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

Endpoint summary

Description of key information

oral LD50 rat: > 1460 mg/kg bw (read-across from BAY 54-9085, taking into account the different molecular weight) (Renhof, 2000)

dermal LD50 rat: > 2000 mg/kg bw (Gillissen, 2015)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute 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

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 1 460 mg/kg bw

Executive summary:

For BAY 43-9006 (sorafenib base) no acute toxicity data are available. Therefore, acute oral toxicity data of BAY 54-9085 (tosylate salt of sorafenib) were used. Under physiological conditions a dissociation of the salt takes place. Therefore, an identical toxicity profile of BAY 54-9085 and BAY 43-9006 is to be expected. Hence, for BAY 43-9006 the result of the acute oral toxicity study with BAY 54-9085 can be taken under correction of the different molecular weight.

In an acute oral toxicity study according to OECD Guideline 401, groups of fasted Wistar rats (5/sex) or NMRI mice (5/sex) were given a single oral dose of BAY 54-9085 in 15 % Pluronic F68, 42.5 % propylene glycol and 42.5 % polyethylene glycol 400 at doses of 500, or 2000 mg/kg bw and observed for 14 days.

A single oral administration of the test substance by gavage to male and female rats or mice in doses up to 2000 mg/kg bw was tolerated without mortalities, effects on body weight gain or gross pathological findings. The LD50 for the source substance was >2000 mg/kg bw. Taking into consideration the differences in molecular weight, the LD50 is converted > 1460 mg/kg for both species.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

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:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Version / remarks:

2008

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system 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)

Key result

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:

other: 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.

Gross pathology:

The necropsies performed at the end of the study revealed no particular findings.

Other findings:

no

Interpretation of results:

GHS criteria not met

Conclusions:

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.

Executive summary:

In an acute dermal toxicity study according to OECD Guideline 402, groups of Wistar rats (5/sex) were dermally exposed to Bay 43-9006 at a dose of 2000 mg/kg bw for 24 h under semiocclusive conditions and observed for 14 days. The administration 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. The dermal LD50 was >2000 mg/kg bw.

 

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Quality of whole database:

The study is GLP compliant and is of high quality (Klimisch score=1)

Additional information

No acute oral toxicity studies were conducted with sorafenib base (CAS 284461-73-0). Instead, data of its tosylate (CAS 475207-59-1) from rat and mouse acute oral studies are used for read-across.

Under physiological conditions a dissociation of the salt takes place. Therefore, an identical toxicity profile of BAY 54-9085 and BAY 43-9006 is to be expected. Hence, for BAY 43-9006 the result of the acute oral toxicity study with BAY 54-9085 can be taken under correction of the different molecular weight. A justification for read-across is attached to Iuclid section 13.

An acute dermal toxicity study was conducted with sorafenib base (CAS 284461-73-0) itself. There was no relevant acute toxicity observed in any of these studies.

 

Acute oral toxicity

In an acute oral toxicity study according to OECD Guideline 401, groups of fasted Wistar rats (5/sex) were given a single oral dose of BAY 54-9085 in 15 % Pluronic F68, 42.5 % propylene glycol and 42.5 % polyethylene glycol 400 at doses of 500, or 2000 mg/kg bw and observed for 14 days.

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. The LD50 was >2000 mg/kg bw for males and females (Renhof, 2000).

 

In an acute oral toxicity study according to OECD Guideline 401, groups of fasted NMRI mice (5/sex) were given a single oral dose of BAY 54-9085 in 15 % Pluronic F68, 42.5 % propylene glycol and 42.5 % polyethylene glycol 400 at doses of 500, or 2000 mg/kg bw and observed for 14 days.

The single oral administration of the test substance by gavage to male and female mice in doses up to 2000 mg/kg bw was tolerated without mortalities, clinical signs, effects on body weight gain or gross pathological findings. The LD50 was >2000 mg/kg bw for males and females (Renhof, 2000).

 

Taking into consideration the differences in molecular weight, the LD50 is converted > 1460 mg/kg for both species.

 

Acute dermal toxicity

In an acute dermal toxicity study according to OECD Guideline 402, groups of Wistar rats (5/sex) were dermally exposed to Bay 43-9006 at a dose of 2000 mg/kg bw for 24 h under semiocclusive conditions and observed for 14 days. The administration 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. The dermal LD50 was >2000 mg/kg bw (Gillissen, 2015).

 

Acute toxicity studies for sorafenib tosylate and sorafenib base

 

	Sorafenib tosylate (source) CAS 475207-59-1	Sorafenib base (target) CAS 284461-73-0
Study type	Acute oral
Study no./ Report no.	T 9069220 (mouse) & T 5069226 (rat) / PH-29961 Renhof, 2000	Read-Across   Converted to LD50 > 1460 mg/kg for both species
GLP/ OECD TG/ deviations	GLP, according to OECD 401 Dev.: 2 doses instead of 3 and 2 sexes instead of 1
Species; animals/ group	Mouse (NMRI), n=5 female/ male Rat (Wistar), n=5 female/ male
Doses/ route/ schedule	500 & 2000 mg/kg 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	14d
Results	·         Mouse: no clinical signs ·         Rat: soft feces; transient ·         No substance-related findings within gross necropsy   LD50 > 2000 mg/kg for both species
Reliability	1
Study type	Acute dermal
Study no./ Report no.	No data	T102023-8 / PH-38609 Gillissen, 2015
GLP/ OECD TG/ deviations		GLP, according to OECD 402 (limit study) Dev.: 2 sexes instead of 1
Species; animals/ group		Rat (Wistar), n=3 female/ male
Doses/ route/ schedule		2000 mg/kg, single treatment, dermal application (semi-occlusive) for 24h
Formulation		·         Batch no. BXR6UZH; purity 98.1% ·         Pure solid test substance used
observation period		14d
Results		·         Clinical signs: reddish encrustations of the nose in all animals ·         No animal died ·         No findings within gross necropsy   LD50 > 2000 mg/kg
Reliability		1

 

Justification for classification or non-classification

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