Evaluation of the safety and nutritional equivalence of a genetically modified cottonseed meal in a 90-day dietary toxicity study in rats.

Meal prepared from Cry1F/Cry1Ac transgenic/genetically modified cottonseed (WIDESTRIKE Insect Protection, hereafter referred to as WIDESTRIKE) was compared to cottonseed meal prepared from four conventionally bred lines of cotton (three commercial non-transgenic line controls (PHY72, PHY78 and 98M-2983), and a near isoline non-transgenic control (PSC355) in a 90-day dietary study to evaluate safety and nutritional equivalence. Diets were formulated with 10% WIDESTRIKE cottonseed meal equivalent to 7,235 mg/kg/day for males and 7,935 mg/kg/day for females. Animals were evaluated by cage-side and hand-held detailed clinical observations, body weight, and feed consumption. Functional tests, motor activity and ophthalmic examinations were conducted pre-exposure and prior to study termination. Standard hematology, clinical chemistry, prothrombin time and urinalysis parameters were evaluated. All rats had a complete necropsy and selected organs were weighed. Histopathologic examinations were performed on all rats fed the diets containing the near isoline non-transgenic control or WIDESTRIKE. Following 90 days of feeding, no adverse effects were observed during the conduct of clinical observations or in any of the parameters measured in this study. This study demonstrated that rodent diets prepared with 10% cottonseed meal from WIDESTRIKE cottonseeds do not produce any untoward effects and are nutritionally equivalent to cottonseed meals prepared from other, non-transgenic cottonseeds.

Repeated dose toxicity and developmental toxicity of diisopropanolamine to rats.

The repeated dose oral and dermal toxicity of diisopropanolamine (DIPA) was evaluated in rats and compared to the reported toxicity of the related secondary alcohol amine, diethanolamine (DEA). Fischer 344/DuCrl rats were given up to 750 mg/kg/day by dermal application, 5 days/week, for 4 weeks; or up to 1,000 mg DIPA/kg/day by drinking water for 13 weeks to evaluate potential toxic effects. Time-mated female CRL:CD(SD) rats were given up to 1,000 mg/kg/day by gavage on gestation days (GD) 6-20 for evaluation of maternal and fetal effects. In the dermal toxicity study, no adverse treatment-related in-life effects other than mild irritation at the site of dermal application at >or= 500 mg/kg/day were observed. There were no systemic effects in rats given up to 750 mg/kg/day. In the subchronic oral toxicity study, the most significant effects were an increase in absolute and relative kidney weights, unaccompanied by histopathologic changes, at >or= 500 mg/kg/day DIPA. The latter effect was ameliorated following a 4-week recovery period. In the developmental toxicity study, there were no maternal or developmental effects at any dose level evaluated. The toxicity of DIPA contrasts with that of DEA which has been shown to affect a number of organ systems when repeatedly administered orally or dermally at similar or lower dosages.

Ethylene glycol developmental toxicity: unraveling the roles of glycolic acid and metabolic acidosis.

This study sought to determine the relative roles of glycolic acid (GA), a toxicologically important metabolite of ethylene glycol (EG), and metabolic acidosis in causing developmental toxicity in Sprague-Dawley rats. To tease apart these two interrelated factors, we developed an experimental approach in which high blood glycolate levels could be achieved, in either the presence or absence of metabolic acidosis. Initially, rats previously implanted with a carotid artery cannula were given, on gestation day (gd) 10, 40.3 mmol/kg (2500 mg/kg) of EG via gavage, 8.5 mmol/kg (650 mg/kg) of GA via gavage, 8.5 mmol/kg (833 mg/kg) of sodium glycolate (NaG; pH 7.4) via subcutaneous (sc) injection, or distilled water via gavage (control). Peak serum glycolate was nearly identical (8.4-8.8 mM) in the EG, GA, and NaG groups and, as expected, EG and GA caused a metabolic acidosis, but acid base balance was normal with NaG. Subsequently, these treatments were given on gd 6-15 to groups of 25 time-mated rats, followed by fetal evaluation on gd 21. EG and GA decreased fetal body weights and caused a similar spectrum of developmental effects, including numerous axial skeleton malformations. NaG treatment also caused slight decreases in fetal body weight, increases in skeletal variations, and totally malformed fetuses. These results indicate that glycolate, in the absence of metabolic acidosis, can cause the most sensitive of EG's developmental effects, whereas metabolic acidosis appears to interact with glycolate at very high doses to markedly enhance teratogenesis. These results support previous studies, which indicated that glycolate is the proximate developmental toxicant for EG, and that GA toxicokinetic parameters can be used to define a quantitative, physiologically based threshold for EG-induced developmental effects.

Significance of 2-methoxypropionic acid formed from beta-propylene glycol monomethyl ether: integration of pharmacokinetic and developmental toxicity assessments in rabbits.

Commercial grade propylene glycol monomethyl ether (PGME), which is composed of > 99.5% alpha-isomer and < 0.5% beta-isomer, has been shown in several studies to have a low potential for developmental toxicity. Nonetheless, questions have been raised about potential human developmental toxicity due to beta-PGME, because it can be metabolized to 2-methoxypropionic acid (MPA), a compound bearing structural similarity to the teratogen, methoxyacetic acid (MAA). Accordingly, a series of in vivo developmental toxicity, whole embryo culture, and in vivo pharmacokinetic experiments were conducted in New Zealand White rabbits (highly sensitive to these compounds) to better understand the developmental toxicity potential of MPA and the kinetics of its formation from beta-PGME. For the in vivo developmental toxicity studies, groups of 20 inseminated rabbits were gavaged with 0, 10, 26, or 78 mg/kg/day of MPA on gestation day (GD) 7-19, followed by fetal evaluation on GD 28. Results with MPA were compared with those of rabbits similarly dosed with 0, 2.5, 7.5, or 15 mg/kg/day of MAA. Developmental toxicity no-observable-effect levels (NOEL) were approximately 10-fold higher for MPA (26 mg/kg/day) than for MAA (2.5 mg/kg/day). Also, the severity of effects caused by MPA was less than that of MAA, and unlike MAA, MPA was not selectively toxic to the fetus. This differential toxicity was also seen in whole embryo cultures of GD 9 rabbit embryos, in which there were no adverse effects of MPA (1.0, 5.0 mM) or its parent compound, beta-PGME (0.5, 2.0 mM), but severe dysmorphogenesis in 100% of embryos cultured in 5.0 mM MAA. The pharmacokinetics study showed rapid and complete conversion of beta-PGME to MPA, with a relatively long elimination half-life (33-44 h) for MPA. However, peak and AUC concentrations of MPA in blood associated with the MPA LOEL dose of 78 mg/kg/day were 1.3 mM and 52.9 mM-h/l, respectively, suggesting a relatively high threshold based on internal dosimetry. Taken together, these data indicate a negligible risk of developmental toxicity due to MPA formation from the small amounts of beta-isomer present in commercial PGME.

Bioavailability and pharmacokinetics of microencapsulated 1,3-dichloropropene in rats.

The potential oral toxicity of 1,3-dichloropropene (1,3-D) has been evaluated in a number of dietary toxicity studies. The relatively high vapor pressure of 1,3-D, its short half-life in drinking water, and its reactivity with constituents of feed necessitated the use of a microencapsulated formulation (starch-sucrose shell) of 1,3-D in these studies. The bioavailability of ingested microencapsulated 1,3-D was determined by characterizing and comparing the kinetics of 1,3-D in the blood of female F344 rats coadministered microencapsulated 1,3-D and neat 13C-1,3-D (25 mg/kg each) via gavage. Blood concentrations of total or cis- and trans-isomers of 1,3-D in treated rats were determined using gas chromatography-mass spectroscopy (GC-MS) or in situ membrane extraction MS. Urine was also collected and analyzed by GC-MS for the presence of the mercapturate excretion product of 1,3-D [N-acetyl-S-(3-chloropropenyl-2)-L-cysteine; 1,3-DMA]. Blood levels of 1,3-D and 13C-1,3-D displayed similar kinetics, peaking within 10 min of dosing followed by a rapid biphasic elimination. Higher peak blood levels and greater blood curve areas (AUC) were attained for trans- than cis-1,3-D and 13C-1,3-D and greater amounts of cis- than trans-1,3-DMA and 13C-1,3-DMA were excreted in the urine consistent with the known rapid and disproportionate glutathione conjugation of the cis-isomer in the gastric mucosa. Slightly higher cis-1,3-D than cis-13C-1,3-D blood levels and AUCs were also consistently noted while the reverse was true for urinary excretion of cis-13C-1,3-DMA and cis-1,3-DMA suggesting that 1,3-D derived from microencapsulated test material may be absorbed and/or metabolized in the stomach mucosa at a slightly slower rate than that from neat material. The latter, however, would be of no consequence during the administration of 1,3-D to animals via their diets as competing test materials would not be present and 1,3-D blood kinetics were unaffected. Overall, the results of this study demonstrate the ready bioavailability of microencapsulated 1,3-D and rapid elimination of 1,3-D from the blood of rats.

Age and dose dependency of the pharmacokinetics and metabolism of bisphenol A in neonatal sprague-dawley rats following oral administration.

Previous studies demonstrated the rapid clearance of bisphenol A (BPA) from blood following oral administration to adult rats with the principal metabolite being BPA-monoglucuronide (BPA-glucuronide). Since the ontogeny of glucuronyl transferases (GT) differs with age, the pharmacokinetics of BPA were studied in neonatal animals. (14)C-BPA was administered via gavage at 1 or 10 mg/kg body weight to rats at postnatal day (pnd) 4, pnd 7, pnd 21, or to 11 week old adult rats (10 mg/kg dose only). Blood (neonates and adults) and selected tissues (neonates) were collected at 0.25, 0.75, 1.5, 3, 6, 12, 18, and 24 h postdosing. BPA and BPA-glucuronide in the plasma were quantified by high-performance liquid chromatography; radioactivity in the plasma and tissues was quantified by liquid scintillation spectrometry. The data indicate that neonatal rats at all three ages metabolized BPA to BPA-glucuronide, although an age dependency in the number and concentration of plasma metabolites was observed, consistent with the ontogeny of GT. BPA-glucuronide and BPA concentrations in the plasma were greater in neonates than in adults, except at 24 h postdosing, suggesting an immaturity in the development of hepatic excretory function in neonatal rats. Nevertheless, the half-lives for the elimination of BPA-glucuronide in plasma were more rapid in neonatal animals than in adults, likely due to reduced microflora beta-glucuronidase activity and an absence of enterohepatic recirculation. A dose dependency in the metabolism and pharmacokinetics of BPA administered to neonates was also observed with nearly complete metabolism of BPA to BPA-glucuronide (94-100% of the plasma radioactivity) at a dose of 1 mg/kg. This was in contrast to finding up to 13 different plasma metabolites observed at the 10 mg/kg dose. These data indicate that, from early in neonatal life through pnd 21, there is sufficient GT activity in rats to efficiently metabolize BPA to its nonestrogenic metabolite at low doses.

Metabolism and pharmacokinetics of bisphenol A (BPA) and the embryo-fetal distribution of BPA and BPA-monoglucuronide in CD Sprague-Dawley rats at three gestational stages.

The pharmacokinetics of bisphenol A (BPA), including the quantification of the major BPA metabolite BPA-monoglucuronide conjugate (BPA-glucuronide) was studied in Sprague-Dawley rats at different stages of gestation. 14C-BPA was administered orally at 10 mg BPA/kg body weight (0.2 mCi/rat) to nongravid rats and to other groups on gestation days (GD) 6, 14, and 17. GD 0 was when the vaginal smear was sperm positive or a copulatory plug was observed. Radioactivity derived from 14C-BPA was quantified in the maternal blood, selected tissues, and the embryo or fetus. BPA and BPA-glucuronide were quantified in maternal plasma and excreta. Additional rats were dosed orally at 10 mg 14C-BPA/kg (0.2 mCi/rat or 0.5 mCi/rat) on GD 11, 13, and 16 to further study the distribution of BPA and BPA-glucuronide to the embryo/fetal tissue. The tissue distribution, metabolism, or the rates or routes of excretion of BPA, or the plasma concentration-time profiles of BPA-glucuronide did not appear to be altered at any stage of gestation as compared to nonpregnant rats. In the GD 11 group, neither BPA nor BPA-glucuronide was detected in the yolk sacs or embryos, except for trace concentrations of BPA-glucuronide in the yolk sacs at 15 min postdosing. In the GD 13 group, both BPA and BPA-glucuronide were detected in the yolk sacs of the conceptus but not in the embryos/fetuses, except for BPA at 15 min. For the animals dosed with 0.2 mCi/rat on GD 16, both analytes were detected in the placentae at 15 min and 12 h, but not at 96 h. Traces of both analytes were detected in fetal tissue in two of five specimens at 15 min only. In rats dosed on GD 16 with 0.5 mCi/rat, the BPA-glucuronide and BPA concentrations in maternal plasma at 15 min were 1.7 and 0.06 mug equivalents (eq)/g plasma, respectively. At the same time postdosing in these animals, the placental BPA-glucuronide concentrations were lower (0.34 mug eq BPA [as glucuronide]/g), and the BPA concentrations were about equivalent (0.095 mug/g). Fetal BPA-glucuronide and BPA concentrations were markedly lower, 0.013 and 0.018 mug eq/g, respectively. Therefore, no selective affinity of either yolk sac/placenta or embryo/fetus for BPA or BPA metabolites relative to maternal plasma or tissues was observed in this study.

Pharmacokinetics and metabolism of triclopyr 3,5,6-trichloro-2-pyridinyloxyacetic acid) in Fischer 344 rats.

Triclopyr, (3,5,6-trichloro-2-pyridinyloxyacetic acid) is the active component of GARLON (trademark of the Dow Chemical Company) brand herbicide. [14C]Triclopyr was administered orally to groups of 5 rats/sex as a single 3 and 60 mg/kg body weight dose and as a multiple 3 mg/kg nonradiolabeled dose for 14 days followed by a single 3 mg [14C]triclopyr/kg dose on day 15. A fourth group (5 rats/sex) was administered a single 3 mg/kg intravenous dose of [14C]triclopyr. In addition, two groups of male rats (3/dose) were used to obtain 14C plasma time-course data and were orally administered [14C]triclopyr at doses of 3 and 60 mg/kg. Between 94 and 97% of the administered radioactivity was recovered, and the principal route of excretion was the urine (89-95%). The feces contained less than 3% of the dose and the expired 14CO2 and cage wash accounted for less than 0.2 and 1% of the dose, respectively. The tissues and carcass accounted for less than 2% of the radioactivity at 72 h post-dosing. [14C]Triclopyr was rapidly and completely absorbed after oral administration of 3 and 60 mg/kg. The radioactivity was cleared from the plasma of male rats at 3 mg/kg in a mono-exponential manner, with an apparent first-order elimination half-life of 3.6 h. The primary difference between the 3 and 60 mg/kg dose kinetics was the saturation of renal elimination of triclopyr through 9 h post-dosing for the 60 mg/kg group. [14C]Triclopyr was primarily excreted unchanged in the urine (81-96% of the urinary radioactivity), although 4 minor urinary metabolites were noted. Aside from the initial saturation of renal elimination of triclopyr at 60 mg/kg, there were no appreciable differences in the absorption, disposition, or metabolism of [14C]triclopyr, based on sex, or prior exposure.

Disposition and metabolism of [14C]1,2-dichloropropane following oral and inhalation exposure in Fischer 344 rats.

The objective of this study was to compare the disposition and metabolism of [14C]1,2-dichloropropane [( 14C]DCP) following oral and inhalation exposure since these two routes are of interest with regards to occupational and accidental exposure. [14C]DCP was administered orally to groups of four rats of each sex as a single dose of 1 or 100 mg/kg and as a multiple 1 mg/kg nonradiolabeled dose for 7 days followed by a single 1 mg [14C]DCP/kg dose on day 8. In addition, four rats of each sex were exposed to [14C]DCP vapors for a 6-h period in a head-only inhalation chamber at target concentrations of 5, 50 and 100 ppm. [14C]DCP was readily absorbed, metabolized and excreted after oral or inhalation exposure. For all treatment groups the principal routes of elimination were via the urine (37-65%) and expired air (18-40%). The tissues, carcass, feces and cage wash contained less than 11, 9.7 and 3.8% of the dose, respectively. The major urinary metabolites, as a group, from the oral and inhalation exposures were identified as three N-acetylcysteine conjugates of DCP, N-acetyl-S-(2-hydroxypropyl)-L-cysteine, N-acetyl-S-(2-oxopropyl)-L-cysteine and N-acetyl-S-(1-carboxyethyl)-L-cysteine. The majority (61-87%) of the expired volatile organic material was found to be parent DCP in all samples analyzed. Increasing the dose/concentration of [14C]DCP resulted in an increase in the amount of exhaled [14C]-volatile organics. The peak DCP blood concentrations (inhalation exposure) were not proportional to dose, indicating a dose-dependency in the blood clearance of DCP. Nonetheless, upon termination of exposure, DCP was rapidly eliminated from the blood. In all treatment groups, following oral and inhalation exposure the majority of the radioactivity was eliminated by 24 h postdosing and no differences were noted between sexes. Therefore, it can be concluded that in the rat the pharmacokinetics and metabolism of [14C]DCP are similar regardless of route of exposure or sex.

Determination of the effect of tridiphane on the pharmacokinetics of [14C]-atrazine following oral administration to male Fischer 344 rats.

The absorption, distribution, metabolism and excretion of [14C]-atrazine was studied in male Fischer 344 rats administered a 30 mg [14C]-atrazine/kg of body weight oral dose with or without pretreatment with a non-radiolabeled oral dose of 60 mg tridiphane/kg of body weight. The objective of this study was to determine whether tridiphane had any meaningful effect on the pharmacokinetics and/or metabolism of atrazine in the rat. The 14C plasma time-course exhibited a mono-exponential decrease with an absorption and elimination half-life of approximately 3 h and 11 h, respectively for both treatment groups. In addition, at 72 h after the administration of [14C]-atrazine, approximately 93% of the administered radioactivity was recovered and the primary route of excretion was via the urine (67%) for both treatment groups. The feces accounted for approximately 18% of the dose, and less than 10% remained in the carcass, skin, and red blood cells (RBCs). The urine excreted in the first 24 h post-dosing contained approximately 57% of the administered radioactivity for both treatment groups. There were no appreciable differences in the metabolite distribution between treatment groups, and the major urinary metabolite of atrazine was found to be 2-chloro-4,6-diamino-1,3,5-triazine (II; 64-67%). Additionally, S-(2-amino-4-methylethylamino-1,3,5-triazin-6-yl)-mercapturi c acid (V; 13-14%), and S-(2,4-diamino-1,3,5-triazin-6-yl)-mercapturic acid (III; 9%) were tentatively identified based upon similar HPLC retention times as seen with synthesized standards. These data indicate that there are no meaningful differences in the absorption, distribution, metabolism, and excretion between rats administered only [14C]-atrazine and those administered both tridiphane and [14C]-atrazine. Therefore, it can be concluded that tridiphane has no meaningful effect on the pharmacokinetics and/or metabolism of atrazine in the rat.

Dosimetry considerations in the enhanced sensitivity of male Wistar rats to chronic ethylene glycol-induced nephrotoxicity.

Male Wistar rats have been shown to be the most sensitive sex, strain and species to ethylene glycol-induced nephrotoxicity in subchronic studies. A chronic toxicity and dosimetry study was therefore conducted in male Wistar rats administered ethylene glycol via the diet at 0, 50, 150, 300, or 400 mg/kg/day for up to twelve months. Subgroups of animals were included for metabolite analysis and renal clearance studies to provide a quantitative basis for extrapolating dose-response relationships from this sensitive animal model in human health risk assessments. Mortality occurred in 5 of 20 rats at 300 mg/kg/day (days 111-221) and 4 of 20 rats at 400 mg/kg/day (days 43-193), with remaining rats at this dose euthanized early (day 203) due to excessive weight loss. Increased water consumption and urine volume with decreased specific gravity occurred at 300 mg/kg/day presumably due to osmotic diuresis. Calculi (calcium oxalate crystals) occurred in the bladder or renal pelvis at > or =300 mg/kg/day. Rats dying early at > or =300 mg/kg/day had transitional cell hyperplasia with inflammation and hemorrhage of the bladder wall. Crystal nephropathy (basophilic foci, tubule or pelvic dilatation, birefringent crystals in the pelvic fornix, or transitional cell hyperplasia) affected most rats at 300 mg/kg/day, all at 400 mg/kg/day, but none at < or =150 mg/kg/day. No significant differences in kidney oxalate levels, the metabolite responsible for renal toxicity, were observed among control, 50 and 150 mg/kg/day groups. At 300 and 400 mg/kg/day, oxalate levels increased proportionally with the nephrotoxicity score supporting the oxalate crystal-induced nephrotoxicity mode of action. No treatment-related effects on the renal clearance of intravenously infused (3)H-inulin, a marker for glomerular filtration, and (14)C-oxalic acid were observed in rats surviving 12 months of exposure to ethylene glycol up to 300 mg/kg/day. In studies with naïve male Wistar and F344 rats (a less sensitive strain), a significant difference was observed in oxalate clearances between young rats (i.e. Wistar clearance < F344) but not in age-matched old rats. Regardless, the ratios of oxalate:inulin clearances in these two strains of rats, including those exposed to ethylene glycol, were all < 1, suggesting that a fraction of the filtered oxalate is reabsorbed. Other species, including humans, typically have clearance ratios >1 and are more effective at clearing oxalic acid by both glomerular filtration and active secretion. Thus, the lower renal clearance and kidney accumulation of oxalates in male Wistar rats enhances their sensitivity, which will be a factor in human risk assessments. The benchmark dose values (BMD05, BMDL05) were 170 mg/kg/day and 150 mg/kg/day for nephropathy, and 170 mg/kg/day and 160 mg/kg/day for birefringent crystals, using incidence times severity data in each case. The NOAEL of 150 mg/kg/day is the same as that reported after 16-week exposure and appears to be a threshold dose below which no renal toxicity occurs, regardless of exposure duration.

Blood-flow distribution in the mouse.

Blood-flow distribution was determined in pentobarbital-anesthetized male B6C3F1 mice, using intracardially administered 141Ce-radiolabelled microspheres (10 micro Ci). The proportion of cardiac output and blood flow per g tissue was determined in 18 organs and tissues, including the nasal cavity, lobes of the liver, individual kidneys and sections of the intestinal tract. To provide comparative data, blood-flow distribution was also determined in pentobarbital-anaesthetized male Fischer 344 rats. In general, there was close agreement between the distribution of blood flow between these two rodent species. The bladder and large intestine of mice appear to receive more, while the testes receive less, of the cardiac output than in rats. Rat liver and kidney, however, appear to receive approximately twice the amount of blood on a weight basis as in the mouse.

Comparative pharmacokinetics of [14C]metosulam (N-[2,6-dichloro-3-methylphenyl]-5,7-dimethoxy-1,2,4- triazolo[1,5a]-pyrimidine-2-sulfonamide) in rats, mice and dogs.

This study was conducted to provide data on the pharmacokinetics of [14C]metosulam (N-[2,6-dichloro-3-methylphenyl]-5,7-dimethoxy-1,2,4-triazolo-[1,5a]- pyrimidine-2-sulfonamide). Groups of male Sprague-Dawley rats, CD-1 mice and Beagle dogs were given a single oral gavage dose of 100 mg [14C]metosulam kg-1 body weight and blood, urine, feces and selected tissue specimens were collected up to 168 h for rats and mice and 216 h post-dosing for dogs. Two of these dogs received a second oral dose of 100 mg kg-1 and were humanely euthanized at 12 h post-dosing and selected tissues were collected. The third dog was administered an intravenous dose of 1 mg kg-1 and plasma, urine and feces were collected for 72 h post-dosing. Specified tissue specimens were analyzed for 14C activity and selected tissues were evaluated for localization of 14C activity by histoautoradiography. Selected urine and plasma specimens were also profiled for metabolites by high-performance liquid chromatography. [14C]Metosulam was absorbed rapidly (t1/2 < 1 h) in all three species. Mice and dogs absorbed ca. 20% of the orally administered dose of [14C]metosulam, compared to > 70% absorption in the rat. Analysis of 14C activity and histoautoradiography of the dog eyes indicated that the retina, a target for toxicity in the dog, did exhibit affinity for the radiotracer. There was no evidence of 14C localization in the kidneys of dogs or in the eyes of rats. In rats and mice the 14C plasma time-course was fit to a two-compartment pharmacokinetic model, whereas the dog was fit to a one-compartment model. The half-lives for the rapid initial (alpha) and slower terminal phases (beta) were 9 h and 60 h for the rat and 20 h and 155 h for mice, respectively. The dog had an elimination t1/2 of 73 h. In all three species, [14C]metosulam and metabolites were excreted in the urine and quantitatively the relative amount of [14C]metosulam metabolism followed the pattern of mice > rats > dogs. These data suggest that the observed ocular lesion in dogs is due to metosulam and may in part be due to its selective affinity for the dog retina.