2-Pyridinecarboxamide, 4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-

Carcinogenicity

Description of key information

BAY 54-9085 (tosylate salt of BAY 43-9006) has no carcinogenic potential in rats and mice.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

HYPOTHESIS FOR THE ANALOGUE APPROACH

Regarding human health toxicity results from animal studies and human data are available for either sorafenib base or sorafenib tosylate to fulfill REACH requirements of Annex VIII (10-100 t/a). Sorafenib base (BAY 43-9006, CAS 284461-73-0) is the active ingredient of BAY 54-9085, the tosylate salt of sorafenib (CAS 475207-59-1). Under physiological conditions in solution a dissociation of the tosylate takes place and therefore an identical pharmacological and toxicological effect of sorafenib base (BAY 43-9006, CAS 284461-73-0) and sorafenib tosylate (BAY 54-9085, CAS 475207-59-1) is to be expected at slightly different doses, taking into account the conversion factor of 1.3705.
Under physiological conditions a dissociation of p-toluene sulfonic acid of sorafenib tosylate takes place releasing sorafenib as active ingredient into the body.
Therefore, an identical toxicity profile of sorafenib base (BAY 43-9006, CAS 284461-73-0) and sorafenib tosylate (BAY 54-9085, CAS 475207-59-1) is to be expected, taking into account the differences in molecular weight (conversion factor 1.3705).
A detailed justification for read-across is attached on iuclid section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Route of administration:

oral: feed

Dose descriptor:

NOAEL

Effect level:

0.73 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: neoplastic

Remarks on result:

other: correction for difference in molecular weight

Executive summary:

BAY 43-9006 is the active ingredient (free base) of BAY 54-9085, the tosylate salt of sorafenib. Under physiological conditions a dissociation of the salt takes place and therefore an identical toxicity profile of BAY 54-9085 and BAY 43-9006 is to be expected. Hence, for BAY 43-9006 the results of the carcinogenicity studies with BAY 54-9085 can be taken under correction of the different molecular weight. The conversion factor between BAY 43-9006 and BAY 54-9085 is 1.37

 

In order to investigate a possible carcinogenic potential of BAY 54-9085 a systemic toxicity study was performed in rats according to OECD TG 451. For this purpose BAY 54-9085 was administered orally dose-adjusted via diet to 50 male and 50 female Wistar rats per dose group in daily doses of 0, 0.1, 0.3 or 1.0 mg/kg bw for a period of up to 747 days. Dose selection was based on MTD criteria in a 13-week dose finding study.

 

The evaluation of neoplastic lesions did not give any evidence of a treatment-related effect since the number of animals with neoplasms, more than one primary neoplasm, metastatic tumors, benign or malignant tumors was unaffected by dosing with the test compound as was the number of benign or malignant neoplasms per group.

 

Hence, there was no evidence of a carcinogenic potential of BAY 54-9085. Under the conditions described the no observed adverse effect level (NOAEL) for oral administration of BAY 54-9085 via the diet was 1.0 mg/kg bw /day in male and female rats with regard to carcinogenicity. Taking into consideration the differences in molecular weight, the NOAEL is converted to 0.73 mg/kg.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

0.73 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

The study is GLP compliant and is of high quality (Klimisch score=1)

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the study results a classification according to Regulation (EC) No.1272/2008 (CLP) is not required.

Additional information

BAY 43-9006 is the active ingredient (free base) of BAY 54-9085, the tosylate salt of sorafenib. Under physiological conditions a dissociation of the salt takes place and therefore an identical toxicity profile of BAY 54-9085 and BAY 43-9006 is to be expected. Hence, for BAY 43-9006 the results of the repeated dose toxicity studies with BAY 54-9085 can be taken under correction of the different molecular weight. The conversion factor between BAY 43-9006 and BAY 54-9085 is 1.37. A justification for read-across is attached to Iuclid section 13.

 

In order to investigate a possible carcinogenic potential of sorafenib tosylate (CAS 475207-59-1) a chronic toxicity study was performed in rats according to OECD TG 451 (Schladt and Rühl-Fehlert, 2013). The evaluation of neoplastic lesions did not give any evidence of a treatment-related effect since the number of animals with neoplasms, more than one primary neoplasm, metastatic tumors, benign or malignant tumors was unaffected by dosing with the test compound as was the number of benign or malignant neoplasms per group. Hence, there was no evidence of a carcinogenic potential of sorafenib tosylate (CAS 475207-59-1). Under the conditions described the no observed adverse effect level (NOAEL) for oral administration of sorafenib tosylate (CAS 475207-59-1) via the diet was 1.0 mg/kg bw /day in male and female rats with regard to carcinogenicity (highest dose tested).

 

In a second chronic study according to OECD TG 451 a possible carcinogenic potential of sorafenib tosylate (CAS 475207-59-1) was investigated in mice (Schladt and Lawrenz, 2013). In the course of hyperplasia and chronic inflammation of the intestinal mucosa two high dose females developed adenocarcinoma of the colon wall. Historical control data characterize colonic adenocarcinoma as a sporadically tumor in mice. The incidence of two carcinomas demonstrates a minimal increase towards latest historical control data. With regard to the induced diffuse hyperplastic and inflammatory lesions, an influence of the test item on the development of colon adenocarcinoma cannot be fully excluded. This would however not indicate a direct carcinogenic effect of sorafenib tosylate (CAS 475207-59-1). Therefore, the study did not reveal a clear evidence of a carcinogenic potential of sorafenib tosylate (CAS 475207-59-1) in mice. Under the conditions described the no observed adverse effect level (NOAEL) for oral administration of sorafenib tosylate (CAS 475207-59-1) via the diet was 137.4 mg/kg bw /day in males and 94.8 mg/kg bw /day in females with regard to carcinogenicity (highest dose tested).

 

Carcinogenicity studies with sorafenib tosylate in rats and mice

	Sorafenib tosylate (source) CAS 475207-59-1	Sorafenib base (target) CAS 284461-73-0
Study type	Combined chronic toxicity and carcinogenicity studies (rats & mice)
Study no./ Report no.	T8076320 / PH-37557 Schladt/ Rühl-Fehlert, 2013	Read-Across   Converted to NOAEL 0.73 mg/kg/d
GLP/ OECD TG/ deviations	GLP, according to OECD 451 (Carcinogenicity)
Species; animals/ group	Rat (Wistar), n=50 female, n=50 male / dose group
Doses/ schedule	0, 0.1, 0.3 and 1.0 mg/kg body weight per day (doses selected in a prior DRF study)
Formulation	·         Batch no. BXA44KS; purity 98.5% ·         Mixed with diet ·         Homogeneity and stability tested, mixture prepared weekly
Observation period	24 months (747d treatment)
Parameters assessed	Body weights, food / water intakes, hematology, clinical chemistry, urinalyses, ophthalmology, neurotoxicity, necropsy, organ weights, histopathology, toxicokinetics
Results	·         Mortality not affected by treatment ·         Clinical observation and other parameters without relevant finding ·         Histopathological findings (vascular changes) in abdominal organs in 1 mg/kg dose group ·         Slightly elevated teeth fracture/ dysplasia in males of 1 mg/kg dose group ·         Treatment-independent spontaneous development of neoplasms   NOAEL 1 mg/kg (both sexes, carcinogenicity)
Reliability	1
Study no./ Report no.	T4079666 / PH-37556 Schladt/ Lawrenz, 2013	Read-Across   Converted to NOAEL 100.3 mg/kg/d (males) and 69.2 mg/kg/d (females)
GLP/ OECD TG/ deviations	GLP, according to OECD 451 (Carcinogenicity)
Species; animals/ group	Mouse (CD-1), n=60 female, n=60 male / dose group
Doses/ schedule	0, 12.7. 35.3 and 137.4 mg/kg/d males; 0, 6.8, 22.9, and 94.8 mg/kg/d females (doses selected in a prior MTD study)
Formulation	·         Batch no. BXA44KS; purity 98.5% and BXA4XHH; purity 99.8% ·         Mixed with diet ·         Homogeneity and stability tested, mixture prepared weekly
Observation period	24 months (106 weeks treatment)
Parameters assessed	Body weights, food / water intakes, hematology, clinical chemistry, urinalyses, ophthalmology, neurotoxicity, necropsy, organ weights, histopathology, toxicokinetics
Results	·         Increased mortality related to hyperplastic and inflammatory changes observed in the intestine ·         Survival rates at the end of study (week 106): 63%, 63%,40% and 12% in males, and 42%,45%, 38% and 15% in females ·         Several secondary effects observed ·         No direct carcinogenic effect   NOAEL 137.4 mg/kg bw/d in males and 94.8 mg/kg bw /d in females (carcinogenicity)
Reliability	1