Pentanedioic acid, compd. with (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (1:1)

Carcinogenicity

Description of key information

Two studies conducted on an analogue material to assess carcinogenicity in rats provided the following information:

Goldenthal, 2001 - 104 oncogenicity study in mice: The test article, 1592U89, was administered orally by gavage to Charles River CD-1 (R) mice for 2 years at dose levels of 55, 110, or 330 mg/kg/day. Under the conditions of this study, 1592U89 is considered to be oncogenic in male mice at equal to or greater than 110 mg/kg/day and female mice at equal to or greater than 330 mg/kg/day.

Goldenthal, 2001 - 104 oncogenicity study in rats: The test article, 1592U89, was administered orally by gavage to Han Wistar rats for 2 years at a dose levels of 30, 120 and 600 mg/kg/day. Under the conditions of the study, 1592U89 is considered to be oncogenic in male and female rats at 600 mg/kg/day.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

110 mg/kg bw/day

Study duration:

chronic

Species:

mouse

Justification for classification or non-classification

Although both studies were carried out on an analogue material, the analogue is considered to be sufficiently similar to the substance of interest (please see attached data matrix and justification in Section 13 for additional details) for it to be used for the purposes of health and environment risk assessments.

Carcinogenicity effects were noted in both studies in particular neoplasms were noted in the preputial glands of males and clitoral glands of females in both mice and rats.

Under classification and labelling guidelines a test material can be considered to be classified as Category 1B for Carcinogenicity when animal experiments carried out on two separate species show sufficient evidence of carcinogenicity. As mentioned above, both studies showed a greater incidence of neoplasms in both sexes of mice and rats exposed to the analogue material.

Based on the analogues similarities with the material of interest, the test material Abacavir Glutarate can be considered to be classified as a Category 1B Caricinogen.

Additional information

Two studies have been carried out on an analogue of the substance of interest to assess for carcinogenicity.

Both studies concluded that the test material should be considered to be carcinogenic.

Both studies were performed according to recognised guidelines and are therefore considered to be reliable. As these studies are not a requirement at the current tonnage level they have been included as supporting studies.

Goldenthal, 2001 - 104 oncogenicity study in mice

Survival in males at 55 and 330 mg/kg/day was less than that of the controls during the second year of the study. Survival in females at 330 mg/kg/day was less than that of the controls during the last 6 months of the study. Survival was similar to controls on the other treatment groups. During the last 7 weeks of the study, dosing was discontinued in males at 330 mg/kg/day because of this decreased survival. An increase in the number of masses in the anogenital region in males at 330 mg/kg/day was seen during the second year of the study. No effect of treatment on body weights was seen.

The main finding in the study was test article-related, statistically and biologically significant increases in the incidence of neoplasms in males and females at 330 mg/kg/day compared to controls. In males, these neoplasms consisted of squamous cell carcinoma of the preputial gland and hepatocellular adenomas of the liver. In females, squamous cell carcinoma of the clitoral gland, hepatocellular adenoma of the liver, and adenoma of the Harderian gland were increased. Statistical significance was observed in the Cochran-Armitage trend test and by Peto analysis, and, in the case of squamous cell carcinoma of the preputial gland in males and adenoma of the Harderian gland in females, by the Fischer's exact test. The only biologically significant neoplastic findings at 110 mg/kg/day were preputial gland squamous cell carcinomas in two males. Carcinoma of the Harderian gland and mammary gland and rhabdomyosarcoma of the subcutis skin in females at 330 mg/kg/day were statistically significant by the Peto analysis, but the differences in tumor incidences were small and not considered biologically significant or related to treatment. The few test article-related and biologically significant non-neoplastic lesions seen at 330 mg/kg/day consisted of increased incidences of altered foci in the liver and cardiomyopathy in both males and females.

Goldenthal, 2001 - 104 oncogenicity study in rats

Survival was low in males at 600 mg/kg/day than that of controls throughout most of the study, resulting in cessation of dosing in this sex group during Week 84 and early terminal sacrifice in Week 94. Survival was lower in females at 600 mg/kg/day compared to controls during the second year of the study, resulting in cessation of dosing in Week 100. Survival in the other treated groups was similar to controls. No test article-related clinical findings were observed throughout the study except for a higher incidence of anogenital masses in females at 600 mg/kg/day during the second year of the study. During the second year of the study, body weights were statistically significantly lower in males at 600 mg/kg/day throughout the study and slightly lower in females when compared to their respective controls. No test article-related alterations were seen in any of the hematology parameteres evaluated at the termination of the study.

The main finding in this study was test article-related and biologically significant increases in the incidence of neoplasms in males and females at 600 mg/kg/day compared to controls. In males, these neoplasms consisted of squamous cell carcinoma of the preputial gland and hepatocellular adenomas of the liver. In females, these neoplasms consisted of squamous cell carcinoma of the clitoral gland, hepatocellular adenoma and carcinoma of the liver, and follicular adenoma of the thyroid gland. Liver and thyroid neoplasms occurred with a significant postive trend (Cochran-Armitage trend and Peto analysis). Because only preputial and clitoral gland tissues with macroscopic lesions were available for microscopic examination, statistical analysis for preputial and clitoral neoplasms were not comparable to other results. In addition, one transitional cell papilloma and one transitional cell carcinoma of the urinary bladder were seen in females at 600 mg/kg/day and one transitional cell papolloma of the urinary bladder was seen in males at 600 mg/kg/day. Statistically significant increases by Peto analysis were seen for a few other neoplasms but the differences in incidences were small and not considered biologically meaningfull or related to treatment. Test article-related, non-neoplastic lesions seen primarily at 600 mg/kg/day consisted of myocardial degeneration; altered foci in the liver, lymphocytic infiltration, pyelonephritis, and tubular degeneration and regeneration of the kidney; and uroethial hyperplasia of the urinary bladder.

Carcinogenicity: via oral route (target organ): glandular: other