedule* has set Gem back in work schedules. It further states that the extension is necessary to afford full and thoughtful considerakms to the questions raised hi this proemting and to prepare intelligent cammed*. 3. We ere of the view that the re quested mtensian of time is warranted and woMt save the public interest. Ac cordingly. it is ordered. That the time for filing umiifTits in the above docket Is extended to and including October 2, and to OctokK 13, 1272, for the filing of reply moments. 4. Thisaction is taken pursuant to au thority femd in sections 4(i). and 303(r) at the cminumications Act of 1934, as amended, snd i 0291(d) (8) of the Com mission's mics and regulations. Adopted Septonber 12,1972. Released: September 13,1972. tSXAl.1 Wallace E. Jobwsow, Chief. Broadcast Buxom. [nt Docaa-ieeoa yum 9-i9~ri;e:w u) FEDERAL REGISTER, V L 37, NO. 163--WEDNESDAY, SfiPTEMMi 30, 1*72 ASI 00003445