"This study was conducted in accordance with the Protocol dated August 27, 1998, and Protocol Amendment Nos. 1, 2, and 3. The protocol, protocol amendments, and protocol deviations are in Appendix 1.

Group Designations and Dose Levels

The animals were examined by a laboratory animal veterinarian on August 31, 1998, and found to be suitable for study consideration. Selection of animals for the study was based on clinical observations, body weights, ophthalmic examinations, and other data as appropriate. Animals were assigned to treatment groups using a computerized blocking procedure designed to achieve body weight balance with respect to treatment group. At

the time of randomization, the weight variation of the animals for each sex used did not exceed ±2 standard deviations of the mean weight. Group mean body weights were analyzed using Levene's test for homogeneity of variance at the 5.0% probability level and found to be homogeneous. "

Dose Preparation

Dietary concentrations were based on the test material as supplied. Before initiation of treatment, diets of 1, 3, 30, 100, and 500 ppm concentrations were mixed. Diets were prepared for stability analyses at the 1-ppm and 500-ppm concentrations and for homogeneity analyses at the 3, 30, and 100 ppm concentrations. Diets were prepared once every 4 weeks for use in the in-life phase. Preparation of Diet for Group 1. The appropriate amount of diet was weighed into a labeled container and acetone was added at the same concentration as the high-dose concentration. The combination of the diet and acetone was then mixed for 15 minutes. Preparation of Diets for Groups 2 through 3. Each dose level was prepared independently. A specified amount of diet was weighed into a labeled container and a specified amount of diet for Group 4 was weighed for each diet. A trench was formed in the feed in the mixing bowl and the amount of diet for Group 4 was transferred to the trench. The contents of the mixing bowl were thoroughly mixed for 15 minutes. Preparation of Diet for Group 4. A specified amount of diet was weighed into a labeled container. The required amount of test material was weighed and transferred into a labeled container. Approximately 5 mL of acetone was added to the container and mixed

manually. Increments of approximately 5 mL acetone were added as necessary until the test material had dissolved. To prepare a premix, the diet was transferred into a labeled Hobart® mixing bowl The test material and acetone were added to the mixing bowl, overlaid with a portion of diet from the mixing bowl, and thoroughly mixed. A portion of diet from the mixing bowl was transferred to a second mixing bowl, mixed manually to

recover residual test material, and returned to the first mixing bowl. The contents of the mixing bowl were thoroughly mixed. Samples for dose analyses were taken directly from the mixing bowl. The prepared test diets were stored at room temperature in covered containers until

dispensed into feeding jars. Retention Samples During the in-life phase, samples (approximately 100 g) were taken from each dose

preparation for dose analyses and stored at room temperature. These samples were discarded on May 11, 1999 (see Protocol Deviations for exceptions).

Method of Administration

Dietary admixture was used because the potential route of exposure in humans is oral. The dose preparations were administered ad libitum for at least 13 weeks, unless otherwise specified.

Dose Analysis

Analyses for the concentration of test material in the dose preparations were done by Covance using an analytical method, MP-M324-MA, supplied by the Sponsor and validated by Covance. Homogeneity was determined for the 3-ppm, 30-ppm, and 100-ppm dose preparations once pretest. One sample (approximately 100 g) each from the top, middle, and bottom of the dose preparations mixed for homogeneity analyses were collected, divided into three subsamples for extraction and analysis, and analyzed for test material content. All samples were stored at room temperature until analyzed within 7 days of mixing. Four samples (approximately 100 g each) were taken from the I-ppm dose level concentration of diet preparations mixed pretest. One sample was analyzed on the day of mixing and used as the baseline value. One sample was stored at room temperature for at

least 19 days, then analyzed. A third sample was stored at room temperature for at least 32 days, then analyzed. The remaining sample was stored in a freezer set to maintain -10 to -30°C for 8 weeks, then analyzed. In addition, two samples (approximately 100 g each) were taken from the 500-ppm dose preparation mixed pretest. One sample was analyzed on the day of mixing. The second sample was stored at room temperature after

at least 32 days, then analyzed. Two additional samples (approximately 100 g each) were taken from the 3-ppm dose preparation mixed for Weeks 9 through 12. One sample was stored at room temperature for at least 19 days, then analyzed. The second sample was stored at room temperature for at least 32 days, then analyzed. The sample collected for dose confirmation analysis was used as the baseline sample. During the in-life phase, samples (approximately 100 g) from all dose preparations were collected and analyzed for dose confirmation. All samples were stored at room

temperature until analyzed."

Male Crl:CD (SD) IGS BR rats