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Carcinogenicity

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Nine studies on rats with sufficient reliability are available. The study periods varied between 36 to 100 weeks. The carcinogenic effect of sodium barbital was investigated in seven studies using only male rats and in two studies using both sexes.

 

Most of the studies investigated the effects of sodium barbital treatment with prior administration of cancer initiating agents.

These investigations revealed the following with regard to the renal system and the bladder:

- The occurrence of renal cortical adenomas and carcinomas and the mean number of lesions/kidney in male rats treated with sodium barbital after nickel(II) acetate tetrahydrate initiation were found to be elevated. Female rats and different dose levels were not examined (Kasprzak et al., 1990).

- Sodium Barbital enhanced the development of renal tubular adenomas and carcinomas at 78 weeks in N-nitrosodiethylamine treated male rats (n=15). Female rats and different dose levels were not examined (Diwan et al., 1985).

- The long latency of OTA-induced renal tumourigenesis was not notably susceptible to accelerated promotion by barbitate (Mantle et al., 2010). Different dose levels were not examined

- In an investigation of transplacental carcinogenic effects of cis-dichlorodiammineplatinum (cis-DDP) in F344 rats, postnatal administration of NaBB enhanced renal cell tumors in male but not female rats (Diwan 1995).

- Sodium barbital at 4000 ppm for 52 weeks had a tumor promoting effect on the development of renal cortical tubular cells in male rats following initiation with streptozotocin. A prolonged administration (more than 52 weeks) of sodium barbital is necessary to promote renal tubular cell neoplasms. Female rats and different dose levels were not examined (Konishi et al.,1990)

- Sodium barbital promotes bladder carcinogenesis initiated by either N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) or N-nitrosobutyl-4-hydroxybutylamine (BBN) in male F344 rats (max.13 rats per group). Reducing the total initiating exposure to FANFT by a factor of 3, from 6 weeks of feeding to 2, drastically reduced the apparent promoting effect of sodium barbital. Female rats and different dose levels were not examined (Diwan et al., 1989).

All in all, tumor promoting effects were found in male rats but were not confirmed in the studies that have been conducted with females. All studies have small treatment group, exposure times less than 24 months and often only one dose, which reduces the explanatory power. Nevertheless, male rat-specific effects could be assumed.

 

Male rat-specific effects may occur for example due to renal alpha2u-globulin accumulation within renal phagolysosomes. Kurata et al. 1994 (see repeated dose toxicity IUCLID entry) showed that sodium barbital increased levels of renal alpha2u-globulin (male rat-specific protein), which is associated with hyaline droplet nephropathy in male rats. Chronic exposure and persistant protein droplet accumulation may then lead to chronic increases in levels of cell replication, renal tubular hyperplasia and neoplasia. This finding may also explain the induction of papillomas of the transitional epithelium of the renal pelvis and renal tubular cell adenomas in male rats after sodium barbital alone exposure (Konishi et al.,1990).

Wolf et al. (2000) conducted a study with male Tsc2 mutant rats given sodium barbital in the feed from 9 weeks of age to either 6 or 12 months of age. Sodium barbital-treated male rats necropsied at 12 months of age had numbers of lesions that were not different from controls. Sodium barbital caused progression to the stage of spontaneous renal lesions in Tsc2 mutant male rats (a hereditary tumor model) but did not increase their overall number (Wolf et al., 2000). Female rats were not examined.

Investigations on the effects of sodium barbital treatment with prior administration of cancer initiating agents on liver cells revealed:

- N-nitrosodiethylamine treated male rats showed enhanced the development of hepatocellular foci, hepatocellular adenomas, and trabecular carcinomas at 78 weeks after exposure to sodium barbital. (Diwan et al., 1985)

- Diwan et al. (1995) showed that NaBB administered to male and female rats failed to promote liver carcinogenesis initiated by transplacental cis-DDP.

- No excess incidence of nickel-initiated tumors was found in liver of sodium barbital treated male rats (Kasprzak et al., 1990).

A tumor promoting effect on liver cells cannot be concluded from this data.

Finally, the criteria of CLP-regulation (EC) 1272/2008 for a classification and labelling of carcinogenicity are not fulfilled. A classification with regard to carcinogenicity is not required.

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