Developmental toxicity evaluation of triclopyr butoxyethyl ester and triclopyr triethylamine salt in the CD rat.
Triclopyr (3,5,6-trichloro-2-pyridyloxyacetic acid) is an herbicide used extensively in the control of woody plants and broadleaf weeds, and is often formulated as a triethylamine salt (T-TEA) or butoxyethyl ester (T-BEE). This study evaluated the developmental toxicity of T-TEA or T-BEE in time-mated CD rats gavaged on gestation days 6-15 with 0, 30, 100 or 300 mg/kg body weight(bw)/day. The doses of each compound were equimolar and equivalent to 22, 76, 216 mg/kg bw/day of triclopyr, based on prior studies indicating rapid cleavage of the salt or ester and equivalent pharmacokinetics for the active ingredient. T-TEA caused maternal toxicity, evidenced by the death of one high-dose dam, reduced body weight gain, increased relative liver and kidney weights (300 mg/kg bw/day), reduced feed consumption, and increased water consumption (100 and 300 mg/kg bw/day). Developmental effects were limited to slightly decreased fetal body weight and reduced skeletal ossification at the high dose level. T-BEE caused similar, albeit slightly more severe, maternal toxicity, with three maternal deaths at 300 mg/kg bw/day, and slight maternal effects at 30 mg/kg bw/day. Due to an equivocal increase in malformations, which were mainly clustered in litters from three high dose dams with marked maternal toxicity, the T-BEE study was repeated using 30 dams/group, investigator-blind fetal evaluations, and an additional dose group (5 mg/kg bw/day). In the repeat study, the only reproducible fetal effect was an increased incidence of 14th thoracolumbar rib at 300 mg/kg bw/day. Overall analysis of the two T-BEE studies suggested that the fetal malformations unique to the initial study likely reflected a combination of spontaneous events, exacerbated by marked maternal toxicity. The combined weight of evidence from these developmental toxicity studies, coupled with their known pharmacokinetic equivalence, indicates that T-BEE and T-TEA are not selectively toxic to the fetus. The respective maternal toxicity no-observed effect levels (NOEL) for T-BEE and T-TEA were 5 and 30 mg/kg bw/day, while the NOEL for developmental toxicity was 100 mg/kg bw/day for both compounds.
Carney
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Toxicology & Environmental Research and Consulting, The Dow Chemical Company, 1803 Building, Midland, MI 48674, USA.
Billington
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R
Barlow
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SM
D000014:Abnormalities, Drug-Induced; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000196:embryology; D004305:Dose-Response Relationship, Drug; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D020567:Fetal Weight / Q000187:drug effects; D006016:Glycolates / Q000633:toxicity*; D006540:Herbicides / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008136:Longevity / Q000187:drug effects; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D006016:Glycolates; D006540:Herbicides; C032742:triclopyr