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

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

In the 4-,13- and 26- week studies in rats, treatment-related effects on reproductive organs at a dose of 25 mg/kg/day of sorafenib were observed (in male affected reproductive organs included retardation in testes, epididymides, prostate and seminal vesicles; in females there were retarded ovaries and central necrosis of corpora lutea).

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

With regards to effects on fertility, the available information from the repeated dose toxicity studies is taken into account. In general, histopathological examinations of reproductive tissues in rodents in repeated dose toxicity studies are of high value and high sensitivity for evaluation of that endpoint, as confirmed by literature (Sanbuissho et al., J Toxicol Sci 34, 2009, Special Issue SP1-SP22; Janer et al., Reproductive Toxicol 24, 2007, 103-113; Dent, Reg Toxicol Pharm 48, 2007, 241-258; Mangelsdorf. et al., Reg Toxicol Pharm 37, 2007, 356-369; Ulbrich & Palmer, J Am Coll Toxicol 14, 1995, 293-327). Histopathological changes in the reproductive organs in repeated dose toxicity studies are indicative of effects on fertility. In regard of this repeated dose toxicity studies should be considered sensitive and sufficient information to evaluate toxicity on fertility if histological examination of the reproductive organs is covered.

In the 4-,13- and 26- week studies in rats, treatment-related effects on reproductive organs at a dose of 25 mg/kg/day of sorafenib were observed (in male affected reproductive organs included retardation in testes, epididymides, prostate and seminal vesicles; in females there were retarded ovaries and central necrosis of corpora lutea).

Effects on developmental toxicity

Description of key information

BAY 54-9085 (tosylate salt of BAY 43-9006) revealed a reprotoxic potential in rats and rabbits (NOAEL for intrauterine development in rats: 0.27 mg/kg bw /day), corresponding to 0.15 mg/kg bw/d as BAY 43-9006.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

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:

rabbit

Strain:

Himalayan

Route of administration:

oral: gavage

Duration of treatment / exposure:

days 6 to 20 of gestation

Frequency of treatment:

once daily

Dose descriptor:

NOAEL

Basis for effect level:

clinical signs

Remarks on result:

not determinable

Remarks:

A NOAEL cannot be established conservatively due to cold ears already in lowest dose-group

Abnormalities:

effects observed, treatment-related

Localisation:

placenta

Description (incidence and severity):

decreased gestation with one abortion and three total resorptions, increased placental findings, increased postimplantation loss with subsequently reduced number of fetuses in the high dose group

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

external malformations

skeletal malformations

Remarks on result:

other: correction for difference in molecular weight

Abnormalities:

not specified

Localisation:

skeletal: rib

skeletal: vertebra

visceral/soft tissue: urinary

Description (incidence and severity):

A treatment related effect is assumed for the increased incidence of fetal malformations (mainly malformations of kidneys, vertebrae, and ribs) in the high dose group, known as common malformations in the rabbit strain used.

Skeletal development (retardations/variations) revealed an increased incidence of fused sternebrae and retarded ossification of cervical vertebral bodies and frontal bones in the high dose group.

Developmental 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.

 

Twenty inseminated female Himalayan rabbits each were treated orally by gavage with BAY 54-9085 with daily doses of 0, 0.41, 1.37, or 4.11 mg/kg (corresponding to 0, 0.3, 1.0 or 3.0 mg/kg/day BAY 43-9006) from day 6 to day 20 post conceptionem. On day 29 of gestation the fetuses were delivered by cesarean section. Three additional females per group were treated with BAY 54-9085 doses of 0.41, 1.37, and 4.11 mg/kg/day from day 6 to day 20 post conceptionem for determination of BAY 43-9006 and metabolites in the plasma of the females.

One female at 4.11 mg/kg aborted after signs of mild systemic toxicity. Furthermore, an increased incidence of females with cold ears transiently occurred at 4.11 mg/kg. Transiently marginally decreased mean feed intake correlating with reduced, soft, and light colored feces, and reddish excretion occurred at 4.11 mg/kg. Absolute body weight gain during the treatment period was marginally decreased at 4.11 mg/kg. No treatment-related gross pathological findings were evident at dose levels up to and including 4.11 mg/kg.

The gestation rate of the 4.11 mg/kg group was decreased by the abortion of one female, and by three females, which showed total resorptions. Increased incidences of placental findings (partly necrotic placentas) occurred at 4.11 mg/kg. The placental weights in all dose-groups were unaffected by treatment.

The postimplantation loss in females with viable fetuses was increased at 4.11 mg/kg, mainly caused by late resorptions. Correspondingly, the mean number of fetuses was decreased at 4.11 mg/kg. Fetal sex distribution was shifted to 40 % males at 4.11 mg/kg. Although fetal sex is already determined before start of treatment, and the value are only marginally below the normal range of historical controls, a treatment related effect, based on marginally higher lethality of male fetuses, cannot be excluded. The fetal weights in all dose groups did not differ to a meaningful extent from the control value.

A treatment-related effect is assumed at 4.11 mg/kg for the increased incidence of fetal malformations (mainly malformations of kidneys, vertebrae, and ribs), known as common malformations in the rabbit strain used. A treatment-related effect on external and visceral deviations (findings other than malformations) was not evident at doses up to and including 4.11 mg/kg. Skeletal development (retardations/variations) revealed an increased incidence of fused sternebrae and retarded ossification of cervical vertebral bodies and frontal bones at 4.11 mg/kg.

Based on a possibly increased incidence of females with cold ears at 0.41 and 1.37 mg/kg, for which a treatment related effect is unlikely, but cannot be excluded, a conservative systemic maternal no-observed-adverse-effect-level (NOAEL) was not established in this study. Therefore, under the conditions described the NOAEL for systemic maternal toxicity (cold ears) in rabbits was < 0.41 mg/kg/day and the NOAEL for intrauterine development in rabbits was 1.37 mg/kg/day.

 

Taking into consideration the differences in molecular weight, NOAEL for intrauterine development in rabbits was 1 mg/kg/day.

Reference 2

Endpoint:

developmental toxicity

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

Strain:

Wistar

Route of administration:

oral: gavage

Duration of treatment / exposure:

days 6 to 17 of gestation

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

body weight and weight gain

early or late resorptions

total litter losses by resorption

Remarks on result:

other: correction for difference in molecular weight

Abnormalities:

effects observed, treatment-related

Localisation:

placenta

Description (incidence and severity):

impaired gestation rate (one total late resorption), increased postimplantation loss (late resorptions), increased incidence of necrotic placental borders and pale placentas

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: skeletal retardations and possibly an aortic malformation

Remarks on result:

other: correction for difference in molecular weight

Abnormalities:

effects observed, treatment-related

Localisation:

visceral/soft tissue: cardiovascular

Description (incidence and severity):

treatment relationship could not be completely excluded for this malformation ofthe aortic arch in the 1mg/kg group of the acutal study since the same finding occurred at a higher incidence in the 2.5 mg/kg dose group

Developmental effects observed:

yes

Lowest effective dose / conc.:

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

Treatment related:

yes

Relation to maternal toxicity:

developmental effects in the absence of maternal toxicity effects

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.

 

Twenty-two inseminated female Wistar rats each were treated orally by gavage with BAY 54-9085 with daily doses of 0, 0.27, 1.37 or 3.43 mg/kg (corresponding to 0, 0.2, 1.0 or 2.5 mg/kg/day BAY 43-9006) from day 6 to day 17 post conceptionem. Five additional females per group were treated likewise and were used for toxicokinetic analysis on BAY 43-9006 and metabolites. Females of these satellite groups were sacrificed on day 18 post conceptionem after the last blood sampling and status of pregnancy was ascertained. In the main groups the fetuses were delivered by cesarean section on day 20 of gestation. Investigations were performed on general tolerance of the test compound by the females and possible effects on intrauterine development in the main groups, only.

Maternal findings were restricted to the high-dose (3.43 mg/kg) group, and comprised reddish vaginal excretion in two females which revealed either total resorption or a high number of late resorptions, marginally impaired feed intake at the end of treatment and slightly impaired body weight gain during treatment and the overall gestation period. Effects on body weight development might be related to lower litter size and impaired fetal weights at 3.43 mg/kg.

With respect to the parameters of intrauterine development, treatment-related effects were evident at 3.43 mg/kg and included impaired gestation rate (one total late resorption), increased post-implantation loss (late resorptions) in the remaining litters and consequently decreased mean litter size, increased incidence of necrotic placental borders and pale placentas, decreased placental and fetal weights, retarded fetal skeletal ossification in relation to reduced fetal weights and increased incidence of external and visceral deviations (pale appearance, missing innominate artery) and skeletal variations (supernumerary 14th ribs). Incidence of generally common fetal malformations of different types was as well increased at 3.43 mg/kg. At 1.37 mg/kg, treatment-relationship could not be excluded for retarded ossification of few localizations (single bones of forepaws and sternum, thoracic vertebrae), and a single malformation of the aorta (retroesophageal aortic arch).

In summary, BAY 54-9085 produced maternal toxicity at a dose of 3.43 mg/kg/day. Developmental toxicity was observed at doses of 1.37 mg/kg/day and above. Therefore, under the conditions described the no-observed-adverse-effect-level (NOAEL) for systemic maternal toxicity in rats was 1.37 mg/kg/day and the NOAEL for intrauterine development in rats was 0.27 mg/kg/day.

 

Taking into consideration the differences in molecular weight, the NOAEL for systemic maternal toxicity in rats was 1 mg/kg/day and the NOAEL for intrauterine development in rats was 0.197 mg/kg/day.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

0.197 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

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 developmental toxicity studies in rats and rabbits 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.

 

Twenty-two inseminated female Wistar rats each were treated orally by gavage with BAY 54-9085 with daily doses of 0, 0.27, 1.37 or 3.43 mg/kg (corresponding to 0, 0.2, 1.0 or 2.5 mg/kg/day BAY 43-9006) from day 6 to day 17 post conceptionem. Five additional females per group were treated likewise and were used for toxicokinetic analysis on BAY 43-9006 and metabolites. Females of these satellite groups were sacrificed on day 18 post conceptionem after the last blood sampling and status of pregnancy was ascertained. In the main groups the fetuses were delivered by cesarean section on day 20 of gestation. Investigations were performed on general tolerance of the test compound by the females and possible effects on intrauterine development in the main groups, only.

Maternal findings were restricted to the high-dose (3.43 mg/kg) group, and comprised reddish vaginal excretion in two females which revealed either total resorption or a high number of late resorptions, marginally impaired feed intake at the end of treatment and slightly impaired body weight gain during treatment and the overall gestation period. Effects on body weight development might be related to lower litter size and impaired fetal weights at 3.43 mg/kg.

With respect to the parameters of intrauterine development, treatment-related effects were evident at 3.43 mg/kg and included impaired gestation rate (one total late resorption), increased post-implantation loss (late resorptions) in the remaining litters and consequently decreased mean litter size, increased incidence of necrotic placental borders and pale placentas, decreased placental and fetal weights, retarded fetal skeletal ossification in relation to reduced fetal weights and increased incidence of external and visceral deviations (pale appearance, missing innominate artery) and skeletal variations (supernumerary 14th ribs). Incidence of generally common fetal malformations of different types was as well increased at 3.43 mg/kg. At 1.37 mg/kg, treatment-relationship could not be excluded for retarded ossification of few localizations (single bones of forepaws and sternum, thoracic vertebrae), and a single malformation of the aorta (retroesophageal aortic arch).

In summary, BAY 54-9085 produced maternal toxicity at a dose of 3.43 mg/kg/day. Developmental toxicity was observed at doses of 1.37 mg/kg/day and above. Therefore, under the conditions described the no-observed-adverse-effect-level (NOAEL) for systemic maternal toxicity in rats was 1.37 mg/kg/day and the NOAEL for intrauterine development in rats was 0.27 mg/kg/day (Klaus, 2004).

 

Taking into consideration the differences in molecular weight, the NOAEL for systemic maternal toxicity in rats was 1 mg/kg/day and the NOAEL for intrauterine development in rats was 0.197 mg/kg/day.

 

Twenty inseminated female Himalayan rabbits each were treated orally by gavage with BAY 54-9085 with daily doses of 0, 0.41, 1.37, or 4.11 mg/kg (corresponding to 0, 0.3, 1.0 or 3.0 mg/kg/day BAY 43-9006) from day 6 to day 20 post conceptionem. On day 29 of gestation the fetuses were delivered by cesarean section. Three additional females per group were treated with BAY 54-9085 doses of 0.41, 1.37, and 4.11 mg/kg/day from day 6 to day 20 post conceptionem for determination of BAY 43-9006 and metabolites in the plasma of the females.

One female at 4.11 mg/kg aborted after signs of mild systemic toxicity. Furthermore, an increased incidence of females with cold ears transiently occurred at 4.11 mg/kg. Transiently marginally decreased mean feed intake correlating with reduced, soft, and light colored feces, and reddish excretion occurred at 4.11 mg/kg. Absolute body weight gain during the treatment period was marginally decreased at 4.11 mg/kg. No treatment-related gross pathological findings were evident at dose levels up to and including 4.11 mg/kg.

The gestation rate of the 4.11 mg/kg group was decreased by the abortion of one female, and by three females, which showed total resorptions. Increased incidences of placental findings (partly necrotic placentas) occurred at 4.11 mg/kg. The placental weights in all dose-groups were unaffected by treatment.

The postimplantation loss in females with viable fetuses was increased at 4.11 mg/kg, mainly caused by late resorptions. Correspondingly, the mean number of fetuses was decreased at 4.11 mg/kg. Fetal sex distribution was shifted to 40 % males at 4.11 mg/kg. Although fetal sex is already determined before start of treatment, and the value are only marginally below the normal range of historical controls, a treatment related effect, based on marginally higher lethality of male fetuses, cannot be excluded. The fetal weights in all dose groups did not differ to a meaningful extent from the control value.

A treatment-related effect is assumed at 4.11 mg/kg for the increased incidence of fetal malformations (mainly malformations of kidneys, vertebrae, and ribs), known as common malformations in the rabbit strain used. A treatment-related effect on external and visceral deviations (findings other than malformations) was not evident at doses up to and including 4.11 mg/kg. Skeletal development (retardations/variations) revealed an increased incidence of fused sternebrae and retarded ossification of cervical vertebral bodies and frontal bones at 4.11 mg/kg.

Based on a possibly increased incidence of females with cold ears at 0.41 and 1.37 mg/kg, for which a treatment related effect is unlikely, but cannot be excluded, a conservative systemic maternal no-observed-adverse-effect-level (NOAEL) was not established in this study. Therefore, under the conditions described the NOAEL for systemic maternal toxicity (cold ears) in rabbits was < 0.41 mg/kg/day and the NOAEL for intrauterine development in rabbits was 1.37 mg/kg/day (Langewische, 2004).

 

Taking into consideration the differences in molecular weight, NOAEL for intrauterine development in rabbits was 1 mg/kg/day.

 

 

 

 

Developmental toxicity studies with sorafenib tosylate in rats and rabbits

	Sorafenib tosylate (source)	Sorafenib base (target)
CAS No.	475207-59-1	284461-73-0
BAY No.	54-9085	43-9006
Study no./ Report no.	T 0063010 / PH-33514 (Klaus, 2004)	Read-Across   Converted to NOAELs: 1.0 mg/kg/d maternal toxicity; 0.197 mg/kg/d developmental toxicity
GLP/ OECD TG/ deviations	GLP, equivalent to OECD TG 414 (Prenatal Development; version 2001) Deviation: treatment stopped 3d before cesarean
Species; animals/ group	Rat (Wistar), n=22 female / dose group
Doses/ schedule/ route	0, 0.27, 1.37 and 3.43 mg/kg/d; oral gavage (doses selected via prior DRF study)
Formulation	·         Batch no. 011121; purity 98.8% ·         Suspension of 0.5% methylhydroxyethyl-cellulose (Tylopur MH 300 G4) ·         Homogeneity and stability tested
Duration of study	20 days, treatment d6-d17 after insemination, caesarean on d20
Parameters assessed	Body weight, food/ water intake, maternal tolerance (gestation, pre- and postimplantation loss), intrauterine development/ examination of fetuses (external, skeletal and soft-tissue alterations), toxicokinetics of dams
Results	·         Maternal findings restricted to 3.43 mg/kg/d dose group with increased resorptions ·         Severe findings in intrauterine development at 3.43 mg/kg: impaired gestation rate, increased postimplantation loss, decreased mean litter size, decreased placental and fetal weights, common fetal malformations etc. ·         retarded fetal skeletal ossification already in 1.37 mg/kg dose group   NOAELs: 1.37 mg/kg/d maternal toxicity 0.27 mg/kg/d developmental toxicity
Reliability	1
Study no./ Report no.	T4063177 / PH-33531 (Langewische, 2004)	Read-Across   No conservative NOAEL established
GLP/ OECD TG/ deviations	GLP, equivalent to OECD TG 414 (Prenatal Development; version 2001) Deviation: treatment stopped 9d before caesarean
Species; animals/ group	Rabbit (Himalayan), n=20 females /dose group
Doses/ schedule	0, 0.41., 1.37 and 4.11 mg/kg/d (dose selection based on a pilot study)
Formulation	·         Batch no. 011121; purity 98.8% ·         Suspension of 0.5% methylhydroxyethyl-cellulose (Tylopur MH 300 G4) ·         Homogeneity and stability tested
Duration of study	29 days, treatment d6-d20 after insemination, caesarean on d29
Parameters assessed	Body weight, food/ water intake, maternal tolerance (gestation, pre- and postimplantation loss), intrauterine development/ examination of fetuses (external, skeletal and soft-tissue alterations), toxicokinetics of dams
Results	·         Increased incidence of animals with cold ears in all groups ·         in 4.11 mg/kg group: transiently reduced food uptake with soft feces and reduced BW gain, no gross pathological findings in dams, decreased gestation with one abortion and three total resorptions, increased placental findings, increased postimplantation loss with subsequently reduced number of fetuses, increased incidence of fetal malformations, retardation of skeletal development   NOAELs: Cannot be established conservatively due to cold ears already in lowest dose-group
Reliability	1

 

Summing up, findings in the repeat-dose general toxicity studies and embryo fetal development studies performed with BAY 54-9085 indicate a potential risk to humans regarding male and female fertility as well as a risk during pregnancy and lactation. The lowest dose that caused reproductive toxicity in animals was in the range of 1.37 mg/kg bw /day (= LOAEL) corresponding to 1.0 mg/kg bw /day of the free base BAY 43-9006.

Justification for classification or non-classification

Since neither repeated dose toxicity data nor reproductive 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 a self classification of BAY 43-9006 according to Regulation (EC) No.1272/2008 (CLP) is recommended as follows:

GHS: Repr. 1B (H360Df: May damage the unborn child, suspected of damaging fertility) - Additional category for effects on or via lactation (H362: May cause harm to breast-fed children)