Thiophanate-methyl

Endpoint summary

Description of key information

Absorption

In rats, the absorption from the gastro-intestinal tract of low doses of the test item was rapid and represented approximately 89% of the administered dose, based on excretion in urine, bile and faeces. A clear shift from mainly urinary excretion at low doses to predominantly faecal excretion following high dose administration of the test item was detected, suggesting a decrease in oral absorption at high doses. The results from measurements of radioactivity in blood in the same studies provide some support to the statement - there seems to be a less than proportional increase of the AUC in relation to the increase in dose following high dose administration of the test item – but the level of detail in the studies was too low for any conclusion to be drawn. Another explanation to the observation may be that excretion of the test item via bile increases at high doses compared to low doses, meaning that the fraction absorbed by the oral route would be independent of dose. Unfortunately, there are no studies available on excretion via bile following high dose administration of the substance to help elucidate this matter.

Based on the study according to OECD TG 427 the dermal absorption in rats was 3 % for the concentrate (500 g/L).

Absorption via the respiratory route depends on physico-chemical properties like vapor pressure, log Pow and water solubility. In general, highly volatile substances are those with a vapor pressure greater than 25 kPa or boiling point below 50°C. Substances with log Pow values between -1 and 4 are favored for absorption directly across the respiratory tract epithelium by passive diffusion. Due to its low vapor pressure of < 9.0E-6 Pa the substance is unlikely to be available as a vapor. However, since the substance is a solid the formation of inhalable dust can be assumed. Mean mass median diameter was between 3.7 and 4.5 µm have been reported from an acute inhalation study according OECD TG 403.

Distribution

The substance is widely distributed in the body. In rats, at 96 hours post dosing (single low-, repeated low-, and single high dose administration) substance related radioactivity was mainly found in thyroid, liver, and kidneys. The substance was also present in testes and ovaries at levels above or similar to the ones in blood. In male mice, after administration of a single low dose, the highest radioactivity was found in liver, followed by kidney and blood. Low levels of radioactivity was also found in thyroid and testis.

Metabolism

The results of the metabolism studies in rat showed that neither the dose level nor the duration of exposure resulted in a major change in the metabolites, identified in urine. The most important urinary metabolite at both low and high doses was 5-OH-carbendazim-S which accounted for up to 42% of the total radioactivity following single low dose administration. The formation of 5-OH-carbendazim-S is proposed to occur via two competing pathways; one with carbendazim as an intermediate. In rats, there was an indication of possible gut microfloral enzyme induction, and/or possible biotransformation enzyme induction following repeated exposure, as indicated by the lower residue levels in excreta following repeated dosing relative to single low dose administration.

Excretion

Excretion in rats, mice and dogs occurred rapidly via urine and faeces. The excretion was almost complete within 24 to 96 hours depending on dose level and species, and the excretion patterns were comparable between the three species. Excretion via expired CO2 was negligible in rats. At low doses, most of the substance was excreted with urine (70% and 74 % in rats and dogs, respectively), and to a lesser extent via faeces (30% and 14% in rats and dogs, respectively). After high dose administration the relationship was reversed and most test item was recovered from faeces (70% and 73% in rats and mice, respectively), and to a lesser extent via urine (30% and 26% in rats and mice, respectively. During repeated low dosing of rats, every day during the treatment about 90% of the administered radioactivity was excreted via urine (54%) and faeces (35%). Hence, there is no indication that the substance accumulates in the body. Excretion via bile was investigated in one study in rats following single low dose administration. Excretion was found to be driven by both urine (47%) and bile (40%). Only 7% of the administered radioactivity was recovered from faeces.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential