Chronic Dietary Toxicity/Oncogenicity Studies on 2,4-Dichlorophenoxybutyric Acid in Rodents,

Charles, J

doi:10.1006/toxs.1998.2502

Cited by 4 publications

(6 citation statements)

References 8 publications

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“…Chronic toxicity in the eye, kidney, thyroid and liver of the rat were like effects found in subchronic studies [51]. Eye lesions were associated only with high doses of 150 mg/kg/day [51].…”

Section: Animalsmentioning

confidence: 75%

“…Changes in blood and thyroid parameters, organ weight ratios, and body weight gain were noted at 100 and 300 mg/kg/day doses [50]. Chronic toxicity in the eye, kidney, thyroid and liver of the rat were like effects found in subchronic studies [51]. Eye lesions were associated only with high doses of 150 mg/kg/day [51].…”

Section: Animalsmentioning

confidence: 89%

“…No oncogenic effects were observed in rats or mice following 2 years of dietary exposure of 2,4-D with concentrations ranging from 5-150 mg/kg/day or 5-300 mg/kg/day, respectively [51]. Similarly, researchers did not observe immune-toxic or oncogenic responses in dogs dosed with 1.0-7.5 mg/kg/day for either 13 weeks or 1 year [52].…”

Section: Animalsmentioning

confidence: 96%

“…A sub-chronic no observable effect level was established at 15 mg/kg/day based on studies in rats [50]. The chronic toxicity no observable effect level (NOEL) in rats and mice was determined to be 5 mg/kg/day in two-year studies [43,51]. The maximum tolerated dose in the two-year rat study was 150 mg/kg/day in male rats and 75 mg/kg/day in females [50].…”

Section: Animalsmentioning

confidence: 99%

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A Review of 2,4-D Environmental Fate, Persistence and Toxicity Effects on Living Organisms

Jote

2019

OMCIJ

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Section: Animalsmentioning

confidence: 75%

Section: Animalsmentioning

confidence: 89%

Section: Animalsmentioning

confidence: 96%

Section: Animalsmentioning

confidence: 99%

See 2 more Smart Citations

A Review of 2,4-D Environmental Fate, Persistence and Toxicity Effects on Living Organisms

Jote

2019

OMCIJ

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“…DISCUSSION Although there is abundant literature concerning the hepatic effects of peroxisome proliferators, reports of the renal effects of this class of compounds, even for strong prototypical peroxisome proliferators such as WY-14643, are less numerous. Di(2-ethylhexyl)phthalate (DEHP) is one peroxisome proliferator known to be a renal toxicant, inducing papillary mineralization and exacerbated nephropathy following chronic exposure (9). That the renal effects of DEHP are only partly abrogated in PPARa-null mice suggests that renal toxicity may be mediated by some PPARa-independent pathways (36).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Unique Renal Tubule Changes Induced in Rats and Mice by the Peroxisome Proliferators 2,4-Dichlorophenoxyacetic Acid (2,4-D) and WY-14643

et al. 2001

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Peroxisome proliferators are non-mutagenic carcinogens in the liver of rodents, acting both as initiators and promoters. The National Toxicology Program (NTP) conducted a study of several peroxisome proliferators (PPs), including Wyeth (WY)-14643 as a prototypical PP and 2,4-dichlorophenoxyacetic acid (2,4-D) as a weak PP, in Sprague-Dawley rats. B6C3F1 mice, and Syrian hamsters. In the kidney, an unusual change was observed in the outer stripe of the outer medulla, especially in rats treated with 2,4-D or WY-14643. This change was characterized by foci of tubules that were partially or completely lined by basophilic epithelial cells with decreased cytoplasm and high nuclear density. Changes typical of chronic nephropathy such as interstitial fibrosis or basement membrane thickening were not associated with these foci. Results of immunohistochemical staining for catalase and cytochrome P-450 4A in the kidney indicated increased staining intensity in renal tubular epithelial cells primarily in the region where the affected tubules were observed: however, the altered cells were negative for both immunohistochemical markers. Ultrastructurally, affected cells had long brush borders typical of the P3 tubule segment. The most distinguishing ultrastructural change was a decreased amount of electronlucent cytoplasm that contained few differentiated organelles and, in particular, a prominent reduced volume and number of mitochondria; changes in peroxisomes were not apparent. In addition to the lesion in rats, mice treated with the highest dose of 2,4-D, but not WY-14643, manifested similar renal tubular changes as seen by light microscopy. Neither chemical induced renal tubular lesions in hamsters. Hepatocellular changes characteristic of PPs were present in all 3 species treated with WY-14643, but not 2,4-D. These results indicate that the rat is the species most sensitive to the nephrotoxic effects of PPs and there is a site specificity to this toxicity related to areas of PP-related enzyme induction. Although 2,4-D is considered a weak PP for the liver, it was the most effective at inducing renal lesions, indicating that the toxic potency of various PPs will depend on the target organ.

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Developmental Toxicity Studies in Rats and Rabbits and Two-Generation Reproduction Study in Rats on 4-(2,4-DichIorophenoxy)butyric Acid

Charles¹,

Henwood

Leeming

1999

Int J Toxicol

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4-(2,4-Dichlorophenoxy)butyric acid (2,4-DB) is principallyused in the USA on peanuts, soybeans, and alfalfa. The developmental toxicity in rats (25/group) was studied at dose levels of 0, 31.25, 62.5, and 125 mg/kg/day. The maximum tolerated dose (MTD) was clearly exceeded at 125 mg/kg/day, as evidenced by a net weight loss in the dams during the dosing period, resulting in four dams totally resorbing their fetuses.The no-observed-effectlevel (NOEL) for maternal toxicity was 31.25 mg/kg/day based on a slight, but consistent, body weight effect at 62.5 mg/kg/day. The NOEL for embryo/fetal toxicity was 31.25 mg/kg/day based on increases in fetal skeletal variations at 62.5 mg/kg/day. The developmental toxicity in rabbits (16/group) was evaluated at dose levels of 0, 15, 30, or 60 mg/kg/day. The MTD was clearly exceeded at 60 mg/kg/day as evidenced by severe weight-gain depression during the dosing period in the does, resulting in two does aborting and two does being sacri® ced in a moribund condition. The NOEL for maternal toxicity was 30 mg/kg/day based on the above noted effects at 60 mg/kg/day. The NOEL for embryo/fetal toxicity was 60 mg/kg/day due to the lack of any effects noted. The reproductive toxicity of 2,4-DB was investigated in a two-generation study with two litters bred per generation. Rats (28/sex/group for the F0 generation and 24/sex/group for the F1 generation) were fed dietary concentrations of 0, 60, 300, and 1500 ppm during the ® rst generation, but because it proved impossible to rear a ® lial generation at 1500 ppm, the second generation was continued at doses of 0, 60, and 300 ppm. Mating performance, fertility, and pregnancy rate were unimpaired. A NOEL for reproductive toxicity was 1500 ppm (111.8 mg/kg/day for males and 110.6 mg/kg/day for females); however, severe postnatal toxicity was produced at this level. The NOEL for postnatal toxicity was 300 ppm (22.5± 32.6 mg/kg/day for males and 26.4± 36.7 mg/kg/day for females depending on the generation). The NOELs for developmental and reproductive toxicity are in general agreement with those reported for 2,4-dichlorophenoxyacetic acid (2,4-D), the major metabolite of 2,4-DB.4-(2,4-Dichlorophenoxy)butyric acid (2,4-DB) is principally used in the USA as a foliar-applied, selective systemic auxintype herbicide on peanuts, soybeans, and alfalfa for the control of many annual and perennial broad-leaved dicotyledenous weeds. After application, 2,4-DB is readily absorbed by the leaves and roots and is then translocated around the plant. 2,4-DB owes its selectivity to the ability of susceptible broad-leaved plants to translocate and rapidly oxidize it via b -oxidation to the acetic acid (2,4-dichlorophenoxyacetic acid; 2,4-D), which is the toxicant. Leguminous plants are not adversely affected because they perform b -oxidation so slowly that the amounts formed do not reach toxic dose levels.Long-term studies in dogs, rats, and mice indicate low chronic toxicity of 2,4-DB and a lack of oncogenic response to 2,4-DB following chronic dietary exposur...

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Chronic Dietary Toxicity/Oncogenicity Studies on 2,4-Dichlorophenoxybutyric Acid in Rodents,

Cited by 4 publications

References 8 publications

A Review of 2,4-D Environmental Fate, Persistence and Toxicity Effects on Living Organisms

A Review of 2,4-D Environmental Fate, Persistence and Toxicity Effects on Living Organisms

Unique Renal Tubule Changes Induced in Rats and Mice by the Peroxisome Proliferators 2,4-Dichlorophenoxyacetic Acid (2,4-D) and WY-14643

Developmental Toxicity Studies in Rats and Rabbits and Two-Generation Reproduction Study in Rats on 4-(2,4-DichIorophenoxy)butyric Acid

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