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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.75 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):
25
Modified dose descriptor starting point:
NOAEC
Value:
68.8 mg/m³
Explanation for the modification of the dose descriptor starting point:

8 h exposure time, extrapolation from 50% bioavailability oral to 100% bioavailability inhalation, no inhalation study available.

AF for dose response relationship:
1
Justification:
not required, starting point is NOAEL
AF for differences in duration of exposure:
2
Justification:
extrapolation from sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
not for concentrations
AF for other interspecies differences:
2.5
Justification:
default factor for remaining differences
AF for intraspecies differences:
5
Justification:
Default AF for worker
AF for the quality of the whole database:
1
Justification:
not required
AF for remaining uncertainties:
1
Justification:
not required
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
135 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
NOAEC
Value:
1 688 mg/m³
AF for dose response relationship:
1
Justification:
not required, starting point is NOAEL
AF for interspecies differences (allometric scaling):
1
Justification:
not for concentrations
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining differences
AF for intraspecies differences:
5
Justification:
Default AF for worker
AF for the quality of the whole database:
1
Justification:
not required
AF for remaining uncertainties:
1
Justification:
not required

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:
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

According to the REACH Guidance on information requirements and chemical safety assessment, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

Short-term toxicity

According to the REACH guideline (R8, Appendix R 8-8), a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential risk for high peak exposures. The substance is classified for acute inhalation toxicity. For short term exposure to barium fluoride, a DNEL has been derived based on the results of an acute inhalation study according to the REACH guidance. Barium fluoride is not considered to be irritating or sensitizing to the skin, while it is considered as irritating to eyes.Therefore, no local dermal DNELs need to be derived.

 

Long-term toxicity

Barium fluoride will dissociate under physiological conditions to form barium and fluoride ions. Since no data on the repeated dose toxicity are available for barium fluoride, the available studies with sodium fluoride and barium chloride were used to assess the systemic toxicity of Ba2 + and F- ions. For barium a relevant study (Dietz, 1992) for repeated dose toxicity, oral route performed with barium chloride dihydrate is available that results in an NOAEL of 61 mg Ba/kg bw/d which corresponds to 78 mg BaF2/kg bw/d.

For fluoride reliable repeated dose toxicity studies are available in which sodium fluoride was administered via drinking water to rats and mice for 6 months (NTP, 1990). In the rat study a NOAEL of 100 ppm NaF in the drinking water (approx. 2.8 mg fluoride/kg bw/day) was considered a NOAEL. In the mouse study a NOAEL of 10 ppm NaF in the drinking water corresponding to fluoride doses of 1.6 mg/kg bw/day was obtained for systemic toxicity in mice. This value refers to approx. 7.4 mg barium fluoride/kg bw/day.

In the absence of substance specific quantitative data on absoption, 100% absorption is assumed for the inhalation and 50% for the oral route. For the dermal route, 0.19% absorption is assumed.

Long-term DNEL inhalation, systemic effects

Based on the available repeated dose toxicity studies with barium and fluoride, the critical systemic toxic effects of barium fluoride will be due to fluoride. By comparison, long-term systemic DNELs for inhalation have been derived based both on a point-of-departure for a soluble barium substance (barium chloride) and for soluble inorganic fluorides.

Fluoride

The critical systemic effect for fluoride exposure is skeletal fluorosis. The SCOEL have recommended (1998) an IOEL value of 2.5 mg/m3 (8 -hour TWA) for inorganic fluorides (equivalent to 11.5 mg/m3 barium fluoride).

They concluded that the 8-hour TWA was sufficient to protect against systemic effects (fluorosis). This IOELV covers all inorganic fluoride salts including the highly soluble salts.

Barium

As inhalation repeated dose toxicity studies with barium fluoride are not available, route to route extrapolation was applied to derive a DNEL for the inhalation route, based on the results of a sub-chronic oral study with barium chloride in rat (Dietz, 1992) where an NOAEL of 78 mg BaF2/kg bw/day was derived.

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 78 mg BaF2/kg bw/day

A NOAEL of 61 mg Ba/kg bw/d in male rats (study performed with barium dichloride dihydrate) was identified from the 13 -week drinking water study by Dietz et al. (1992).

Step 2) Modification of starting point

2

0.38 m3/kg bw

 

 

 

 

 

6.7 m3/10 m3

The REACh Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 2 in case of oral to inhalation exposure.

Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance on information requirements and chemical safety assessment (R.8.4.2).

 

Correction for activity driven differences of respiratory volumes in workers compared to workers in rest.

Modified dose-descriptor

78 x (1/2) x (1/0.38) x (6.7/10) = 68.8 mg/m3

Step 3) Assessment factors

 

 

Interspecies

2.5

No factor for allometric scaling is needed in case of inhalation exposure.A default factor of 2.5 for remaining uncertainties is used.

Intraspecies

5

Default AF for workers

Exposure duration

2

Extrapolation to chronic exposure based on a sub-chronic toxicity study

Dose response

1

 

Quality of database

1

Step 4) Calculate DNEL

68.8 / (2.5 x 5 x 2 x 1 x 1) = 2.75 mg/m3

Short-term – inhalation, systemic effects

Based on the available acute inhalation toxicity study with barium fluoride in rats (Charles River, 2018).

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC: 1000 mg/m3

In the acute inhalation study with barium fluoride no deaths occurred and no abnormalities were found at macroscopic examination. Therefore, 1000 mg/m3 is interpreted as a NOAEC.

Step 2) Modification of starting point

3√(10003x 16)

 

 

 

 

 

 

 

 

 

 

 

6.7/10

In the REACH guidance (R.8, Appendix R. 8-8), it is mentioned: ‘If a DNEL for acute toxicity needs to be established, this should be derived only for a specified fraction of the daily exposure duration (usually 15 minutes)’. The most appropriate approach is the modified Haber’s law (Cn* t = k). For extrapolation from longer to shorter durations a default value of n=3 should be used.

 

Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3).

Step 3) Assessment factors

 

 

Interspecies

2.5

For inhalation studies only a factor 2.5 is used, and no correction is made for differences in body size, because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animals and humans breathe at a rate depending on their caloric requirements.

Intraspecies

5

Default AF for workers

Exposure duration

1

 

Dose response

1

Quality of database

1

 

Step 4) Calculate DNEL

3√(10003x 16) x (6.7/10) / (2.5 x 5 x 1 x 1 x 1) = 135 mg/m3

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.68 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):
50
Modified dose descriptor starting point:
NOAEC
Value:
33.9 mg/m³
Explanation for the modification of the dose descriptor starting point:

24 h exposure time, extrapolation from 50% bioavailability oral to 100% bioavailability inhalation, no inhalation study available.

AF for dose response relationship:
1
Justification:
not required, starting point is NOAEL
AF for differences in duration of exposure:
2
Justification:
extrapolation from sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
not for concentrations
AF for other interspecies differences:
2.5
Justification:
default factor for remaining differences
AF for intraspecies differences:
10
Justification:
Default AF for general population
AF for the quality of the whole database:
1
Justification:
not required
AF for remaining uncertainties:
1
Justification:
not required
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
101 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Value:
2 520 mg/m³
AF for dose response relationship:
1
Justification:
not required, starting point is NOAEL
AF for interspecies differences (allometric scaling):
1
Justification:
not for concentrations
AF for other interspecies differences:
2.5
Justification:
default factor for remaining differences
AF for intraspecies differences:
10
Justification:
Default AF for general population
AF for the quality of the whole database:
1
Justification:
Not required
AF for remaining uncertainties:
1
Justification:
Not required

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:
low hazard (no threshold derived)

Additional information - General Population

General population DNELs

The general population may be directly exposed to barium fluoride through some of the supported uses of the substance. The indirect exposure of the general population to barium fluoride is of limited relevance. The substance will dissociate in the environment to form fluoride and barium ions and will further interact with other ionic species naturally present in the environment. The contribution of the substance to the total fluoride intake of the general population is likely to be very small in comparison to the contribution of fluoride from natural sources, predominantly throught the diet and drinking water.

Long-term DNEL inhalation, systemic effects

Based on the available repeated dose toxicity studies with barium and fluoride, the critical systemic toxic effects of barium fluoride will be due to fluoride. By comparison, long-term systemic DNELs for inhalation have been derived based both on a point-of-departure for a soluble barium substance (barium chloride) and for soluble inorganic fluorides.

Fluoride

The critical systemic effect for fluoride exposure is skeletal and dental fluorosis. The SCOEL have recommended an IOEL value of 2.5 mg/m3 to protect against the systemic effects of fluoride exposure in workers. A systemic inhalation DNEL for the general population may be derived by the application of an assessment factor of 5 to the worker DNEL value of 2.5 mg/m3 fluoride (11.5 mg/m3 barium difluoride) to take into account the potential greater sensitivity, breathing rate (20 m3/day) and longer potential exposure period (24 hours/day) of the general population. A long-term systemic general population DNEL value of 0.5 mg/m3 fluoride is therefore calculated (equivalent to approximately 2.3 mg BaF2/m3).

Barium

As inhalation repeated dose toxicity studies with barium fluoride are not available, route to route extrapolation was applied to derive a DNEL for the inhalation route, based on the results of a sub-chronic oral study with barium chloride in rat (Dietz, 1992) where an NOAEL of 78 mg BaF2/kg bw/day was derived.

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 78 mg BaF2/kg bw/day

A NOAEL of 61 mg Ba/kg bw/d in male rats (study performed with barium dichloride dihydrate) was identified from the 13 -week drinking water study by Dietz et al. (1992).

Step 2) Modification of starting point

2

1.15 m3/kg bw

 

 

 

The REACh Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 2 in case of oral to inhalation exposure.

Standard respiratory volume of a rat, corrected for 24 h exposure, as proposed in the REACH Guidance on information requirements and chemical safety assessment (R.8.4.2)

Modified dose-descriptor

78 x (1/2) x (1/1.15) = 33.9 mg/m3

Step 3) Assessment factors

 

 

Interspecies

2.5

No factor for allometric scaling is needed in case of inhalation exposure.A default factor of 2.5 for remaining uncertainties is used.

Intraspecies

10

Default AF for general population

Exposure duration

2

Extrapolation to chronic exposure based on a sub-chronic toxicity study

Dose response

1

 

Quality of database

1

Step 4) Calculate DNEL

33.9 / (2.5 x 10 x 2 x 1 x 1) = 0.68 mg/m3

Short-term – inhalation, systemic effects

Based on the available acute inhalation toxicity study with barium fluoride in rats (Charles River, 2018).

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEC: 1000 mg/m3

In the acute inhalation study with Barium fluoride no deaths occurred and no abnormalities were found at macroscopic examination. Therefore, 1000 mg/m3 is interpreted as a NOAEC.

Step 2) Modification of starting point

3√(10003x 16)

 

 

 

 

 

 

 

 

 

 

In the REACH guidance (R.8, Appendix R. 8-8), it is mentioned: ‘If a DNEL for acute toxicity needs to be established, this should be derived only for a specified fraction of the daily exposure duration (usually 15 minutes)’. The most appropriate approach is the modified Haber’s law (Cn* t = k). For extrapolation from longer to shorter durations a default value of n=3 should be used.

Step 3) Assessment factors

 

 

Interspecies

2.5

For inhalation studies only a factor 2.5 is used, and no correction is made for differences in body size, because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animals and humans breathe at a rate depending on their caloric requirements.

Intraspecies

10

Default AF for general population

Exposure duration

1

 

Dose response

1

Quality of database

1

 

Step 4) Calculate DNEL

3√(10003x 16) / (2.5 x 10 x 1 x 1 x 1) = 101 mg/m3