Comparative metabolism of 2,4-dichlorophenoxyacetic acid (2,4-D) in rat and dog.
1. There is a significant species difference in the toxicity of 2,4-dichlorophenoxyacetic acid (2,4-D). The oral no overall adverse effect level (NOAEL) for chronic toxicity of 2,4-D in rat is 5 mg kg(-1) day(-1) and in dog is 1 mg kg(-1) day(-1). The maximum tolerated dose (MTD) in rat is 150 and 75 kg(-1) day(-1) for male and females, respectively. The MTD in dog is 7.5 mg kg(-1) day(-1) for males and females. 2. In an attempt to explain the increased sensitivity to 2,4-D in dog, male and female rats and dogs were orally dosed with either 5 or 50 mg kg(-1) 14C-2,4-D. The rates and routes of excretion were investigated along with plasma toxicokinetics and biotransformation of the compound. 3. Elimination of the radioactive dose of 2,4-D from rat plasma was significantly faster than in dog. The approximate t(1/2) were 1.3-3.4 h for rat and 99-134 h for dog following a 5 or 50 mg kg(-1) dose, respectively. This led to large differences in the calculated AUC(0-infinity) 21-57 microg eq. h g(-1) for rat and 4889-5298 microg eq. h g(-1) for dog at 5 mg kg(-1), and 122-2358 microg eq. h g(-1) for rat and 34,110-44,296 microg eq. h g(-1) for dog at 50 mg kg(-1)). 4. In rat, the major route of excretion was in the urine. Excretion was essentially complete after 24 h for the low dose and after 48 h for the high dose. For dog, elimination was incomplete over the sampling period with only about 50% of the dose recovered. Urine was the principal route of excretion at the low dose, but about equal amounts were excreted in urine and faeces at the high dose over 120 h. 5. In rat, 2,4-D was unmetabolized and excreted in urine as the parent compound. In dog, the dose was excreted mainly following metabolism. 2,4-D in dog was conjugated forming the taurine, serine, glycine, glutamic acid, cysteine, sulphate and glucuronide conjugates, plus an unidentified metabolite, which were excreted in urine. Plasma, however, only contained unmetabolized 2,4-D. 6. The results show that the body burden of 2,4-D in dog is significantly higher than in rat for an equivalent dose, which is consistent with the increased sensitivity of dog to 2,4-D toxicity.
van Ravenzwaay
B
B
BASF AG, Product Safety, Ludwigshafen, Germany. bennard.ravenzwaay@basf-ag.de
Hardwick
T D
TD
Needham
D
D
Pethen
S
S
Lappin
G J
GJ
D015084:2,4-Dichlorophenoxyacetic Acid / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D000284:Administration, Oral; D000818:Animals; D002250:Carbon Radioisotopes; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006540:Herbicides / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D008297:Male; D015394:Molecular Structure; D051381:Rats; D011916:Rats, Inbred F344
D002250:Carbon Radioisotopes; D006540:Herbicides; D015084:2,4-Dichlorophenoxyacetic Acid