For parental animals:

"PREPARATION OF DOSING SOLUTIONS: VEHICLE - Justification for use and choice of vehicle (if other than water): Based on trial formulations performed at Charles River Den Bosch. - Concentration in vehicle: Formulations (w/w) were prepared daily within 6 hours prior to dosing and were homogenized to a visually acceptable level. Formulations were prepared at one concentration only for all dose groups; dose volume was adjusted to reach the correct dose levels. No adjustment was made for specific gravity/density of the vehicle. Adjustment was made for specific gravity/density of the test item (1.67 at 25°C). No correction was made for the purity/composition of the test. Actual dose volumes were calculated according to the latest body weight.

- Amount of vehicle (if gavage): Group 1: 5 mL/kg body weight. Group 2: 0.5 mL/kg body weight. Group 3: 1.5 mL/kg body weight. Group 4: 5 mL/kg body weight.

- Lot/batch no. (if required): 1% Aqueous carboxymethyl cellulose (carboxymethyl cellulose: BUFA, IJsselstein, The Netherlands; water: Elix, Millipore S.A.S., Molsheim, France or Milli-Q. Millipore, Bedford, MA, USA) with 3% Tween 80 (Merck-Schuchardt, Hohenbrunn, Germany).

Analyses were conducted during the treatment phase according to a validated method (Test Facility Study No. 515115). Due to analytical problems during analysis of formulation samples taken on 27 September 2016, new samples were taken on 11 October 2016. Results from the rst measurement were not reported, but kept in the raw data. Samples of formulations were analyzed for homogeneity (formulation containing test item, used for Groups 2 - 4) and accuracy of preparation (formulation used for Group 1 (vehicle only), and formulation used for Groups 2-4). The accuracy of preparation was considered acceptable if the mean measured concentrations were 85 - 115% of the target concentration. Homogeneity was demonstrated if the coefficient of variation was ≤ 10%."

"Males were dosed for 29 days, i.e. 2 weeks prior to mating, during mating, and up to the day prior to scheduled necropsy

Females that delivered were dosed for 50-64 days, i.e. during 2 weeks prior to mating (with the objective of covering at least two complete estrous cycles), the variable time to conception, the duration of the pregnancy and at least 13 days after delivery up to and including the day before scheduled necropsy. The two females which failed to deliver healthy offspring were treated for 43 and 53 days, respectively.

Female nos. 47 (Group 1), 57, 58, 60 (Group 2) and 76 (Group 4) were not dosed at the time of littering. The omission of one day of dosing over a period of several weeks was considered not to affect the toxicological evaluation.

Frequency of treatment is once daily for 7 days per week, approximately the same time each day with a maximum of 6 hours difference between the earliest and latest dose.

F1 parental animals: Pups were not dosed directly but were potentially exposed to the test item in utero, via maternal milk or from exposure to maternal urine/feces."

Frequency of treatment: Once daily for 7 days per week, approximately the same time each day with a maximum of 6 hours difference between the earliest and latest dose.

Lactation Index

Endpoint Details

Dataset

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