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

Endpoint summary

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

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: 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 in iuclid section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Species:

rat

Sex:

male/female

Route of administration:

oral: gavage

Duration of treatment / exposure:

4 weeks

Dose descriptor:

NOAEL

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Dose descriptor:

LOAEL

Effect level:

1.1 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

Critical effects observed:

yes

Lowest effective dose / conc.:

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

System:

musculoskeletal system

Organ:

bone marrow

tooth

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

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 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

BAY 54-9085 doses of 35 or 170 mg/kg were not tolerated and resulted in increased mortality. 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.

Taking into consideration the differences in molecular weight, the LOAEL is converted to 1.1 mg/kg.

 

Reference 2

Endpoint:

sub-chronic toxicity: 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 in iuclid section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Species:

rat

Sex:

male/female

Route of administration:

oral: gavage

Analytical verification of doses or concentrations:

yes

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

haematology

histopathology: non-neoplastic

Remarks on result:

other: correction for difference in molecular weight

Dose descriptor:

LOAEL

Effect level:

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

Based on:

test mat.

Sex:

female

Basis for effect level:

histopathology: non-neoplastic

Remarks on result:

other: correction for difference in molecular weight

Critical effects observed:

not specified

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 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

Under the conditions described the administration of BAY 54-9085 orally by gavage was tolerated without adverse effects at 0.14 mg/kg/day. Due to the dentin degeneration a no-(adverse)-effect Ievel could not be established for females.

Taking into consideration the differences in molecular weight, the NOAEL established for males is converted to 0.1 mg/kg.

Reference 3

Endpoint:

chronic toxicity: 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 in 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

Analytical verification of doses or concentrations:

yes

Key result

Dose descriptor:

NOAEL

Effect level:

0.22 other: mg/kg bw/day (dose-adjusted via diet)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Remarks on result:

other: correction for difference in molecular weight

Critical effects observed:

not specified

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 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

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.

Taking into consideration the differences in molecular weight, the NOAEL established for males is converted to 0.22 mg/kg.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

0.22 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

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.

 

Studies in rodents

Subacute study

Groups of 10 male and 10 female Wistar rats were treated orally by gavage for 4 weeks according to EU Method B.7 at the following doses of BAY 54-9085: 0, 1.5, 7, 35, or 170 mg/kg. 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 from femurs 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 increased mortality. 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 (Renhof and Bach, 2000).

 

Subchronic 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 for a period of up to 191 days. 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 histopathological 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) were reduced; 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 Kupffer cells (3.43 mg/kg both sexes) were seen.

Increased activities of APh (females 3.43 mg/kg), of ASAT (females 3.43 mg/kg) 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 concentrations were 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.

Gross and histopathological investigations into other organs and tissues gave no indication of test-compound-related functional or morphological changes in both sexes.

Under the conditions described the administration of BAY 54-9085 orally by gavage was tolerated without adverse effects at 0.14 mg/kg/day corresponding to 0.1 mg/kg/ day BAY 43-9006 by males. Due to the dentin degeneration a no-(adverse)-effect Ievel could not be established for females (Wirnitzer and Bach, 2003).

 

Chronic studies

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 (Schladt and Rühl-Fehlert, 2013).

 

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 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-1 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 females with regard to systemic toxicity (Schladt and Lawrenz, 2013).

 

Repeated dose toxicity studies with sorafenib tosylate in rats and mice

	Sorafenib tosylate (source) CAS 475207-59-1	Sorafenib base (target) CAS 284461-73-0
Study type	Subacute toxicity study, rats
Study no./ Report no.	T 3068937 / PH-30261 Renhof/ Bach, 2000	Read-Across   converted to LOAEL 1.1 mg/kg body weight
GLP/ OECD TG/ deviations	GLP, according to Directive 84/449/EEC, EU B.7
Species; animals/ group	Rat (Wistar), n=10 female, n=10 male / dose group
Doses/ route/ schedule	0, 1.5, 7, 35 and 170 mg/kg/d p.o.
Formulation	·         Batch no. 990722; purity 97.1% ·         Suspension in 15% Pluronic F68, 42.5% propylene glycol and 42.5% polyethylene glycol 400 ·         Homogeneity and stability of formulated samples tested & confirmed
Observation period	4 weeks treatment, partly: 29d recovery period
Parameters assessed	Body weights, food / water intakes, clinical laboratory investigations, urinalyses, liver enzymes, biochemical investigation in liver, fluoride content in femurs and teeth
Results	·         35 and 170 mg/kg not tolerated -> increased mortality ·         Slight (in 1.5 and 7 mg/kg dose group) to severe (in 35 and 170 mg/kg dose groups) toxic signs in most of investigated parameters ·         Histopathological findings in liver and kidneys not reversible ·         Findings in teeth and bone marrow already in some males of 1.5 mg/kg dose group in addition to increased AST & ALT   LOAEL 1.5 mg/kg body weight
Reliability	1
Study type	Subchronic toxicity study
Study no./ Report no.	T5071052 / PH-32607 Wirnitzer/ Bach, 2003	Read-Across   Converted to NOAEL 0.1 mg/kg/d (male rats)
GLP/ OECD TG/ deviations	GLP, according to OECD 452
Species; animals/ group	Rat (Wistar), n=20 female, n=20 male / dose group
Doses/ route/ schedule	0, 0.14, 1.4 and 3.43 mg/kg/day, orally
Formulation	·         Batch no. 000217; purity 96% ·         Suspension in 15% Pluronic F68, 42.5% propylene glycol and 42.5% polyethylene glycol 400 ·         Homogeneity and stability of formulated samples tested & confirmed
Observation period	Treatment for up to 191 days
Parameters assessed	Body weights, food / water intakes, hematology, clinical chemistry, urinalyses, ophthalmology, neurotoxicity, necropsy, organ weights, histopathology, toxicokinetics
Results	·         No mortalities ·         Effects on red and white blood cells, APH, AST and ALT ·         Trend to proteinuria; nephropathy observed at highest dose ·         No indication of neurotoxicity ·         Dentin degeneration and osteodystrophy of jaw   NOAEL 0.14 mg/kg/d (male rats)
Reliability	1
Study type	Chronic toxicity studies (rats & mice)
Study no./ Report no.	T8076320 / PH-37557 Schladt/ Rühl-Fehlert, 2013	Read-Across   Converted to NOAEL 0.22 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 0.3 mg/kg (both sexes)
Reliability	1
Study no./ Report no.	T4079666 / PH-37556 Schladt/ Lawrenz, 2013	Read-Across   Converted to NOAEL 9.3 mg/kg/d (males) and 5.0 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 12.7 mg/kg/d for males and 6.8 mg/kg/d for females.
Reliability	1

 

Studies in non-rodents

The findings in rodents were supported by (sub)chronic studies in dogs. In a chronic toxicity study after the administration of 30 mg/kg of sorafenib once-daily for 3 or 12 months in dogs, effects on the GI tract (bloody diarrhoea) and on the skin (hair loss, inflammation) were observed. At histopathology, degenerative and regenerative processes were seen dose-dependently in multiple tissues including kidneys, lymphoreticular/ hematopoietic system, GI tract, adrenals, teeth and bone. Marked morphological changes were observed in the liver and skin.

 

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 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)