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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.08 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Modified dose descriptor starting point:
NOAEC
Value:
0.386 mg/m³
Explanation for the modification of the dose descriptor starting point:
No repeated dose toxicity study available for the inhalation route
AF for dose response relationship:
1
Justification:
see "Discussion"
AF for differences in duration of exposure:
1
Justification:
see "Discussion"
AF for interspecies differences (allometric scaling):
1
Justification:
see "Discussion"
AF for other interspecies differences:
1
Justification:
see "Discussion"
AF for intraspecies differences:
5
Justification:
see "Discussion"
AF for the quality of the whole database:
1
Justification:
see "Discussion"
AF for remaining uncertainties:
1
Justification:
see "Discussion"
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:
0.01 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
Value:
0.219 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No repeated dose toxicity study available for the dermal route.
AF for dose response relationship:
1
Justification:
see "Discussion"
AF for differences in duration of exposure:
1
Justification:
see "Discussion"
AF for interspecies differences (allometric scaling):
4
Justification:
see "Discussion"
AF for other interspecies differences:
1
Justification:
see "Discussion"
AF for intraspecies differences:
5
Justification:
see "Discussion"
AF for the quality of the whole database:
1
Justification:
see "Discussion"
AF for remaining uncertainties:
1
Justification:
see "Discussion"
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 endpoints after exposure to BAY 43-9006 are repeated dose toxicity and developmental toxicity.

Derivation of a systemic long-term DNEL for workers on hazard via the inhalation route

Relevant starting point from oral 2-year carcinogenicity study in rats with BAY 54-9085:

NOAEL: 0.219 mg/kg bw /day (referring to the free base BAY 43-9006)

Modification of dose-descriptor to the correct starting point (according to ECHA Guidance on Information Requirements and Chemical Safety Assessment - Chapter R.8, Example B.3 (Version 2.1, Nov. 2012):

corrected inhalatory NOAEC (in case of workers 8 hours/day exposed)

= oral NOAEL * sRVrat-1* ABSoral-rat/ABSinh-human* sRVhuman/wRV

= 0.219 mg/kg bw * (0.38 m³ /kg bw)-1 * 1.0 * 0.67 = 0.386 mg/m³

sRVrat = default respiratory volume rat, 8 h exposure = 0.38 m³ /kg bw

ABSoral-rat/ABSinh-human = the absorption of rats after oral exposure is assumed to be 100 % of the human absorption after inhalation = 1

sRVhuman = standard respiratory volume human, 8 h exposure = 6.7 m³/person

wRV = respiratory volume light activity for worker, 8 h exposure = 10 m³/person

 

According to ECHA Guidance on Information Requirements and Chemical Safety Assessment - Chapter R.8 (Version 2.1, Nov. 2012) a series of

assessment factors (AF) were applied to the corrected NOAEC and are summarized in the table below:

 

Type of assessment

 

 

Assessment factor (AF)

 

Justification

 

Dose-response relationship

 

 

1

When the starting point for the DNEL derivation is a NOAEC, the default assessment factor, as a standard procedure, is 1.

 

 

Differences in duration of exposure

 

 

1

The assessment factor suggested by ECHA Guidance, Chapter R.8 (Nov. 2012) for chronic exposure duration is 1.

 

 

Interspecies differences rat vs. human (allometric scaling)

 

 

1

No allometric scaling factor required according to ECHA Guidance, Chapter R.8, Table R.8-4 (Nov. 2012) since already covered by correction of starting point.

 

Other interspecies differences

 

 

1

A factor of 2.5 is suggested by the ECHA Guidance, Chapter R.8 (Nov. 2012) 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 szenario.

 

 

Intraspecies differences (workers)

 

 

5

For intraspecies variability, the default assessment factor for workers is 5.

 

 

Quality of whole database

 

 

1

The default assessment factor to be applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements, is 1.

 

 

Overall assessment factor

 

 

5

 

 

Therefore, the overall assessment factor (AF) is 5. Corrected inhalatory NOAEC of 0.386 mg/m³ : 5 = 0.08 mg/m³

 

Worker DNELsystemic, long-term for inhalation route = 0.08 mg/m³

Derivation of a systemic long-term DNEL for workers on hazards via the dermal route

Relevant starting point from oral 2-year carcinogenicity study in rats with BAY 54-9085:

NOAEL: 0.219 mg/kg bw /day (referring to the free base BAY 43-9006)

Modification of dose-descriptor to the correct starting point (according to ECHA Guidance on Information Requirements and Chemical Safety Assessment - Chapter R.8, Example B.5 (Version 2.1, Nov. 2012):

corrected dermal NOAEL (in case of workers 8 hours/day exposed)

= oral NOAEL * ABSoral-rat/ABSdermal-human

= 0.219 mg/kg bw * 1 = 0.219 mg/kg

ABSoral-rat/ABSdermal-human = no specific data available; the absorption of rats after oral exposure is assumed to be identical to the absorption of humans after dermal exposure (worst case) = 1

 

According to ECHA Guidance on Information Requirements and Chemical Safety Assessment - Chapter R.8 (Version 2.1, Nov. 2012) a series of

assessment factors (AF) were applied to the NOAEL and are summarized in the table below:

                                                                                                                                                                                                                                                

 

Type of assessment

 

 

Assessment factor (AF)

 

Justification

 

Dose-response relationship

 

 

1

 

When the starting point for the DNEL derivation is a NOAEL, the default assessment factor, as a standard procedure, is 1.

 

 

Differences in duration of exposure

 

 

1

The assessment factor suggested by ECHA Guidance, Chapter R.8 (Nov. 2012) for chronic exposure duration is 1.

 

 

Interspecies differences rat vs. human (allometric scaling)

 

 

4

 

For allometric scaling rat to human the standard factor is 4.

 

 

Other interspecies differences

 

 

1

A factor of 2.5 is suggested by the ECHA Guidance, Chapter R.8 (Nov. 2012) 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 szenario.

 

 

Intraspecies differences (workers)

 

 

5

 

For intraspecies variability, the default assessment factor for workers is 5.

 

 

Quality of whole database

 

 

1

 

The default assessment factor to be applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements, is 1.

 

 

Overall assessment factor

 

 

20

 

Therefore, the overall assessment factor (AF) is 20. Corrected dermal NOAEL of 0.219 mg/kg bw /day : 20 = 0.01 mg/kg bw /day

 

Worker DNELsystemic, long-term for dermal route = 0.01 mg/kg bw /day

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
no hazard identified
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:
no hazard identified
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

Additional information - General Population