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Administrative data

Link to relevant study record(s)

Description of key information

After oral exposure, MON 13900 appears to be extensively absorbed and rapidly eliminated with elimination occurring primarily via the feces. For the purpose of risk assessment, an oral absorption of 100% is considered as a worst-case. In the absence of further data, default dermal and inhalation absorption values of 100% are also taken.

Key value for chemical safety assessment

Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information

A pharmacokinetics and metabolism study was conducted with MON 13900 in rats according to EPA Guideline OPP 85-1 in compliance with GLP. Young adult male and female Sprague-Dawley rats received either single or repeat oral gavage doses, or intravenous doses of the test substance labeled with14C. The oral doses were administered at 1.25 or 125 mg/kg bw in Emulphor EL-620 and the intravenous doses at 1.25 mg/kg bw in Emulphor:ethanol:saline (1:1:8 v/v). The study consisted of six preliminary experiments (groups P1-P5 and H) designed to determine CO2expiration, blood plasma concentration after oral and intravenous administration, tissue distribution by whole body autoradiography and biliary excretion, and a definitive study consisting of four groups (single intravenous low dose, single oral low dose, repeat oral low dose and single oral high dose).

Total recovery for all groups ranged from 87.7 to 95.1% of the dose. The feces represented the major route of elimination accounting for approximately 58 to 77% of the dose. Urine accounted for approximately 11 to 24% of the dose (groups P1 and A-D). Expired gases, collected for 24 h after dosing, contained only 0.11-0.13% of the dose. The radioactivity associated with the residual carcass, excluding the tissues removed at necropsy, accounted for a maximum of 0.56% of the administered dose at 7 d after dosing. The tissues collectively (including blood and gut contents) contained 0.52-1.12% of the dose. Thus, the total radioactivity remaining in the rat (tissues, blood, gut contents and carcass) constituted a maximum of 1.65% of the dose at 7 d after dosing. The extent of absorption was determined by comparison of urinary excretion between orally dosed rats and the intravenously dosed rats. Absorption following administration of14C-test substance at the low oral dose and repeated low oral dose was approximately 70 and 68.5%, respectively, for males, and 83 and 85%, respectively, for females. Absorption at the high dose was lower, at approximately 54 and 66% for males and females, respectively. Thus, there appeared to be some dose dependency on the extent of absorption. Also, females demonstrated a higher percentage of absorbtion than males. Analysis of the rate of excretion of radioactivity in the urine revealed a biexponential elimination process with a half-life for the initial phase of approximately 4.8 - 8.6 h and for the terminal elimination phase of 41.9 - 118 h. Determination of whole body elimination revealed similar elimination rates. Excretion was rapid with greater than 80% of the dose eliminated within 48 h. Analysis of tissue distribution at 7 d after dosing demonstrated generally low levels of radioactivity in most tissues, with no tissue accounting for more than 1% of the dose. The liver was the only tissue that showed any evidence of significant amounts of radioactivity following oral administration, accounting for 0.33 - 0.88% of the dose. The only other tissues which exceeded 0.1% of the dose in any group were kidney (0.06 - 0.11% for the intravenous dose, 0.02 - 0.03% for the oral doses), muscle (0.09 - 0.18% of the dose) and skin (0.05 - 0.18% of the dose). Blood, at the 7 d sacrifice, contained 0.26 - 0.29% of the dose which was localized almost exclusively in red blood cells. In terms of concentration, only the liver (0.07 - 0.23 ppm) and red blood cells (0.07 - 0.10 ppm) of all groups, and the lung (0.12 - 0.16 ppm) and kidney (0.08 - 0.13 ppm) of the intravenous group approached or exceeded levels of radioactivity higher than 0. 1 ppm (dose adjusted for high dose group). The concentration of radioactivity in the liver, in comparison with blood levels, demonstrated a liver to blood ratio of 1.8 to 4.5. Only the liver and red blood cells of all groups, and the lung and kidney of the intravenous group, had tissue to blood ratios significantly greater than one. Liver to blood ratios were slightly higher in the females compared to the males. In contrast, blood levels were comparable between the sexes. There was no significant effect of pre-treatment of animals for 14 d at 1.25 mg/kg bw on the liver to blood ratio. However, the ratio did appear slightly lower at the high dose level (125 mg/kg bw) compared to the low dose (1.25 mg/kg bw). It was found that following intravenous administration the tissue to blood ratios in lung and kidney were greater than unity, and significantly different than those observed following oral administration. The finding of higher tissue to blood ratios in the lung and kidney following intravenous administration, compared to oral administration, suggests either a pharmacokinetic or metabolic effect due to the different routes of administration. Repeated dosing, on the other hand, appeared to have no significant effect on tissue accumulation nor was there any significant effect of dose level on tissue distribution or tissue levels. The significance of these higher tissues to blood ratios in the lungs and the kidneys, which are highly-perfused organs, is difficult to interpret since the red blood cells also demonstrated a higher affinity for the test substance-derived radioactivity than did plasma. At this stage, the nature of the radioactivity associated with these tissues or the red blood cells is not known. The overall tissue distribution was also studied by whole body autoradiography which confirmed that the liver contained higher levels of radioactivity than other tissues at sacrifice. Whole body autoradiography also confirmed the higher liver levels in females compared to males at both the low and high dose levels. Low levels of radioactivity were observed in the highly perfused organs (heart, kidney, lung and spleen), blood and the gastrointestinal tract, as well as the nasal turbinates (high dose only). No other significant localization of radioactivity was observed.

In conclusion, the test substance appears to be well absorbed and rapidly eliminated, with elimination occurring primarily via the bile into feces. No tissue level accounted for more than 1% of the dose and only the liver (oral and intravenous), lung (intravenous, only) and kidney (intravenous, only) demonstrated any evidence of accumulation, as reflected by tissue to blood ratios significantly greater than one. In addition, the total radioactivity associated with the tissues and carcass accounted for less than 1.7% of the administered dose. Females demonstrated slightly higher tissue levels (liver, lung and kidney) than males and there was no significant effect of dose level or pre-treatment with the test substance. The nature of the blood cell and tissue associated radioactivity is unknown. However, as mentioned, this data should be interpreted with caution in view of the apparent affinity of the test substance-derived radioactivity for red blood cells.