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Carcinogenicity

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Description of key information

No long-term studies have been conducted on Santicizer 261a. For read-across purposes, data on the structurally related phthalates, DINP and BBP, can be used to provide insight into the expected carcinogenicity potential of S261a.
In three oral carcinogenicity bioassays on DINP, increases in tumour incidence were observed in the liver and kidney at around 800 mg/kg bw/day and in the blood (mononuclear cell leukemia, MNCL) from 400 mg/kg bw/day in one rat study, in the blood (MNCL) from around 175 mg/kg bw/day in a second rat study, and in the liver of mice from 200 mg/kg bw/day. The EU RAR on DINP puts forward persuasive arguments for why these three tumour types are not likely to be relevant to humans.
A significantly higher incidence of MNCL has also been reported in female rats in an NTP feeding study with BBP (at 600 mg/kg bw/day), but this was not reproducible in a later study in the same rat strain at twice the dose. In the earlier study, the male rat data were not considered reliable due to premature deaths, but in the later study BBP showed some evidence of carcinogenic activity in males (increased pancreatic tumours) at around 500 mg/kg bw/day, and equivocal evidence of carcinogenic activity in females (marginally increased incidences of pancreatic tumours and of transitional epithelial papilloma of the urinary bladder) at the top test dose of around 1200 mg/kg bw/day. BBP showed no evidence of carcinogenic potential in mice at a dose of up to around 1560 mg/kg bw/day. The EU RAR on BBP notes it may be a borderline case between no classification for carcinogenicity and Carc. Cat. 3 (under Directive 67/548/EEC, i.e. substances which cause concern for man owing to possible carcinogenic effects), but it opts for no classification due to the lack of genotoxic effects.

Key value for chemical safety assessment

Additional information

No long-term studies have been conducted on Santicizer 261A. For read-across purposes, data on the structurally related phthalates, DINP and BBP, can be used to provide some insight into the likely (lack of) carcinogenicity of S261A.

In a study by Lington et al. (1997), groups of male and female F344 rats (110/sex/dose) were fed DINP (68515-48-0) in the diet at 0, 0.03, 0.3 or 0.6% (equivalent to about 0, 17, 175 or 350 mg/kg bw/day) for up to 2 years. Ten rats/sex/group were scheduled for interim sacrifice after 6, 12 or 18 months, the remaining animals were killed after 2 years. Treatment-related effects on the liver, kidney and spleen, the blood and urine, body weight, and mortality were seen in the mid- and/or high-dose groups of exposed males and/or females. No treatment-related increases in tumour incidence were observed in rats fed DINP in the diet at any dose at 6, 12 or 18 months. At 2 years, a statistically significant increase in the incidence of mononuclear cell leukemia (MNCL) was seen in the mid- and high-dose groups of both sexes when compared to the controls. MNCL is unique to the rat and and is a common finding in ageing F344 rats. The incidence is influenced by a number of variables, including diet and spleen damage. No histologically comparable tumour is found in humans. The general view of the Expert Groups is that a finding of increased MNCL in ageing F344 rats is not toxicologically relevant to humans (e.g. European Chemicals Bureau, 2003b: EU Risk Assessment Report on DINP). In this study, a clear NOAEL (no-observed-effect level) was demonstrated for systemic toxicity and carcinogenicity in rats administered DINP in the diet at 0.03% (about 17 mg/kg bw/day).

In an unpublished study by Butala et al. (1996), available only as a brief abstract, male and female rats were fed diets containing DINP (68515-48-0) at 0, 500, 1500, 6000 or 12000 ppm (equivalent to about 0, 35, 100, 400 or 800 mg/kg bw/day) for 104 weeks, and an additional group received the top dose for 78 weeks followed by a control diet for a further 26 weeks (recovery group). A number of important details are missing from the abstract of this study, which prevents a full assessment of its quality and of the validity of the findings, including whether the study was carried out according to current regulatory guidelines (e.g. OECD) and performed to GLP. Relative increases in liver and kidney weights were seen at 6000 ppm and above, but these changes were not observed in the recovery groups. In addition, no “pathology in the livers” of the 6000-ppm rats was reported. At the top dose, hepatocellular carcinomas were reported (presumably in both sexes) after week 79 and kidney tubule cell carcinomas were seen in the males (also at 12000 ppm), although tumour incidences are not given in the abstract. MNCL was seen in both sexes at 6000 ppm and above, and in the 12000 ppm recovery groups. No discussion is provided (in the abstract) concerning the relevance to humans of the observed liver and kidney tumours, or of the MNCL. Based only on the data presented in the abstract, the NOAEL (no-observed-adverse-effect level) for systemic toxicity and carcinogenicity is 1500 ppm (about 100 mg/kg bw/day).

An equivalent mouse study was also conducted by Butala et al. (1997), also unpublished and available only as a short abstract. Male and female mice were fed diets containing DINP (68515-48-0) at 0, 500, 1500, 4000 or 8000 ppm (equivalent to 0, 70, 200, 530 or 1070 mg/kg bw/day) for 104 weeks. An additional group received the top dose for 78 weeks followed by a control diet for a further 26 weeks (recovery group). A number of important details are missing from the abstract of this study, which prevents a full assessment of its quality and of the validity of the findings, including whether the study was carried out according to regulatory guidelines (e.g. OECD) and performed to GLP. A significant increase in the incidence of hepatocellular carcinomas was seen in both sexes at 1500 ppm and above, and in the 8000 ppm recovery groups. In males, the respective incidences were 23, 30, 47, 44 and 38% at 0, 1500, 4000, 8000 ppm and 8000 ppm+recovery. In females the equivalent incidences were 4, 17, 18, 46 and 36%. (The actual numbers of tumours or tumour-bearing animals were not given in the abstract.) The investigators noted that biochemical analyses of the high-dose liver tissue revealed a statistically significant increase in liver weight, hepatocellular protein content and palmitoyl CoA activity (but not cellular labelling or content) compared to the control group. This suggests that peroxisome proliferation may be responsible for the increased liver tumours, a mechanism not considered of relevance to humans. No treatment-related increases in any other type of tumour were apparently seen at any dose level (although the extent of examination is not possible to assess from this abstract). Based only on the data provided in the abstract, the NOAEL for carcinogenicity is 500 ppm (about 70 mg/kg bw/day).

The above three studies indicate that DINP induces liver tumours in rats and mice, and kidney tumours and MNCL in rats. The EU RAR on DINP (European Chemicals Bureau, 2003a) puts forward persuasive arguments for why these three tumour types are not likely to be relevant to humans. Thus, peroxisome proliferation is considered likely to be responsible for the increased liver tumours, a mechanism not considered of relevance to humans. The kidney tumours are attributed to a species- and sex-specific mechanism, involving alpha 2u globulin, with the EU RAR citing a study by Caldwell (1999b) to support this contention. MNCL is described as a common neoplasm in ageing F344 rats, and the EU RAR considers that the increased incidence is likely a strain-specific effect with little relevance for humans.

 

Groups of 50 mice of each sex were given BBP in the diet for 103 weeks at concentrations of 0, 6000 or 12000 ppm (equivalent to around 0, 780 or 1560 mg/kg bw/day). The mice were observed daily for clinical signs of toxicity, body weight changes were recorded every 4 weeks, and the animals were sacrificed at 106 weeks. A comprehensive range of organs and tissues was examined for gross and microscopic changes. A dose-related decrease in mean body weights of both male and female mice was observed throughout the study. Statistical significance was not reported, but the reduction in body-weight gain appeared to be around 5% and 5-10% in low-dose males and females respectively, and 15% and 10-25% in high-dose males and females respectively. No other compound-related clinical signs were observed, and survival was comparable in the treated and control groups. The tumours observed in male and female mice showed no relation to treatment, and were within the normal historical incidence limits observed in B6C3F1 mice. Similarly the non-neoplastic effects observed were considered unrelated to administration of the test substance and also fell within the range of historical controls. No toxic lesions were seen. Thus, BBP showed no evidence of carcinogenic potential in male or female mice at up to 12000 ppm in the diet (around 1560 mg/kg bw/day) for 103 weeks (NTP, 1982).

In the equivalent 2-year rat study involving the same test doses (0, 6000 or 12000 ppm BBP, equivalent to around 0, 300 or 600 mg/kg bw/day), only the data for females (50/dose group) were considered reliable as the males died prematurely from internal haemorrhaging. (By week 28, 70% of the high-dose group had died, and some deaths also occurred amongst the low-dose males.) The females were observed twice daily for clinical signs of toxicity, body weight changes were recorded every 4 weeks, and the animals were sacrificed at 106 weeks. A comprehensive range of organs and tissues was examined for gross and microscopic changes. There was a slight, dose-related decrease in body-weight gain throughout the study in the treated groups, probably due to reduced food consumption (which was 70-80% that of the controls). No other treatment-related clinical effects were observed. The incidence of mononuclear cell leukemia (MNCL) affecting multiple organs was 36% in the 12000 ppm dose group compared to 14% in the control group and low-dose (6000 ppm) groups. No differences were apparent in the tissue distribution or cytologic characteristics of this neoplasm between groups. Other neoplasms and non-neoplastic effects were unrelated to the test substance, occurring at a similar frequency in all groups. However, the compound does not appear to have been tested up to the maximum tolerated dose. Although the F344/N strain, unlike other strains of rat, is predisposed to develop MNCL, the NTP nevertheless concluded that BBP was "probably carcinogenic" to female rats on the basis of the observed increase in comparison with concurrent and historical controls (NTP, 1982).

 

In a subsequent 2-year feeding study in the same strain of rats (NTP, 1997a), groups of 60 males and 60 females were given BBP in the diet at up to 12000 ppm (males) or 24000 ppm (females), while similar groups of animals received the untreated diet. Blood was sampled from 10 rats of each sex at various time intervals for haematology and serum hormone levels, and after 15 months of exposure these rats were evaluated for haematology, hormone levels, organs weights (epididymis, kidney, liver and testis) and histopathology. At study termination a comprehensive range of organs and tissues was examined microscopically. Survival in all exposed groups was similar to that of the controls, but there was a dose-related decrease in body-weight gain throughout the study; during the later stages of the study the highest dose caused a decrease of about 10% in males and 25% in females, when compared to controls. In males dosed at 12000 ppm, the incidence of pancreatic acinar cell adenomas was 41% (compared with 11% in control males) and one treated male had a pancreatic carcinoma (a neoplasm which apparently had not been observed in 1919 historical control males from NTP 2-year feeding studies). In females in the 24000 ppm group, two pancreatic acinar cell adenomas were detected. The incidence of acinar focal hyperplasia was also increased in treated males, but not in females. Transitional epithelial papillomas of the urinary bladder were observed in two females in the 24000 ppm group (exceeding the range of historical controls from NTP 2-year feeding studies) and in one control female. The high-dose females also showed a higher incidence of mild to moderate hyperplasia in the urinary bladder. Thus, in this study BBP showed some evidence of carcinogenic activity in male rats based on an increased incidence of pancreatic acinar cell adenoma and of acinar cell adenoma and carcinoma (combined) at the top test dose of 12000 ppm (equivalent to around 500 mg/kg bw/day). In female rats there was equivocal evidence of carcinogenic activity based on marginally increased incidences of pancreatic acinar adenoma and of transitional epithelial papilloma of the urinary bladder at the top test dose of 24000 ppm (equivalent to around 1200 mg/kg bw/day) (NTP, 1997a).

In its consideration of this and other carcinogenicity studies, the EU RAR notes that BBP may be a borderline case between no classification for carcinogenicity and Carc. Cat. 3 (under Directive 67/548/, i.e. substances which cause concern for man owing to possible carcinogenic effects), but it opts for no classification due to the lack of genotoxic effects (EU, 2007).

 

The draft OECD report on the high-molecular weight phthalate esters (HMWPE) category (OECD, 2004) provides some reassurance about the likely lack of human carcinogenic potential of S261a. It argues that, although no chronic biossays have been conducted on these category members (compounds with a carbon backbone of C7 or greater), there is a low likelihood that they are genotoxic carcinogens in view of the negative genotoxicity data for the category as a whole. Furthermore, although high doses might produce proliferative changes in the liver in rodents (on the basis of previous experience with a wide range of phthalates), these effects are not relevant to humans.

 

Justification for classification or non-classification

Although both DINP and BBP have induced tumours in long-term oral cancer studies in rodents, neither compound is considered to require classification for carcinogenicity under the EU CLP regulations, and the same is likely to be true for S261A.