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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 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):
1
Dose descriptor starting point:
LOAEC
Value:
10 mg/kg bw/day
Modified dose descriptor starting point:
LOAEC
Value:
10 mg/m³
Explanation for the modification of the dose descriptor starting point:

Consistent with earlier estimates of oral uptake, the dose descriptor for inhalation uptake evaluation is derived from injection studies that identify 10 mg/kg bw/d as a systemic LOAEL. Given a 70 kg human, this LOAEL would equate to an uptake of 700 mg of antimony.

The aerosol concentrations that would yield uptake of 700 mg of antimony by workers can be estimated assuming inhalation of 10 m3(light activity inhalation estimate) of occupational aerosols over an 8 h work shift. Correcting for molecular weight, 700 mg of antimony uptake would result from:

LOAEC Uptake of 1418 mg of sodium hexahydroxoantimonate.

The concentration of compound in an aerosol that would yield the requisite uptake amount to achieve the LOAEC can be calculated as follows, assuming 10 m3of inhalation during light activity per 8 h shift and using the previously generated estimates of total fractional pulmonary uptake from inhaled aerosols:

 

LOAEC uptake = 10 m3aerosol X (aerosol concentration x fractional uptake rate)

Or

Aerosol concentration = (LOAEC uptake/10)/pulmonary uptake rate

 

Aerosol concentrations corresponding to the LOAEC would thus be:

·      26,259 mg/m3for sodium hexahydroxoantimonate

AF for dose response relationship:
1
Justification:
This AF is not used for the final DNEL-derivation (see Explanation for hazard conclusion). However, an AF of 3 would be applicable to convert from LOAEC to NOAEC if final DNEL was based on initial modified Dose descriptor of 26259 mg/m3.
AF for differences in duration of exposure:
1
Justification:
This AF is not used for the final DNEL-derivation (see Explanation for hazard conclusion). However, an AF of 2 would be applicable to convert from subchronic to chronic if final DNEL was based on initial modified Dose descriptor of 26259 mg/m3.
AF for interspecies differences (allometric scaling):
1
Justification:
This AF is not used for the final DNEL-derivation (see Explanation for hazard conclusion)
Justification:
This AF is not used for the final DNEL-derivation (see Explanation for hazard conclusion)
AF for intraspecies differences:
1
Justification:
This AF is not used for the final DNEL-derivation (see Explanation for hazard conclusion). However, an AF of 5 would be applicable (workers) 1if final DNEL was based on initial modified Dose descriptor of 26259 mg/m3.
AF for the quality of the whole database:
1
Justification:
This AF is not used for the final DNEL-derivation (see Explanation for hazard conclusion).
AF for remaining uncertainties:
1
Justification:
This AF is not used for the final DNEL-derivation (see Explanation for hazard conclusion). However, an AF of 2 for route extrapolation would be applicable if final DNEL was based on modified Dose descriptor of 26259 mg/m3.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.695 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
3
Dose descriptor:
other: HEC-adjusted NOAEC, expressed as mg Sb/m3
Value:
1.03 mg/m³
AF for dose response relationship:
1
Justification:
Adequate data available
AF for differences in duration of exposure:
1
Justification:
Subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
In as much as antimony is not metabolized, interspecies variability from this source would not be expected. Moreover, the HEC calculations performed account for expected toxicokinetic differences related to pulmonary deposition and clearance, further reducing uncertainty in extrapolation between species. Since the HEC calculations address and correct for a difference assessment factors are designed to address, the application of both would be redundant. A minimal Assessment Factor of 1.0 is thus appropriate for HEC corrected local effects in the lung.
AF for other interspecies differences:
1
Justification:
No need for additional assessment factor
AF for intraspecies differences:
3
Justification:
An additional assessment factor is suggested to account for variability in response between workers. Assessment factors recommended range from 5 in the ECHA R8 to 3 as suggested by ECETOC (2003). An assessment factor of 3 appears to be applicable to antimony (V) compounds since the pulmonary impacts of concern are local and do not entail metabolism of deposited aerosols (ECETOC, 2010).
Hattis and Silver (1994) similarly concluded in an analysis of variability in toxicodynamic responses for local irritants (including pulmonary toxicants) that an assessment factor of 3 was more appropriate. Justification for lower assessment factors was also found in greater homogeneity of worker populations where occupational hygiene regimens and other risk management practices are in place to reduce sources of variability in responses to exposure. For example, routine monitoring of urinary antimony excretion and pulmonary function (by both spirometry and annual radiographic evaluations of the lungs) essentially precludes the development of pneumonitis in workers.
AF for the quality of the whole database:
1
Justification:
The need for application of further assessment factors was considered and were not deemed as necessary. For example, the DNEL derivation is based upon chronic inhalation data and correction for exposure duration is not warranted.
Moreover, three other chronic rat inhalation studies have been conducted and there is reasonable consistency in the inflammatory responses that have been produced (Newton et al., 1994; Groth et al., 1986; Watt, 1983)
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:
67.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
30
Dose descriptor starting point:
LOAEL
Value:
10 mg/kg bw/day
Modified dose descriptor starting point:
LOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

In the absence of studies defining systemic toxicity from dermal exposure, route-to-route extrapolation is required to identify an appropriate dose descriptor. As outlined in Section 3.2, systemic DNELs indexed to human treatment trial using Sb (V) compounds for the treatment of parasitic disease are likely to be the most accurate. 

A systemic dose of 10 mg Sb(V)/kg bw/d administered by injection is selected as the relevant starting point dose descriptor for a LOAEL.

Because the route of exposure in human clinical trials (injection) is not the same for which extrapolations to humans are to be made (dermal), adjustment of the human LOAEL starting point will be needed. In principle, this entails comparison of rates of uptake to be expected via the two different exposure routes. In the specific case of the antimony compounds under consideration, uptake rates after dermal exposure are quite limited. In vivo dermal uptake studies are lacking, but in vitro percutaneous absorption studies suggest that dermal uptake does not exceed 0.1%. Dermal uptake rates are thus comparable to, or less than, oral uptake rates, which are generally in the range of 0.3 – 0.5% with a maximum uptake estimate of 1.0%. 

 In the derivation of DNELs for antimony (III) compounds, uptake via the oral and dermal uptake routes (1.0 %) were assumed to be the same. A dermal uptake rate of 1.0% will thus be assumed for consistency in the derivation of dermal DNELs for antimony (V) compounds too. Actual dermal uptakes will likely be lower than oral uptake, building additional conservatism into calculated DNELs that impart an extra margin of safety.Injected compounds can be assumed to be taken up into the body with 100% efficiency whereas oral or dermal administration would be associated with a maximum uptake of 1%. 

An injected dose of 10 mg/kg bw/d would thus be equivalent to a dermal dose of 1000 mg Sb(V)/kg bw/d.

AF for dose response relationship:
3
Justification:
LOAEL to NOAEL conversion
AF for differences in duration of exposure:
2
Justification:
Subchronic (40d) to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Since data were based upon human observational studies, corrections for interspecies variability are not needed.
AF for other interspecies differences:
1
Justification:
Since data were based upon human observational studies, corrections for interspecies variability are not needed.
AF for intraspecies differences:
5
Justification:
An assessment factor of 5 has been applied for occupational exposures since, although antimony is not metabolized, medical surveillance procedures will not be focused upon endpoints related to dermal exposure. The dermal uptake rate being assumed (equivalent to oral) is further somewhat higher than is realistically plausible.
AF for the quality of the whole database:
1
Justification:
No need for a further assessment factor
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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 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):
1
Dose descriptor starting point:
LOAEC
Value:
10 mg/kg bw/day
Modified dose descriptor starting point:
LOAEC
Value:
10 mg/m³
Explanation for the modification of the dose descriptor starting point:

Consistent with earlier estimates of oral uptake, the dose descriptor for inhalation uptake evaluation is derived from injection studies that identify 10 mg/kg bw/d as a systemic LOAEL. Given a 70 kg human, this LOAEL would equate to an uptake of 700 mg of antimony.

The aerosol concentrations that would yield uptake of 700 mg of antimony by the general public can be estimated assuming inhalation of 20 m3. Correcting for molecular weight, 700 mg of antimony uptake would result from:

LOAEC Uptake of 1418 mg of sodium hexahydroxoantimonate.

Aerosol concentrations corresponding to the LOAEC would thus be:

·      13,130 mg/m3for sodium hexahydroxoantimonate

AF for dose response relationship:
1
Justification:
This AF is not used for the final DNEL-derivation (see Explanation for hazard conclusion). owever, an AF of 3 would be applicable to convert from LOAEC to NOAEC if final DNEL was based on initial modified Dose descriptor of 13130 mg/m3.
AF for differences in duration of exposure:
1
Justification:
This AF is not used for the final DNEL-derivation (see Explanation for hazard conclusion). However, an AF of 2 would be applicable to correct for duration (subchronic to chronic) if final DNEL was based on initial modified Dose descriptor of 13130 mg/m3.
AF for interspecies differences (allometric scaling):
1
Justification:
This AF is not used for the final DNEL-derivation (see Explanation for hazard conclusion).
AF for other interspecies differences:
1
Justification:
This AF is not used for the final DNEL-derivation (see Explanation for hazard conclusion).
AF for intraspecies differences:
1
Justification:
This AF is not used for the final DNEL-derivation (see Explanation for hazard conclusion). However, an AF of 10 would be applicable (general population/consumers) if final DNEL was based on initial modified Dose descriptor of 13130 mg/m3.
AF for the quality of the whole database:
1
Justification:
This AF is not used for the final DNEL-derivation (see Explanation for hazard conclusion).
AF for remaining uncertainties:
1
Justification:
This AF is not used for the final DNEL-derivation (see Explanation for hazard conclusion). However, an AF of 10 would be applicable to extrapolate for route of exposure (injection vs inhalation) if final DNEL was based on initial modified Dose descriptor of 13130 mg/m3.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.209 mg/m³
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor:
other: HEC-adjusted NOAEC, expressed as mg Sb/m3
Value:
1.03 mg/m³
AF for dose response relationship:
1
Justification:
Adequate data available
AF for differences in duration of exposure:
1
Justification:
Subchrlonic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
In as much as antimony is not metabolized, interspecies variability from this source would not be expected. Moreover, the HEC calculations performed account for expected toxicokinetic differences related to pulmonary deposition and clearance, further reducing uncertainty in extrapolation between species. Since the HEC calculations address and correct for a difference assessment factors are designed to address, the application of both would be redundant. A minimal Assessment Factor of 1.0 is thus appropriate for HEC corrected local effects in the lung.
AF for other interspecies differences:
1
Justification:
No need for additional assessment factor
AF for intraspecies differences:
10
Justification:
Given lack of any indication that children will be more susceptible to local effects from inhalation exposure to antimony (V) compounds, and indications that humans are less susceptible to pulmonary impacts than the rodents upon which the DNELs are based, no additional assessment factors are proposed for children.
AF for the quality of the whole database:
1
Justification:
The need for application of further assessment factors was considered and were not deemed as necessary. For example, the DNEL derivation is based upon chronic inhalation data and correction for exposure duration is not warranted.
Moreover, three other chronic rat inhalation studies have been conducted and there is reasonable consistency in the inflammatory responses that have been produced (Newton et al., 1994; Groth et al., 1986; Watt, 1983)
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:
33.8 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
60
Dose descriptor starting point:
LOAEL
Value:
10 mg/kg bw/day
Modified dose descriptor starting point:
LOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

In the absence of studies defining systemic toxicity from dermal exposure, route-to-route extrapolation is required to identify an appropriate dose descriptor. As outlined in Section 3.2, systemic DNELs indexed to human treatment trial using Sb (V) compounds for the treatment of parasitic disease are likely to be the most accurate. 

A systemic dose of 10 mg Sb(V)/kg bw/d administered by injection is selected as the relevant starting point dose descriptor for a LOAEL.

Because the route of exposure in human clinical trials (injection) is not the same for which extrapolations to humans are to be made (dermal), adjustment of the human LOAEL starting point will be needed. In principle, this entails comparison of rates of uptake to be expected via the two different exposure routes. In the specific case of the antimony compounds under consideration, uptake rates after dermal exposure are quite limited. In vivo dermal uptake studies are lacking, but in vitro percutaneous absorption studies suggest that dermal uptake does not exceed 0.1%. Dermal uptake rates are thus comparable to, or less than, oral uptake rates, which are generally in the range of 0.3 – 0.5% with a maximum uptake estimate of 1.0%. 

 In the derivation of DNELs for antimony (III) compounds, uptake via the oral and dermal uptake routes (1.0 %) were assumed to be the same. A dermal uptake rate of 1.0% will thus be assumed for consistency in the derivation of dermal DNELs for antimony (V) compounds too. Actual dermal uptakes will likely be lower than oral uptake, building additional conservatism into calculated DNELs that impart an extra margin of safety.Injected compounds can be assumed to be taken up into the body with 100% efficiency whereas oral or dermal administration would be associated with a maximum uptake of 1%. 

An injected dose of 10 mg/kg bw/d would thus be equivalent to a dermal dose of 1000 mg Sb(V)/kg bw/d.

AF for dose response relationship:
3
Justification:
LOAEL to NOAEL conversion
AF for differences in duration of exposure:
2
Justification:
Subchronic (40d) to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Since data were based upon human observational studies, corrections for interspecies variability are not needed.
AF for other interspecies differences:
1
Justification:
Since data were based upon human observational studies, corrections for interspecies variability are not needed.
AF for intraspecies differences:
10
Justification:
General population
AF for the quality of the whole database:
1
Justification:
No need for a further assessment factor
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:
33.8 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):
60
Dose descriptor starting point:
LOAEL
Value:
10 mg/kg bw/day
Modified dose descriptor starting point:
LOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Original study applied intravenous injection as route of exposure: starting dose descriptor was derived from human injection studies of antimony (V) compounds applied in the treatment of parasitic diseases such as Leishmaniasis. 

Intravenous or intramuscular injection of antimony (V) compounds, typically administered at a dose of 20 mg Sb/kg bw/d for forty days, is the standard treatment regimen recommended by the World Health Organization. Clinical trials have evaluated the treatment efficacy and side effects of doses ranging from 5 to 60 mg/kg bw/d, with studies administering 10 mg Sb (V)/kg bw/d providing the most consistent and coherent data consistent with a LOAEL. Effects observed at this dosage level includemild reversible side effects such as arthralgia, neuralgic pain, joint and muscle stiffness. Transient changes in cardiovascular parameters, such as flattening of ECG T-waves have also been observed although this effect is most commonly observed at higher doses of admininstration.

Intravenous injection is not an exposure route with physiological relevance for consumers or the general population. This dose can be converted to an estimated oral exposure via simple toxicokinetic assumptions. Injected compounds can be assumed to be taken up into the body with 100% efficiency whereas oral administration would be associated with a maximum uptake of 1% as estimated by ICRP (1981) or 0.5% as measured in studies of SHHA (Hansen, 2017). 1% oral uptake is assumed to provide a more conservative estimate of a LOAEL.

Assuming an uptake of 1%, an injected dose of 10 mg/kg bw/d would thus be equivalent to an oral dose of 1000 mg Sb(V)/kg bw/d. Note that this oral LOAEL value is for the antimony (V) content of a compound and is not compound specific.

AF for dose response relationship:
3
Justification:
Conversion from LOAEL to NOAEL
AF for differences in duration of exposure:
2
Justification:
Sub-chronic (40 days) to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Human health data are used as starting point
AF for other interspecies differences:
1
Justification:
Human health data are used as starting point
AF for intraspecies differences:
10
Justification:
General population
AF for the quality of the whole database:
1
Justification:
No need for a further assessment factor
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