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

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

49.3 µg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

5

Dose descriptor starting point:

NOAEL

Value:

0.2 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

0.247 mg/m³

Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:

1

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

1

Justification:

Since developmental toxicity is the most sensitive endpoint and organoid development is fully covered by the exposure period within this study the default AF is corrected to 1.

AF for interspecies differences (allometric scaling):

1

Justification:

Default (DNEL calculator)

AF for other interspecies differences:

1

Justification:

A factor of 2.5 is suggested by the ECHA Guidance for remaining interspecies differences but justified deviations are possible. In this case a 2-year carcinogenicity study in a second species, the mouse, is available and provided evidence that the rat is the more sensitive species with regard to repeated dose toxicity. In mice the LOAELs were 35.3 mg/kg bw /day for males and 22.9 mg/kg bw /day for females compared to the rat LOAEL of 1.0 mg/kg bw /day for both sexes. Therefore, in this case an assessment factor of 1 for remaining interspecies differences provides sufficient protection, as the calculation based on the most sensitive species already includes a worst-case scenario.

AF for intraspecies differences:

5

Justification:

Default (DNEL calculator)

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

14 µg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other:

Overall assessment factor (AF):

20

Dose descriptor starting point:

NOAEL

Value:

0.2 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

0.28 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:

1

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

1

Justification:

Since developmental toxicity is the most sensitive endpoint and organoid development is fully covered by the exposure period within this study the default AF is corrected to 1.

AF for interspecies differences (allometric scaling):

4

Justification:

Default (DNEL calculator)

AF for other interspecies differences:

1

Justification:

A factor of 2.5 is suggested by the ECHA Guidance for remaining interspecies differences but justified deviations are possible. In this case a 2-year carcinogenicity study in a second species, the mouse, is available and provided evidence that the rat is the more sensitive species with regard to repeated dose toxicity. In mice the LOAELs were 35.3 mg/kg bw /day for males and 22.9 mg/kg bw /day for females compared to the rat LOAEL of 1.0 mg/kg bw /day for both sexes. Therefore, in this case an assessment factor of 1 for remaining interspecies differences provides sufficient protection, as the calculation based on the most sensitive species already includes a worst-case scenario.

AF for intraspecies differences:

5

Justification:

Default (DNEL calculator)

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Preliminary remarks

BAY 43-9006 (sorafenib base) is a multi-kinase inhibitor. It is also a dual action anti-tumor agent that exhibits its activity by affecting important pathways of cell growth and angiogenesis.

 

BAY 43-9006 is the active ingredient (free base) of BAY 54-9085, the tosylate salt of sorafenib. Both have been used in non-clinical development. 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 for DNEL derivation under correction of the different molecular weight. The conversion factor between BAY 43-9006 and BAY 54-9085 is 1.37.

 

BAY 54-9085 is approved as an oral anti-cancer drug under the tradename Nexavar®.

 

 

Selection of the relevant starting point for the derivation of systemic long-term DNELs (inhalation and dermal route) for workers

 

There are no repeated dose toxicity studies available with BAY 43-9006 or BAY 54-9085 for the dermal or inhalation route.

 

In a 2-year carcinogenicity study in rats according to OECD Guideline 451 with oral doses of BAY 54-9085 up to 1.0 mg/kg bw/day (dose-adjusted via diet) a NOAEL of 0.3 mg/kg bw/day was established for males and females (Schladt and Rühl-Fehlert, 2013). 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. There was no evidence of a carcinogenic potential of BAY 54-9085.

 

In a developmental toxicity study female 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 bw from day 6 to day 17 post conceptionem (Klaus, 2004). 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 this study the NOAEL for systemic maternal toxicity in rats was 1.37 mg/kg bw /day and the NOAEL for intrauterine development in rats was 0.27 mg/kg bw /day.

 

In summary, based on the above mentioned effects, the NOAEL of 0.3 mg/kg bw /day BAY 54-9085 (corresponding to 0.219 mg/kg bw /day BAY 43-9006) from the 2-year feeding study in rats will be taken as the most relevant starting point for the DNEL calculation of systemic long-term effects. The NOAEL of 0.27 mg/kg bw /day BAY 54-9085 (corresponding to 0.197 mg/kg bw /day BAY 43-9006) from the developmental toxicity study in rats is close to the NOAEL of the 2-year rat study. Therefore, the most sensitive endpoint after exposure to BAY 43-9006 is developmental toxicity and selected as POD..

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.7 µg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor starting point:

NOAEL

Value:

0.2 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

87 µg/m³

Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:

1

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

1

Justification:

Since developmental toxicity is the most sensitive endpoint and organoid development is fully covered by the exposure period within this study the default AF is corrected to 1.

AF for interspecies differences (allometric scaling):

1

Justification:

Default (DNEL calculator)

AF for other interspecies differences:

1

Justification:

A factor of 2.5 is suggested by the ECHA Guidance for remaining interspecies differences but justified deviations are possible. In this case a 2-year carcinogenicity study in a second species, the mouse, is available and provided evidence that the rat is the more sensitive species with regard to repeated dose toxicity. In mice the LOAELs were 35.3 mg/kg bw /day for males and 22.9 mg/kg bw /day for females compared to the rat LOAEL of 1.0 mg/kg bw /day for both sexes. Therefore, in this case an assessment factor of 1 for remaining interspecies differences provides sufficient protection, as the calculation based on the most sensitive species already includes a worst-case scenario.

AF for intraspecies differences:

10

Justification:

Default (DNEL calculator)

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 µg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other:

Overall assessment factor (AF):

40

Dose descriptor starting point:

NOAEL

Value:

0.2 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

0.2 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:

1

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

1

Justification:

Since developmental toxicity is the most sensitive endpoint and organoid development is fully covered by the exposure period within this study the default AF is corrected to 1.

AF for interspecies differences (allometric scaling):

4

Justification:

Default (DNEL calculator)

AF for other interspecies differences:

1

Justification:

A factor of 2.5 is suggested by the ECHA Guidance for remaining interspecies differences but justified deviations are possible. In this case a 2-year carcinogenicity study in a second species, the mouse, is available and provided evidence that the rat is the more sensitive species with regard to repeated dose toxicity. In mice the LOAELs were 35.3 mg/kg bw /day for males and 22.9 mg/kg bw /day for females compared to the rat LOAEL of 1.0 mg/kg bw /day for both sexes. Therefore, in this case an assessment factor of 1 for remaining interspecies differences provides sufficient protection, as the calculation based on the most sensitive species already includes a worst-case scenario.

AF for intraspecies differences:

10

Justification:

Default (DNEL calculator)

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 µg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other:

Overall assessment factor (AF):

40

Dose descriptor starting point:

NOAEL

Value:

0.2 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

0.2 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:

1

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

1

Justification:

Since developmental toxicity is the most sensitive endpoint and organoid development is fully covered by the exposure period within this study the default AF is corrected to 1.

AF for interspecies differences (allometric scaling):

4

Justification:

Default (DNEL calculator)

AF for other interspecies differences:

1

Justification:

A factor of 2.5 is suggested by the ECHA Guidance for remaining interspecies differences but justified deviations are possible. In this case a 2-year carcinogenicity study in a second species, the mouse, is available and provided evidence that the rat is the more sensitive species with regard to repeated dose toxicity. In mice the LOAELs were 35.3 mg/kg bw /day for males and 22.9 mg/kg bw /day for females compared to the rat LOAEL of 1.0 mg/kg bw /day for both sexes. Therefore, in this case an assessment factor of 1 for remaining interspecies differences provides sufficient protection, as the calculation based on the most sensitive species already includes a worst-case scenario.

AF for intraspecies differences:

10

Justification:

Default (DNEL calculator)

AF for the quality of the whole database:

1

Justification:

Default (DNEL calculator)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified