National Academies Press: OpenBook

Drinking Water and Health,: Volume 1 (1977)

Chapter: VI ORGANIC SOLUTES

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Suggested Citation:"VI ORGANIC SOLUTES." National Research Council. 1977. Drinking Water and Health,: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/1780.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Vl Organic Solutes INTRODUCTION Selection of Agents . In selecting agents to be included in the organic contaminants section of this report, a number of tabulations of organic contaminants detected in drinking water were examined. From these lists, agents were selected that have been reported to be present in one or more drinking-water supplies at relatively high concentrations and for which there were data to suggest toxicity in man or animals. Also included were several agents that exhibit a structural relationship to other compounds for which toxicity data were available and all of the agents listed in the current interim standards, as well as those specific compounds listed in the Federal Register of December 24, 1975. A total of 298 volatile organic compounds were considered and 74 of these were selected for evaluation. Similar criteria were used to select the organic pesticides for inclusion In this report. Several additional agents were added after examination of the usage patterns for all major types of organic pesticides, as well as a number of agents that were considered to be potential contaminants of drinking-water supplies because of the large quantities produced. A total of 55 organic pesticides were selected for evaluation. 489

490 DRINKING WATER AND H"LTH Evaluation of Toxicity A critical review of the available literature on the toxicology of each agent (or group of related agents) was carried out as the first stage in the evaluation. Although the primary focus in these reviews was on carcinogenesis and other chronic toxic effects, test results and data on teratogenesis, mutagenesis, reproductive ejects, metabolism, acute toxicity, and other types of studies were included when available. Information on the current production, manufacturing methods, and environmental distribution was included for some pesticides and other organic compounds. In the second stage of the evaluation, both the quantity and quality of the information in each of the critical reviews was considered to determine whether the data would permit judgments to be made regarding carcinogenicity or estimation of a maximum no-observed- adverse-e~ect level. The hazards of ingesting compounds that were assessed as confinned or suspected carcinogens were evaluated in terms of dose-related risks, as described below and in Chapter II. It is recognized that extrapolation of high-dose animal bioassay data to low-dose human exposures is beset by limitations, and that it is difficult to reconcile the results of experiments on animals that may show different target-organ responses, and may metabolize carcinogens at different rates and by different pathways. Such risk assessment and extrapolation procedures are further compromised by the limited information that is available concerning the mechanisms by which these agents act (e.g., as initiators, promoters, modifiers) and the almost total lack of data regarding the potentially synergistic and antagonistic interactions of these agents with each other and with other environmental agents. Despite these and other uncertainties, the "risk estimate" approach has been adopted as the basis for analyzing the data on carcinogenicity rather than the "safety factor" approach. After a substance had been identified as a carcinogen, the risk to man was expressed as the probability that cancer would be produced by continued daily ingestion over a 70 yr lifetime of 1 liter of water containing a standard quantity (1 ,ug/liter) of the substance in question. Estimates expressed in this form may then be used to calculate risk due to the concentrations actually found in drinking-water and the daily consumption. To make such estimates from the results of animal feeding studies, two steps are necessary. The first involves conversion of the standard human dose to the physiologically equivalent dose in the animal. This was performed on the basis of relative surface area (details are given in Hoel

Organic Solutes 491 et al., 1975, Chapter II). The second step requires use of a risk model relating dose to eject. The model used for this purpose is p (~) = I - c,-(A,, + A, ~ + At d' + . . . A'. d') where P(a) is the lifetime probability that dose d (total daily intake) will produce cancer, K = the number of events in the carcinogenic process, and Ao,\~,A2, etc. . . . are nonnegative parameters (see Chapter II). At low doses, the higher-order terms in d2,a~, etc., may be neglected and P (d) ~ I _ {,-(A,, + APO ~ A`, + A, d No representing the background rate. When two or more sets of results of lifetime animal feeding studies were available, experimental values of P(a), the fraction of test animals developing cancer, and d, the total daily dose, were fitted to the equation to determine how many of the terms Ao,A~d,A2d2, etc., were necessary to give the best fit. Corresponding values Of Ao,A,, or X0, Al and \2, etc., were used to calculate Pep for the low-dose of interest, namely the animal dose that was physiologically equivalent to the standard dose for man. If the animal experiments involved only one dose level, the Aid term, alone, was used in the calculation. Upper confidence limits in the estimated low-dose risk were also calculated by use of maximum likelihood theory (Guess and Crump, 1976, Chapter II), and these values were tabulated. Since the animal data were obtained from lifetime feeding studies, the risk estimates calculated from them for the low-doses that were estimated to be physiologically equivalent to the human dose were taken to represent the lifetime risks for man. The background rate, obtained from the cancer incidence in the control groups of experimental animis and represented by the parameter ho, was excluded from the tabulated values of P(a), which therefore represent the incremental risks due to ingestion of the compounds in water. It was felt that predictions that are risk-related provide a more meaningful first approximation of hazard than safety-related predictions. The risk estimate approach may provide unique advantages for other areas of toxicological evaluations, such as mutagenesis, and it is recommended that the usefulness of this procedure be evaluated as a new predictive method in toxicology. For agents that were not considered to be known or suspected carcinogens and for which there were adequate toxicity data from prolonged ingestion studies in man or animals, the more traditional approach was utilized of combining the maximum dose producing no- observed-adverse-e~ects with an uncertainty (risk) factor to calculate an

492 DRINKING WATER AND H"LTH ADI (acceptable daily intake). Several alternative terms, other than ADI, were considered, but it was concluded that the introduction of new terms might well lead to confusion and that the use of a widely recognized and generally acceptable term would be preferable for this report. The ADI has been used previously as an internationally established standard for the toxicologic evaluation of food additives and contaminants and the concept is applicable to other ingestion exposure situations. The ADI represents an empirically derived value that reflects a particular combina- tion of knowledge and uncertainty concerning the relative risk of a chemical. The uncertainty factors used to calculate ADI values in this report represent the level of confidence that was judged to be justified on the basis of the animal and human toxicity data. All calculations for an ADI were based on chronic feeding studies, but other considerations, e.g., mutagenicity, teratogenicity, and lack of sex and strain information, influenced the choice of the uncertainty factor. ADI values were not calculated for agents where the data were considered to be inadequate. Since the calculation of the ADI values is based on the total amount of a chemical that is ingested, the ADI values calculated in this report do not represent a safe level for drinking water. However, a suggested no- anticipated-adverse-e~ect level has been calculated for these chemicals in drinking water using two hypothetical exposures (where water constitutes 1% and 20~o of the total intake of the agent), and similar calculations can readily be made for other exposures. Conclusions The organic contaminants that have been identified in drinking water constitute a small percentage of the total organic matter present in water. Although approximately 9OYo of the volatile organic compounds in drinking water have been identified and quantified, these represent no more than logo of the total organic material. Of the nonvolatile organic compounds comprising the remaining 90~o of the total organic matter in water, only 5 to logo have been identified. From the 74 nonpesticide organic compounds and 55 organic pesticides selected for study, 22 have been identified as known or suspected carcinogens, 46 as having sufficient toxicity data to permit the calculation of an ADI value or a suggested no- adverse-effect level for drinking water, 6 as mutagens and 7 as teratogens. There were 61 agents for which the toxicity data were judged to be inadequate for establishing any recommendations. (See Tables VI-63 and 64 in "Summary of Organic Solutes.") It is evident that this effort constitutes only the beginning of a very large task. However, in preparing these reports and recommendations, an ~_

Organic Solutes 493 attempt has been made to use procedures that will enable efforts in the future to be focused on revisions and additions to the estimates, adding to and updating, rather than on redoing, the task. Also identified are certain priorities for the selection of agents to be studied and the research needs in toxicology and epidemiology to facilitate the evaluation of the potential health hazards associated with organic agents that are or may be present in our drinking-water supplies. PESTICIDES: HERBICIDES Chloropheno~s 2,4D Introduction 2,4-D, or 2,4dichlorophenoxyacetic acid, was introduced as a plant growth-regulator in 1942 (USEPA, 1974b). It is registered in the United States as an herbicide for control of broadleaf plants and as a plant growth-regulator. Domestic use of 2,4-D is estimated at 40-50 million pounds a year, approximately 84% of which is used agriculturally and about 16% nonagriculturally (mainly for forest brush control). 2,4-D is produced commercially by chlorination of phenol to form 2,4 dichlorophenol, which reacts with monochloroacetic acid to form 2,4D (USEPA, 1974b). Commercial 2,4-D formulations are generally com- posed of the salts or esters (ethyl, isopropyl, buty1, amyl, hepty1, octyl, etc.) of the acid. Analysis of 28 samples of technical 2,4-D by gas chromatography showed that hexachlorodioxins were present in only one sample, at less than 10 ppm (Woolson et al., 1972~. The dioxin most likely to be formed, 2,7-dichlorodibenzo-p-dioxin, was not found. The major impurity in technical 2,4-D was identified as bis-~2,4dichIorophenox- y~methane, at 30 ppm (Huston, 1972~. The solubility of 2,4-D in water is 540 ppm at 20°C; its major breakdown product, 2,4-dichlorophenol, is soluble at 4,500 ppm (USEPA, 1974b). The 2,4D salts are in general highly soluble, but the esters are much less soluble. 2,4D is chemically quite stable, but its esters are rapidly hydrolyzed to the free acid. Microbial degradation of 2,4-D contributes to its rapid breakdown (half-time, 1 week) in water (USEPA, 1974b). When exposed to sunlight or ultraviolet irradiation, aqueous 2,4D solutions decompose to 2,4-dichlorophenol, 4chlorocatechol, 2-hydroxy-4chlorophenoxy

494 DRINKING WATER AND H"LTH acetic acid, 1,2,4benzene trial, and polymeric humic acids. The overall breakdown rate of 2,4D in aqueous solution is fairly high, and 2,4- dichlorophenol is even more photolabile. Most 2,4-D residues are retained in the soil, where breakdown usually occurs within 6 weeks. Between 1964 and 1970, only 50 samples of food were found to be contaminated with 2,4-D; the concentrations detected were 0.021~.16 ppm (USEPA, 1974b). Residues were found in 1% or less of dairy products, oils, fats and shortening, and fruit, in 1.9% of leafy vegetables, and in 22.1% of sugar and adjuncts. 2,4D is found in water (Marigold and Schulze, 1969~. Concentrations as high as 70 ppb have been detected in Oregon streams after aerial application to forestland (Hiatt, 1976~. 2,4-D was detected in raw water at 0.05 ,ug/liter, in Lafayette, Indiana (USEPA, 1975j). The EPA has set an interim standard for 2,4-D in finished water of 0.1 mg/liter (USEPA, 1975i). Metabolism When 2,4-D with labeled carbon was administered orally to sheep, 96% of the dose was excreted unchanged in the urine in 72 h, slightly less than 1.4% in the feces (Clark et al., 1964~. When adult sheep and cattle were fed 2,4-D in the diet for 28 days at up to 2,000 ppm, the kidney contained the highest and the liver somewhat lower concentrations of 2,4-D and its breakdown product 2,4-dichlorophenol (Clark et al., 1975~. Withdrawal from treatment for 7 days resulted in almost complete elimination of 2,4- D and its major metabolite from the tissues. In rats that received 1-10 mg of 2,4D, there was almost complete excretion in the urine and feces in 48 h; at higher doses, some accumulation occurred in tissues (Khanna and Fang, 1966~. After subcutaneous injection of 2,4-D and its butyl and isoocty} esters into mice at 100 mg/kg, the esters were eliminated rapidly, and only 5- 10% of the 2,4-D remained after 1 day (USEPA, 1974b). No 2,4 dichlorophenol was detected in extracts of the treated mice. In feeding studies of 2,4-D with dairy cows and steers, unchanged 2,4- D was found only in the urine (Bache et al., 1964a, b; Guteman et al., 1963a, b; Lisk et al., 1963~. Other studies (Burchfield and Storrs, 1961; Klingman et al., 1966) demonstrated that 2,4D was eliminated in the milk of cows maintained in pastures treated with 2,4-D or its butyl or isooctyl ester. The pharmacokinetic profile of 2,4D has been determined in five male human volunteers (Sauerhoff et al., 1976~. After ingestion of a single 5- mg/kg oral dose, 2,4-D was eliminated from plasma in an apparent first

Organic Solutes 495 order process with an average half-life of 11.7 h. All subjects excreted 2,l D in the urine with an average half-life of 17.7 h, mainly as free 2,4-D (82.3~o), with a smaller amount excreted as a 2,~D conjugate (12.8~o). Health Aspects Observations in Man A 46-yr-old male farmer accidentally ingested a 2,4-D formulation; the dose was estimated to contain 2,4-D at 100 mg/kg, S-ethyldipropylthiocarbamate at 230 mg/kg, and epichlorohy- drin at 2.3 mg/kg (Berwick, 1970~. The clinical picture was indicative of 2,4-D poisoning with symptoms including fibrillate twitching and muscular paralysis. Serum glutamic oxalacetic transaminase, glutamic pyruvic transaminase, lactic dehydrogenase, aldolase, and creatine phosphate were increased, and both hemoglobinuria and myoglobinuria were observed. After recovery of the patient, there was also a 4-month loss of sexual potency. In testing 2,4-D for possible use in disseminated coccidiomycosis, 18 intravenous doses were administered to a patient over a 33-day period, with no observed side effect (Seabury, 1963~. The dosage was 15 mg/kg for the last 12 doses, except that the eighteenth was increased to 37 mg/kg. Following the nineteenth and final dose of 67 mg/kg, the patient exhibited fibrillary twitching and general hyporeflexia. The patient later died, apparently owing to the disease. After a 23-yr-old man used 2,4-D in suicide, the lethal dose was estimated to be over 90 mg/kg (Nielsen et al., 1965~. Assouly (1951) is reported to have taken 2,4-D daily at 8 mg/kg for 3 weeks without harmful erects. Data from Dow Chemical Co. (Johnson, 1971) on 220 workers exposed to 2,4-D at 0.43-0.57 mg/kg/day over a period of 0.5-22 yr showed no significant differences from data on an unexposed human population. Observations in Other Species Acute Elects The acute toxicity of 2,4-D is moderate in a number of animal species, with LD50 values of 10~541 mg/kg for rats, mice, guinea pigs, chicks, and dogs (Drill and Hiratzka, 1953; Rowe and Hymas, 1954~. Salts and esters of 2,4-D show an even lower degree of acute toxicity. The acute oral toxicity of the major 2,4-D breakdown product 2,4- dichlorophenol is 580 and 1,625 mg/kg for the rat and the mouse, respectively (Toxic Substances List, 1974~.

496 DRINKING WATER AND H"LTH Subchronic and Chronic Effects Young adult female rats were given oral doses of 2,4-D in olive oil at 0, 3, 10, 30, 100, and 300 mg/kg five times a week for 4 weeks (Rowe and Hymas, 1954~. No adverse effects were noted at 30 mg/kg and below, but depressed growth rates, liver pathology, and gastrointestinal irritation occurred at 300 mg/kg. In another experiment (Rowe and Hymas, 1954), depressed growth, liver pathology, mortalities, and increased liver/body weight ratios were observed in rats fed 1,000 ppm 2,4-D for 113 days. 2,4-D was administered orally to dogs at dosage levels of 0, 2, 5, 10, and 20 mg/kg 5 days a week for 13 weeks (Drill and Hiratzka, 1953~. Three of four animals receiving 20 mg/kg dose died within 49 days. These animals showed a definite decrease in the percentage of lympocytes in the peripheral blood. The surviving animals in all groups did not show any hematological abnormalities. Dietary levels of 0, 5, 25, 125, 625, and 1,250 ppm technical grade 2,4-D were fed to female and male Osborne-Mendel rats for 2 yr (Hansen et al., 1971~. No significant ejects were observed on growth, survival rate, organ weights, or hematologic parameters. There was also no elevated incidence of tumors over that seen in controls. In a parallel study (Hansen et al., 1971), groups of 6-8-month-old beagle dogs received 0, 10, 50, 100 and 500 ppm of technical 2,4-D for 2 years. No 2,4-D related ejects were noted. None of the lesions observed in the 30 dogs were believed related to the treatment. The no-adverse-effect level of 2,4-D in the dog has been established at 8 mg/kg/day (Lehman, 1965~. Mutagenicity 2,4-D was unable to induce point mutations in four microbial systems (Andersen et al., 1971) and showed no activity in Drosophila (Vogel and Chandler, 1974~. Saccharomyces cerevisiae strain D4 (5 x 106) was treated with 2 ml of an aqueous 2,4-D suspension (trade name, U46D-Fluid) (Siebert and Lemperle, 1974~. The mitotic gene conversion frequency of the ade 2 locus was increased fivefold above control values; that of the try 5 locus was increased sixfold above control values. Carcinogenicity Studies on the in vitro and in viva eject of 2,~D on the growth of Ehrlich ascites tumor in BALB/c mice showed that the herbicide was inhibitory at 45 mg/kg or more (Walker et al., 1972~. There was no significant increase in the incidence of tumors in various mouse strains initially given 2,4-D or its esters at 46.4 mg/kg/day orally on days 7-28 followed by dietary feeding up to 323 ppm for 18 months (USEPA, 1974b). In another study, mice that received 2,4-D orally for their life

Organic Solutes 497 span showed no increased incidence of tumor formation (Vettorazzi, 1975b). A study (Arkhipor and Kozlova, 1974) reported that two rats developed fibroadenoma and one hemangioma 27-31 months after receiving one-tenth the LD50 of the amine salt of 2,4-D. Administration of 0.1 the LD50 dose of the amine salt orally or subcutaneously to mice produced no tumors after 33 months. The herbicide, however, had a cocarcinogenic erect in mice when it was applied to the skin with 3- methylcholanthrene. DNA synthesis was increased, and there was a loss of cell differentiation in cultured chicken muscle after treatment with high concentrations of 2,4-D (Haag et al., 1975~. 2~4-Dichlorophenol has not been tested for carcinogenicity alone (USEPA, 1974b), but it is an initiator for skin carcinogenesis (Boutwell and Bosch, 1959~. Reproduction In a three-generation, six-litter Osborne-Mendel rat reproduction study, no deleterious erects due to technical 2,4-D at dietary doses of 100 or 500 ppm were observed (Hansen et al., 1971~. At 1,500 ppm, however, 2,4-D, although affecting neither fertility of either sex nor litter size, sharply reduced the percentage of pups that survived to weaning and the weights of the weanlings. Teratogenicity In studies of CD-1 mice, Courtney (cited in EPA, 1974b) found that 2,4-D at 221 mg/kg per day increased fetal mortality, but produced no cleft palates. Various 2,4-D esters (isopropyl ester at 147 mg/kg/day, n-butyl ester at 155 mg/kg/day, and isooctyl ester at 186 mg/kg/day) had no erect on the incidence of cleft palate or fetal mortality, but did affect fetal weight. A significant increase in cleft palate was found, however, after administration of the propylene glycol butyl ether ester at 195 mg/kg/day. A statistically significant increase in the proportion of abnormal fetuses was reported in mice that received maximally tolerated subcutaneous doses of the isooctyl ester, and two isopropyl esters of 2,4-D (130, 100, and 94 ,ug/kg, respectively), in dimethyl sulfoxide (DMSO) solution (Mrak, 1969~. DMSO itself, however, is a teratogen (Caujolle et al., 1967~. Bage et al. (1973) observed teratogenic and embryotoxic erects in NMRI mice that received 50- or 110-mg/kg injections of 2,4-D on days ~14 of gestation. Pregnant rats were treated orally with 2,4-D at 12.5, 25, 50, 75, and 87.5 mg/kg/day (maximal tolerated dose) or equimolar doses of propylene glycol butyl ether ester of 2,4-D up to 142 mg/kg/day or isooctyl ester of 2,4-D up to 131 mg/kg/day on days ~15 of gestation (Schwetz et al.,

498 c L. _ 3 C) US ~ Ct i_ -4 LO 2 C. O ~ a.) ~ 'C: ~ ~ > cez ~ 3 V, ._ In ~ _ <( _~ 0 3= · O ma ~ Ct PA o 4 - ._ ._ o m O ~ _ 3 Ct ~q o3 `,_ ._ C) C~ ~0N V ~_ ', y^~\ _ ~ ~1 C ~- (~) ~C) x 2 x o o o _ ~ _ C C ~ ~o y E E C ~ E - o.8= ~oo ~ V~ - Ct - _ Cd 0,, - C) ~.O X ~_ ._ o - o ~ _ ~ o o C: C Ct - o ~ r~ - - u) cd - ~ . o - .o~ xct -- o~ d c) v~ - ~L CL ~ (t - ~rC . - o ^ `,, 8^ ~_ os ~ 0 0 0 ~Y ~1 ~o ~ 3 ,, 3 ;^ ~c _ r ~'d 3 Ct ~0 os as os _ _ ·C O O O Ct ~oo ~ C o o C,, 11 ._ ~ ~_ ~o Ct 3 x ._ Ye ._ ._ - - :7 E E E 4° E E ~ ~ e -~ ~6 ~ v) 00- bO-~ OD O o O O O t30 o X - o o - 6 - - Y 0c - o o 11 O . o _ _ V) r~ o 11 os o o C ~d ~o r~ o 3 0 C _ O ~ ~_ ~n O ._ ~o C. _ 4 - C ._ ~ o 11 - O~ _O C(_ ~· ·= C~ ~ .O r~ ~ eD C`' ~ ed t c (~, ~ ~ 3 C ~ (LI) ~ _ a~ ,^ 1 ~o o ~ ~ 11 ~ ~ Ool) _ t,_ ~ ~ o C 3 °c ~c C ~o ~ oo o ~ ~o _ C 3 11 ^-C ~ ~ O ~ ~ 3 ~ c~ c~ ~o 3 ~ C ~ C V) ~ _ ~ ~ ~ Ct U) ~ ~ ;> ~

Organic Solutes 499 1971~. Fetotoxic responses were seen at the high dosages, but teratogenic ejects were not seen at any dosage. The authors suggested that the no- adverse effect dosage of 2,4-D (or the molar equivalent, in the case of the esters) was 25 mg/kg/day. Prenatal studies on 2,4-D in Wistar rats showed that it induced fetotoxic ejects and an increased incidence of skeletal anomalies after single oral doses of 100 150 mg/kg/day on days 6 15 of gestation (Khera and McKinley, 1972~. At the highest dosage of 150 mg/kg/day, the isooctyl ester, and butyl ester, and butoxyethynol and dimethylamine salts of 2,4-D were all associated with significantly increased teratologic incidence. The butyl and isooctyl esters also tended to decrease fetal weight. At a lower dosage, 2,4-D and its salts and esters induced no apparent harmful effects. Pregnant hamsters received technical 2,4-D (three samples) at 20, 40, 60, and 100 mg/kg/day orally on days 6 10 of gestation (Collins and Williams, 1971~. Terata were produced occasionally with 2,4-D, and the fetal viability per litter decreased; but neither eject was clearly dose- related. The lowest dose causing fetal anomalies with the three technical 2,4-D samples was 60 mg/kg/day. Conclusions and Recommendations The acute toxicity of 2,4-D is moderate. No-adverse-effect doses for 2,4- D were up to 62.5 mg/kg/day and 10 mg/kg/day in rats and dogs, respectively. Based on these data, an ADI was calculated at 0.0125 mg/kg/day. The available data on subchronic and chronic toxicity and calculations of ADI are summarized in Table VI- 1. The acceptable daily intake of 2,4-D has been established at 0.3 mg/kg by FAD/WHO. On the basis of electron-capture gas chromatography, the detection limit for 2,4-D in water is 1 ppb. There are substantial disagreements in the results of subchronic and chronic toxicity studies with 2,4-D, perhaps reflecting the use of different formulations or preparations. In view of these deficiencies and the variability of the results, additional, properly constituted toxicity studies should be undertaken. 2,4,5-T AND TCDD Introduction 2,4,5-T, or 2,4,5-trichlorophenoxyacetic acid, was introduced in 1944 as a translocated, selective herbicide; it is applied after emergence and is

500 DRINKING WATER AND HEALTH elective on woody plants (Spencer, 1973; Thomson, 1975; Weed Society of America, 1974~. 2,4,5-T and its salts and esters are registered in the United States for noncrop areas, especially on woody plants, pastures, and rangelands (Thomson, 1975~. It is still used for weed control on rice and sugarcane. The 1971 U.S. production of2,4,5-Tanditsderivativesis estimated at 6 million pounds (NAS, 1975~. 2,4,5-T is produced by interaction of 2,4,5-trichlorophenol with the sodium salt of monochloroacetic acid (Spencer, 1973~. Esters of 2,4,5-T are synthesized by esterification of the acid with the appropriate alkyl alcohol. The solubility of 2,4,5-T in water at 25°C is 278 ppm (Spencer, 1973~; 2,4,5-T salts are water-soluble. but the esters are Generally insoluble. 2,4,5-T is more stable than 2,4-D. The 2,4,5-T esters are rapidly hydrolyzed after spraying, and the 2,4,5-T is then further decomposed by bacterial action. The major product of 2,4,5-T photodecomposition is 2,4,5-trichlorophenol (Crosby and Wong, 1971~. Other products iden- tified including 4,6-dichlororesorcinol, 4-chlororesorcinol, 2,5-dichloro- phenol, 2-hydroxy-4,5-dichlorophenoxyacetic acid, and 2,4,5-trichlo- roanisole. 2,4,5-T is rapidly adsorbed onto particulate matter or broken down in water. Nevertheless, in the period 1965-1968, 2,4,5-T was detected in surface water at concentrations of 0.01-0.07 ppb (Johnson, 1971~. Very little 2,4,5-T was found in food in analyses of raw agricultural products and in the Market Basket Survey samples (Advisory Committee on 2,4,5-T, 1971~. Of about 10,000 food and feed samples examined from 1964 to 1969, only 25 contained trace amounts of 2,4,5-T (less than 0.1 ppm), and only two contained measurable amounts (0.19 and 0.29 ppm). The Advisory Committee on 2,4,5-T (1971) concluded that 2,4,5-T did not accumulate in the biosphere and that the risk of human exposure in food, air, or water was negligible. Technical 2,4,5-T contains traces of the highly toxic compound 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) as an impurity (Advisory Commit- tee on 2,4,5-T, 1971~. In addition, about 0.0002% of 2,4,5-T is converted to TCDD when wood or brush containing 2,4,5-T is burned (Stein] and Lauparski, 1974~. 2,4,5-T preparations formerly contained TCDD at 1-80 ppm, a concentration sufficiently high to cause chloracne in industrial workers and to impart specific toxic properties that were characteristic of TCDD to the 2,4,5-T. It has not been feasible to eliminate TCDD completely from technical 2,4,5-T, but it is now reported to be present in commercial 2,4,5-T at less than 0.1 ppm (Advisory Committee on 2,4,5-T, 1971~. Water transport of TCDD is limited, because it is soluble in water at

Organic Solutes 501 only 0.2 ppb (Advisory Committee on 2,4,5-T, 1971~. TCDD is decom- posed photochemically (Crosby e! al., 1971, 1973~. It is firmly bound to soil, where it tends to persist for more than a year. The Advisory Committee on 2,4,5-T (1971) concluded that there was no indication that TCDD accumulates in air, water, or plants, although it might accumulate in soils after heavy applications of 2,4,5-T. Metabolism 2,4,5-T is readily absorbed and rapidly excreted by animals, including man. Rats and pigs given single 100-mg/kg doses of the amine salt of 2,4,5-T showed plasma half-lives of 3 and 10 h, respectively (Erne, 1966a,b). There was little buildup in tissues, and the compound was excreted mainly in the urine. During the first 24 h, 75% of the radioactivity was excreted in the urine and 8.2% in the feces of female Wistar rats that had been given 0.17, 4.3, and 41 mg/kg orally of ~4C-carbonyl labeled 2,4,5-T (Fang et al., 1973~. No i4C was found in the expired air. Radioactivity was detected in all tissues, with the highest concentration appearing in the kidneys. Radioactivity was detected in the fetuses of pregnant rats, and the average half-life of 2,4,5-T radioactivity in the organs was 3.4 h for the adult rats and 97 h for the newborns. The half-life values for the clearance of carbon-14 activity from the plasma of rats given single oral doses of i4C-carboxyl-labeled 2,4,5-T at 4, 50, 100, and 200 mg/kg were 4.7, 4.2, 19.4, and 25.2 h, respectively (Piper et al., 1973~. Half-lives for elimination from the body were 13.6, 13.1, 19.3, and 28.9 h, respectively. Cumulative excretion over a 144 h period was 82.6, 92.9, 78.3, and 68.4% of the administered dose of S. 50, 100, and 200 mg/kg, respectively. A small amount of an unidentified metabolite was detected in the urine at the two highest dosages. In dogs given ~4C-carboxyl-labeled 2,4,5-T at 5 mg/kg, half-life values for clearance and from the body were 77.0 and 86.6 h, respectively (Piper et al., 1973~. This low rate of clearance may explain why 2,4,5-T is more toxic in dogs than in rats. Some 42% of the dose was eiimated in the urine and 20tYo in the feces over a 9-day period. Three unidentified metabolites were found in the urine. Five human male volunteers ingested a single S-mg/kg dose of 2,4,5-T that contained TCDD at less than O.OS ppm (Gehring et al., 1973~. Clearance of 2,4,5-T from the plasma and its excretion from the body occurred with a half-life of 23.1 h. Essentially all the 2,4,5-T was absorbed and excreted unchanged in the urine. After oral administration of 2,4,5-T to rats and mice, the unchanged

502 DRINKING WATER AND H"LTH herbicide was the main excretion product in the urine (Grunow et al., 1971; Grunow and Bohme, 1974~. Other urinary metabolites were identified as the glycine and taurine conjugates of 2,4,5-T, as well as 2,4,5- trichlorophenol. In addition to 2,4,5-T, 2,4,5-trichlorophenol residues appeared in the tissues of sheep and cattle fed the herbicide (Clark et al., 1975~. After a single oral 1-pa/kg dose of i4C-labeled TCDD in rats, radioactivity was found only in the feces, and the half-life of radioactivity in the body was 30.4 days (Rose et al., 1976~. Liver and fat contained carbon-14 concentrations ten times greater than those in other tissues examined 22 days after ingestion. The carbon-14 activity in the liver was associated with TCDD. TCDD reaches essentially steady-state concen- trations after 90 days of daily exposure, and that period is independent of the administered dose for the range of 0.01-1.0 ,ug/kg/day. TCDD is excreted primarily via the feces; only 4.5% of the radioactivity from an oral dose of labeled TCDD was eliminated in urine during 21 days (Allen et al., 1975~. A large percentage of the radioactivity remaining in the body at the end of this period was in the liver over 90~O within the microsomal fraction. TCDD apparently undergoes little if any metabolism (Fullerton et al., 1974~. Health Aspects Observations in Man Data compiled by Dow Chemical Company showed that 126 manufacturing personnel exposed to 2,4,5-T at an estimated 1.~8.1 mg/day (0.02 0.12 mg/kg/day) for periods of up to 3 yr developed no herbicide-related illness (Advisory Committee on 2,4,5-T, 1971~. The results were entirely different in another plant, where the 2,4,5-T produced contained a high proportion of TCDD (Bleibey et al., 1964; Poland et al., 1971~; 18% of the men suffered moderate to severe chloracne, and several cases of porphyria were found. Chromosomal analysis of 52 workers exposed for various periods up to 960 days to 2,4,5- T (containing TCDD at <1 ppm) at 1.6 8.1 mg/day failed to show any abnormalities (Johnson, 1971~. Observations in Other Species Acute Effects Rowe and Hymas (1954) reviewed the early toxicologic information on 2,4,5-T and concluded that the oral LD50 for male rats, male mice, guinea pigs, and chicks were 500, 389, 381, and 310 mg/kg,

Organic Solutes 503 respectively. They also concluded that the acute toxicity of the butyl, isopropyl, and amyl esters of 2,4,5-T in the rat, guinea pig, and chicken was all greater than that listed above. Johnson (1971) has reported acute oral toxicity studies with commercial 2,4,5-T in which the LD50 were 500 mg/kg in the rat and 380 mg/kg in the guinea pig. The oral LD50 of 2,4,5- T in the dog was greater than 100 mg/kg (Drill and Hiratzka, 1953~. It is not clear, however, how much TCDD contamination was present in the 2,4,5-T used in these studies. TCDD is extremely toxic, as shown by oral LD50 values ranging between 0.6 and 115 ,ug/kg for several animal species (Schwetz, 1973~. In the rat, oral LD50s were 22 and 45 ,ug/kg for males and females, respectively, with death occurring 9-47 days after administration. The guinea pig was much more sensitive, with LD50 values of 0.6 and 2.1 ,ug/kg for males and females, respectively. Limited data showed that dogs were less sensitive to TCDD than rabbits. The LD50 for TCDD was 114 ,ug/kg in 3-month-old male C57B1/6 mice (Vos et al., 1974~. Rats that received a single 100 ,ug/kg dose of TCDD showed 43% mortality, severe liver damage, thymic atrophy, and icterus (Gupta et al., 1973~. Animals given 50 and 25 ,ug/kg showed severe and moderate thymic atrophy and liver damage. In guinea pigs given 3.0 ,ug/kg, there was a 90% mortality, the appearance of hemorrhage, atrophy of adrenal zone glomerulosa, and depletion of lymphoid organs. Female rats given a single oral dose of TCDD of up to 300 ,ug/kg showed delayed mortality over a 90-day period (Greig et al., 1973~. It was not possible to estimate an LD50 value, because of the irregular distribution of deaths in the treatment groups. The mean time to death was 40.4 days for animals that received 200 ,ug/kg. The animals lost weight, and significant changes in liver constitution appeared after 3 days. The liver showed pathologic changes in later periods, particularly the formation of multinucleate parenchymal cells. Gastric hemorrhage and jaundice also were common. Pericardial edema and death in chickens followed a single oral dose of 25-50 ~g/kg . Subchronic and Chronic E~ects In work by Dow Chemical Co. reported in 1961 (Advisory Committee on 2,4,5-T, 1971), the monopropy- lene, dipropylene, and tripropylene glycol butyl ether esters of 2,4,5-T were administered orally to rats over a 90-day period at up to 186 mg of 2,4,5-T/kg/day. At the highest dosage and at 62 mg/kg/day, toxicity was observed, but no deleterious e~ects were seen at dosages of 18.6 and 6.2 mg/kg/day. Ninety-day feeding studies with 2,4,5-T containing TCDD at 0.5 ppm were reported in 1970 by McCollister and Kociba (Advisory Committee

504 DRINKING WATER AND H"LTH on 2,4,5-T, 1971~. The herbicide was administered to rats at 3, 10, 30, and 100 mg/kg/day. No adverse ejects were observed in animals that received 30 mg/kg/day or less, but growth was decreased and changes in serum enzyme concentrations were observed at 100 mg/kg/day. Maternal mice given four to eight doses of a technical preparation containing 97.9% 2,4,5-T at 120 mg/kg/day often developed myocardial lesions, hypocellularity of the bone marrow, and depletion of lympho- cytes in the thymus, spleen, or lymph nodes (Highman and Schumacher, 1974~. To determine whether the previous effects were due to 2,4,5-T alone or to TCDD, further studies were conducted in which female mice received, on nine successive days, either technical 2,4,5-T or a purified preparation of 2,4,5-T orally at 60 and 120 mg/kg/day (Highman et al., 1975~. All mice given 60 mg/kg and some of which given 120 mg/kg appeared normal at sacrifice and showed little or no pathologic change. Mice susceptible to 120 mg/kg became ill or moribund after one to eight doses, and few survived 11 days; 34 of 66 moribund mice given the technical and 23 of 31 given the purified 2,4,5-T had myocardial lesions, and more showed lesions in other organs. These findings support the view that the lesions are due primarily to 2,4,5-T, rather than to dioxins in the technical preparation. Drill and Hiratzka (1953) found no adverse ejects in dogs that were fed 2,4,5-T five times a week for 90 days at 2.5 and 10 mg/kg. Four dogs treated at 20 mg/kg died during the experiment. A study was conducted in which rats received TCDD at 0.001, 0.01, 0.1, or 1.0 ,ug/kg 5 days a week for 13 weeks (Kociba et al., 1976~. No discernible adverse eject occurred in rats that received 0.01 or 0.001 ,ug/kg TCDD, but 0.1,ug/kg caused degenerative changes in the liver and thymus, porphyria, altered serum enzyme concentrations, and loss in body weight. Four-month-old male C57B1/6 mice received TCDD at 0.2, 1.0, 5.0, and 25 ,ug/kg orally once a week for 2 or 6 weeks (Vos et al., 1974~. Some deaths and growth retardation occurred in the 25-,ug/kg group. Sig- nificantly increased liver and decreased thymus weights were found in the 1.0, 5.0, and 25-pa/kg groups. Total neutrophils were increased sig- nificantly, whereas hemoglobin values and mean corpuscular hemoglobin concentrations were decreased significantly after six doses of 25 ,ug/kg. Total serum proteins and globulins also were decreased. TCDD was porphyrogenic, probably as a result of liver damage. At the lowest dosage, 0.2 ,ug/kg, slight but consistent centrilobular fatty changes were observed in the liver. Gross pathologic and histopathologic examinations were performed on rats, guinea pigs, and mice that received daily or weekly treatments with

Organic Solutes 505 TCDD for up to 8 weeks (Gupta et al., 1973~. In rats and guinea pigs, the dose ranged from a no-adverse-effect dose to one that produced death. Lymphoid organs, primarily the thymus, were consistently affected over a wide range of dosage in all species examined. Thymic atrophy is a very sensitive index of TCDD exposure. The severity of liver pathology was quite variable between species, the most severe effects being found in the rat and the degenerative and necrotic changes being markedly lower in the guinea pig and mouse. Surprisingly, no adequate chronic toxicity tests have been conducted with 2,4,5-T. In a long-term exposure study, mice received 21.5 mg/kg daily from the first through the fourth week and thereafter received 60 ppm (equivalent to 9 mg/kg) in the diet until 18 months had elapsed (Innes- et al., 1969~. It is presumed that all animals survived the test period, but this was not stated. Dogs and rats are said to tolerate oral intake of 2,4,5-T at 10 mg/kg/day for long periods (Advisory Committee on 2,4,5-T, 1971~. Mutagenicity 2,4,5-T was unable to induce point mutations in four different microbial systems (Anderson et al., 1972~. Buselmaier et al. (1972) conducted host-mediated assays in NMRI mice with mutants of Salmonella typhimurium and Serratia marcescens and produced no mutagenic effect with 2,4,5-T at 500 mg/kg or the n-butyl ester of 2,4,5-T at 1,000 mg/kg. These investigators also reported on dominant lethal tests in NMRI mice; no adverse eject was noted with 2,4,5-T at 1,000 mg/kg. The herbicide had no mutagenic eject in Drosophila melanogaster (Vogel and Chandler, 1974~. Inhibition of mitosis and the development of abnormalities in plants by 2,4,5-T formulations have been shown to be due to TCDD contamination (Jackson, 1972~. A great number of chromosomal abnormalities were induced in bone marrow cells of gerbils given 2,4,5-T at 150, 250, or 350 mg/kg (Majumdai and Hall, 1973~. ~ Khera and Ruddick (1973) conducted dominant lethal tests in which male Wistar rats received TCDD orally at 4 or 8 ,ug/kg/day for 7 days. Later reproduction studies failed to show any dominant lethal mutations during 35 days after treatment. TCDD is apparently negative in a mutagenicity test with Salmonella typhimurium (Fullerton et al., 1974~. It also appears to have no potential for producing chromosomal aberrations in the bone marrow of male rats (Green and Moreland, 1975~. Although many reports indicate that TCDD is not mutagenic, Hussain et al. (1972) reported that TCDD is strongly mutagenic in various bacterial systems.

506 DRINKING WATER AND H"LTH Carcinogenicity No significant increase in the incidence of tumors was seen in two strains of mice that received 2,4,5-T (containing TCDD at approximately 30 ppm) at 21.5 mg/kg/day from the end of the first week through the fourth week and at 60 ppm in the diet thereafter until the age of 18 months (Innes et al., 1969~. In one experiment, intraperitoneal injections of TCDD at 1 and 10 mg/kg induced liver lesions that "appeared to be malignant" (Buu-Hoi et al., 1972~. The significance of this report is highly questionable, because the lowest TCDD dose was almost 50 times greater than the oral LD~o for female rats (Sparschu et al., 1971~. Intraperitoneal 2,4,5-T at 50 mg/kg/day for 5 days inhibited in vivo development of Ehrlich ascites tumor in mice (Walker et al., 1972~. Teratogenicity The results of a study by Bionetics Research Laboratories released in 1969 indicated that 2,4,5-T was teratogenic in two stocks of mice 113 mg/kg/day when given during organogenesis (Courtney et al., 19701. Cleft palate, cystic kidneys, intestinal hemor- rhage, and fetal mortality occurred in higher percentages of treated than of control mice, although a clear dose-response relation was not evident at low dosages. The 2,4,5-T sample used in this study contained TCDD at 27 + 8 ppm, and TCDD itself is a teratogen. To clarify these results, additional sudies were conducted on rats, mice, hamsters, rabbits, sheep, and rhesus monkeys with samples of 2,4,5-T containing varying concentrations of TCDD. No maternal ejects, no increases in prenatal mortality, and no fetal malformations resulted when Sprague-Dawley rats were given daily oral doses of a 2,4,5-T preparation containing TCDD at 0.5 ppm on days 5-15 of gestation at up to 24 mg/kg (Emerson et al., 1971~. Slight impairment of fetal growth was observed at the highest dosage, i.e., 24 mg/kg/day. In another study by the same group (Johnson, 1971), female rats received were given a 2,4,5-T preparation containing TCDD at 0.5 ppm daily on days ~15 of gestation at 50 and 100 mg/kg or on days 6 10 at 100 mg/kg. The only effects noted at the lower dosage were one case of intestinal hemorrhage and a slight increase in the frequency of delayed ossification of skull bones. Maternal deaths and reabsorptions occurred at 100 mg/kg/day. 2,4,5-T containing TCDD at 0.5 ppm TCDD was teratogenic in Charles River rats at 80 mg/kg/day, but no fetal or maternal effects were found when the animals received 50 mg/kg/day (Courtney and Moore, 1971~. In Wistar rats, 2,4,5-T containing TCDD at less than 0.5 ppm induced fetopathy and increased incidence of skeletal anomalies after daily oral doses of 100 150 mg/kg on days 6 15 of gestation (Khera and McKinley, 19721.

Organic Solutes 507 Rats were given 50 mg/kg/day "pure" 2,4,5-T (probably containing TCDD at 0.05 ppm) to which TCDD was added at 0.01, 0.03, 0.06, 0.125, 0.5, or 1.0 ,ug/kg/day, on days 6-15 of gestation. Cleft palate occurred in some fetuses, mainly the ones that received the 2,4,5-T with TCDD added at 0.5 mg/kg/day (Advisory Committee on 2,4,5-T, 1971~. Teratogenic and embryotoxic ejects were seen when NMRI mice were given 2,4,5-T at 50 and 110 mg/kg/day subcutaneously on days 6-14 of gestation (Bage et al., 1973~. Moore (cited by the Advisory Committee on 2,4,5-T, 1971) found no appreciable difference in teratogenic and embryolethal potency between 2,4,5-T as the free acid and its butyl, isooctyl, and butyl ether esters. Konstantinova (1974) observed embryotoxic ejects and maternal toxicity including CNS and hematologic ejects after feeding 0.1, 0.42, and 4.2 mg/kg/day of 2,4,5-T butyl ester (0.082, 0.34, 3.4 mg 2,4,5-T equivalent/kg/day) to pregnant albino rats during their entire pregnancy. The no-adverse-e~ect level was reported to be 0.01 mg/kg/day (0.0082 mg 2,4,5-T equivalent/kg/day). Studies in CDT, C57B1/6J, and DBA/2J mice strains dosed with 50, 100, 113, 125, or 150 ma/ kg/day of 2,4,5-T containing <1, 0.5, or <0.05 ppm TCDD on days 6-15 of gestation showed some teratogenicity at dosages of 100 mg/kg/day in all three herbicide samples (Courtney and Moore, 1971~. Maternal weight was depressed in the C57B1 strain at 100 mg/kg and increased fetal mortality was observed only in CD1 mice at 150 mg/kg. In another study by the Bionetics Research Laboratories (Advisory Committee on 2,4,5-T, 1971), CD1 mice were given 2,4,5-T from two sources (both containing TCDD at <0.5 ppm) at 100 mg/kg/day subcutaneously on days 6-15 of gestation. Mean fetal weights were slightly reduced, and there was an increased incidence of cleft palate. . The teratogenic eject of technical 2,4,5-T was studied in large numbers of C57B1/6, C3H-He, CALB/C, and A/JAX inbred strains and CL-1 stock mice (Gaines et al., 1975~. The animals were given daily oral doses of 2,4,5-T at 15-120 mg/kg on days 6-14 of gestation. A dosage of 15 mg/kg was teratogenic in A/JAX mice, whereas the other strains and the CD-1 mice showed teratogenicity at 30 mg/kg, the lowest dos'age tested. Significant differences in types and frequencies of malformations were observed between the different mice strains. With the dose-response relationship for the production of cleft palate in mouse fetuses, the ED50 single dose of 2,4,5-T (containing TCDD at <0.02 ppm) for NMRI mice was estimated to be 2,000 mg/kg/day (Neubert et al., 1973~. Golden hamsters were treated orally on days 6-10 of gestation with

508 DRINKING WATER AND H"LTH 2,4,5-T at 20-110 mg/kg/day. The 2,4,5-T had seven sources that contained no detectable TCDD or TCDD at 34, 2.9, 0.5, and 0.1 ppm (Collins and Williams, 1971~. 2,4,5-T was feticidal and teratogenic in the hamsters, with the incidence and severity of effects increasing with TCDD content. Significantly reduced fetal viability was observed with 2,4,5-T at 20 and 40 mg/kg/day and either no detectable TCDD or 0.5 ppm, whereas significantly increased fetal abnormalities were seen with the same 2,4,5-T samples at 80 and 100 mg/kg/day. In studies with rabbits (Emerson et al., 1971), no maternal or fetal effects were seen at 2,4,5-T dosages of 40 mg/kg/day. In a study conducted in Sweden (Advisory Committee on 2,4,5-T, 1971), pregnant rhesus monkeys received 2,4,5-T (containing TCDD at 0.5 ppm) at levels of 5, 10, 20, and 40 mg/kg 3 times a week for 4 weeks between days 20 and 48 of gestation. There were no maternal effects, and all fetuses were apparently normal. Similar effects were seen in rhesus monkeys that received doses of 0.05, 1.0 and 10 mg/kg/day of 2,4,5-T (containing less than 0.05 ppm TCDD) on days 22 through 38 of gestation (Dougherty et al., 1975~. TCDD proved to be a potent fetotoxic agent in various animal species. Fetal weights were slightly decreased and there was a slight increase in intestinal hemorrhage and edema in fetuses from Sprague-Dawley rats that had received TCDD at 0.125 ,ug/kg/day (Sparschu et al., 1971~. The number of fetuses was reduced and fetal death was increased at 0.5 ,ug/kg/day. No teratogenic effects were seen at 0.03 ,ug/kg/day. Fetal kidney malformations were observed when Charles River rats received TCDD subcutaneously at 0.5 ,ug/kg/day on day 9, day 10, or days 13 and 14 of gestation (Courtney and Moore, 1971~. A low frequency of cleft palate and kidney abnormalities was observed in three mouse lines that received TCDD at 1.0 or 3.0 ,ug/kg/day (Courtney and Moore, 1971~. With a dose-response relationship, Neubert et al. 0973) estimated that the ED50 causing cleft palate in fetuses was 40 ,ug/kg/day for NMRI mice. The "just nonteratogenic dose" for days ~15 of gestation was estimated at 2 ,ug/kg/day for this mouse strain. Gastrointestinal hemorrhage was noted in hamster fetuses after administration of TCDD at 0.5 ,ug/kg/day on days ~10 of gestation (Advisory Committee on 2,4,5-T, 1971~. Conclusions and Recommendations Although pure 2,4,5-T is moderately toxic, contamination of the herbicide with TCDD, which is very toxic, greatly increases the toxicity. No-adverse-effect doses were: for 2,4,5-T, 10 mg/kg/day in dogs and

Organic Solutes 509 mice and up to 30 mg/kg/day in rats; and for TCDD, O.Ol ,ug/kg/day in rats. Based on these data ADI's were calculated at 0.1 mg/kg/day for 2,4,5-T and 1O-4 ,ug/kg/day for TCDD. The available data on chronic 2,4,5-T and TCDD toxicity and calculations of ADI's are summarized in Tables VI-2 and VI-3. There are substantial differences in the reported toxicity of 2,4,5-T, probably because of vaporing degrees of contamination with TCDD. A number of the subchronic, carcinogenicity, etc., studies should be repeated with 2,4,5-T of very high purity. Apparently, no adequate 2-yr chronic-toxicity studies have been conducted with 2,4,5-T, and 2-yr feeding studies are needed. The data available are largely from relatively short-term exposure experiments; these data, however, are fairly consis- tent. An exception is the Russian study in rats that reported toxic ejects in mothers and their pups at extremely low maternal doses of 2,4,5-T butyl ester and a no-adverse-e~ect dosage only one-thousandth as high as that found by other investigators. The 2,4,5-T butyl ester used by Konstantinova may have been heavily contaminated with TCDD, but the reason for this large discrepancy is still unexplained and should be resolved. 2,4,5-TP AND MCPA Introduction 2,4,5-TP, or 2,4,5-trichlorophenoxypropionic acid (Silvex), was intro- duced in 1952 as a selective herbicide for both before and after emergence (USEPA, 1975k; Spencer, 1973; Thomson, 1975; Weed Society of America, 1974~. It is available as the amine as well as sodium salts and various esters. The U.S. production is estimated at 3 million pounds per year in 1971 (NAS, 1975) and 3.7-4.1 million pounds per year currently (USEPA, 1975k). MCPA, or 2-methyl-4-chlorophenoxyacetic acid, was introduced in 1945 as a selective, translocated, postemergence herbicide (USEPA, 1975f; Spencer, 1973; Thomson, 1975; Weed Society of America, 1974~. It is formulated as amine salts and low-volatility esters. Estimated domestic use of MCPA in 1973 was 3.5-4.5 million pounds (USEPA, 1975f). 2,4,5-TP is produced by reaction of 2,4,5-trichlorophenol with the sodium salt of a-chloropropionic acid (USEPA, 1975k). Commercial 2,4,5-TP contains TCDD at 0.1 ppm or less. It is soluble in water at 180 ppm at 25°C tweed Science Society of America, 1974~. MCPA is manufactured by chlorination of o-cresol to form 2-methyl-4

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Organic Solutes 513 chlorophenol, and then coupling with monochloroacetic acid (USEPA, 1975f). Technical MCPA has a typical composition of: MCPA, 94-96%; 2-methyl-6-chlorophenoxyacetic acid, 1.5-3.0%; a mixture of 2-methyl- 4,6-dichlorophenoxyacetic acid, 2-methylphenoxyacetic acid, 2-chloro- phenoxyacetic acid, 4chlorophenoxyacetic acid, and 2,6-dimethyI chlorophenoxyacetic 0.5-1.5%; chloro-o-cresol, 0.5%; and water, loo. In the FDA Market Basket Survey during 1965-1968, 2,4,5-TP and MCPA were detected at maximal concentrations of less than 0.1 ppm and 0.4 ppm, respectively (Johnson, 1971~. During the same period, 2,4,5-TP residues in surface waters from 15 western states ranged between 0.01 and 0.21 ppb. 2,4,5-TP was also detected in the finished water (USEPA, 1976d). The EPA has set an interim standard for 2,4,5-TP in finished water of 0.01 mg/liter (USEPA, 1975i). Metabolism The tissue distributions of 2,4,5-TP and its metabolite, 2,4,5-trichlorophe- nol, were determined in adult sheep and cattle fed for 28 days a diet containing 2,4,5-TP at 300, 1,000, and 2,000 ppm (Clark et al., 1975~. Significant residues of both were found only in the liver and kidneys of the treated animals. The metabolism of MCPA has not been studied extensively, but a metabolite, 2-methylfchlorophenol, was detected in milk of dairy cows and in kidneys of sheep and cattle (USEPA, 1975f). Some unaltered MCPA was detected in the milk, liver, and kidneys of dairy cows. Health Aspects Observations in Man No available data. Observations in Other Species Acute Elects The oral LD50 of 2,4,5-TP is reported to be 650 mg/kg and 500 mg/kg in rats Toxic Substances List, 1974; Rowe and Hymas, 1954) and 850 mg/kg in guinea pigs. In rats and rabbits, the oral LD50 of the mixed butyl esters and propylene glycol esters ranged between 500 and 1,000 mg/kg (Rowe and Hymas, 1954~. The oral LD50 of MCPA is 700-1,410 mg/kg in rats, and 560 mg/kg in mice (Toxic Substances List, 1974; Vershunren et al., 1975), 550 mg/kg in female guinea pigs, 813 mg/kg in female rabbits, and 940 mg/kg in

514 DRINKING WATER AND HEALTH female chickens. LD50 values in the rat and mouse by intraperitoneal administration are 400 and 500 mg/kg, respectively. Subchronic and Chronic Elects The propylene glycol butyl ether ester of Silvex (Kuron) was fed to male and female rats in the diet at 10, 30, 100, 300, and 600 mg/kg/day for 90 days (Mullison, 1966; USEPA, 1975k). Mortalities were observed at 600 mg/kg/day, growth decrease at 300 and 600 mg/kg/day, and increased liver weight at 30 mg/kg/day and above. No toxic eject was found in animals receiving 10 mg/kg/day. In another 90-day study (Mullsion, 1966; USEPA, 1975k), male and female rats received the sodium salt of 2,4,5-TP in the diet at 100, 300, 1,000, 3,000, and 10,000 ppm. Growth was decreased at 300 ppm (277 ppm 2,4,5-TP equivalent) and above, and liver weight was increased at 100 ppm (2,4,5-TP equivalent, 92 ppm). Histopathologic examination showed liver and kidney damage at all dietary concentrations, except that the kidneys of females were not affected at 100 ppm. Beagles were fed Kurosol SI (a formulation containing the potassium salt of 2,4,5-TP at 60~o, or the equivalent of 2,4-TP at 53~O) of 100, 300, and 1,000 ppm for 89 days (Mullison, 1966; USEPA, 1975k). No adverse ejects were noted at 100 ppm or 300 ppm (2,4,5-TP equivalents 53 or 160 ppm), but growth decrease occurred at 1,000 ppm in females. In a 90-day feeding study of MCPA in rats, growth retardation and increased kidney: body-weight ratios were observed at 400 ppm or more (Vershuuren et al., 1975~. The 50-ppm dietary content of MCPA was considered to be the no-adverse-effect content for rats by the authors. In another 90-day feeding study in Charles River rats (USEPA, 1975i), significant growth decrease was observed with technical MCPA at 100 ppm, and histopathologic alterations of liver and kidneys were seen in both sexes at 25 ppm or higher. In a later study with the same rat strain, no abnormalities were seen after 90 days in animals fed technical MCPA at 4, 8, and 16 mg/kg/day (note that 4 mg/kg/day is approximately equivalent to a dietary content of 25 ppm). Some dogs that received daily oral doses of technical MCPA over a 13- week period died, and all showed severe weight loss at 50 mg/kg/day, whereas more moderate weight losses but no mortalities occurred at 25 mg/kg/day (USEPA, 1975f). In another 13-week study, decreased testicular weight and histopatholog~c changes of the~testes and prostate were seen in dogs fed technical MCPA at 640 ppm. Male and female rats were fed Kurosol SI at 10, 30, 100, and 300 ppm for 2 yr (Mullison, 1966; USEPA, 1975k). Increased kidney weight was seen in males that received 300 ppm, but there were no adverse ejects at 10, 30, and 100 ppm. The no-adverse-effect concentration was considered

Organic Solutes 515 to be 100 ppm (2,4,5-TP equivalent, 53 ppm) (Mullison, 1966~. The same formulation was fed to beagles 56, 190, and 560 ppm for 2 yr (Mullison, 1966; USEPA, 1975k). Dogs fed 560 ppm showed severe liver pathology after 1 yr. At 190 ppm, liver pathology was seen in females sacrificed after 1 yr, but not in animals sacrificed at 2 yr; in males, no liver pathology was seen at 1 yr, but it was present at 2 yr. The no-adverse-e~ect content thus was 56 ppm (2,4,5-TP equivalent, 30 ppm) for males and 190 ppm (2,4,5- TP equivalent, 101 ppm) for females (Mullison, 1966~. Another report cited 5 mg/kg/day as the no-adverse-effect dosage for 2,4,5-TP in rats and dogs in 2-yr feeding studies (Johnson, 1971~. When technical MCPA was fed to rats for 7 months, some deaths occurred at 2,500 ppm, and a significant reduction in weight occurred at 1,000 and 2,500 ppm (USEPA, 1975f). No apparent toxic effects were noted in animals that received 100 and 400 ppm (66.8 mg/kg/day). Mutagenicity 2,4,5-TP did not cause point mutations in histidine- requiring mutants of Salmonella typhimurium or bacteriophage T (Ander- sonetal., 1972~. MCPA has been found to be a weak mutagen in Drosophila melanogas- ter (Vogel and Chandler, 1974~. Carcinogenicity Young male and female mice of the (C57BL/6xC3H/Anf)F and the (C57BL/6xAKR)F strains received 2,4,5-TP orally at 46.4 mg/kg/day on days 7-28 and thereafter were placed on a diet containing 2,4,5-TP at 121 ppm for approximately 18 months (Innes et al., 1969~. There was no increase in the incidence of tumors above control values for either strain. Teratogenicity Courtney (1975) examined the effect of 2,4,5-TP containing TCDD at less than 0.1 ppm on pregnant CD-1 strain mice and their o~spring. Animals received daily 2,4,5-TP at 398 mg/kg/day orally or subcutaneously on days 12-15 of gestation. Controls had no cleft palates, whereas the herbicide produced 3% (oral) or 7% (subcutaneous) cleft palates in the fetuses. There was also a significant increase in maternal river: body-weight ratios in the treated mice. In a study conducted by Dow (USEPA, 1975k), Sprague-Dawley rats were given 2,4,5-TP at 25, 50, 75, 100, or 175 mg/kg/day on days 6-15 of gestation or 50, 75, or 100 mg/kg/day from day 6 of gestation through lactation. A few maternal deaths occurred at 100 mg/kg/day; the dosage of 75 mg/kg/day produced alopecia and vaginal bleeding. Minor alopecia was seen at 50 mg/kg/day. Terata were seen at 50 mg/kg/day, but were m~nor and related to incomplete ossification of the skull. Mean

516 DRINKING WATER AND HEALTH pup weights were significantly decreased at 50 mg/kg/day and above. The dosage with no-adverse-fetotoxic effects was considered to be 25 mg/kg/day. The teratogenic potential of the propylene glycol butyl ether ester of 2,4,5-TP (containing TCDD at less than 0.05 ppm) was tested in rats (USEPA, 1975k). Significant increases in minor skeletal abnormalities were observed at 50 mg/kg/day; at 35 mg/kg/day of 2,4,5-TP. No overt teratogenicity was seen. Female Wistar rats were fed MCPA (ethyl ester) at 1, 40, 500, 1,000, and 2,000 ppm in the diet on days 8-15 of gestation (USEPA, 1975f). Fetal mortalities occurred at 2,000 ppm, and a dose-dependent decrease in fetal weight and an increase in fetal abnormalities occurred at 1,000 ppm. Female mice were fed technical MCPA at 5, 25, and 100 mg/kg/day on days 6-15 of gestation (USEPA, 1975f). Litter and mean pup weights were reduced at 100 mg/kg/day, but no major malformations were observed. Pregnant Wistar rats were fed with MCPEE (the ethyl ester of MCPA) at 30, 500, 1,000, and 2,000 ppm (about 2.7, 30, 60, and 100 mg/kg/day) on days 8-15 of gestation (Yasuda and Maeda, 1972~. No adverse effects were noted at 30 and 500 ppm, but 1,000 and 2,000 ppm caused a decrease in fetal weight and increased teratogenesis. The highest dosage also caused a reduction in maternal weight. Conclusions and Recommendations In 2-yr feeding studies the no-adverse-effect doses for 2,4,5-TP are at up to 5 mg/kg/day and 6.8 mg/kg/day in dogs and rats, respectively. In 9~ day feeding studies no-adverse-effect doses were reported at up to 10 mg/kg/day for MCPA in rats, but histopathologic changes in livers and kidneys were reported once at 1.25 mg/kg/day. Based on these data ADI's were calculated at 0.00075 mg/kg/day for 2,4,5-TP and 0.00125 mg/kg/day for MCPA. The available chronic toxicity data and calculations of ADI's on 2,4,5- TP and MCPA are summarized in Tables VI-4 and VI-5. There is considerable variation in the no-adverse-e~ect and minimal- toxic-effect dosages found in the various subchronic-toxicity experiments with MCPA. The reasons for these differences are not apparent, and further work is needed to resolve them. There have been no 2-yr chronic- toxicity tests with MCPA, and such studies should be undertaken. Moreover, very little is known about the reproductive, mutagenic, and

517 C) c _ 3 Cd Cd O ~ ~ ~ a ~ at, ~ _ ~ it, - oo O ~ 3 a: Z X V' _' o ;^ ._ ._ x o Em - m U. ~ 2 ' ho lo, o o Cd o _ ~ ho ._ Q Cat ~r ~ ~P4 ~ ~cnAIn~ ~_ _ ~ _ _ UP ~ Cat _ {~\ ~ (~ _ C7s ~ ~ ~ <5~ _ ~ _ _t ~ ~ ~ .~ tS -t ~ ~ ~O 0~ Cd U' _ - ~ - - ~ .~ ~ x ~ x x o ~ o o o o o o ~os y ~ y v) o ~ ~ · o - ~ - ~ ~ - ~ ~ ~ ~ ~ O~ r~ ~- oN . - o v) - ~- au ~ . -. - . - c ~ p4.~: E 8 S~= - 1 1 1 o o o - ._ 3 ~ _ _ _ · ~ ~ C} .> ,~ ~ ~ ~ ~ o ~ ~ ~ ~ ~ o .o .O .Q Cd ~ ~ X X X ~o o o . ~ `: ~ - ._ ._ Ck ~L g r~ C~ i o cn ~ Ct Ct -8 o~ o X Ct Ct ~ s oa oo Y ~X ~ U~ ~ U' ._ 3 c ._ . - .= - ;> - a~ a~ os cd y o os o ~ u, 1 OD o oo u, au ~c o - o o - ~ :^ ~ . c 3 C: e~ e3D r. ._ oa _ ~o _ _ 04 _ o Ct o Ct Cd o Cd ~a ~:~ . . o - o ~O - Cd V) 8. o 11 - o x c o r~ x V~ o - Ct 00 y o 11 08 O _ 11 00 o o c 00 o o 11 U, au _ c: ~ - ~ t4 _ ~ O 00 C ~ C. 4, 3 ° Ck.- ~ t-, ' C. cd 00 U, ·= ~ - ~ ~ ~ _ t4 ~ 11 ~ o ° E 42 ~l o a: O o ~ ~ ~o ~ ~o -.C :3 11 _ ._ - ,= a' "C o 3 .§ ' tt, Fo 3 8 8 ~ 8 ~ ~ I, 6 <: ~ ~

518 o ._ ._ o EM _. m EM - - I: C) Cal Ct Cd O ~ ~ _ · ~ _ U' ~ ' 0,, 4 - °~ o ~ 3 X Z - . _ 00 CL o o o o _ ~ U. ho ._ U. Vi _ ;~ 04 o ~ o .Q ~ O os Yos 04C r~u~ .. _~ __ ~ - ~ ~ Ct cL ~o C~ ~ V~ ax _ _ 6 os _ Ct .. O I_ Cd _ ._ ._ ~O O ._ _ ~ ~g CO - y 04 - - - O4 C. o ._._ ~C: . -. - CLCL ~c ~E 8 8 _r ~0 11 oo Ct~ oo - Ct C~ au 3 - - . _ cn ~C U, ~ ~ o o t4_ o~ Ct ~oCt Cd o ~ ~ ~ ~= ~ ~, - P. 04 os Ct, o Ce sa ~ ~, _ Q ~o o _ . . ~n 3 - o en c ° ,~ _ _ os ~ ._ ~ C) ._ - Ct 3 os ._ c ._ c - - ,. ~L, C~ o ~ ~ 3 , Y ~ Y ~ g _ ~ ~ 1 1 1 °6 o o o ~ C~ _ - o o C) 3 ~ r ~ _ ._ Cd Ct oo .~ 3 - ._ o o o 11 ' - o x - x ~, - 8. o r - ;^ Ct 04 Yoo U~ - o o 11 _ ~ 3 o tn v) o 11 o o c C~ o ~li ~_ C . ~ · - ,~ t_ ~a ~ 0 _ ~ ._ ~o C ~ ~ <,., 3 ° O' ~L, o ;> o 3 ~ . C C C~ 9 ~ ~4 ~ oo · 11 ~ ~ ° E 8 11 11 o ~ ° - ,, ~ o 5), C .= ,# _ .C ~ 11 ·" ^.,c Cn 3 ~ ~ ~ b° "-C 3§ o 3 C y ~ C ~ =, ~ C~

Organic Solutes 519 carcinogenic properties of MCPA. Additional research is needed, particularly in view of the reported weak mutagenic activity of MCPA. Further studies on 2,4,5-TP are also needed to determine whether the observed toxicity and teratogenicity are intrinsic in the herbicide or are due to contamination with TCDD. There appears to be a complete lack of data on human toxicity related to either herbicide. Benzoics AMIBEN Introduction Amiben, or 3-amino-2,5-dichlorobenzoic acid (Chloramben) is used as a selective preemergence herbicide (Spencer, 1973; Thomson, 1975~. It was introduced in 1958. Annual production of amiben in the United States is estimated at 20 million pounds (NAS, 1975~. The herbicide is formulated as the ammonium salt and the methyl ester. Amiben is synthesized by chlorination of benzoic acid, followed by interaction and reduction (Spencer, 1973~. Water solubilityofAmibenis 700 ppm at 25°C (Weed Science Society of America, 1974~. Metabolism No available data. Health Aspects Observations in Man No available data. Observations in Other Species Acute Effects The oral LD50 of Amiben in rats is 3,500-5,620 mg/kg, and the dermal LD50 in rabbits is 3,136 mg/kg (Ben-Dyke et al., 1970~. Chronic Elects Amiben was fed to Charles River rats over a period of 2 years at dietary concentrations of 100, 1,000, and 10,000 ppm (Hazelton et al., 19641. No adverse ejects were found on growth, food consumption, mortality, tumor incidence, hematologic characteristics, or tissue mor- phology.

520 _ _ 3 Ct LL1 ~ Cd O C _ ~ ~ 4- , .°0 o ~ 30 ~ % ED ·e o ;^ ·O ._ X o EM m - in .2 a., ~-O a. . ~ au 0 ° FEZ ~ C ~ C ;~ o ~ ·_ :' {t Vat ~o U) ._ U' .. __ <5~ CC oo 4_~ a' h~ Cd __4 ~, ~C) ._._ XX 4_4_ oo CC . . UO - C. ~o ~.5" U. ._ 3 os C . ~ c - C C. oo oloo~ I I ~ C~ ~ ° o g - o . - os - 11 - o x o x os os ~o y I-ca g ~ c., o ~ oo ~ o o - - r~ eD lc- ~ t Lc o c ·c. c. os t4 , ~. c o ct v) o a - Cd V~ o 11 o c Ct r~ o o 11 3~ 6 U) ._ t ~Ct C . ~ ~o ° Ct C C ~ 3 ° Ck - o, ~ au ,,O, - e5 OD ~ , ;~ C ~ C . ~ ~ o. ~ C ~ ° ,_ ~ ~ 11 _ ° ~ ° o cd ce O 3 c o ~c ,y ~ ~r ~o ~ ~o _ C 5 11 . ~ - .C ,_ 3 ~ ~ ~o o. ~ ~ - 3.§ ce ct o 3 C C ~ C ~ ~ ,8 U,

Organic Solutes 521 Male and female beagles were fed Amiben at concentrations of 100, 1,000, and 10,000 ppm for an unspecified period; there were no dose- related ejects on mortality, growth, hematologic values, biochemical characteristics, or tissue histopathology (Hazelton et al., 1964~. Mutagenicity No mutagenic activity for Amiben was noted in bacteria (Anderson et al., 1972~. Carcinogenicity No available data other than the Hazelton study (Hazelton et al., 1964~. Teratogenicity No available data. Conclusions and Recommendations The available data on Amiben are very sparse. Much additional information is needed regarding its chronic toxicity, teratogenicity, and carcinogenicity before limits can be confidently set. It is possible that many pertinent studies have been conducted by the manufacturer and could be made available for evaluation. No-observed-adverse-e~ect doses for Amiben were at 250 mg/kg/day and 500 mg/kg/day in dogs and rats, respectively, in feeding studies. Based on these data an ADI was calculated at 0.25 mg/kg/day. The limited data available and calculations of the ADI are summarized in Table VI-6. DICAMBA Introduction Dicamba, or 2-methoxy-3,6-dichlorobenzoic acid, is used as a preemer- gence herbicide for control of annual broadleaf and grassy weeds (USEPA, 1975c). Annual production of Dicamba in the United States has been estimated at 6 million pounds (NAS, 1975), but total domestic use was believed to be 1.2 million pounds in 1974 (USEPA, 1975c). Dicamba is synthesized from hexachlorobenzene via 1,2,4-trichloro- benzene to 2,5-dichlorophenol to 2-hydroxy-3,6-dichlorobenzoic acid (USEPA, 1975c). The composition of technical-grade Dicamba is 2- methoxy-3,6-dichlorobenzoic acid, 8~93%; 2-methoxy-3,5-dichloroben- zoic acid, 7-20~o; and 3,6-dichlorosalicylic acid, 0.5-5%. Dicamba formulations usually involve the alkali metal or aLkylamine salts, and it is

522 DRINKING WATER AND H"LTH often formulated in combination with other herbicides (MCPA, 2,4-1?, etc.~. Dicamba is soluble at 4,500 ppm in water. It is chemically resistant to breakdown, and it persists in soils for 7-10 months. It is not strongly adsorbed onto soils, and it is readily leached by runoff waters. Volatilization of Dicamba is low. It is resistant to oxidation and reasonably resistant to hydrolysis, but is degraded by ultraviolet light to 3,6-dichlorosalicylic acid and unidentified compounds. In field tests, runo~-water residues of Dicamba from field plots were found to be 1.6 4.8 ppm after 24 h (Trichell et al., 1968~. Rapid loss occurs, however, in water. No residues of Dicamba have been found in foods in the FDA "total diet" samples (Manske and Johnson, 1975~. Golavan (1970) reported that the smell and taste threshold for Dicamba in water was about 200 ppm. On the basis of various toxicity tests, the USSR recommended maximal permissible concentration of Dicamba in water is 15 ppm. Metabolism When i4Carboxyl-labeled Dicamba was administered orally to male and female Charles River CD rats, 0.8-1.1% of the radioactive dose was recovered in the feces, 92.88-99.1% in the urine, 0.0-0.3% in the gastrointestinal tract, and 0.5-2.1% in the tissues after 72 h (Tye and Engel, 1967~. In a second experiment, groups of Charles River CD rats were fed ~4C-labeled Dicamba in the diet at 10, 100, 1,000, 10,000, or 20,000 ppm over a 24-day period. Fecal excretion averaged 3.8~.4Yo, whereas excretion in the urine was 97.4% of the administered radioactive dose. Approximately two-thirds of the urinary radioactivity was in unchanged Dicamba, and 12-20% was in the glucuronide conjugate of Dicamba. No evidence of the sulfate conjugate or of 3,6-dichlorosalicylic acid was found. Urine contained 73% of the Dicamba fed to a Holstein cow after 7 days (St. John and Lisk, 1969~. Unchanged Dicamba and 2,6-dichlorosalicylic acid have been identified in the urine of a heifer fed Dicamba (USEPA, 1975c). In studies conducted in a model ecosystem (Yu et al., 1975), Dicamba was shown to persist in water in conjugated and in anionic forms. It was slowly transformed to 5-hydroxydicamba in water (about 10% after 32 days) and was slowly decarboxylated. No evidence of food-chain magnification of Dicamba was obtained.

Organic Solutes 523 Health Aspects Observations in Man No available data. Observations in Other Species Acute Effects Reported acute oral LD50 values for technical Dicamba in rats range between 757 and 2,900 mg/kg (Edson and Sanderson, 1965; USEPA, 1975c; Golavan, 1970~. Salts of Dicamba showed similar acute toxicities to rats (oral LD50, 1,000 2,000 mg/kg). The acute LD50 of technical Dicamba in male rats on intraperitoneal injection, however, was only 80 mg/kg. Male rats were more susceptible to orally admin- istered technical dicamba (LD50, 757 mg/kg) than were females (LDso, 1,414 mg/kg). Inasmuch as pure Dicamba had an oral LD50 in female rats of more than 2,560 mg/kg, contaminants of the technical herbicide may be more toxic than the herbicide. The oral LD50 in rats of 3,6- dichlorosalicylic acid, the major Dicamba decomposition product, was 1,440 mg/kg. The oral LD50 of technical Dicamba in mice was 1,189 mg/kg whereas oral LD50's for various Dicamba salts in mice, rabbits, guinea pigs, and chickens were over 4,640, 566, 566, and 673 mg/kg, respectively (Edson and Sanderson, 1965; USEPA, 1975c). Signs of acute Dicamba poisoning in animals include muscle spasms, bradycardia, and inhibited voluntary and involuntary reflexes. Death occurs within 3 days. Subchronic and Chronic Elects Concentrations of Banvel D (Dicam- ba, 41.3%; dimethylamine, 14.6%; and water, 44.1~o) ranging from 658 to 23,500 ppm were fed to weanling Charles River CD strain rats for 3 weeks, with no significant erect (USEPA, 1975c). In another study, male and female Sprague-Dawley rats were fed diets Banvel D at 100, 500, 800, and 1,000 ppm for 13 weeks. Hypersensitivity was noted in the rats fed 1,000 ppm (equivalent to Dicamba at 413 ppm). Moderate necrosis and vacuolization of the liver were seen in rats fed 1,000 ppm (equivalent to Dicamba at 413 ppm), slight liver pathology in rats fed 800 ppm (330 ppm Dicamba), and no adverse erect in rats fed 500 ppm (206 ppm Dicamba) (USEPA, 1975c). In a third study, Wistar rats were fed diets containing Dicamba at 31.6, 100, 316, 1,000, or 3,162ppmfora 15-week period (Edson and Sanderson, 1965~. Liver: body-weight ratios were increased in animals receiving Dicamba at 1,000 and 3,162 ppm, and the no-adverse-e~ect dosage was estimated to be 316 ppm (19.3 mg/kg/day). Purebred beagles of both sexes were fed diets containing Dicamba at

524 DRINKING WATER AND H"LTH 100 or 250 ppm for 90 days (USEPA, 1975c). The only adverse finding was a slight yellowish cast to the liver in two of the four dogs on the 100 ppm diet and one of the four dogs on the 250-ppm diet. Dicamba was administered orally to an unspecified strain of rat for 6 months at 0.075, 0.75, or 7.5 mg/kg/day (Kudzina and Golovan, 1972~. Unspecified toxicity was seen at 7.5 mg/kg/day. In another study, Sprague-Dawley rats of both sexes were fed diets containing technical Dicamba (90% Dicamba) at 5, 50, 100, 250, or 500 ppm for 2 yr (USEPA, 1975c; Velsicol Chemical Corp., 1967~. These diets did not produce differences in survival, body weight, food consumption, organ weights, hematologic values, or histopathologic findings. Purebred beagles of both sexes were fed diets containing technical Dicamba (moo Dicamba) at 5, 25, or 50 ppm for 2 yr (USEPA, 1975c; Velsicol Chemical Corp., 1967~. No major differences were seen between control and treated groups in mortality, growth, feed consumption. organ weights, hematologic values, or histopathology. r ~ Mutagenicity No mutations were noted in the Salmonella/microsome test with Dicamba (USEPA, 1975c), and no mutagenic effects were noted in other systems (Anderson et al., 1972~. Carcinogenicity No evidence of tumor induction by Dicamba has been reported. Reproduction In a three-generation Charles River CD rat reproduc- tion study, no significant effects were observed in animals receiving diets containing Banvel D at up to 500 ppm (206 ppm Dicamba) (USEPA, 1975c; Velsicol Chemical Corp., 1967~. A similar study in Sprague- Dawley rats showed no effect at a dietary Dicamba concentration of 500 ppm. Teratogenicity A 20~o reduction in hatchability was noted in chicken eggs into which Dicamba was injected at 200 ppm (USEPA, 1975c). Conclusions and Recommendations The acute toxicity of Dicamba is relatively low. Dicamba produced no adverse effect when fed to rats at up to 19.3 mg/kg/day and 25 mg/kg/day in subchronic and chronic studies. The no-adverse-effect dose in dogs was 1.25 mg/kg/day in a 2-yr feeding study. Based on these data an ADI was calculated at 0.00125 mg/kg/day. The available data on

Organic Solutes 525 subchronic and chronic toxicity and calculations of ADI are summarized in Table VI-7. A detection limit of 1 ppb for Dicamba by electron-capture gas chromatography has been reported (Norris and Montgomely, 1975~. Additional studies are needed to clarify the finding of toxicity in subchronic experiments on various strains of rats in the absence of adverse effects in rats fed higher Dicamba concentrations over a 2-yr period. Because toxicity was not observed in chronic toxicity studies in dogs, additional chronic studies should be conducted at higher dosages to establish a m~nimal-toxic-effect dosage. Amides ALACHLOR, BUTACHLOR, AND PROPACHLOR Introduction Among the several herbicidal compounds based on N-substituted acetanilide are the compounds Alachlor, or 2-chloro-2',6'-diethyl-N- (methoxymethyl)-acetanilide; Butachlor, or 2-chloro-2',6'-diethyl-N-(bu- toxymethyl)-acetanilide; and Propachlor, or 2-chloro-N-isopropyI-N-ac- etanilide. These are used as preemergence herbicides and, under the trade names of Lasso (Alachlor), Machete (ButachIor), and Ramrod (Propach- lor), are achieving a strong position in that market. Alachlor and Propachlor have major use in corn and soybean producton, and Butachlor is used primarily in rice production. In the United States in 1971, farmers used 14.8 million pounds of Alachlor and 23.7 million pounds of Propachlor (NAS, 1975~. It was estimated that 20 million pounds of AlachIor and 23 million pounds of Propachlor were produced in the United States in 1961 (NAS, 1975~. These compounds are slightly soluble in water: Alachlor at 242 ppm at 25°C, Butachlor at 23 ppm at 24°C, and Propachlor at 580 ppm at 20°C (Weed Science of America, 1974~. They are rated as having good resistance to photodecomposition with no ultraviolet absorption above 280 nm, which lies below the minimal wavelength of solar radiation received at the earth's surface. It has been reported that Alachlor and Propapachlor are labile in an aquatic environment, and there was no evidence to indicate that the metabolites or degradation products were accumulated in the biota (Yu, et al., 1975~. Alachlor and Butachlor have been found in the finished water of New

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Organic Solutes 527 Orleans area at 2.9 ,ug/l for Alachlor and 1.21 ,ug/1 for Butachlor (USEPA, 1975n). Metabolism Rapid excretion of i4C(carbonyl)-Propachlor administered to rats was observed, with 54~4% of the carbon-14 appearing in the urine within 24 h (Lamboureux et al., 1975~. Three major urinary products were found, one of which was identified as the mercapturic acid resulting from glutathione conjugation with Propachlor. The mercapturic acid excreted within 24 h accounted for 20~o of the dose. The other major metabolites were not identified, but were not related to glutathione conjugation. Health Aspects Observations in Man No available data. Observations in Other Species Acute Elects These products are generally well tolerated. Alachlor, as the emulsifiable concentrate, ~ has a rat oral LD50 of 1,800 mg/kg; Butachlor, 3,300 mg/kg; and Propachlor, 710 mg/kg (Weed Science Society ofAmerica, 1974~. Subchronic and Chronic Effects Subchronic toxicities in rats are reported to be over 2,000 ppm in the diet, at least over 2,000 ppm, and over 133.3 mg/kg/day for Alachlor, Butachlor, and Propachlor, respec- tively. With Alachlor, the growth patterns of rats and dogs were normal at 20, 200, and 2,000 ppm for a 90-day period; some growth decrease was observed at a higher rate of feeding. Butachlor administration at those concentrations produced similar results, except for slight growth decrease at 2,000 ppm in rats. Increased liver weight was observed in female rats fed Butachlor at 200 and 2,000 ppm. Propachlor was tolerated, without adverse clinical erects or gross or microscopic pathology, by rats and dogs fed at 1.3-133.3 mg/kg/day for 90 days (Herbicide Handbook, 1974~. However, Propachlor has been reported to cause dystrophic changes in the liver and kidneys of rats, mice, and rabbits when administered at 100 1,800 mg/kg. The erects depended on dosage and were accompanied by decreased activities of various enzyme markers of cellular organelles (Strateva et al., 1974~. No data on long-term toxicity are available.

528 DRINKING WATER AND H"LTH Mutagenicity No available data. Carcinogenicity Teratogenicity No available data. No available data. Conclusions and Recommendations Although the toxicity data on this group of compounds are meager, they appear to be fairly well tolerated by mammals. Propachlor, the most toxic of the group, has received somewhat more attention. Tolerances of 0.2~.75 ppm for peanut, soybean, and other legume forages has been established for Alachlor; it is also tolerated at 0.05 ppm in fresh corn (kernels) and peanuts. A 0.02-ppm (negligible residue) tolerance for Alachlor applies to meat, eggs, and milk. The maximal tolerated dosage of Propachlor without adverse eject is reported as 133.3 mg/kg/day in both rats and dogs. Other workers reported slight organ pathology in rats, mice, and rabbits at 100 mg/kg/day or higher; this agrees approximately with the former data. Both Alachlor and Butachlor are apparently tolerated by rats at up to 100 mg/kg/day in the diet, except for increased liver weight in female rats fed Butachlor. The existing toxicity data for these compounds are largely those produced by the manufacturer for registration purposes. Based on the above available data, ADI's were calculated at 0.1, 0.1, and 0.01 mg/kg/day for Alachlor, Popachlor, and Butachlor, respectively. The available data on subchronic toxicity and calculation of ADI's are summarized in Table VI-8. Apparently, no long-term toxicity studies have been completed that would contribute information on reproductive effects or carcinogenic potential of these acetanilides or their degradation products, which include aniline derivatives. These studies are needed. PROPANIL Introduction Propanil, or 3',4'-dichloropropionanilide, is a preemergence herbicide registered for use in rice to control grasses, sedges, and some broadleaf weeds. Use in the United States has been primarily in the rice-growing regions of Texas, Arkansas, Louisiana, and Mississippi; little has been used in California. Domestic consumption was around 8-9 million

Organic Solutes 529 pounds in 1973 (USEPA, 1975O). Propanil is produced by reaction of 3,4- dichloroaniline with propionic acid at high temperature (Melnikov, 1971~. It is soluble in water at 500 ppm (Weed Science Society of America, 1974~. Metabolism Propanil is hydrolyzed by the action of hepatic acylamidase, forming 3,4- dichloroaniline and propionic acid (Williams et al., 1966~. The enzyme has been shown to be present in the liver of rats, mice, rabbits, and dogs. Other conversions are brought about either on propanil itself or on dichloroaniline, giving rise to at least six metabolites in urine; these metabolites constitute about 95% of the urinary products (Yih et al., 1970~. Little radioactivity from labeled propanil appeared in tissues in short-duration experiments with rats, mice, and dogs; this indicates that the propensity for accumulation of propanil or its metabolites in tissues is slight (USEPA, 1975O). Methemoglobin formation occurs in mice treated with propanil. After a large dose (400 mg/kg), cyanosis becomes apparent, although no other symptoms of toxicity occur (Chow et al., 1975~. The methemoglobin formation is due to the dichloroaniline liberated by acylamidase. Health Aspects Observations in Man No available data. Observations in Other Species Acute Elects Ambrose et al. found oral LD50 values of 1,384 mg/kg for rats and 1,217 mg/kg for dogs (Ambrose, 1972~; these values were observed with technical propanil. Proprietary data summarized by Midwest Research Institute indicated that rats of both sexes tolerated repeated doses of up to 60 mg/kg for 30 days and dietary administration at up to 200 ppm for 90 days without any ejects (USEPA, 1975O). Ambrose et al. (1972) fed technical propanil to Wistar rats for 90 days at 100, 333, 1,000, 3,300, 10,000, and 50,000 ppm in the diet. Mortality was 100% at 50,000 ppm; body weight was depressed at 3,300 and 10,000 ppm, and there was a significant increase in polychromatophilia and other evidence of hemolytic anemia. Dogs were unaffected by propanil fed at 2,000 ppm for 4 weeks, but 10,000 and 50,000 ppm caused decreased food consumption and weight loss (Ambrose et al., 1972~.

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532 DRINKING WATER AND H"LTH Chronic Effects Two-year feeding trials with rats were conducted by Ambrose et al. (1972) with dietary concentrations of 100, 400, and 1,600 ppm. No ejects were observed, except 1,600 ppm (of both sexes). Males experienced increased mortality at 20 months, females had significantly reduced hemoglobin concentrations, and both sexes experienced body- weight decrease and increased spleen: body-weight ratios. No histopatho- logic alternations were found. Dog feeding studies with propanil at 100, 600, and 3,000 ppm (4,000 ppm after week 5) were carried out for 2 yr (Ambrose et al., 1972~. No mortalities occurred, nor were any clinical, gross pathologic or histo- pathologic changes found; the only effect observed was decreased feed efficiency at 4,000 ppm. Mutagenicity Propanil and its degradation products, dichIoroaniline and 3,3',4,4'-tetrachloroazobenzene (TCAB), were tested for back muta- tions of Aspergillus nidular~s (Prasad 1970~. Propanil did not increase the frequency of reversion when added to fungal conidia in concentrations of 5-200 ,ug/ml of medium. However, 3,4-dichloroaniline and TCAB both caused severalfold increases in reversion rates. Propanil has also been found negative in tests of induction of point mutations in three microbial systems (Anderson et al., 1972~. Carcinogenicity No available data. Reproduction A three-generation reproduction study in Wistar rats was reported by Ambrose et al. (1972~. Dietary concentrations of 100, 300, and 1,000 ppm were fed to groups of females for 11 weeks before they mated with males receiving similar diets. No changes in reproductive performance were found in any generation (to the F3) at any dosage, nor were fetal abnormalities observed in fetuses born dead or alive or in rats necropsied with fetuses in utero. Teratogenicity No available data. Conclusions and Recommendations Propanil is well tolerated by experimental animals on a chronic basis, and there is little or no indication of mutagenic or oncogenic properties of the compound. The highest no-adverse-e~ect concentration of propane based on reproduction in the rat and acute, subchronic, and chronic

Organic Solutes 533 studies in rats and dogs is 400 ppm in the diet. Based on these data an ADI was calculated at 0.02 mg/kg/day. The available data on chronic toxicity and calculations of ADI are summarized in Table VI-9. Triazines ATRAZI~, SWINE, PROPOSE, CAY Introduction These four herbicides are all derivatives of cyanuric chlorides and are closely related in environmental properties. Atrazine is 2-chloro-4- ethylamino-6-isopropylamino-S-triazine, Simazine is 2-chloro-4,6-dieth- ylamino-S-triazine, Propazine is 2-chloro-4,6-diisopropylamino-S-tria- zine, and Cyanazine is 2-chloro-441-cyano-1-methylethylamino)-6-ethyl- amino-S-triazine. These herbicides are used largely in preemergence applications for corn, sorghum, and sugarcane, with minor use on pineapple, macadamia orchards, and turf grasses, especially Atrazine. Simazine is also used in citrus, deciduous fruits, pineapple, turf grasses, ornamentals, and nursery plantings (WSSA, 1974~. U.S. production is estimated as: Atrazine, 90 million pounds; Simazine, 5 million pounds; Propazine, 4 million pounds; and Cyanazine, 1 million pounds (NAS, 1975~. Atrazine is the pesticide most heavily used in the United States. The solubilities of the triazine herbicides in water at 25°C are: Atrazine, 70 ppm; Simazine, 5 ppm, Propazine, 8.6 ppm; and Cyanazine, 171 ppm (WSSA, 1974~. Atrazine was found in the New Orleans water supply at 4.7-5.} ppb, and diethylatrazine at 0.27~.51 ppb (USEPA, 1974a). Atrazine was monitored in down surface and ground water in Iowa by Richard et al. (1975~. In the Skunk River residues declined from 12.0 ppb on June 9,1974 to 0.250 ppb on September 12, and in Indian Creek from 42 ppb in June 9 to 0.300 ppb on August 25. The finished water supply of Cedar Rapids contained 0.483 ppb; Davenport, 0.405; Iowa City, 0.20; and Des Moines, 0.03 ppm. These seasonal changes in Atrazine content in water reflect agricultural runoff following spring preemergence application. All the water examined in Iowa contained atrazine. Propazine, Simazine, and Cyanazine were also detected in finished water in the United States (USEPA, 1976d).

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Organic Solutes 535 Metabolism In animals, the dominant metabolic reaction is N-dealkylation, and rats have produced 20 metabolites from Atrazine, including amino-N-ethyl-,4-amino-N-isopropyl-, 4,6-diamino-, 4-amino-N-acetyl-, and 4-amino-N-isopropionyl-2-chloro-S-triazines. Rabbits also excreted N-(chloro-4-amino-S-triazinyl-6~-glucoside (Menzie 1969~. No firtn evi- dence of ring cleavage has been found in degradation studies with bacteria, plants, or animals. Cyanazine degradation proceeds initially by hydrolysis of the nitrite group and slower hydrolysis of the 2-chloro group. 2-Hydroxycyanazine is the major metabolite found in rat feces. The rat also produces the 4-amino derivative and the N-acetylcysteinyl derivative and hydrolyzes; the cyano group to the corresponding amide and carboxv derivatives (Menzies, 1974~. In a laboratory model ecosystem study, with carbon-14 ring-labeled Atrazine, the environmental degradation products were 2-amino4chloro- 6-isopropylamino-S-triazine and 2-amino-4-chloro-6-ethylamino-S-tria- zine. There was only a slight degree of food-chain transfer of Atrazine (ecologic magnification 11 times in fish) or any of its degradation products (Metcalf and Sanborn,1975~. Simazine residues from water treated at 2.5 ppm rose to a maximum of 2.2 ppm in bluegill after 28 days and declined to 0.76 ppm after 60 days; in bass, they rose to 1.50 ppm after 28 days and declined to 0.88 ppm after 60 days (USEPA, 1976c). Health Aspects Observations in Man No case of poisoning in man from Simazine, Atrazine, Propazine, or Cyanazine has been reported, although exposure to Simazine has caused acute and subacute dermatitis in the USSR, characterized by erythema, slight edema, moderate pruritus, and burning lasting (5 days (Elizarov, 1972~. Observations in Other Species Acute Toxicity The acute oral toxicity of Simazine in rats, mice, rabbits, chickens, and pigeons was 5,000 >5,000 mg/kg. The acute dermal toxicity in rabbits was over 8.16 g/kg. For Atrazine, the oral LD50 is 3,080 mg/kg in rats and 1,750 mg/kg in mice. For Propazine, the oral LD50 is over 5,000 mg/kg in rats and mice. For Cyanazine the oral LD50

536 DRINKING WATER AND H"LTH is 334 mg/kg in rats, and the dermal LD50 is over 2,000 mg/kg in rabbits (WSSA, 1974~. Chronic Toxicity Simazine fed to rats for 2 yr at 1.0, 10, and lOO ppm produced no difference between treated and control animals in gross appearance or behavior. The rats fed lOO ppm had approximately twice as many thyroid and mammary tumors as the control animals, but it was stated that these were not attributable to Simazine (USEPA, 1976c). Propazine at 250 mg/kg for 130 days produced no gross signs of toxicity or pathologic changes (WSSA, 1974~. Atrazine, in 2-yr chronic-feeding studies at 100 ppm in the diet of rats, produced no gross or microscopic signs of toxicity (WSSA, 1974~. Cyanazine in 2-yr feeding studies in rats and dogs showed no signs of toxic effects at levels up to 25 ppm (WSSA, 1974~. A 2-yr chronic-feeding study of Simazine in dogs with Simazine 80W fed at 15, 150, and 1,500 ppm showed only a slight thyroid hyperplasia at 1,500 ppm and slight increases in serum alkaline phosphatase and serum glutamic oxalacetic transaminase in several of the dogs fed 1,500 ppm (USEPA, 1976c). Mutagenicity Simazine and Atrazine were inactive in a standard mutagenicity screen with microorganisms, e.g., Simazine was negative with four strains of Salmonella typhimurium (USEPA, 1976c). Plewa and Gentile (1975) demonstrated that extracts of maize seedlings grown on soil treated with Atrazine at recommended rates contain an agent that is highly mutagenic in Saccharomyces cerevisiae (D4~. Further study (Gentile and Plewa, 1976) has shown that the kernels of maize grown on Atrazine-treated plots contain this mutagenic agent, which produces mutation rates up to 30 times that of untreated maize. These data strongly suggest that maize plants can metabolize Atrazine into a mutagenic agent and generate considerable concern about ubiquitous triazine residues in water supplies. Carcinogenicity Atrazine, Propazine, and Simazine were fed to 2 strains of mice at 21.5, 46.4, and 215 mg/kg/day respectively for 80 weeks (Innes et al., 1969~. The incidences of hepatomas were: 4.24% in controls, 5.6% in Atrazine treated, 5.7% in Propazine treated, and 5.6% in Simazine treated. Reproduction Simazine at 50 and 100 ppm in the diet had no adverse effects on reproduction of rats or offspring over three generations (USEPA, 1976c). Similar experiments with chickens and quail showed

Organic Solutes 537 anomalies in the urogenital tracts of male chickens when eggs were sprayed with 0.5, 0.7, 1.0, and 1.5% aqueous solutions of Simazine (Dicier and Lutz-Ostertag,1972~. Teratogenicity No available data. Conclusions and Recommendations Atrazine, Propazine, and Simazine all appear to have low chronic toxicity. The only good carcinogenicity feeding study done on these compounds did not reveal a significant increase in cancer incidence over controls. On the basis of these chronic studies, an ADI was calculated for each of these compounds. The ADI for Atrazine is 0.0215 mg/kg/day, for Propazine 0.0464 mg/kg/day, and for Simazine 0.215 mg/kg/day. The available chronic toxicity data for Atrazine, Simazine, and Propazine are summarized in Table VI- 10. Uracil BROMACIL Introduction Bromacil, or 5-bromo-3-sec-butyl-6-methluracil, is one of several substi- tuted uracils that were introduced as broad-spectrum herbicides in 1972. Trade names include Hyvar, Krovar (Bromacil plus Diuron), and Isocil (Spencer, 1973~. It is estimated that 3 million pounds of this agent was used in the United States in 1972 (von Rumker et al., 1975) and 8 million pounds was produced in 1971 (NAS, 1975~. Bromacil is used primarily for the control of annual and perennial grasses and broadleaf weeds, both nonselectively on noncrop lands and selectively for weed control in a few crops (citrus and pineapple). It appears to act in plants by inhibiting photosynthesis and to be primarily abosrbed through the roots. Bromacil is manufactured by the reaction of phosgene and ammonia with sec-butylamine to produce sec-butylurea, which reacts with ethyl- acetoacetate to produce 3-sec-butyl-6-methyluracil, which is then bromi- nated to produce Bromacil (USEPA, 1975a). Bromacil is soluble in water at 815 ppm at 25°C, and it is stable in water, aqueous bases, and common organic solvents. It decomposes slowly in strong acids (USEPA, 1975a). Bromacil undergoes photochemical decomposition and is degraded in

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540 DRINKING WATER AND H"LTH soil. The degradation in soil appears to follow first-order kinetics and to be nonenzymatic. However, Bromacil is subject to microbial decomposi- tion under moist soil conditions (USEPA, 1975a). Metabolism Bromacil is absorbed from the gastrointestinal tract and appears to be excreted primarily in the urine. The major metabolite in rodents and man is 5-bromo-3-sec-butyl-6-hydroxymethyluracil, which can be detected as a glucuronide conjugate. Other minor metabolites include 5-bromo-3-~2- hydroxy-1-methylpropyl)-6-methyluracil, 3-sec-butyl-6-hydroxymethyl- uracil, 5-bromo-3-~3-hydroxy-1-methylpropyl)-6-methyluracil, and an unidentified bromine-containing compound (Gardiner et al., 1969~. 5- Bromouracil was not found in hydrolyzed or nonhydrolyzed urine samples from humans exposed to Bromacil (USEPA, 1975a). Health Aspects Observations in Man No available data. Observations in Other Species Acute Effects The acute oral LD50 of Bromacil in rats is 5,200 mg/kg, and the acute inhalation toxicity is greater than 4.8 mg/liter per 4 h. The acute dermal toxicity of Bromacil was estimated to be at 5,000 mg/kg in rabbits. Application of Bromacil (80% wettable powder) to abraded guinea pig skin produced only mild irritation, without evidence of induced skin sensitization. Because Bromacil causes emesis in dogs, its acute oral toxicity has not been determined in this species, but oral doses of 250 mg/kg produce toxicity (weight loss or abnormal gait) in sheep, chickens, and cattle. Toxic symptoms in poisoned animals also include anorexia, depression, tympanites (in cattle and sheep), and increased respiratory rate (in dogs) (USEPA, 1975a). Subchronic and Chronic Elects Male rats were given Bromacil (as a 15% aqueous solution of the 80% AI wettable powder) for 2 weeks (5 days/week) at 650, 1,035, and 1,500 mg/kg. There were six animals in each dose group; five rats died after 5 doses at the highest dosage level, and one died after 10 doses at the intermediate dosage. There were no deaths in the low-dosage group, but these animals exhibited focal cell hypertrophy and hyperplasia of the liver, which were also seen in the

Organic Solutes 541 higher-dosage groups. In another subchronic study in which 10 male and 10 female rats were fed Bromacil at 50, 500, 2,500, 5,000, 6,000, and 7,500 ppm for 90 days, there were no signs of mortality or toxicity; but microscopic examination of the tissues from these animals revealed increased thyroid activity in rats fed 5,000 ppm higher (Zapp, 1965~. Bromacil (83% AI wettable powder) was also fed to rats for 2 yr at 50, 250, and 1,250 ppm. Additional controls in this study were corn-oil- vehicle groups, and there were initially 36 male and 36 female rats per diet group. Rats from each diet group were sacrificed at the end of 3, 6, and 12 months of feeding; weight loss in the female rats fed 1,250 ppm was the only toxic eject observed. Histopathologic examination of the tissues from these rats revealed hyperplasia in the light and follicular cells of the thyroid, and there was a follicular cell adenoma in one of the females fed 1,250 ppm (Sherman et al., 1963~. A 2-yr feeding study in dogs has also been carried out with Bromacil in which three male and three female dogs were fed 0.005, 0.025, and 0.925% Bromacil. No toxic ejects were observed, although one dog (0.005% diet) died from non- Bromacil effects (Hazelton Labs, 1966~. Mutagenicity The mutagenic potential of Bromacil has been investi- gated in several studies, because 5-bromouracil is mutagenic. However, 5- bromouracil is not a metabolite of Bromacil, and Bromacil was not found to be mutagenic in any of these tests (USEPA, 1975a). Carcirlogenicity No available data. Reproduction No significant reproductive ejects were observed in a two-generation rat study in which indexes of fertility, gestation, viability, and lactation were observed. The dosages for these studies were 50, 250, 1,250 ppm, and there were 12 male and 12 female rats in each group (USEPA, 1975a). No gross manifestations of teratogenic ejects were observed in the fetuses of rabbits fed Bromacil in the diet at 50, 250, 1,250 ppm (USEPA, 1975a). Conclusions and Recommendations Bromacil is low in both acute and chronic toxicity. It appears that 1,250 ppm is a no-adverse-e~ect dietary concentration of Bromacil in dogs. However, rats fed this concentration of Bromacil in the diet exhibited abnormal thyroid pathology. In a 2-yr feeding study the no-adverse-effect dose for rats was 12.5 mg/kg/day. Based on these data an ADI was

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Organic Solutes 543 calculated at 0.0125 mg/kg/day. The available data on chronic oral toxicity and calculations of ADI are summarized in Table VI- 1 1. Bipyridl PARAQUAT Introduction Paraquat, or 1,1'-dimethyl-4,4'-dipyridylium, is a general weed-killer of the bipyridyl family of herbicides. It is available either as a dichloride or as a dimethysulfate salt. Both compounds are water-soluble. It is registered as a contact herbicide for noncrop use. During recent years paraquat has been used extensively in California 374,009 lb in 1973, and 272,361 lb in 1974. In 1975, 248,070 lb were used during the first three quarters of the year (University of California Pesticide Data Bank, 1975~. It is used primarily for general weed control and as a desiccant. Paraquat kills plants by acting on the green parts, not on woody stems, and is rapidly inactivated by contact with clay in the soil. Apparently, the molecule itself can penetrate into the crystal lattice of clay minerals, where it is firmly bound by physical bonding (Hayes et al., 1975~. Under these circumstances, paraquat cannot be attacked by soil microorgan- isms, because they cannot penetrate the lattice. In the bound form, paraquat is biologically inert, and it has been demonstrated that it does not cause any harm to either plant or animal life. When paraquat is in an environment that does not have clay particles, it is readily degraded by microorganisms. Under these circumstances, it is generally accepted that paraquat is environmentally safe, because its associated toxicologic hazard presents no major problems. Apparently, paraquat is not extensively metabolized in plants; it has been demonstrated that there is no metabolic breakdown of paraquat in tomato, broad bean, and maize tweeds Science Society of America, 1974~. The herbicidal activity and organic chemical reactions of paraquat formulations depend solely on the paraquat cation and are not influenced by the nature of the associated anion, because the salts are largely dissociated in aqueous solution. Paraquat is readily decomposed by ultraviolet light. Two major decomposition products are 1-methyl-4-carboxypyridinium ion (Funder- burk et al., 1966) and methylamine hydrochloride. Experiments have

544 DRINKING WATER AND HEALTH demonstrated that paraquat solutions degrade rapidly in ultraviolet light, with very little remaining after 48 h of exposure. Health Aspects Observations in Man Paraquat is acutely toxic to man. As a result, many accidental and suicidal deaths have been reported (Kimbrough, 1974; Copland et al., 1974; van Dijk et al., 1975; Carson, 1972; Beebeejaum et al., 1971~. It has been estimated that a lethal dose in man is about 14 ml of a 40% solution of paraquat (Kimbrough, 1974~. The symptoms of poisoning include burning of the mouth and throat, nausea and vomiting, respiratory distress, and transient erects on the kidneys, heart, and nervous system. Death is usually due to progressive fibrosis and epithelial proliferation in the lungs. Dermal exposure to paraquat concentrates may result in severe skin irritation, while nosebleeds may result from exposure of the nasal mucosa, and several severe eye injuries have resulted from eye exposure. Absorption studies have shown that paraquat is readily absorbed through the skin of both humans and animals. There is no elective antidote for paraquat poisoning in man, although a few patients have recovered after ingesting doses thought to be fatal (Jones and Owen-Lloyd, 1973; Galloway and Petrie, 1972~. Observations in Other Species Acute Effects Paraquat is acutely toxic to both man and animals. The oral LD50 reported in rats is 11~173 mg/kg (Mehani, 1972; Murry and Gibson, 1972~. In the mouse, the LD50 is 9~120 mg/kg. The LD50 in monkeys is 50 mg/kg, and in guinea pigs it is 22 mg/kg (Murry and Gibson, 1972~. Animals poisoned by inhalation do not show major damage to the lungs, as is usually found when paraquat is administered orally. Apparently, after ingestion it acts similarly to a powerful irritant, such as phosgene, and the changes in the lung are typical of such erects. Death at sufficiently high doses occurs within a short period, and animals that do not die within this period recover completely; delayed fibrosis does not occur (Conning, 1969~. Chronic Effects Two-year feeding studies with rats have shown that paraquat at up to 170 ppm in the diet does not produce significant abnormalities in any of the several characteristics investigated (Chevron

Organic Solutes 545 Chemical Co., 1975~. Dogs fed paraquat at 7.2 and 34 ppm in the diet over a period of 27 months have not developed significant abnormalities. However, some changes were observed at 85 and 170 ppm. Kimbrough and Gaines (1970) have conducted 90-day feeding studies in rats with dietary paraquat concentrations of 300, 400, 500, 600, and 700 ppm. Clinical signs of acute and chronic poisoning included diarrhea, wheezing, irregular and rapid breathing, and red stains around the snout. All animals that died showed morphologic changes in their lungs. Mutagenicity No available data. Carcinogenicity No available data. Reproduction arid Teratognicity Administration of paraquat to mice, at 1.67 and 3.35 mg/kg intraperitoneally or 20 mg/kg orally, daily on days 8-16 of gestation induced no significant teratogenic effects, although a slight increase in nonossification of sternebrae was observed (Bus et al., 1975~. The same investigators reported that, when paraquat was adminis- tered to rats on single days of gestation, an average of 7.6% of the fetuses were found dead or being resorbed. Radioactivity reaching the mouse embryo after intraperitoneal or oral administration of [~4C]Paraquat on the eleventh day of gestation was low. Conclusions and Recommendations Paraquat is a highly elective, general herbicide that is acutely toxic to man and animals in its concentrated form (20% liquid concentrate). Oral exposure to high doses of paraquat frequently results in death, which is usually due to progressive fibrosis and epithelial proliferation in the lungs. However, in 2-yr feeding studies in rats, paraquat did not produce any significant abnormalities. Paraquat is rapidly inactivated by contact with clay particles in soil and is firmly bound physically. In this form, it is biologically inactive and apparently does not have any immediate or prolonged harmful ejects. Thus, it is unlikely that paraquat would be found in large amounts in drinking water. Based on a 2-yr feeding study in rats, an ADI was calculated at 0.0085 mg/kg/day. The available toxicity data and calculations of ADI are summarized in Table VI-12.

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Organic Solutes 547 Dinitroanile TRIFL~IN, NIT~IN, AND BENEFIN Introduction The dinitroaniline herbicides are an important group of compounds whose use is expanding. The most prominent member of the group is trifluralin, or a,a,~-trifluoro-2,6-dinitro-N-dipropyl-p-toluidine (Treflan), which was first marketed in 1963 for use on cotton. It is now registered on more than 50 crops. Other members of the group that have been used include nitralin, or 4-(methylsulfonyl)-2,6-dinitro-N,N-dipropylaniline (Planavin), and benefin, or N-butyl-N-ethyl-a,a,~x-trifluoro-2,6-dinitro-p- toluidine (Balan). A summary of dinitroaniline compounds used or under development as herbicides is given by Helling (1976~. These compounds are particularly elective against annual grasses and some broadleaf weeds. It is estimated (N AS, 1975) that 11.4 million pounds oftrifluralin and 2.7 million pounds of nitralin were used in the United States in 1971. Virtually all of this material was used in agriculture. Another estimate (Helling, 1976) indicates the consumption of about 17 million pounds of trifluralin in the United States in 1972. About 60~o of the material is used on soybeans, 30% on cotton, and logo on other crops. Most of the use is in the north-central and south-central states, especially Illinois, Iowa, and Mississippi, which consume about three-fourths of the total production. The dinitroaniline herbicides probably account for 8-lO~o by volume of domestic herbicide use. Because trifluralin is by far the most important member of this group, with respect to total volume of use, this report will concentrate on it, with some supporting information on several others. Trifluralin is synthesized by the reaction of p-chlorobenzotnfluoride with fuming nitric acid to produce 3,5-dinitro-4-chiorobenzotrifluoride, which then reacts with di-n-propylamine to produce trifluralin. The technical material contains the desired product at more than 95%. It is soluble in water at 0.2~.4 ppm at 25°C. The dinitroanilines are strongly adsorbed by soil and moderately persistent in soil. In the annual Market Basket Surveys conducted by the Food and Drug Administration, tr~fluralin residues have never been detected (Cornelius- sen, 1970, 1972; Manske and Corneliussen, 1974~. Triflurain is tolerated at 0.05 ppm by most crops; exceptions are alfalfa hay (0.2 ppm), carrots (! ppm), and mung beans (2 ppm). The FAD/WHO has not established an acceptable daily intake of trifluralin or any other dinitroaniline herbicide.

548 DRINKING WATER AND H"LTH Trifluralin was detected in finished water in the United States (USEPA, 1976d). Metabolism Studies on the metabolism of trifluralin have been rather limited. Emmerson and Anderson (1966) studied the metabolism of trifluralin in rats and dogs. Approximately 80% of the ingested compound was excreted in the feces, the remainder in the urine. Analysis of the feces revealed the parent compound and one metabolite, the amino derivative resulting from reduction of one nitro group. Ten different materials in the urine were separated by thin-layer chromatography. Only three were identified; they were the products of nitro reduction or removal of one or both propyl groups. Several investigators have reported on the behavior of trifluralin in dairy animals (Fisher et al., 1965; Golab et al., 1969; Williams and Fell, 1971~. Trifluralin is deaLkylated in the rumen, losing one or both propyl groups; the nitro groups are reduced to one or two amino groups. The two types of reactions occur simultaneously, leading to a trifluoromethyltriaminobenzene. Unidentified polar products were also produced in rumen fluid. The acute toxicity of some of these metabolites has been determined. Metabolites with free amino groups tend to be somewhat more acutely toxic in test species, although the maximal toxicity is still quite low, at 1,800 mg/kg for the diamino compound in the mouse. Nelson et al. (1976) studied three structurally related dinitroaniline herbicides trifluralin, profluralin, and fluchioralin-in rat hepatic microsomal systems. All three were extensively metabolized by both normal and phenobarbital-induced microsomal systems. Identification of the metabolites extractable with ethylacetate from the aqueous incuba- tion mixtures indicated that aliphatic hydroxylation of the N-aLkyl substituents, N-deaLkylation, reduction of a nitro group, and cyclization to form benzimidazoles (and, in the case of fluchloralin, a quinoxaline) were the predominant metabolic routes for these herbicides in vitro. Of particular interest was the formation of the benzimidazole metabolites. Health Aspects Observations in Man No controlled studies have been conducted with dinitroaniline compounds in humans. Since 1969, 16 episodes of trifluralin poisoning have been reported. There have been no fatalities,

Organic Solutes 549 and only one case required hospitalization. Ten of the 16 cases involved symptoms that appeared to be related to the solvent, rather than trifluralin itself. In general, adverse ejects of dinitroaniline herbicides in humans have been few and minor (Verhulst, 1974~. Observations in Other Species Acute Effects The dinitroaniline herbicides are very low in acute toxicity. The following oral LD50 values have been reported for various dinitroaniline compounds in rats: technical trifluralin, greater than 10,000 mg/kg; benefin, greater than 10,000 mg/kg; nitralin, greater than 6,000 mg/kg (Berg, 1976~. The acute oral LD50 of the trifluralin emulsifiable concentrate formulation in rats is 3,700 mg/kg. The acute oral toxicity of dinitroanilines in other animals is similarly low. The oral LD50 of trifluralin in mice is 5,000 mg/kg; of nitralin, greater than 2,000 mg/kg (Berg, 1976~. The acute oral LDso of trifluralin in dogs, chickens, and rabbits is greater than 2,000 mg/kg. The dermal LD50's of trifluralin and nitralin in rabbits were greater than 2,000 mg/kg after 25 h of exposure (Worth, 1970~. Rabbits exposed to 500 mg of technical trifluralin in a standard Draize skin irritation study had a score of zero, indicating no dermal irritation (Worth, 1970~. Technical trifluralin also caused no damage when tested in rabbit eyes. Subchronic and Chronic Effects Chickens, which are sensitive to the cataractogenic properties of compounds, were exposed to trifluralin. There was no effect in the trifluralin-treated chickens, whereas 14 of the 16 chickens in the positive control had obvious lens opacities by the third day of the study conducted by Worth (1970~. In a 10-day study of cattle, sheep, and chickens orally treated with trifluralin, benefin, and nitralin, the no-adverse-effect dosage was 100 mg/kg/day for trifluralin in cattle, sheep, and chickens. For benefin, poisoning and changes were observed at 25 mg/kg/day in cattle and 50 mg/kg/day in sheep and chickens. For nitralin, poisoning and death were observed at 250 mg/kg/day in cattle and 375 mg/kg/day in sheep; the no-adverse-e~ect dosage was 500 mg/kg/day in chickens (Palmer, 1972~. Harlan rats (six males and six females in each group) were fed technical trifluralin at 20, 200, 2,000, and 20,000 ppm in the diet for 2 yr. At the highest dosage level, rats showed significant growth retardation and bile duct proliferation and survived a maximum of 460 days. In all other groups, there were no significant differences between treated animals and controls in growth, mortality, food intake, efficiency of food utilization, gross pathologic ejects, and microscopic examination of major organs

550 DRINKING WATER AND H"LTH and tissues. The no-adverse-e~ect dosage, therefore, was established as 2,000 ppm, which is equivalent to approximately 100 mg/kg/day, according to Elanco (1967~. However, with the assumptions on food consumption and animal weight of this report, 2,000 ppm is equivalent to 333 mg/kg/day. Another 2-yr study was conducted with 25 male and 25 female Cox rats fed trifluralin at 200, 1,000, and 2,000 ppm trifluralin. Several male rats at the two higher dosages exhibited enlargement of the thyroid. Two male rats at 1,000 ppm and one male at 2,000 ppm had pheochromocytomas. Neither of these responses was dosage-related. Hence, the no-adverse- effect dosage was reported to be 2,000 ppm (Elanco 1967~. Three studies on the chronic toxicity of trifluralin in dogs have been conducted. In one, eight mongrel dogs were given daily oral doses in capsules over a 2-yr period. One male and one female in each group were given 2.5 mg/kg, 5 mg/kg, and 25 mg/kg. Two females were given 10 mg/kg. There were no adverse ejects at any dosage. In another study, beagles were treated at 1, 2.5, 5, and 10 mg/kg. With two animals per group (except for the lowest, which included four animals), no adverse effects were found at any dosage. In a 3-yr study, purebred beagles were given trifluralin orally at 10 and 25 mg/kg. Each treatment group included two animals of each sex, and a control group was established with three animals of each sex. At 25 mg/kg, an increased liver:body- weight ratio was observed. Therefore, the no-adverse-effect dosage was considered to be 10 mg/kg (Worth, 1970~. Two-year feeding studies of nitralin in rats and dogs have been conducted by the Stanford Research Institute (Burdett, 1968a,b). At dietary concentrations of 2.5, 10, 40, 160, and 2,000 ppm in both male and female rats, no adverse ejects were found. Therefore, the no-adverse- e~ect dosage of nitralin is at least 2,000 ppm (333 mg/kg/day). Nitralin was also fed to 30 male and 30 female beagles in the diet at 2.5, 10, 40, 160, and 2,000 ppm for 2 yr. No adverse e~ects were seen at any dosage. Measured were weight gain, hematologic values, serum alkaline phospha- tase levels, blood urea nitrogen, organ weight ratios between experimen- tal animals and controls, and histopathology. Again, the no-adverse- e~ect dosage is at least as high as 2,000 ppm (40 mg/kg/day). Mutagenicity In a large screening study of many herbicides, Ander- son et al. (1972) noted that trifluralin did not induce point mutations in any of three microbial systems. Carcinogenicity There are no reports of carcinogenic or tumorigenic effects of trifluralin or other dinitroaniline herbicides.

Organic Solutes 551 Reproduction Groups of 6 male and 12 female rats were fed trifluralin in the diet at 200 and 2,000 ppm in a four-generation reproducti