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Toxicological information

Carcinogenicity

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Description of key information

- Several oral carcinogenic studies performed on rats and hamsters are available. These studies showed only an increased incidence of forestomach 
tumours. Such effects are not relevant for humans.
- No impact on tumour incidence were observed in mice and rabbits after PMP dermal long term exposure.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
other: several species
Quality of whole database:
Studies well described.

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
other: mouse and rabbit
Quality of whole database:
Study well described.

Additional information

Oral route: 5 studies are referenced in this section for carcinogenicity assays by oral route, PMP introducing in feed:

- Hagiwara et al., 1996 (a) and Asakawa et al., 1994, reliability 2:

In these carcinogenicity studies, PMP was administered to 30 Fisher 344 rats/ sex/ dose in diet at dose levels of 0 or 2% (equivalent to 0 and 500 mg/kg bw/d) for 104 weeks. The experiment clearly demonstrated forestomach carcinogenicity for PMP. Males were more susceptible than females to induction of forestomach tumours. Dosing was considered adequate based on the decrease in body weight in the treated animals.However, only one dose level was tested.

The LOAEL resulting from these studies were:

LOAEL = 500 mg/kg bw/d for male and female rats, for non carcinogenotoxic effects: decreasing body weights and weight gains, increasing relative liver, kidney weights and hyperplasia in the glandular stomach.

and LOAEL = 500 mg/kg bw/d for male and female rats, for carcinogenotoxic effects: tumour lesions in the forestomach

In This study, tumour lesions were observed only in forestomach of rats. However, such effects are not relevant for humans.

- Hagiwara et al., 1996 (b) and Asakawa et al., 1994, reliability 2:

In the same type of studies (PMP administered to Fisher 344 male rats in diet at dose levels of 0 or 2% PMP (equivalent to 0 and 500 mg/kg bw/d))

, other conclusions were reported: PMP clearly inhibited the development of naturally occurring GST-P+ hepatocytic foci in aged rats, as predicted from the results of medium-term liver bioassays (Ito test).

Moreover, chemopreventive effects of PMP on liver carcinogenesis could not be demonstrated in the previous long-term study (Hagiwara et al., 1996 (a)), since the incidences of spontaneous liver tumours were too low to allow assessment of inhibition.

- Ito et al., 1986 and Hirose et al., 1986, reliability 2:

In these carcinogenicity studies, PMP was administered to male Syrian hamsters (15 animals/ dose) in diet at dose levels of 0 and 1.5% (equivalent to 0 and ca. 225 mg/kg bw/d) for 20 weeks. PMP induced hyperplasia in the forestomach, but no tumorous lesions. The labelling index in the forestomach epithelium and glandular stomach were significantly increased by addition to the diet of PMP. PMP induced epithelial damage and regenerative hyperplasia of the pyloric region. No histopathological lesions were observed in the urinary bladder epithelium. Based on these data, the authors of this study concluded that PMP may act as promotor in two-stage forestomach carcinogenesis.

A LOAEL of 225 mg/kg bw/d has been derived for significant forestomach hyperplasia in male hamsters.

And NOAEL(male hamster) > 225 mg/kg bw/d for tumor incidence (none tumours were noted)

- Hirose et al., 1988, reliability 2:

In this carcinogenicity study, PMP was administered to male F344 rats (15 animals/ dose) in diet at dose levels of 0 or 1.5% (equivalent to 0 and ca. 375 mg/kg bw/d) for 51 weeks. No effects were observed in the mortality or the body weight gain of the treated animals. Liver and kidney weights were significantly higher in animals treated with PMP, when compared to the corresponding control group. PMP induced forestomach hyperplasia in all animals tested. At the dose tested, there was not a treatment related increase in tumor incidence when compared to controls.

LOAEL male rats = 375 mg/kg bw/d for non carcinogenic effects: increase of liver and kidney weight, forestomach hyperplasia.

NOAEL male rats > 375 mg/kg bw/d for tumor incidence (none tumours were noted).

- Hirose et al. 1997, reliability 2:

In this carcinogenicity study, PMP was administered to male F344 rats (30-31 animals/ dose) in diet at dose level of 0 or 0.4% (equivalent to 0 and ca. 100 mg/kg bw/d) for 104 weeks. Final body weights of rats treated with PMP were lower than the control rats. PMP increased significantly the incidence of forestomach papillar or nodular (PN) hyperplasia, as compared with the basal diet. Slightly increased incidences (not significant) of forestomach papillomas were found in the PMP group. At the dose tested, there was not a treatment related increase in tumor incidence when compared to controls.

LOAEL male rats = 100 mg/kg bw/d for non carcinogenic effects: decreased body weight, and increased forestomach findings.

NOAEL male rats = 100 mg/kg bw/d for forestomach tumor incidence (there was not a treatment related increase in tumour incidence).

Dermal route: one study is available for dermal route, from Stenback, 1977 (reliability 2), on mouse or rabbits:

- In a carcinogenicity study, 4-hydroxyanisole was administered to 50 female Swiss mice per dose by cutaneous route at dose levels of 5 and 10 % in methanol or acetone for lifetime (up to 120 weeks). At the doses tested, there were no treatment related effects on clinical signs, body weight or tumor incidence when compared to controls.

Based on this study a dermal NOAEL of 10% in vehicle can be derived for female mice.

- In a carcinogenicity study, 4-hydroxyanisole was administered to 5 New Zealand rabbits per group by cutaneous application in ear at dose levels of 5 or 10 % in acetone or methanol for lifetime, up to 90 weeks. At the doses tested, there were no treatment related effects on survival rate, clinical signs, body weight or tumor incidence when compared to controls.

Based on this study a dermal NOAEL of 10% in vehicle can be derived for rabbits.

All these 7 studies are of reliability 2 as test conditions and results are sufficiently described, even if they didn't totally satisfy the EU or OECD guidelines.

In conclusion, based on oral data, PMP given in diet to rats or hamsters affected only the forestomach, in a manner carcinogenic (papillomas and squamous cell carcinomas) and induced glandular stomach hyperplasia.

Forestomach tumorous lesions observed on rats or hamsters are not relevant for Humans.

Cutaneous application of PMP has no impact on tumour incidence (mice and rabbits).


Justification for selection of carcinogenicity via oral route endpoint:
Several studies were taken into account for assessment and different NOAEL values were identified depending on the study selected.

Justification for selection of carcinogenicity via dermal route endpoint:
Two studies are available, on in mice and the other one in rabbits.

Justification for classification or non-classification

PMP is not considered as carcinogenic based on seven oral data showing only tumour lesions in the forestomach in rats and hamsters and based on one dermal data on which no impact on tumour incidence were observed in mice and rabbits.