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

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because a pre-natal developmental toxicity study is available

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

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.

 

Cross-reference 2

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

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.

Cross-reference 3

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

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.

Results and discussion

Overall reproductive toxicity

Reproductive effects observed:

not specified