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Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: non-standard study; non-GLP
Objective of study:
toxicokinetics
Principles of method if other than guideline:
other: toxicokinetic study
Mesamoll concentration was measured in fat and liver tissue at different timepoints during / after dosing
GLP compliance:
not specified
Species:
rat
Strain:
Wistar
Sex:
male
Route of administration:
other: gavage/feed
Vehicle:
other: Lutrol
Duration and frequency of treatment / exposure:
Experiment1)
Single dose; 100 mg/kg; animals were killed 1, 3, 7, 14, 21 and 34 days after dosing

Experimet 2)
Single dose 1000 mg/kg; animals were killed 1, 3, 7, 14, 21 and 34 days after dosing

Experiment 3)
rats were fed diet containing 100 ppm compound for 49 days. Animals were sacrificed on day 1,3, 7, 14, 21 and 43 day.

Experiment 4a)
rats were fed diet containing 1000 ppm compound for 49 days. Animals were sacrificed on day 1,3, 7, 14, 21, 28, 35, 42 and 49. (see experiment 3)

Experiment 4b)
rats were fed diet conaining 1000 ppm compound for 27 days; thereafter rats were fed a diet without Mesamoll. Animals were sacrificed on day 1,3, 7, 14, 21, 28, and 43.
Remarks:
Doses / Concentrations:
100 mg/kg bw and 1000 mg/kg bw. (gavage study); 100 ppm and 1000 ppm feeding studies.
No. of animals per sex per dose:
30/sex/dose (gavage study); 30/sex/dose (feeding study 100 ppm); 50/sex/dose (feeding study 1000 ppm).
Control animals:
yes
Details on excretion:
20 - 30 % of the dose was excreted in the feces within 24 h.
Toxicokinetic parameters:
half-life 1st: The half-life of Mesamoll in fat tissue after single oral application 1000 mg/kg was 8 days.
Toxicokinetic parameters:
half-life 2nd: The half-life of Mesamoll in fat tissue after repeated oral application of 1000 mg/kg was 15 days.
Toxicokinetic parameters:
other: No accumulation was observed in the liver. 20 - 30 % of the dose was excreted in the feces within 24 h.

Mesamoll concentration in the liver was low in all experiments (actual concentration below or slidely above LOD)

Mesamoll concentrations in fat:

Experiment 1) Cmax 22 µg/g fat (day 3); Mesamoll concentration below LOD on day 14

Experiment 2) Cmax 65 µg/g fat (first timepoint measured; day 1); elemination half-life 8 days; 20 -30% of dose eleminated by feces during the first 24 h.

Experiment 3) Mesamoll concentrations in fat increased linear over time until the end of the experiment

Experiment 4a) Mesamoll concentrations in fat increased linear over time until day 21 (ca. 235 µg/g fat) and slightly increased therafter (ca. 290 µg/g fat on day 49).

Experiment 4b) Elemination half-life: approx. 15 days

Executive summary:

The half-life of Mesamoll in fat tissue after single oral application and repeated oral application of 1000 mg/kg was 8 days and 15 days, respectively. No accumulation was observed in the liver. 20 - 30 % of the dose was excreted in the feces within 24 h.

Description of key information

The half-life of Mesamoll in fat tissue after single oral application and repeated oral application of 1000 mg/kg was 8 days and 15 days, respectively. No accumulation was observed in the liver. 20 - 30 % of the dose was excreted in the feces within 24 h.

Key value for chemical safety assessment

Bioaccumulation potential:
high bioaccumulation potential

Additional information

Mesamoll concentration in the liver and fat were investigated in limited experiments by Schmidt 1975. Rats were dosed with Mesamoll by gavage in acute experiments and in feeding experiments up to 49 days. No significant Mesamoll concentrations were reported in the liver in any experiment. After single dosing with 1000 mg/kg the Cmax concentration in fat was 65 µg/g fat (day 1) and the elimination half-life reported was 8 days; 20 -30% of dose was eliminated by feces during the first 24 h. Cmax value increased to 235 µg/g fat with a half-life of 15 days after exposure to 1000 ppm Mesamoll in the diet for 27 days. The feeding studies showed an increase of tissue concentrations after prolonged exposure. In the 1000 ppm dose group a concentration of 280 µg/g fat tissue was measured after 7 weeks of exposure (Schmidt U., Bayer AG, 1975). There are no toxicokinetic studies after the dermal application of Mesamoll. Based on low water solubility (0.002 g/l; 22 oC) and the high logPow value dermal absorption is anticipated to be low. This assumption is in line with an acute dermal toxicity experiment in which no symptoms of toxicity were reported up to the highest dose tested to (1055 mg/kg). Conclusion: Overall, based on the limited data available Mesamoll is absorbed after oral intake and there is an accumulation potential which is in line with the high logPow > 6.