Prometryn

Endpoint summary

Description of key information

- Absorption: rapid and extensive absorption of approximately 95 % of a single orally administered dose of 0.46 or 470 mg/kg in the rat.

- Distribution: highest residue levels were found in red blood cells followed by organs with high blood perfusion: lung, spleen, heart and liver. Tissue residues were slightly lower in males compared to females.  

- Metabolism: the test substance was extensively metabolized within first 4–8 h in the rat with <2 % of recovered radioactivity representing the parent. All identified 29 metabolites found in the faeces were also identified in the urine. In bile-duct cannulated rats, the major biliary metabolite fraction accounted to about 10% of the administered dose. None of the metabolic fractions in bile and urine corresponded to unchanged parent while in the faeces of bile-duct cannulated rats, the major fraction of radioactivity (0.9 % of the dose) corresponded to parent.  

- Excretion: Rapid excretion after administration of a single oral dose of 0.5 mg/kg body weight to female rats. In bile duct-cannulated rats, 67 %, 24 % and 4 % of the administered substance was excreted via the bile, urine and faeces, respectively within two days, hence a significant part of substances excreted in faeces was absorbed and re-eliminated via intestinal tract by biliary excretion. The pattern of elimination was not dependent on sex or dosing regimen.

- Bioaccumulation potential: No evidence of accumulation after repeated dosing.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

95

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

 The fate of the test substance was investigated in female rats using [U-14C]triazine-labelled test substance. About 90% of an oral dose (0.5 mg/kg) were absorbed from the gastrointestinal tract into the general circulation. Within 48 hours about 67%, 24%, and 4% of the administered dose were excreted with the bile, urine, and faeces, respectively, by bile-duct cannulated rats. The residual radioactivity was determined 8 hours (time point of maximum concentration of radioactivity in the whole blood), 2 days, 5 days, and 11 days (one half of maximum blood concentration) after dosing in spleen, liver, fat, kidneys, muscle, brain, heart, lungs, bone, plasma, ovaries, uterus, red blood cells, and in the remaining carcass. Five days after an oral administration of 0.5 mg/kg body weight the tissue residues were below 0.06 ppm test substance equivalents, except in red blood cells (0.44 ppm). Within eleven days after dosing the tissue residues declined to values <0.02 ppm, except in red blood cells (0.37 ppm), spleen, lungs (0.05 ppm), liver and kidneys (0.02 ppm). The residues in red blood cells corresponded to 3.9%, 4.3%, 2.6%, and 2.3% of the dose at 8 hours, 2, 5, and 11 days after administration, respectively. The half-life time for the depuration of the residues from the red blood cells was calculated to be 4 days for phase 1 (2 to 5 days after administration) and 23 days for the slower phase 2 (5 to 11 days after dosing). These two phases were also observed in the other tissues and organs, demonstrating a non-linear behaviour of the depletion kinetics (assuming first order kinetics). The relatively high residues in the red blood cells and the pronounced slow depuration of these residues is characteristic for methylthio triazines in rats. This class of substances form stable derivatives with rodent and chicken haemoglobins, but do not react with human haemoglobins.

One of the major urinary metabolites was identified as 2,4-bis(isopropylamino)-6-(N-acetyl-cysteinyl)-1,3,5-triazine, the mercapturic acid derivative of the test substance. It accounted for about 4 % of the administered dose. Another urinary metabolite fraction (0.5 % of dose) was identified as 2-amino-4-isopropylamino-6-methylthio-1,3,5-triazine, designated as M4. The major fraction of applied radioactivity (0.9 % of the dose) present in the faeces extract of the bile-duct cannulated rats corresponded to unchanged test substance. The major fraction of applied radioactivity found in the bile (10 % of the administered dose) was identified as 2,4-bis(isopropylamino)-6-gluthathionyl-1,3,5-triazine. Two other major metabolite fractions were identified as metabolite M4 (6.2 % of dose) and metabolite M1, the mono- and bis- dealkylated derivatives of the test substance, respectively. Besides mono- and bis-dealkylation at the amino groups, the glutathione pathway plays an important role for the elimination of the test substance.