Three-month Study in Rats:

In the perinatal portion of the 3-month study, pregnant rats exposed to 40,000 ppm were humanely euthanized due to overt toxicity early in gestation. With the exception of sporadic decreases in maternal body weight and feed consumption during gestation and lactation (approximately 10%–20% lower than control rats), no other toxicologically relevant findings were reported for dams. TCPP exposure also had no effects on littering parameters at concentrations ≤20,000 ppm, and offspring survived through lactation. Offspring in the 20,000 ppm TCPP group did exhibit a time-dependent decrease in weight gain during lactation. Male offspring in the 20,000 ppm group failed to thrive after weaning and were removed from the subchronic portion of the study on day 5; females in this exposure group were kept on study.

For the remainder of the 3-month study, male and female rats survived and displayed no clinical signs of toxicity when exposed to 10,000 ppm TCPP or lower concentrations. Females in the 20,000 ppm TCPP group had a mean body weight that was 12% lower than that of control females, which corresponded with a similar decrease in feed consumption (18%) by study termination. No biologically relevant alterations in hematological parameters were observed in either sex. Serum cholesterol concentrations were significantly increased in both sexes. TCPP did elicit exposure concentration-related effects (i.e., significantly increased organ weights and microscopic changes) in the liver and thymus of rats. In the liver, bile duct hyperplasia was observed in the highest exposure groups for both sexes. Increases in thymus weight were correlated with significantly larger thymic cortices in all males exposed to TCPP and in females in the 10,000 ppm group.

Two-year Study in Rats:

The effect of chronic TCPP exposure was evaluated in rats, beginning in utero and through adulthood, following feed administration at target concentrations of 0, 2,500, 5,000, 10,000, or 20,000 ppm TCPP. TCPP exposure to dams had no toxicologically relevant effects on maternal measurements during gestation or lactation with the exception of a slightly lower mean body weight and feed consumption in the 20,000 ppm group over this perinatal period. An exposure concentration-related decrease in mean body weight relative to control animals was observed in male and female offspring in the 20,000 ppm TCPP group during lactation. At the end of the 2-year study, mean body weights of males and females in the 20,000 ppm group were 8% and 17% lower, respectively, than those of the control groups. Histopathological evaluations identified a positive trend for incidences of hepatocellular adenoma or carcinoma (combined) in male rats. Accompanying significant nonneoplastic lesions included hyperplasia of the bile duct and an increase in basophilic, eosinophilic, mixed-cell foci, and pigment in the liver of males exposed to 20,000 ppm TCPP. A nonsignificant increase in the incidence of hepatocellular adenomas was observed in females exposed to 2,500, 10,000, and 20,000 ppm TCPP, and a spectrum of nonneoplastic lesions, similar to those in male rats, was observed. Histopathological evaluations also identified a positive trend for incidences of uterine adenoma or adenocarcinoma (combined) in female rats, although this was not significant at any exposure concentration.

Three-month Study in Mice:

In the 3-month TCPP study with mice, mortality and clinical signs of toxicity were not observed across the exposure groups ranging from 1,250 to 20,000 ppm. TCPP-exposed male and female mice gained less weight than control mice; however, this response was only concentration related in the males. At the end of the subchronic study, TCPP exposure was associated with a spectrum of organ weight changes and microscopic changes in both sexes. Significantly increased liver weights were observed alongside a significant increase in the incidences of hepatocellular hypertrophy in males and females exposed to 5,000, 10,000, and 20,000 ppm TCPP. A significant increase in the incidences of cytoplasmic alteration was observed in the renal tubules of male mice exposed to 2,500, 5,000, 10,000, and 20,000 ppm TCPP. This observation was not evident in females and was not correlated with an observed decrease in kidney weights of both sexes.

Two-year Study in Mice:

The TCPP exposure groups were different for male and female mice exposed chronically. Exposure concentrations of TCPP in feed were 0, 1,250 (males only), 2,500, 5,000, or 10,000 (females only) ppm. An exposure concentration-related decrease in mean body weights was recorded in males and females relative to their respective control groups; however, survival, clinical observations, and feed consumption measurements were not suggestive of overt toxicity. Lower mean body weight was interpreted as a failure to gain weight. Similar to rats, mice also had a significant increase in liver neoplasms. Male mice had a significant increase in the incidence of hepatocellular carcinoma across all TCPP-exposed groups, but the incidences were similar among these groups. Significant increases in the incidence of hepatocellular adenoma, hepatocellular carcinoma, and hepatocellular adenoma or carcinoma (combined) were also noted in the 10,000 ppm TCPP-exposed female mice relative to the control females. Exposure-related nonneoplastic lesions were not observed in male mice. However, a significant increase in cytoplasmic alteration of hepatocytes was observed in nearly all females of the 10,000 ppm group. Additionally, a significant increase in eosinophilic foci was recorded in all female TCPP-exposed groups.

(This is an abridged version of the abstract. Go to the Abstract page to see the full text and summary table.)