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Organ weight effects but no toxicologically relevant histopathological alterations were recorded in male and female rats  exposed to up to 400 ppm alpha pinene by inhalation for up to 14 weeks. Sub-chronic inhalation toxicity testing in mice revealed hyperplasia of the transitional epithelium of the urinary bladder with a NOAEL of 50 ppm in both sexes.

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Preliminary results are available from two US National Toxicology Program (NTP) studies conducted on alpha pinene in which female and male F344/N rats and B6C3F1 mice were exposed to concentrations ranging from 0 to 400 ppm by inhalation. Alpha pinene is structurally related to Terpenes and terpenoids, turpentine oil, alpha pinene fraction oligomers, however its less complex structure and lower formula weight suggest it is should be more readily available than the oligomer. Hence results from these two sub-chronic inhalation studies will be used to predict the potential systemic toxicity of Terpenes and terpenoids, turpentine oil, alpha pinene fraction oligomers (read-across using the analogue approach).

In the first study (NTP, 2005c), female and male F344/N rats were exposed to 0, 25, 50, 100, 200, or 400 ppm alpha-pinene by inhalation for 6h/days for 14 weeks. In the first study (NTP, 2005), female and male F344/N rats were exposed to 0, 25, 50, 100, 200, or 400 ppm alpha-pinene by inhalation for 6h/days for 14 weeks. All males rats survived to scheduled study termination, however body weight gain was decreased when compared to controls. Absolute and relative liver weights were statistically increased in males exposed to >200 ppm with relative and absolute kidney weights increased >100 ppm. Males also showed statistically significant decreases in sorbitol dehydrogenase activity at 400 ppm, alanine aminotransferase activity at levels ≥50 ppm, and alkaline phosphatase activity at levels ≥100 ppm. None of these changes in enzyme activity were related to organ weight changes or evidence of histopathology. Examination of the male kidneys revealed lesions at all dose levels including granular casts and hyaline droplets indicative of a2u-globulin nephropathy. Based on these observations, the NOEL for male rats was 25 ppm (based on a2u-globulin related changes in kidney), with a NOAEL of 200 ppm, based on increased liver weights (in the absence of associated changes in histopathology) recorded at 400 ppm. In females, six animals from the 400 ppm group were found dead during the study and three animals from this same high exposure group displayed mild tremors. Relative and absolute liver weights were increased in females at exposure levels of ≥50 ppm, but there were no increases in either hepatic enzymes or any evidence of histopathological changes at any of these dose levels. Absolute and relative thymus weights were significantly decreased, and relative lung weight increased, in high dose level females. Alanine aminotransferase activity was decreased at ≥200 ppm, and alkaline phosphatase activity decreased at the 400 ppm, in females. None of these changes in enzyme activity were related to organ weight changes or evidence of histopathology (no evidence of histopathology in any organ at any dose level). The NOAEL for female rats was 200 ppm, based organ weight changes (in the absence of associated changes in histopathology) recorded at 400 ppm.

In the second study (NTP, 2006) female and male B6C3F1 mice were exposed to alpha-pinene via inhalation at concentrations of 0, 25, 50, 100, 200, or 400 ppm for 6h/days per week for 14 weeks. All mice survived until scheduled study termination, and body weight gain were comparable for all test and control animals. At 400 ppm, an increase of absolute liver weights was observed in both sexes. At 200 and 400 ppm, an increase of absolute liver weights were recorded for both sexes. The 400 ppm male group showed decreased absolute and relative thymus weight. No gross or microscopic lesions were associated with these organ weight findings. Histopathological examination of male and female mice exposed to ≥100 ppm of α-pinene revealed evidence of hyperplasia of the transitional epithelium of the urinary bladder. Histopathological examination confirmed that there were no changes in clitoris, ovaries, uterus, epididymis, preputial gland, seminal vesicles, and testes compared to the control groups. Based on these observations, a NOAEL for both male and female mice was concluded to be 50 ppm.

This information is available from the NTP website (http://ntp.niehs.nih.gov/?objectid=BD4A21C3-123F-7908-7B76D9A5ADDD10A3), and the report information will be publicly available in the future.

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