Toxico-Kinetics, Recovery, and Metabolism of Napropamide in Goats Following a Single High-Dose Oral Administration Ajoy K. Pahari, † Suparna Majumdar, ‡ Tapan K. Mandal, ‡ Animesh K. Chakraborty, ‡ Anjan Bhattacharyya, † and Ashim Chowdhury* ,† Department of Agricultural Chemicals, Pesticide Residue Laboratory, Bidhan Chandra Krishi Viswavidyalaya, Mohanpur, Nadia 741252, West Bengal, India, and Department of Pharmacology and Toxicology, West Bengal University of Animal and Fishery Sciences, Mohanpur, Nadia 741235, West Bengal, India Toxicokinetic behavior, recovery and metabolism of napropamide (a pre-emergent herbicide) and its effect on Cytochrome P 450 of liver microsomal pellet were studied following a single high-dose oral administration of 2.5 g kg -1 and continuous (7 days) oral administration of 500 mg kg -1 in black Bengal goat. Napropamide was detected in blood at 15 min and the maximum quantity was recovered at 3 h after administration. The absorption rate constant (Ka) value was low indicating poor absorption from the gastrointestinal tract. High elimination half-life (t 1/2 ) and low body clearance (Cl B ) values coupled with higher transfer of compound from tissue to central compartment (K 21 ) suggest that napropamide persisted in the blood for a long time, i.e., after 72 h of oral administration. The recovery percentage of napropamide, including metabolites, from goats varied from 75.94 to 80.08 and excretion of the parent compound through feces varied from 18.86 to 21.59%, indicating that a major portion of the orally administered napropamide was absorbed from the gastrointestinal tract of goat. Napropamide significantly increased the Cytochrome P 450 content of liver microsomal pellet. The recovery of metabolites from feces, urine, and tissues ranged from 4.2- 6.2, 40.81-49.42, and 2.7-11.6%, respectively, during a 4-7 day period. The material balance of napropamide (including metabolites) following a single high-dose oral administration at 2.5 g kg -1 during 4-7 days after dosing was found to be in the range of 75-80%. Keywords: Napropamide; persistence metabolism; effect on Cytochrome P 450 ; recovery; goat; herbicide; pesticide INTRODUCTION Napropamide [N,N-diethyl-2-(1-naphthalenyloxy) pro- panamide] is widely used as a pre-emergent herbicide for the control of many annual grasses and broad leaf weeds. The herbicidal property of napropamide was first reported by Chan et al. (1). Enhanced biodegradation of the herbicide in soil was observed by Walker et al. (2-4). The photodecomposition of formulated napropa- mide in soil has been demonstrated; its aqueous pho- tolysis produced transformation products involving molecular rearrangement and coupling (5). However, no information on the disposition kinetics and metabolism of napropamide is available in the literature, especially in the animal system. The objective of the present study was to evaluate the toxico-kinetic behavior, distribution, retention, and metabolism of napropamide in different tissues of goat following oral administration of a single high dose. The results obtained from this study will be of value in assessing the possible health hazards posed by the use of napropamide. EXPERIMENTAL PROCEDURES Chemicals. Napropamide (technical grade, purity 97%) and its metabolites R-naphthoxy propionic acid (purity 96.5%), 1,5- dihydroxy naphthalene (purity 97.5%), and N-ethyl napropa- mide (purity 97.5%), the three most probable metabolites, were supplied by M/s. Gharda Chemicals Ltd., Mumbai, India. All these compounds were further purified and were authenticated by HPLC and spectroscopic (UV, IR, MS, and NMR) analyses. All other chemicals and solvents used in this study were of analytical grade (E. Merck, India). Animal Treatment. Clinically healthy adult black Bengal male (nulliparous) and female goats weighing between 9.5 and 12 kg were selected. The goats were acclimated individually in stainless steel metabolism cages and provided with artificial fluorescent lighting, controlled temperature (22 ( 3 °C), water, and standard feed (6). Each animal was fasted overnight before treatment. For ascertaining the minimum oral toxic dose level, four different doses of napropamide suspended in carboxymethyl cellulose (1% w/v) were administered to four groups of goats separately, each group made up of one male and one female. Likewise, for ascertaining the maximum oral nontoxic dose level after administering a single dose for 7 consecutive days, three different doses of napropamide suspended in carboxy- methyl cellulose (1% w/v) were administered to three groups of goats separately, each consisting of one male and one female goat. For the metabolic study of napropamide 14 male and 14 female goats were utilized. Of these, two males and two females were kept as controls and received the vehicle (car- boxymethyl cellulose) only. The remaining male and female goats were divided into four groups, each made up of three male and three female animals, which were orally treated with napropamide suspension in carboxymethyl cellulose. A group of treated animals was sacrificed on each of days 4, 5, 6, and 7 days. * To whom correspondence should be addressed. Tele- phone: 03162 98-460. † Bidhan Chandra Krishi Viswavidyalaya. ‡ West Bengal University of Animal and Fishery Sciences. 1817 J. Agric. Food Chem. 2001, 49, 1817-1824 10.1021/jf991387w CCC: $20.00 © 2001 American Chemical Society Published on Web 03/07/2001