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EC number: 608-209-4 | CAS number: 284461-73-0
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).
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.
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).
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)
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