Registration Dossier

Administrative data

Description of key information

BAY 43-9006 is practically non-toxic after single oral exposure (LD50 rat: > 1460 mg/kg bw) or after single dermal exposure (LD50 rat: > 2000 mg/kg bw).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
Nov 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann, Borchen, Germany
- Strain: Hsd Cpb:WU (SPF)
- Age at study initiation: not specified
- Mean weight at study initiation: 193-211 g (males) or 180-195 g (females)
- Housing: in groups of 5 animals
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-24
- Humidity (%): approx. 30-70
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
oral: gavage
Vehicle:
other: test item was suspended in 15 % Pluronic F68 (42.5 % propylene glycol and 42.5 % polyethylene glycol 400)
Details on oral exposure:
- Application volume: 10 mL/kg bw

Doses:
500 and 2000 mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: at least once daily (clinical signs, mortality) or once weekly (weight gain)
- Necropsy of survivors performed: yes
Statistics:
none
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No animal died after administration of 500 or 2000 mg/kg bw.
Clinical signs:
After administration of 500 and 2000 mg/kg bw soft feces were observed in all animals up to day 3 of the observation period.
Body weight:
Body weight development was not affected.
Gross pathology:
No gross pathological findings were observed.
Other findings:
none
Interpretation of results:
practically nontoxic
Remarks:
Migrated information
Executive summary:

The acute oral toxicity of the test item BAY 54-9085 was low with an LD50 exceeding 2000 mg/kg bw in rats according to OECD TG 401. A single oral administration of the test substance by gavage to male and female rats in doses up to 2000 mg/kg bw was tolerated without mortalities, effects on body weight gain or gross pathological findings. After administration of 500 or 2000 mg/kg bw soft feces was observed in both genders.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
1 460 mg/kg bw
Quality of whole database:
The study is GLP compliant and is of high quality (Klimisch score=1)

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
March to April 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan GmbH (Horst, Netherlands)
- Age at study initiation: 8-14 weeks
- Weight at study initiation: 276-308 g for males and 235-259 g for females
- Fasting period before study: none
- Housing: individually in polycarbonate cages on low dust wood granulate bedding
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 55 +/- 5
- Air changes (per hr): approx. 10
- Photoperiod (hrs dark / hrs light): 12 / 12
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 30 cm2
- % coverage: approx. 10
- Type of wrap if used: gauze patch fixed with an elastic adhesive tape pervious to air

REMOVAL OF TEST SUBSTANCE
- Washing (if done): rinsed with tepid water using soap
- Time after start of exposure: approx. 24 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 18.4-20.5 mg/cm2 (males) and 15.7-17.3 mg/cm2 (females)
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: several times on the day of application as well as at least once daily during observation period (clinical signs, mortality); surviving animals were weighed individually at application, after one week and at the end of the 14-day observation period.
- Necropsy of survivors performed: yes
Statistics:
no (limit test)
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
All male and female animals survived the treatment.
Clinical signs:
At 2000 mg/kg bw reddish encrustations of the nose were observed in all animals. In addition, one female displayed piloerection and sunken flanks on day 15.
Body weight:
There were no toxicologically significant effects on body weight or body weight development. Only one female with clinical signs showed a decrease in body weight in the second week.
Gross pathology:
The necropsies performed at the end of the study revealed no particular findings.
Other findings:
no
Interpretation of results:
practically nontoxic
Remarks:
Migrated information
Executive summary:

The acute dermal toxicity of the test substance was low with an LD50 value > 2000 mg/kg bw for male and female rats according to OECD TG 402. Single semiocclusive administration of 2000 mg/kg bw for 24 hours was tolerated without mortalities, effects on body weight gain or gross pathological findings. Clinical signs (reddish encrustations of the nose) were observed in all male and female animals. In addition, one female displayed piloerection and sunken flanks on day 15.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
2 000 mg/kg bw
Quality of whole database:
The study is GLP compliant and is of high quality (Klimisch score=1)

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 systemic 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.

The acute oral toxicity of the test item BAY 54-9085 was low with an LD50 exceeding 2000 mg/kg bw in rats according to OECD TG 401 (Renhof, 2000). A single oral administration of the test substance by gavage to male and female rats in doses up to 2000 mg/kg bw was tolerated without mortalities, effects on body weight gain or gross pathological findings. After administration of 500 or 2000 mg/kg bw soft feces was observed in both genders. Under consideration of the molecular weight a LD50 value >1460 mg/kg bw was calculated for BAY 43-9006 (sorafenib base) based on the oral LD50 value of BAY 54-9085 (tosylate salt of sorafenib).

The acute dermal toxicity of the test item BAY 43-9006 was low with an LD50 exceeding 2000 mg/kg bw in rats according to OECD TG 402 (Gillissen, 2015). Single semiocclusive administration of 2000 mg/kg bw for 24 hours was tolerated without mortalities, effects on body weight gain or gross pathological findings. Clinical signs (reddish encrustations of the nose) were observed in all male and female animals. In addition, one female displayed piloerection and sunken flanks on day 15.


Justification for selection of acute toxicity – oral endpoint
Only one key study available

Justification for selection of acute toxicity – dermal endpoint
Only one study available

Justification for classification or non-classification

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