Benzyl butyl phthalate

Carcinogenicity

Description of key information

The oral carcinogenicity of butyl benzyl phthalate (BBP) has been investigated in Fischer 344/N rats and B6C3F1 mice. The compound has shown no evidence of carcinogenic potential in male or female mice at up to 12000 ppm in the diet (up to around 1560 mg/kg bw/day) for 103 weeks, but some evidence in female rats on the basis of a significantly higher incidence of mononuclear cell leukemia when compared to concurrent and historical controls (NTP, 1982). A subsequent 2-year feeding study in the same rat strain found no such increase at higher test concentrations (NTP, 1997a). In the earlier NTP 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 12000 ppm (equivalent to 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 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/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

Carcinogenicity: via oral route

Endpoint conclusion

Dose descriptor:

NOAEL

240 mg/kg bw/day

Justification for classification or non-classification

The available long-term rodent studies on BBP provide some evidence of carcinogenicity in male rats (pancreas), and equivocal evidence in female rats (mononuclear cell leukemia in an early study, marginal effects on the pancreas and bladder in a subsequent study). The pancreatic and bladder tumours were mainly benign (apart from one pancreatic carcinoma in high-dose males), and the increased incidence of mononuclear cell leukemia in the earlier NTP study was not reproducible in a later NTP study at higher test doses. An equivalent mouse study showed no evidence of carcinogenicity. As the neoplasms were observed in only one of the two species tested, were either benign (mainly) or not repeatable, and BBP has shown no convincing evidence of genotoxicity, the available findings are not considered sufficient to warrant its classification as a carcinogen.

Additional information

Butyl benzyl phthalate was tested for carcinogenicity by oral administration in one experiment in mice (NTP, 1982) and in three experiments with rats, including a dietary restriction study (NTP, 1982, 1997a, 1999). No increases in the incidence of tumours were observed in mice at doses of up to 12000 ppm (equivalent to around 1560 mg/kg bw/day). The results from the rat studies have been summarised in the EU RAR (Table 4.26), which has been reproduced (with slight corrections) below. An increased incidence of mononuclear cell leukemias was reported in female rats at 12000 ppm BBP (equivalent to around 600 mg/kg bw/day). The increase was within the incidence of historical controls, and the frequency was actually similar to the frequencies found in the two control groups in the second experiment. In two later studies with the same rat strain, no significant increase in the incidence of mononuclear cell leukemias was found although a higher concentration was tested. An increased incidence of benign pancreatic tumours was seen at the highest dose in one conventional study in male rats, but not at a dose twice as high after dietary restriction. A marginally increased incidence of pancreatic adenomas occurred in female rats in a convential study (not statistically significant, p = 0.49), but not after dietary restriction. Papillomas of the urinary bladder were marginally increased in female rats both in the conventional study (p = 0.49) and after dietary restriction. Moreover, after dietary restriction and 32 months a non-significant (p = 0.12) increase in bladder carcinomas was found. The latter results are difficult to interpret as no historical controls are available. In one study in rats, BBP given prior to 7,12-dimethylbenz(a)anthracene inhibited mammary carcinogenesis.

In its consideration of these 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/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.

Table 4.26 Summary of the incidence of neoplasms in rats (Taken from EU RAR)

 

NTP 1982

NTP 1997a

NTP 1997h Dietary restriction  24 months         32 months

0 ppm

6,000 ppm

12,000  ppm

0 ppm

3,000 ppm

6,000 ppm

12,000 ppm

24,000 ppm

0 ppm

24,000 ppm*

0 ppm

24,000 ppm*

Male

Pancreas: adenoma

Terminated after 30 weeks

3/50 (6%)

2/49 (4%)

3/50 (6%)

10/50 (20%)

0/50 (0%)

0/51 (0%)

0/50 (0%)

3/41 (6%)

Female

Pancreas: adenoma

0/47 (0%)

3/46 (7%)

0/46 (0%)

0/50 (0%)

0/50 (0%)

0/50 (0%)

2/50 (4%)

0/50 (0%)

0/50 (0%)

1/50 (2%)

1/50 (2%)

Mononuclear cell leukaemia

7/49 (14%)

7/49 (14%)

18/50 (36%)

21/50 (42%)

20/50 (40%)**

21/50 (42%)

19/50 (38%)

16/50 (32%)

18/50 (36%)

29/50 (58%)

39/50 (78%)

Bladder, papilloma

No data

1/50 (2%)

0/50 (0%)

0/50 (0%)

2/50 (4%)

0/50 (0%)

2/49 (4%)

1/50 (2%)

2/50 (4%)

Carcinoma

No data

0/50 (0%)

0/50 (0%)

0/50 (0%)

0/50 (0%)

0/50 (0%)

0/50 (0%)

0/50 (0%)

4/50 (8%)

 

Bold indicates significant increase compared to control.

* 12,000 ppm for males.

** The historical controls for mononuclear cell leukaemia varies today from 16% to 42% with an average of 29.3% (NTP, 2000)

Carcinogenicity: via oral route (target organ): digestive: pancreas