C. TlMCHALK,* D. R. FlNCO,t AND J. F. QUAST*

FUNDAMENTAL AND APPLIED TOXICOLOGY 36, 47-53 (997) ARTICLE NO FA962285 Evalation of Renal Fnction in Rhess Monkeys and Comparison to Beagle Dogs Following Oral Administration of the Organic Acid Triclopyr (3,5,6-Trichloro-2-pyridinyloxyacetic Acid) C. TlMCHALK,* D. R. FlNCO,t AND J. F. QUAST* *Health and Environmental Sciences, Dow Chemical Company, 803 Bilding, Midland Michigan 48674; and f Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, Georgia 30602 Received Agst, 996; accepted December 27, 996 Evalation of Renal Fnction In Rhess Monkeys and Comparison to Beagle Dogs Following Oral Administration of the Organic Acid Triclopyr (3,5,6-Trichloro-2-pyridinyloxyacetic Acid). TIM- CHALK, C, FINCO, D. R., AND QUAST, J. F. (997). Fndam. AppL ToxicoL 36, 47-53. The crrent stdy evalated the effects of triclopyr (3,5,6-trichloro-2-pyridinyloxyacetic acid) on renal fnction following oral administration in the beagle dog and rhess monkey. Male rhess monkeys were orally administered triclopyr by gavage at a dose of /day, 7 days/week for 28 days, after which the dosage was increased to /day for 02 consective days. Grops of male dogs were administered either a single oral dose of 5 mg/ kg triclopyr or were fed a diet spiked with triclopyr at a dose of /day for 47 consective days. The following fnctional and clinical chemistry parameters were evalated: exogenos phenolslfonphthalein (PSP) excretion, inlin and para-aminohipprate (PAH) clearance (monkeys only), endogenos serm creatinine, and blood rea nitrogen (BUN) at mltiple time points dring the stdy. Creatinine, BUN, and inlin clearance were within the normal range from both species following triclopyr administration which indicates that repeated administration of triclopyr in the dog and monkey had no effect on glomerlar filtration rate (GFR). In monkeys, the percentage excretion of PSP and PAH appeared to increase following triclopyr administration (/day), sggesting that these weak organic acids may be competing for the same plasma protein-binding site enhancing their clearance. More importantly, these data strongly sggest that triclopyr is not competing with PSP or PAH for the active secretory site within the monkey kidney proximal tbles. In contrast, PSP clearance stdies in dogs clearly demonstrated that triclopyr administration (5 mg/kg) can significantly decrease the percentage PSP excretion even following a single dose administration. The decrease in percentage PSP was reversible and inversely related to the plasma triclopyr concentration. Overall, these data clearly indicate that triclopyr effectively competes with PSP for the active secretory site within the dog kidney proximal tbles. In contrast, the monkey was insensitive to the effects of triclopyr on the active secretory process even at doses forfold higher (/day) than the effective dose in the dog (/day). These findings sggest that the effect observed on PSP and PAH excretion in the dog represent a physiological competition for excretion and not toxicity. C 997 Society of Toxicology. Triclopyr (3,5,6-trichloro-2-pyridinyloxyacetic acid) is the active ingredient in Garlon herbicides and is sed in the control of a wide variety of broad leaf and woody plants. Triclopyr is an organic acid which has a moderate acte toxicity; oral LD50 in rats is 73 mg/kg (Worthing, 987). Sbchronic (3 week) dietary administration of 5-250 mg/ kg/day of triclopyr reslted in slight degeneration of the descending proximal tbles (S3 segment) of the kidneys in rats given /day or more (Landry et al., 985). Chronic dietary administration to rats reslted in no tmorigenic response and the no-observed-effect-level (NOEL) was 3 mg triclopyr/kg/day (Eisenbrandt et al, 988). A - year chronic dietary stdy was condcted in the dog at doses of 0, 0.5, 2.5, and /day; the kidney was identified as a target organ (988, npblished report of the Dow Chemical Co., Midland, MI). The NOEL for the chronic dog stdy was 0./day. The kidney effects observed at 2.5 and /day were characterized by a slight redction in phenolslfonphthalein (PSP) excretion, slight increases in BUN and creatinine, and an increase in normally occrring pigment in the proximal tbles of the kidneys. These minor changes were interpreted to be a reversible physiological adaptation associated with excretion of the test material. Therefore, the no-observed-adverse-effect level (NOAEL) was considered to be /day, which was 0 fold greater than the observed NOEL in this same stdy. In comparison, female rhess monkeys demonstrated no treatment-related effects when administered triclopyr acid by gavage at doses of 0, 0, 20, and 30 mg/kg/day for 28 days (976, npblished report of the Dow Chemical Co.). The pharmacokinetics of triclopyr in the dog were markedly different from those in monkey, rat, or hmans (Timchalk etai, 990, 996; Carmichael etal, 989). In hmans, Trademark of DowElanco. 47 0272-0590/97 $25.00 Copyright 997 by the Society of Toxicology. AUrightsof reprodction in any form reserved.

48 TIMCHALK, FINCO, AND QUAST an orally administered dose of 0. or 0. provided no indication of nonlinear pharmacokinetics and was rapidly eliminated with a terminal phase half-life in blood of 5-hr (Carmichael et al., 989). An intravenosly administered dose of 30 mg triclopyr/kg of body weight in a monkey was rapidly eliminated from the plasma (t\ = 6.3 hr), with >95% of the rinary I4 C radioactivity excreted within 24 hr. In contrast, the kinetics of triclopyr excretion in the dog were nonlinear with virtally all the dose excreted in the rine by 72 hr postdosing; however, the fraction excreted in the rine decreased with increasing dose (Timchalk et al., 996). Overall, the slower renal excretion in the dog was a fnction of extensive nonlinear plasma protein binding and tblar reabsorption of triclopyr. These findings were consistent with previos dog stdies with organic acids which sggested that they have a lower capacity than other species for the renal clearance of organic acids (Gehring and Betso, 978; Piper et al., 973; Hook et al, 974, 975; Cherkofsky, 995). The objective of the crrent stdy was to evalate the effects of repeated triclopyr administration on kidney fnction in the monkey, and to compare this response to that observed in the dog following single or repeated exposre. These data provide additional perspective on the relevance of the renal effects observed in the dog chronic toxicity data for hman risk extrapolation. Test Material and Dosing MATERIALS AND METHODS Technical-grade triclopyr (chemicaj prity >99.4%) was obtained from DowElanco (Indianapolis, IN). Dogs were administered the single oral 5 mg triclopyr/kg body wt dose by gavage at a volme of 2 ml/kg as an aqeos soltion. Rhess monkeys were administered triclopyr dissolved in a 0.05 M phosphate bffer (ph 7.0) which was orally administered by gavage at a volme of ml/kg body wt, at a dose of /day, 7 days/ week for 28 days, after which the dosage was increased to /day for an additional 02 days (30 daily doses). Repeated dietary administration in dogs was accomplished by placing a weighted amont of triclopyr into a gelatin capsle which was then mixed with a small amont of grond beef which the dogs were allowed to immediately eat. Dogs received a nominal dose of /day for 47 consective days. No attempt was made to determine the stability of triclopyr within the gelatin capsle/grond beef matrix. However, nmeros stdies within the laboratory have demonstrated that triclopyr is extremely stable in a variety of matrixes, sch as in the diet and as an aqeos soltion (personal commnication). Animals For male Rhess monkeys (Macaco mlatto') were selected from the colony at the International Center of Environmental Safety (Holloman Air Force Base, NM). The monkeys were hosed individally in air-conditioned qarters with feed and tap water available ad libitm throghot the stdy. Eight male beagle dogs were prchased from HRP, Inc. (Cmberland, VA) for se in the single-dose experiment and were acclimated to the laboratory environment. These dogs were hosed in otside rns except dring experimentation and had feed and water available ad libitm. However, dogs were fasted overnight preceding each day that PSP and creatinine clearance were measred. Two male beagle dogs for the repeated dietary administration were prchased from Marshall Research Animals (North Rose, NY), and were likewise acclimated to the laboratory environment. The dogs were hosed in appropriate air-conditioned qarters with feed and tap water available ad libitm throghot the stdy. All for monkeys and all dogs were administered triclopyr with an appropriate preadministration period serving as the control period. Therefore, each animal served as its own control. Single-Dose Administration (Dogs Only) Experimental design. Body weight determinations and baseline vales for PSP excretion and endogenos creatinine clearance were obtained on all dogs 23 hr prior to triclopyr administration. Triclopyr () was administered by gavage to six dogs with two dogs serving as ntreated time controls. Untreated controls did not vary from baseline for any of the parameters evalated (data not shown). PSP excretion was determined as described by Osborne et al. (972). All dogs had PSP and endogenos creatinine clearance measred repeatedly at predose and, 23, and 73 hr postdosing and all procedres were performed in an identical manner dring the for test times. Dogs were placed in Pavlov slings and were given 200 ml of water by gavage to increase rine flow rates. A venos catheter was placed in the saphenos or cephalic vein for se in blood specimen collection and a rethral cadieter was pt in place for collection of rine. Immediately after rinsing the bladder widi sterile water, a clinical test dose of PSP (6 mg/animal) was given intravenosly. Urine was then collected sing a catheter over the following 20 min; the bladder was flshed with sterile water to assre complete collection of PSP and endogenos creatinine. The amont of PSP excreted dring the 20-min interval was expressed as a percentage of the original dose of PSP. A blood specimen was taken at the midpoint of the collection interval and centrifged to obtain plasma which was analyzed for triclopyr and endogenos creatinine. Urine and bladder rinse were pooled and analyzed for creatinine and PSP. The analysis for triclopyr, creatinine, and PSP in specimens of plasma and rine was as previosly described (Carmichael et ai, 989; Finco, 97, 993). Repeated Administration Experimental design. Animals were observed daily for overt signs of toxicity or changes in demeanor and for pharmacologic or other effects. Individal body weights were obtained for the rhess monkeys prior to the initiation of daily dosing and on Days 28,52,66, and 5. Clinical chemistry parameters for the monkeys were evalated predose and following 8, 59, and 5 days of dosing, whereas for dogs, these parameters were evalated predose and on dosing Days 6 and 37. Urinalysis and PSP clearance assays were condcted for the monkeys predose and on Days 8, 24, 52, 65, 00, and 3 days of dosing and for dogs at predose and on Days 7 and 3. Monkeys and dogs were fasted overnight and a clinical test dose of PSP (6 mg/animal) was given intravenosly as previosly described. In general, the PSP excretion evalation was condcted in the morning prior to the daily administration of triclopyr. However, in one instance (Day 3, ), the dose of triclopyr was infsed intravenosly, rather than given orally, dring the 20 min period following injection of PSP in the monkey. This change in triclopyr dose administration had no impact on the reslts of this stdy. In addition to the PSP evalation, inlin and />ara-aminohipprate (PAH) clearance were evalated, in only the monkeys, sing an adaptation of the constant-infsion techniqe of Cole et al. (972), at predose and on Days 26 and 66 of dosing. Priming doses of 40 mg/kg of inlin and 8 mg/kg PAH were initially given intravenosly while a sstained infsion of inlin (2.7-3.4 mg/ml) and PAH (0.4-.4 mg/ml) in physiological saline was administered by a constant-speed infsion pmp (0.7- ml/min) to maintain steady-state blood levels. Blood inlin and

49 TRICLOPYR EFFECTS ON RENAL FUNCTION UU ' 2 60 II CD U 0: Control PSP :\ g - a _o s \ c 73 Time h FIG.. Endogenos creatinine clearance in male beagle dogs administered a single oral dose of 5 mg triclopyr/kg of body weight dose determined at baseline,, 25, and 73 hr postdosing. The vales represent mean SD for six animals. PAH levels for clearance calclations were determined at ~ 4 hr of infsion. Inlin was measred according to the method of Heyrovsky (956). PAH was determined sing the method of Bratton and Marshall (939) as modified by Smith et al. (945)..- Time h FIG. 2. Relationship between plasma triclopyr concentration (O) and percentage PSP excretion ( ) at baseline,, 25, and 73 hr postdosing in beagle dogs administered a single oral dose of 5 mg triclopyr/kg of body weight. The vales represent means SD for six animals. The average control percentage PSP excretion was 36 5%. Vales identified as statistically different are identified with an asterisk (*) (a = 0.05). Statistical Analysis weight at a constant.5 kg, whereas the second dog increased from 2 to 2.3 kg dring the stdy (data not shown). The reslts of serm creatinine and BUN analyses for monkeys and dogs repeatedly administered triclopyr are RESULTS presented in Figs. 3 and 4. Repeated triclopyr administration, in monkeys and dogs, had no biologically meaningfl Dogs administered a single oral dose of 5 mg triclopyr/ impact on creatinine and BUN vales. The vales obtained kg body wt were clinically normal at the initiation of the in monkeys at all time periods and doses were well within stdy and remained normal throghot the trial. The mean the normal limits for the colony. In dogs, serm creatinine body weight at the stdy start was 8.0 0.93 kg. Vales levels (Fig. 4A) following the treatment were for endogenos creatinine clearance (Fig. ) following this slightly elevated from baseline. However, both BUN and single-dose triclopyr administration were not statistically dif- serm creatinine were well within the reported range of ferent from baseline (control) levels. The percentage PSP normal for the beagle dog (Osborne et al., 972; Dncan excretion and triclopyr plasma concentration (/j,g ml~') fol- and Prasse, 986). lowing a single oral dose in dogs are presented in Fig. 2. PSP excretion was significantly decreased to 63 and TABLE 74% of baseline levels at and 25 hr postdosing, respecbody Weights of Monkeys Administered Triclopyr at Doses of tively. However, by 73 hr postdosing PSP excretion had retrned to near baseline levels (96%). The plasma triclopyr /day for 28 Days Followed by /day throgh 30 concentration and percentage PSP excretion were inversely Days Predose vales (baseline) were compared with vales obtained postdosing sing a paired t test (a = 0.05) (Steel and Torrie, 980). related over time. Plasma triclopyr concentration showed a decreasing trend with time, ranging from ~4 (ig/ml ( hr postdosing) to ~ fig/ml (72 hr postdosing). The monkeys and dogs tolerated the repeated administration of triclopyr at doses of 5 and /day (monkeys only) over a 30- or 4-day dosing period, respectively. Body weight changes for the monkeys are shown in Table and increased over the stdy dration. One dog maintained its Dose grop Day of dosing _ is S3 m 5 Vales represent means SD for for animals. Body wt (kg)" 2.78 2.95 2.93 3.43 3.35 0.34 0.34 0.34 0.49 0.54

50 TIMCHALK, FINCO, AND QUAST variability among test days, in general the response exceeded baseline measrements and in no case was PSP excretion significantly redced. On the other hand, PSP excretion in dogs was redced approximately 50% from baseline on Test Days 7 and 3 following the dose. Inlin and PAH clearance also were examined in the monkey as indicators of renal fnction following triclopyr administration (Fig. 6). Inlin clearance following oral administration of triclopyr at /day (Day 26) and / *4.5 A..2 l (. -.0) (0.9 -.).0 (day 8) (day 59) (day 5) (0.9-0.8) 0.8 G 0.6 40l 0.4 0.2 30" 5 0.0 (day 6) (day 37) 20 i (day 8) (day 59) (day 5) FIG. 3. Endogenos creatinine (A) and BUN (B) concentrations in male rhess monkeys repeatedly administered triclopyr at a dose of /day for 28 days followed by an additional 02 days at /day (30 daily doses). The vales represent means SD for for animals. Vales identified as statistically different are identified with an asterisk (*) (a = 0.05). Phenolslfonphthalein excretion in monkeys and dogs is presented in Fig. 5. In monkeys the rate of PSP excretion following 8 daily /day doses of triclopyr was slightly lower than baseline. However, a second PSP evalation at Day 24 () exceeded the baseline response. The PSP excretion was repeatedly (4 times) reevalated after increasing the daily dose of triclopyr to /day. Althogh the PSP excretion demonstrated a considerable degree of (4-23) (7-20) (day 6) (day 37) 6 FIG. 4. Endogenos creatinine (A) and BUN (B) concentrations, on dose Days 6 and 37, in male beagle dogs administered triclopyr at a dose of /day in their diet for 47 days. The vales represent mean for two animals and individal animal data are presented in parentheses. 8

TRTn.OPYR F.FFF.CTS ON RENAL FUNCTION A. baseline clearance, whereas the PAH clearance following 60 days of repeated triclopyr administration at a dose of 20 mg/ kg/day was significantly increased above baseline. 60 50" o 40- I 30" x X T UJ day 8 day 24 day 52 day 65 day 00 day 3J 30 i (24-29) 20" a (2-5) X w c (8-20) a. (day 6) (day 37) FIG. 5. Percentage PSP excretion in male rhess monkeys (A) and beagle dogs (B). Monkeys were gavaged with triclopyr at a dose of 5 mg/ kg/day for 28 days followed by an additional /day for 02 days (30 daily doses). PSP analysis was condcted on Days 8, 24, 52, 65, 00, and 3 of dosing. Dogs were fed triclopyr in their diet at a dose of 5 mg/ kg/day for 47 days and PSP was determined on dose Days 6 and 37. For monkeys, the vales represent means SD for for animals. Vales identified as statistically different are identified with an asterisk (*) (a = 0.05). For dogs, the vales represent mean for two animals and individal animal data are presented in parentheses. day (Day 60) was not significantly different from baseline clearance. para-aminohipprate clearance demonstrated a considerable degree of variability when measred on Day 26 following the /day dose, bt was comparable to Several stdies have sggested that, relative to other species, inclding hmans, the dog has a redced capacity to effectively eliminate organic acids via the kidneys (Timchalk et al., 996; Cherkofsky, 995; Gehring and Betso, 978; Hook et al., 974; Piper et al., 973). This stdy was condcted to evalate the effects of triclopyr administration on kidney fnction in the monkey and to compare their response to that observed in the dog. Blood rea nitrogen and serm creatinine are rotinely tilized to evalate renal fnction, althogh BUN and creatinine have limited sensitivity since renal fnction mst be decreased to 25% of normal or less to be detected by these measrements (Finco, 989; Schster and Seldin, 992). Nonetheless, the lack of an effect on BUN and creatinine levels in monkeys and dogs following repeated triclopyr administration sggests that triclopyr had no effect on normal kidney fnction in both species. Phenolslfonphthalein is a weak organic acid that is excreted by the kidneys primarily by an active secretory process in the proximal tbles (Finco, 980). In monkeys there was no evidence for a decrease in PSP excretion following repeated triclopyr exposre at doses of 5 or /day. In contrast, PSP excretion appeared to increase following repeated triclopyr doses of /day in the monkey. Since both triclopyr and PSP are reported to extensively bind to plasma proteins (Timchalk et al., 996; Ochwadt and Pitt, 962), a possible explanation for increased renal excretion of PSP may be the reslt of competition between triclopyr and PSP for the same plasma protein-binding sites. A shift to greater amonts of non-plasma-bond PSP wold enhance its glomerlar filtration increasing the percentage PSP excreted in the rine. Phenolslfonphthalein excretion in dogs was inversely related to plasma triclopyr concentration. At high plasma triclopyr concentrations (3-5 ^g triclopyr/ml plasma) PSP excretion was clearly depressed bt retrned to baseline as triclopyr plasma concentration decreased (~ ^g/ml). This effect of triclopyr on PSP excretion is consistent with a physiological response de to competition of triclopyr and PSP for the same active secretory system. These findings are consistent with those of Timchalk et al. (996), who sggested that, in the dog, the renal clearance of triclopyr involves both a high-affinity low-capacity active secretory site and glomerlar filtration of non-protein-bond triclopyr. In addition, nmeros stdies have demonstrated decreased renal clearance of organic acids, inclding PSP, when coadministered with other organic acids (Rssel et al., 989, 20- DISCUSSION

52 TMCHALK, FINCO, AND QUAST I s I 0 c (day 26) (day 60) 70" 6050 40 I 30 U 20 0 0 (day 26) (day 60) FIG. 6. Inlin (A) and PAH (B) clearance in male rhess monkeys repeatedly administered triclopyr at a dose of /day for 28 days followed by an additional 02 days at /day (30 daily doses). Analysis was condcted on dose Days 26 and 60. The vales represent means SD for for animals. Vales identified as statistically different are identified with an asterisk ( ) (a = 0.05). 987; Mann et at., 99; Foreman, 984; Weiner, 973). Overall these data clearly indicate that triclopyr effectively competes with PSP for the active secretory site within the dog kidney proximal tbles. In contrast, the monkey appears to be insensitive to the effects of triclopyr on the active secretory process even at doses forfold higher (/ day) than the effective dose in the dog (/day). Inlin and PAH stdies were initiated as a means of fr- ACKNOWLEDGMENTS The athors thank T. Cooper (University of Georgia), S. C. Hansen, L. G. McFadden (The Dow Chemical Co.), and Dr. T. Griffin (International 0 ther evalating renal fnction in the monkey. The glomerlar filtration rate (GFR) as determined by inlin clearance represents a very sensitive test for renal fnction and has been reported to detect abnormalities with decrements as small as 20% (Schster and Seldin, 992). The reslts indicate that GFR as measred by inlin clearance was not affected by triclopyr administration and was well within the reported normal range of 2.2-3.6 ml/min/kg for adlt male monkeys (Altman and Dittman, 974). These data spport the conclsion that triclopyr administration at doses as high as 20 mg/ kg/day did not adversely impact renal fnction or prodce associated renal toxicity in the monkey. para-aminohipprate is a weak organic acid that is extensively plasma protein-bond and is handled by the kidneys in a similar fashion as PSP (Finco, 989). The slightly elevated PAH clearance following the /day dose of triclopyr was consistent with PSP excretion data at this higher dose level. As noted for the effects seen with PSP, competition for plasma protein-binding between triclopyr and PAH is also a reasonable explanation for this slight increase in PAH clearance. The failre of triclopyr to decrease PAH clearance in the monkey provides additional spport for the conclsion that triclopyr does not significantly impact the active secretory process in monkeys. The findings in this stdy indicate that the monkey was insensitive to the effects of triclopyr and spport previos data which indicated that monkeys administered doses of triclopyr as high as 30 mg/kg/day for 28 days exhibited no treatment-related effects (976, npblished report of the Dow Chemical Co.). In contrast, dog renal physiology appears to be more sensitive to the effects of triclopyr administration. Perspective on the sensitivity of the dog to the renal effects of triclopyr and other organic acids sch as phenoxyacid herbicides (2,4-D, 2,4,5-T) and phenoxyalkanoic acids has been previosly reported (Timchalk et ai, 996; Gehring and Betso, 978). Allometric comparisons of triclopyr clearance and half-life between rat, dog, monkey, and hman clearly demonstrated that the dog has a decreased capacity to clear triclopyr relative to other species inclding hmans (Timchalk et ai, 996). Most recently, Cherkofsky (995) compared the pharmacokinetics of the organic acid -aminocyclopropanecarboxylic acid in the mose, rat, monkey, dog, and hman and likewise demonstrated that the dog has a significantly slower clearance and longer half-life for this organic acid. Collectively, these findings sggest that dogs have a redced capacity to clear organic acids, like triclopyr, and are consistent with the effects on renal fnction in dogs in this stdy. This niqe physiological response of the dog, relative to the monkey, raises into qestion the relevance of tilizing renal fnction changes in the dog as endpoints for hman risk extrapolation for organic acids sch as triclopyr.

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