Registration Dossier

Administrative data

Description of key information

BAY 54-9085 (tosylate salt of BAY 43-9006) revealed adverse effects in multiple organs (kidneys, liver, pancreas, lymphoreticular/hematopoetic system, gastrointestinal (GI) tract, adrenals, reproductive organs, skin, bones, teeth) after repeated oral administration to rats and mice (lowest NOAEL from 2-year carcinogenicity study in rats: 0.3 mg/kg bw/day).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
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:
other: OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
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 oral 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
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):
see "Details on results"
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
see also chapter 7.7 "Details on results"
Details on results:
CLINICAL SIGNS AND MORTALITY:
Intercurrent mortality was unaffected by dosing with BAY 54-9085. Causes of death were mostly related to common pathological findings in aging rats and were similar throughout the groups. Only in females of the satellite groups mortality at 1 mg/kg was higher compared to the other groups from 18 months onwards. However, as these unscheduled deaths occurred near the end of the study and as in main groups with a higher number of animals per group this was not observed, a treatment-related effect was not assumed.

At the dose of 1.0 mg/kg b.w./day detailed clinical observations revealed slightly higher incidences of males showing increased urine excretion, narrowed eye lids, emaciation, palpable masses and/or piloerection. However, there were no correlates (e.g. quantitative urinalysis or at histopathological evaluation) and no clear dose dependence occurred. As furthermore findings as emaciation, piloerection and/or narrowed eyelids were noted for animals shortly before unscheduled death these findings are not regarded to indicate a specific test substance related effect.

BODY WEIGHT GAIN:
Body weight development was not relevantly affected by the treatment.

FOOD CONSUMPTION AND COMPOUND INTAKE:
Food intake was not relevantly affected by the treatment.

The test item was administered orally dose-adjusted via diet in intended daily doses of 0, 0.1, 0.3 or 1 mg/kg body weight for a period of up to two years. Homogeneity and stability of the test item in the food mixtures were checked prior to study start. This analytical investigation showed the test item to be homogeneously distributed and stable in the concentration range used during the period of use.
Analyses during the study verified that the test item content agreed with the target concentrations and that the test item was homogeneously distributed in the food mixtures within the defined limits.

Single content values were out of the company defined limits. This is regarded to be due to the very low target concentrations. However, with one exception these mixtures were omitted for treatment of animals. The period of use extended the period of confirmed stability for the low dose diet formulation once during the study. Principally this is no matter of concern because high dose analytical data confirm sufficient stability for the feeding period. Taken together, it can be summarized that the animals were treated according to the scheduled doses and rare exceptions during the long treatment period did not affect the integrity of the study.

WATER CONSUMPTION:
Water intake was not relevantly affected by the treatment. Slightly lower water intake in the last weeks of the study was without treatment-related correlate at clinical pathology or histopathology of kidneys. A toxicological relevance is therefore not assumed.

OPHTHALMOSCOPIC EXAMINATION:
The ophthalmoscopical examinations of the control and 1.0 mg/kg dose group animals performed after about 12 months of treatment afforded no evidence for treatment-related effects. At the end of the dosing phase the examinations revealed an increased incidence of eyes showing diffuse cornea opacity at the dose of 0.3 mg/kg b.w./day and at 1.0 mg/kg b.w./day in males. This finding is known to occur predominantly in older male rats in feeding studies. This finding is not regarded due to the treatment as more as histopathological investigation did not reveal treatment-related effects on eyes.

HAEMATOLOGY AND CLINICAL CHEMISTRY INCL. URINALYSIS:
Hematological and clinico-chemical investigation gave no evidence for treatment-related effects.

ORGAN WEIGHTS:
Determination of organ weights revealed as the only conspicuous finding statistically significant decreased liver weights at 1.0 mg/kg (absolute weight was also decreased at the dose of 0.3 mg/kg b.w./day). A toxicological relevance is not inferred from these data as the differences were relatively slight, as no such observation was present for females and as histopathology gave no treatment-related corresponding findings.

GROSS PATHOLOGY:
In the testes, consistency changes were slightly more often recorded in males at the dose of 1.0 mg/kg b.w./day in the main groups (5/3/7/10) but considering also the satellite groups (2/4/1/0), distribution was similar in all groups. In the parathyroid glands of males, the finding of nodule/s was slightly increased at the dose of 1.0 mg/kg b.w./day (main groups 6/6/7/14, satellite groups 2/2/0/2). Most of these findings were seen in decedents where they did not correlate to any increase in incidence of severe diffuse hyperplasia.

In females, in the liver the incidence of cysts (main groups 8/12/10/4, satellite groups 211/7/1) and of distinct lobulation (main groups 13/10/4/5, satellite groups 1/1/1/0) was particularly low at the dose of 1.0 mg/kg b.w./day.

All other findings were distributed equally throughout the groups.

HISTOPATHOLOGY - NON-NEOPLASTIC CHANGES:
The incidence of vasculopathy was higher in animals of both sexes at the dose of 1.0 mg/kg b.w./day in the abdominal organs which are frequently affected by spontaneous vascular findings. In the stomach both arteritis/periarteritis and vasculopathy were positive in the trend test in males. In the other organs, only vasculopathy showed a positive trend in males (pancreas, spleen, mesentery lymph node). In females, for vasculopathy a positive trend was calculated in the pancreas and in the spleen.

In extraabdominal organs, no effect was discernible. The grade of the findings was most severe in the region of the pancreas and showed high inter-individual variation. No clear increase of severity of vasculopathy or periarteritis could be found up to and including the dose of 1.0 mg/kg b.w./day.

In the pancreas, focal atrophy of acinar cells was significantly increased in males at the dose of 0.3 mg/kg b.w./day and 1.0 mg/kg b.w./day (males 1/1/6*/7*; females 3/3/4/6). This finding is likely related to vascular changes in the abdomen described above.

With respect to possible treatment-related non-neoplastic alterations, in the abdominal organs, an increased incidence of peri-/arteritis and vasculopathy was observed at the dose of 1.0 mg/kg b.w./day. The findings at the dose of 1.0 mg/kg b.w./day were, however, morphologically similar to those of controls and animals dosed at the dose of 0.1 mg/kg b.w./day or 0.3 mg/kg. The mean severity of findings was also not elevated. Vascular changes of this kind tend to develop in animals with advanced stages of chronic progressive nephropathy (CPN). The severity scores of CPN were, however, similar throughout the groups up to and including the dose of 1.0 mg/kg b.w./day. In the pancreas, some animals showed a focal atrophy of acinar cells which was increased at the dose of 0.3 and 1.0 mg/kg. This finding may be related to vascular changes observed in this organ at a higher rate in all groups including control. However, a direct treatment-relation is not assumed since there was only a slight numerical increase but the severity score (mostly minimal or slight) was unaffected by dosing with the test compound.

In the teeth, dysplasia/fracture was significantly increased in incidence and severity in males at the dose of 1.0 mg/kg b.w./day. A treatment-relation is assumed as the finding is in line with findings known from other studies with this test substance.

In the pituitary gland of males, an increased incidence of cholesterol clefts in Rathke's pouch was observed between the pars intermedia and pars distalis. This finding was mostly rated as minimal and was not associated with proliferative of inflammatory changes in the pituitary gland. It is thus not regarded as adverse. A biological relevance is not assumed in humans since Rathke's cleft does not exist in this species.

TOXICOKINETICS:
Toxicokinetic investigation of plasma levels of BAY 43-9006 (free base of BAY 54-9085) showed that there was no evidence of a relevant sex-related difference in exposure and that the observed Cmax concentrations and AUC(0-24) increased dose-dependently in male and female dose groups. An about dose linear increase in terms of Cmax and AUC(0-24) was observed in male dose groups. In female dose groups Cmax and AUC(0-24) increased slightly more than dose-proportional. Peak plasma concentrations were reached in the time frame between 5 and 19 h in the observation period (23:00 to 13:00 CET). The concentration time profile under steady state conditions was flat in the entire observed time frame. Trough plasma concentrations of BAY 43-9006 were in the high range independent of administered dose or gender accounting for 69.5% to 91.9% relative to Cmax in the respective dose groups.
Dose descriptor:
NOAEL
Effect level:
0.3 other: mg/kg bw/day (dose-adjusted via diet)
Based on:
test mat.
Sex:
male/female
Critical effects observed:
not specified
Executive summary:

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

 

Within the scope of a carcinogenicity study the systemic toxicity of BAY 54-9085 was investigated after oral treatment over 2 years (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 main 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 treatment with BAY 54-9085 was well tolerated as e.g. no relevant treatment-related clinical findings, effects on body weight development or on parameters of clinical pathology were observed.

 

At histopathology, in the abdominal organs such as stomach, spleen, pancreas and mesentery lymph nodes, age-related vascular changes arteritis/periarteritis and vasculopathy occurred at an increased incidence in both sexes at a dose of 1.0 mg/kg bw /day. Furthermore, in the teeth, fracture/dysplasia was slightly more frequent in males at the dose of 1.0 mg/kg bw /day. Dental findings are likely of no relevance in humans since permanent growth of teeth is lacking.

 

Thus, under the conditions described the no observed adverse effect level (NOAEL) for oral administration of BAY 54-9085 via the diet was 0.3 mg/kg bw /day in male and female rats with regard to systemic toxicity.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
0.3 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)

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

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.

Within the scope of a carcinogenicity study the systemic toxicity of BAY 54-9085 was investigated after oral treatment over 2 years 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 main 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 treatment with BAY 54-9085 was well tolerated as e.g. no relevant treatment-related clinical findings, effects on body weight development or on parameters of clinical pathology were observed. At histopathology, in the abdominal organs such as stomach, spleen, pancreas and mesentery lymph nodes, age-related vascular changes arteritis/periarteritis and vasculopathy occurred at an increased incidence in both sexes at a dose of 1.0 mg/kg bw /day. Furthermore, in the teeth, fracture/dysplasia was slightly more frequent in males at the dose of 1.0 mg/kg bw /day. Dental findings are likely of no relevance in humans since permanent growth of teeth is lacking. Thus, under the conditions described the no observed adverse effect level (NOAEL) for oral administration of BAY 54-9085 via the diet was 0.3 mg/kg bw /day in male and female rats with regard to systemic toxicity.

In a second carcinogenicity study according to OECD TG 451 the systemic toxicity of BAY 54-9085 was investigated in mice after oral treatment over 2 years (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 in males and 0, 6.8, 22.9 or 94.8 mg/kg bw in females for a period of up to 735 days. Dose selection was based on MTD criteria in two 13-week dose finding studies. Treatment-related mortality starting at mid dose in males and in high dose females was due to these hyperplastic and inflammatory changes of the intestinal mucosa. Several findings (at clinical observation, body weight development, food intake, changes in triglyceride and albumin concentration in peripheral blood, histopathological findings in the mesenteric lymph nodes, liver, spleen, thymus and pancreas) are regarded to be secondary to these effects. Some slight changes in some parameters observed at red blood in males starting at the mid dose and in females at the high dose, and at white blood in high dose groups are attributed to the treatment. Treatment with BAY 54-9085 over a time period of 2 years showed a possible carcinogenic effect (adenocarcinoma) on the colon in female CD-I mice at the high dose, which is regarded to be secondary to the hyperplasia and chronic inflammation of the intestinal mucosa. Thus, under the conditions described the no observed adverse effect level (NOAEL) for oral administration of BAY 54-9085 to mice via the diet was 12.7 mg/kg bw for males and 6.8 mg/kg bw for femaleswith regard to systemic toxicity.

In a subacute (4-week) toxicity study groups of 10 male and 10 female Wistar rats were treated orally by gavage according to EU Method B.7 at the following doses of BAY 54-9085: 0, 1.5, 7, 35, or 170 mg/kg (Renhof and Bach, 2000). In addition, 10 male and 10 females were treated analogously with the test item at 0 and 170 mg/kg for 4 weeks and were observed for a subsequent 4-week treatment-free period for reversibility, continuation or delayed occurrence of possible toxic effects. Further animals were used for toxicokinetic assessment. Study parameters included: clinical signs, body weight, food consumption, water consumption, clinical chemistry, hematology, urinalysis, gross pathology, organ weights, liver enzyme analysis, histopathology, and toxicokinetics. Mortalities prior to the end of 4 weeks treatment in the main group included 3 males (including 2 animals that died during blood sampling) and 9 females at 35 mg/kg, and 3 males and 1 female at 170 mg/kg. In the kinetics group, 2 males and 1 female at 35 mg/kg and in the recovery group 1 female at 170 mg/kg died. One mortality, considered incidental, occurred in the toxicokinetic group treated at 1.5 mg/kg. Dose-dependent clinical signs of toxicity were noted at 7 mg/kg and above. The lowest dose group showed soft feces, only. Most of the symptoms persisted during the recovery period. Food and water intake were decreased in the 25 and 125 mg/kg groups and increased during the recovery period. Body weight gain was lower in these groups and did not reach the controls, especially in males, after recovery. In hematological investigations carried out in week 4, hemoglobin, erythrocytes and the dependant parameters were decreased, beginning at the dose level of 25 mg/kg. Reticulocytes were decreased at 5 mg/kg, but increased at 25 mg/kg and higher. No recovery effects were found. Thrombocytes decreased at 25 mg/kg and higher and this parameter was similar after the recovery period. In the white blood cell differential counts, more immature cell types were found beginning at 25 mg/kg and no recovery effects were seen for this finding. In the clinico-chemical investigations, increases were seen in AST, ALT (beginning at 1.5 mg/kg), GLDH and LDH (at 35 and 170 mg/kg), cholesterol and bilirubin (beginning at 7 mg/kg). An increase was seen in alkaline phosphatase (ALP) at 7 mg/kg with decreases at 35 and 170 mg/kg. Decreases were also seen in protein, calcium (beginning at 35 mg/kg) and phosphate (beginning at 7 mg/kg). In the highest dosing group, all abnormalities recovered completely except GLDH (in the males) and cholesterol, which were only partially recoveredafter 4 weeks post dosing. In urine, increases were seen in protein, urine creatinine (in females only), NAG, and LDH, particularly at 35 and 170 mg/kg. Increases in GGT and ALP were observed in females and decreases in males. Of note, the serum creatinine was not statistically significantly increased, even at the highest doses. The test compound revealed slight decreasing effects on liver enzyme activities, which are more pronounced in the male rats. Partial recovery of protein, NAG and a near full recovery of the LDH were noted 4 weeks after discontinuation of test article. Necropsy revealed findings in the 35 and 170 mg/kg groups, which were mainly related to the poor general condition of the animals (e.g. retardation in size, skinny appearance). Treatment related gross lesions were found in the digestive tract, kidney and adrenal glands. Some organ weight changes were observed, of note were increased weights of the adrenals. Histopathological evaluation revealed treatment-related findings in the majority of animals treated at 35 or 170 mg/kg. The spectrum of histopathological findings was narrower for the 7 mg/kg and the 1.5 mg/kg doses. Overall, the changes were classified as degenerative in the adrenal glands, liver, stomach, duodenum, pancreas, kidneys, heart, and ovaries. Regenerative changes were observed in the liver (bile duct proliferation), pancreas, duodenum and kidneys. Necrosis was observed in the spleen, lymph nodes, and thymus. Hypocellularity was seen in the bone marrow and tongue. Effects in male reproductive organs included retardation in testes, epididymides, prostate and seminal vesicles. Unusual findings were noted in the teeth (alteration of the dentin composition) and proximal growth plate of the femoral bone (irregular thickening, hypocellularity of the bone marrow). Most of the findings could be shown to be reversible. However, after 4 weeks of recovery, bile duct proliferation in the liver as well as basophilic tubules and tubular dilation in the kidneys were observed with almost the same severity when compared to the 170 mg/kg group of the main study. Nearly all treated animals of the recovery groups still showed a prominent decrease in number of mast cells in the tongue. The degenerative processes on incisors were not reversible within 4 weeks but even more pronounced. Furthermore, osteolytic and/or osteodystrophic processes became evident in the 170 mg/kg recovery group. Thickening of the growth plate of the femoral bone was also present in some treated animals of the recovery group. Additionally, increased bone formation beneath the growth plate and bone malformation or epiphysiolysis was observed in some 170 mg/kg animals. In ash fromfemurs and teeth of treated males, a statistically highly significant (30-35%) increase of fluoride concentrations was observed in comparison to the corresponding controls. In summary: BAY 54-9085 doses of 35 or 170 mg/kg were not tolerated and resulted in increasedmortality. Treatment related findings were also seen in the 7 mg/kg group and due to findings in teeth and bone of some males, the dose 1.5 mg/kg was also affected. A NOAEL was not established.

In a 6-month toxicity study BAY 54-9085 (tosylate of BAY 43-9006) was administered orally by gavage to 20 male and 20 female Wistar rats per dose group according to OECD TG 452, in doses of 0, 0.14, 1.4 and 3.43 mg/kg/day (Wirnitzer and Bach, 2003). These doses correspond to 0, 0.1, 1.0 and 2.5 mg/kg/day of BAY 43-9006. Daily observations of the animals revealed emaciation in three females at 3.43 mg/kg, one of which was killed in moribund condition. Open field and functional observation battery investigations gave no indication of a neurotoxicological potential of the test substance. Mortality was unaffected by treatment with BAY 54-9085. Food consumption was comparable to controls in both sexes. Water consumption was decreased in females at 3.43 mg/kg. Body weights of all treated females and males treated at 0.14 mg/kg were comparable to controls. At.1.4 and 3.43 mg/kg males had up to 10% lower body weights. Ophthalmological and hlstopathological investigations gave no indication of an oculotoxic effect of the test compound. Effects on red and white blood cells are derived from several changes: increased hemoglobin concentration and hematocrit at 1.4 and 3.43 mg/kg (both sexes), increased MCV and MCH (both sexes) and MCHC (males) at 3.43 mg/kg, decreased thrombocyte counts at 3.43 mg/kg (both sexes). Thymus weights (both sexes 3.43 mg/kg) werereduced;a histological correlate was missing. Histologically an increase of mast cells in mesenteric lymph nodes (1.4 and 3.43 mg/kg both sexes), fatty replacement of the bone marrow of the sternum (1.4 mg/kg and above males) and minimal pigment storage in Kuptfer cells (3.43 mg/kg both sexes) were seen. Increased activities of APh (females 3.43 mg/kg), of ASAT (females 3.43 mglkg) and of ALAT (both sexes 3.43 mg/kg), decreased glucose concentration (males 1.4 and 3.43 mg/kg), lower protein concentrations (females 3.43 mg/kg) and decreased liver weights (no dose-correlation, females 1.4 and 3.43 mg/kg) were without histological correlates. Urinalyses revealed a trend to higher excreted total protein amounts at 1.4 and 3.43 mg/kg (males) and at 3.43 mg/kg (females). Absolute kidney weights were significantly decreased (males 1.4 mg/kg). Histologically nephropathy was seen at 3.43 mg/kg (both sexes), with a borderline effect at 1.4 mg/kg in males. The test substance is absorbed with a tmax of around 4 hours. In females the plasma concentrationswere slightly higher than in males. Exposure was slightly greater than dose proportional at all doses and sampling dates. Comparing data of week 15 to those of week 1 a large increase in exposure indicates accumulation, while there was no difference in exposure Ievels from week 15 to week 26. In addition, dentin degeneration in the incisors (females 0.14 mg/kg, both sexes 1.4 mg/kg and above) as well as osteodystrophia of the jaw (females 1.4 mg/kg and above) were seen.

In summary, after repeated daily oral treatment of animals with Bay 54-9085 (rats and mice up to 24 months), adverse effects were observed in multiple organs (kidneys, liver, pancreas, lymphoreticular/hematopoetic system, gastrointestinal (GI) tract, adrenals, reproductive organs, skin, bones, teeth ) - consistent with the influence of sorafenib on vital cellular processes. The majority of morphological organ lesions was fully reversible or showed at least a tendency to recover. The lowest dose that induced toxicologically relevant lesions (changes in peripheral blood, morphological changes in kidneys and reproductive organs) was in the range of 1 mg/kg/day (= LOAEL).

 


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Key study with the longest treatment duration (2 years) and the lowest NOAEL in the most sensitive species (rat)

Justification for classification or non-classification

Since no repeated dose toxicity data are available for BAY 43-9006 (sorafenib base), and based on the observed adverse effects after repeated oral administration of BAY 54-9085 (tosylate salt of sorafenib) the above mentioned data were used for the classification of BAY 43-9006. Therefore, based on the classification of BAY 54-9085 (tosylate salt of sorafenib) a self classification of BAY 43-9006 (sorafenib base) according to Regulation (EC) No. 1272/2008 (CLP) is recommended as follows:

GHS: STOT Rep. Exp. 1 (H372: Causes damage to organs (kidneys, liver, pancreas, lymphoreticular/hematopoetic system, gastrointestinal (GI) tract, adrenals, reproductive organs, skin, bones, teeth)