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Carcinogenicity

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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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
March 2009 to March 2011
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Reason / purpose:
reference to same study
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories BV, 5961 Horst, Netherlands
- Strain: Hsd Cpb:Wu (SPF)
- Age at study initiation: approx. 7 weeks
- Weight at study initiation: males: 199-296 g, females: 153-218 g
- Housing: in groups of 2-3 rats in Makrolon® Type IV cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: approx. 3 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): approx. 55
- Air changes (per hr): >= 10
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: March 2009 - March 2011
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
BAY 54-9085 was administered in the diet. The test substance was mixed into the diet at the appropriate concentrations at room temperature and maximally used over the stability period determined by analytical investigation. The test item was blended (using a mixing granulator manufactured by Loedige, Paderbom, Germany) with the diet Provimi Kliba 3883 G4 S15. For the preparation of the mixtures the content of test item was assumed to be nominally 100 %.

To ensure a constant test substance intake on a mean mg/kg body weight basis (separately for males and females) the concentrations of the diet (in ppm) were adjusted weekly, except in weeks 40, 41 and 93, to reach the scheduled dose (in mg/kg bw). The calculations were based on the data obtained from animals of the main groups.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
ANALYSES DONE PRIOR TO THE STUDY
Before the start of this study, the suitability of the test item/food mixtures was confirmed by the analysis of mixtures containing the test item in concentrations covering the concentration range to be used in the study.

- Homogeneity: Dosage forms including the highest and lowest concentration were prepared. Three samples were taken from different places of the mixture and analyzed for concentration of the test material.

- Stability: The dosage forms prepared for homogeneity analysis were analyzed shortly after preparation and 15 days thereafter. The analysis revealed that the test item was stable over this period within the defined limits.

ANALYSES DONE DURING THE IN-LIFE PHASE
The test item concentration (all doses including vehicle control formulation) and homogeneity (low and high dose only) were checked for each part of the formulation (males and females) at begin and termination of the study and about every three months in between as a rule. Additionally, the content was determined for all test item /food mixtures used for day 22 to 28 and day 29 to 35.
Duration of treatment / exposure:
up to 747 days (approx. 24.5 months)
Frequency of treatment:
daily
Post exposure period:
no
Remarks:
Doses / Concentrations:
0, 0.1, 0.3, 1.0 mg/kg bw
Basis:
other: dose-adjusted via diet
No. of animals per sex per dose:
main groups: 50
satellite groups (for laboratory investigations and toxicokinetics): 15
Control animals:
yes, plain diet
Details on study design:
DOSE SELECTION RATIONALE:
The doses were selected based on the results of a preceding 13-week dose finding study (PH-35480) and was agreed with the FDA in the special protocol assessment procedure.
Positive control:
no
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: for morbidity and mortality twice daily; daily from May 03, 2010 onwards

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly for the first 13 weeks

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: before start of treatment all main groups; after 12 months only control and high dose main groups; after 24 months all male main groups as well as control and high dose female main groups

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 6, 12, 18 and 24 months after start of treatment
- Preparation of blood smears: 12, 18 and 24 months after start of treatment
- Anaesthetic used for blood collection: Yes (CO2/room air)
- Animals fasted: Yes
- How many animals: first 10 alive animals per satellite group; blood smears: all alive and moribund main group animals
- Parameters examined - peripheral blood: erythrocyte count, hemoglobin concentration, hematocrit, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, reticulocyte count, erythrocyte morphology, thrombocyte count, thromboplastin time (Hepato-Quick), leukocyte count, differential blood count; blood smears: differential blood count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 6, 12, 18 and 24 months after start of treatment
- Animals fasted: Yes
- How many animals: first 10 alive animals per satellite group
- Parameters examined: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, glutamate dehydrogenase, gamma-glutamyl transferase, glucose, cholesterol, triglyceride, creatinine, potassium, urea, total bilirubin, total protein, albumin, chloride, calcium, inorganic phosphate,
sodium

URINALYSIS: Yes
- Time schedule for collection of urine: 6, 12, 18 and 24 months after start of treatment
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters examined: density, volume, protein concentration, creatinine concentration, protein excretion, creatinine excretion, protein/creatinine ratio, pH, blood, bilirubin, glucose, ketone bodies, urobilinogen, microscopy of sediment

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: toxicokinetics on days 3, 311/312 and 640 after start of treatment in all satellite groups
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
- How many animals: all animals of the main groups living on the date of their scheduled necropsy and all animals killed in moribund state were sacrificed by exsanguination under deep diethyl etheranesthesia, necropsied and their organs and tissues subjected to thorough gross pathological examination; since March 9, 2009 this was true also for all satellite group rats; animals that died spontaneously during the study were necropsied at the earliest opportunity

HISTOPATHOLOGY: Yes
- How many animals: all main group animals
- Organs/tissues examined: abnormalities including tissue masses (tumors), adrenals, aorta, brain (3 regions), cecum, colon, duodenum, epididymitis, esophagus, exorbital lacrimal glands, eyes, femur (with bone marrow/joint), harderian glands, head with skull cap, heart, ileum, jejunum, kidneys, larynx, liver, lungs, lymph node (mandibular), lymph node (mesenteric), lymph nodes (popliteal), nasal cavities/nasopharnyx, ovaries/oviducts, optic nerves, pancreas, Peyer's patches, pharynx, pituitary gland, preputial/clitoral gland, prostate, rectum, salivary glands, sublingual gland, submandibular gland, parotid gland, sciatic nerve, seminal vesicles with coagulation glands, skeletal muscle, skin/mammary region, spinal cord 3x, spleen, sternum (with bone marrow), stomach, teeth, testes, thymus, thyroid/parathyroids, tongue, trachea, uterus with cervix, ureters, urethra, urinary bladder, vagina, zymbal glands
Statistics:
The statistical evaluation of data related to clinical chemistry, hematology, body and organ weights were performed using routines of the validated Pristima System. Statistical evaluations on body weight and organ weight data were done using the Dunnett test. Clinical chemistry and hematology data were evaluated using a Dunnett test, an adjusted U-test or an adjusted Welsh test.

All variables that are not dichotomous are described by sex, dose group and date using appropriate measures of central tendency (mean, median) and general variability (standard deviation, minimum, maximum). Statistical tests were not performed for groups, which are smaller than 3.

Data of food and water intake are reported only as group means, because individual data are not available due to the group wise measurement. In these types of statistical processing of measurement values a large number of comparisons were made, which may also lead to false-positive statements. On account of this problem for the evaluation not only the statistical significance but also the biological and toxicological relevance was considered.

For statistical evaluations of histopathological findings, statistical procedures implemented in the PATHDATA program were used.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
details on histopathological results (non-neoplastic) see chapter 7.5.1
Histopathological findings: neoplastic:
no effects observed
Details on results:
HISTOPATHOLOGY - NEOPLASTIC CHANGES:

The evaluation of neoplastic lesions revealed no 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.
 
The distribution of proliferative lesions revealed a slight increase in islet cell adenomas in the pancreas of females dosed at the dose of 1.0 mg/kg b.w./day, which attained statistical significance in the trend test although it was not statistically significant in the pairwise group comparison. However, combining islet cell hyperplasia and neoplasia, the combined incidences show no dose-response-relationship (in ascending dosages: 16.0/4.0/12.2/16.0% ). Higher values were seen in females compared to males (in ascending dosages: 6.1/8.7/6.4/8.0%).
 
Morphology and cytology of the lesions were similar throughout the groups up to and including the dose of 1.0 mg/kg b.w./day, and cytologically there was generally high similarity between islet cell hyperplasia and islet cell adenoma.
 
Distinction between normal islets and islet cell hyperplasia is based on size (diameter 350 to 700 µm) but not on cytological differences. Adenoma islet cell is larger than 700 µm in diameter and is often cytologically similar to normal islets but may show compression of surrounding tissue, fibrous stroma, ectatic vasculature or slight cellular pleomorphism. Adenocarcinomas show more cellular atypia, mostly moderate mitotic activity and often local invasion (IARC 1994).
 
For islet cell hyperplasia, historical data from the RITA database for in-house studies (same strain, same laboratory) revealed islet cell hyperplasia in 1065 males and 1067 females in a range from 0 to about 12% for both sexes (mean in males 1.7% or in females 2.8%). Thus, the study control is slightly above historical incidences (6% in males, 14% in females) whereas the other groups are within the historical range.
 
For islet cell adenoma, historical values are 0 to 4% for males (mean 1.4%) and 0 to 2% for females (mean 0.6 %). In several groups, the incidence is thus above historical data but without dose correlation. For the carcinoma, islet cell the range of historical data is for both sexes 0 to 2.0% (mean for both sexes 0.1%). Therefore, the incidence of carcinoma is within the historical limits. A possible explanation for the numerical increase of hyperplasia and adenoma in the current study compared to historical control is, that two specimens of pancreatic tissue were investigated (former carcinogenicity studies one specimen). A treatment effect is unlikely considering the distribution of proliferative islet cell lesions throughout the groups, morphology of the lesions and their immunohistochemical properties. Hence, a carcinogenic potential of BAY 54-9085 is not assumed.
 
In the mesenteric lymph node of males, hemangioma showed a significant positive trend (incidences in ascending dosages: 0.0, 2.0, 0.0, 6.0%). However, in the absence of any increase in preceding lesions such as angiomatous hyperplasia and considering the frequency of hemangioma in the mesenteric lymph node of males from the same strain in our laboratory (RITA data from own laboratory: 0.0 to 6.9%, mean 1.8%) this increase is not regarded as adverse.
 
In the adrenal, benign medullary tumors were significantly reduced in incidence in males at the dose of 0.3 mg/kg b.w./day and 1.0 mg/kg b.w./day and in females at 1.0 mg/kg b.w./day. The historical incidences of benign medullary tumors in in-house studies are outnumbered by control (both sexes) and low dose (males) of the present study (males n=1116; incidences 3.4 to 40%, mean 17.7%; females n=1116, incidences 0.0 to 10 %, mean 2.8 %). A toxicological relevance of slight numerical decrease of adrenomedullary tumors is not assumed and was not assessed as adverse.
 
In the mammary gland, a slightly lower incidence was seen for diffuse and focal hyperplasia whereas other age-related findings such as lacteal cysts and galactocele had similar incidences throughout the groups indicating a random event.
 
The incidence of fibroadenoma was significantly higher at the dose of 0.1 mg/kg b.w./day and 0.3 mg/kg b.w./day than in the other groups due to a particularly low incidence in control (8.2, 24.0*, 28.6**, 18.0%). Historical RITA control data from in-house studies indicate spontaneous incidences from 5.1 to 28.0% (mean 14.1%). Thus, the finding was not assumed to be related to the treatment.
Dose descriptor:
NOAEL
Effect level:
0.3 other: mg/kg bw/day (dose-adjusted via diet)
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: Effect type: toxicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
1 other: mg/kg bw/day (dose-adjusted via diet)
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Executive summary:

BAY 54-9085 is the tosylate salt of BAY 43-9006 (sorafenib), which is used as an anti-cancer drug.

 

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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 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

Additional information

BAY 43-9006 is the active ingredient (free base) of BAY 54-9085, the tosylate salt of sorafenib, which is used as an oral anti-cancer drug. 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, the results of the carcinogenicity studies with BAY 54-9085 can be taken for the prediction of a carcinogenic potential of BAY 43-9006.

 

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 (Schladt and Rühl-Fehlert, 2013) . 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 (highest dose tested).

In a second long-term study according to OECD TG 451 a possible carcinogenic potential of BAY 54-9085 was investigated in mice (Schladt and Lawrenz, 2013). For this purpose BAY 54-9085 was administered orally dose-adjusted via diet to 60 male and 60 female CD-1 mice per dose group in mean daily doses of 0, 12.7, 35.3 or 137.4 mg/kg bw for males and 0, 6.8, 22.9 or 94.8 mg/kg bw for females over a period of up to 2 years. Dose selection was based on MTD criteria in two 13-week dose finding studies. 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 BAY 54-9085. Therefore, the study did not reveal a clear evidence of a carcinogenic potential of BAY 54-9085 in mice. Under the conditions described the no observed adverse effect level (NOAEL) for oral administration of BAY 54-9085 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).


Justification for selection of carcinogenicity via oral route endpoint:
Both carcinogenicity studies in rats and mice revealed a negative result. With regard to the NOAEL the rat represents the more sensitive species.

Justification for classification or non-classification

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