Registration Dossier

Administrative data

Workers - 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:
DNEL (Derived No Effect Level)
Value:
0.458 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
0.6
Dose descriptor:
other: HEC-adjusted NOEC - expressed as Sb
DNEL value:
0.155 mg/m³
AF for differences in duration of exposure:
1
Justification:
The DNEL derivation is based upon chronic inhalation data and correction for exposure duration is not warranted.
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. Indeed, the HEC correction lowers the expected human NOAEC by a factor of 6.5, more than twice the recommended default assessment factor of 2.5. A minimal Assessment Factor of 1.0 is thus appropriate for HEC corrected local effects in the lung.
The NOAEC (based upon antimony content) remains at 0.155 mg/m3 after consideration of interspecies differences.For diantimony trioxide, this value becomes 0.185 mg/m3.
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 (III) 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.
Application of an assessment factor of 3 yields a DNEL estimate of 0.052 mg/m3 based upon antimony content. Note that this DNEL is specific to respirable aerosols of water insoluble antimony compounds.
AF for the quality of the whole database:
1
Justification:
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).
AF for remaining uncertainties:
0.2
Justification:
The DNEL calculation is based upon experimentally generated respirable aerosols of antimony trioxide with a MMAD of 1.2 µm. Studies of the particle size distribution of occupational environments engaged in the production or packaging of antimony trioxide have determined that the majority of material in these aerosols is far coarser than the respirable aerosols used rodent inhalation studies (Hughson, 2005). This is further problematic in that majority of occupational exposure data routinely collected in occupational environments is indexed to the inhalable fraction of aerosols. Comparison of the DNEL derived for respirable aerosols is thus difficult to relate to present and historical occupational exposure data unless some means of scaling a respirable DNEL to its inhalable equivalent is employed.
Vetter (2018) analysed the particle size distributions observed by Hughson (2005) and concluded that, on a mass comparison basis, the respirable fraction of occupational aerosols is on average 20% of the total aerosol. A DNEL for a respirable aerosol would most likely be congruent with an inhalable limit approximately five-fold larger. Thus, a respirable DNEL of 0.052 mg/m3 would be comparable to an inhalable measurement of 0.263 mg/m3. For diantimony trioxide, this value becomes 0.315 mg/m3

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:
97.6 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: The DNEL derivation for antimony metal is based on state-of-the-art approaches and using substance-specific information.
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEL
DNEL value:
1 686 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 409 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Selection of the relevant dose-descriptor

In accordance with the diantimony trioxide CSR, the NOAEL of 1686 mg/kg bw/d from a subchronic oral toxicity study in rats is selected as being the most relevant for estimating systemic effects that might be associated with dermal uptake of antimony metal or antimony (III) compounds. In the absence of studies defining systemic toxicity from dermal exposure, route-to-route extrapolation is required.

 

Modification of the dose descriptor to the correct starting point

Because the route of exposure in animal toxicity studies (oral) is not the same for which extrapolations to humans are to be made (dermal), an evaluation must be undertaken to determine if there is a need to adjust the animal NOAEL starting point. In principle this entails evaluation of whether different rates of uptake are to be expected via the two different exposure routes. 

In the specific case of the antimony compounds under consideration, uptake rates after oral or dermal exposure are quite limited and can, for the purpose of DNEL derivation, be presumed to be the same: the absorption of antimony compounds such from the gastrointestinal tract after oral exposure is, based upon studies in rodents, very low and on the order of 0.05 to 0.3%. 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. Indeed, dermal uptake will likely be lower than oral uptake, building additional conservatism into calculated DNELs that impart an extra margin of safety. 

Since the effects of diantimony trioxide are presumed to be mediated by release and subsequent dermal uptake of the Sb (III) oxyanion, read across to other antimony (III) compounds is possible. The NOAEL can thus be adjusted for the antimony content of diantimony trioxide yielding a NOAEL indexed to antimony content of 1409 mg/kg bw/d.

AF for dose response relationship:
1
Justification:
Adequate data available
AF for differences in duration of exposure:
2
Justification:
Subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Correction for differences in metabolic rate (AS)
AF for other interspecies differences:
2.5
Justification:
Remaining differences (e.g. toxicokinetics/dynamics)
AF for intraspecies differences:
5
Justification:
Workers
AF for the quality of the whole database:
1
Justification:
No need for a further assessment factor
AF for remaining uncertainties:
1
Justification:
Route extrapolation: oral to dermal
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:
no hazard identified
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:
0.14 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
2
Dose descriptor:
other: HEC-adjusted NOEC - expressed as Sb
DNEL value:
0.155 mg/m³
AF for differences in duration of exposure:
1
Justification:
The DNEL derivation is based upon chronic inhalation data and correction for exposure duration is not warranted.
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. Indeed, the HEC correction lowers the expected human NOAEC by a factor of 6.5, more than twice the recommended default assessment factor of 2.5. A minimal Assessment Factor of 1.0 is thus appropriate for HEC corrected local effects in the lung.
The NOAEC (based upon antimony content) remains at 0.155 mg/m3 after consideration of interspecies differences.
AF for intraspecies differences:
10
Justification:
Calculation of the inhalable DNELs for chronic, local effects in consumers or for the general population exposed via the environment requires an Assessment factor of 10 for intra-species variability. Given lack of any indication that children or other vulnerable populations will be more susceptible to local effects from inhalation exposure to antimony metal or antimony (III) 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:
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).
AF for remaining uncertainties:
0.2
Justification:
The DNEL calculation is based upon experimentally generated respirable aerosols of antimony trioxide with a MMAD of 1.2 µm. Studies of the particle size distribution of occupational environments engaged in the production or packaging of antimony trioxide have determined that the majority of material in these aerosols is far coarser than the respirable aerosols used rodent inhalation studies (Hughson, 2005). This is further problematic in that majority of occupational exposure data routinely collected in occupational environments is indexed to the inhalable fraction of aerosols. Comparison of the DNEL derived for respirable aerosols is thus difficult to relate to present and historical occupational exposure data unless some means of scaling a respirable DNEL to its inhalable equivalent is employed.
Vetter (2018) analysed the particle size distributions observed by Hughson (2005) and concluded that, on a mass comparison basis, the respirable fraction of occupational aerosols is on average 20% of the total aerosol. A DNEL for a respirable aerosol would most likely be congruent with an inhalable limit approximately five-fold larger. Thus, a respirable DNEL of 0.052 mg/m3 would be comparable to an inhalable measurement of 0.263 mg/m3. For ditantimony trioxide, this value becomes 0.315 mg/m3.
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:
48.8 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):
50
Dose descriptor starting point:
NOAEL
DNEL value:
1 686 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 409 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Selection of the relevant dose-descriptor

In accordance with the diantimony trioxide CSR, theNOAEL of 1686 mg/kg bw/dfrom a subchronic oral toxicity study in rats is selected as being the most relevant for estimating systemic effects that might be associated with dermal uptake of antimony metal or antimony (III) compounds. In the absence of studies defining systemic toxicity from dermal exposure, route-to-route extrapolation is required.

 

Modification of the dose descriptor to the correct starting point

Because the route of exposure in animal toxicity studies (oral) is not the same for which extrapolations to humans are to be made (dermal), an evaluation must be undertaken to determine if there is a need to adjust the animal NOAEL starting point. In principle this entails evaluation of whether different rates of uptake are to be expected via the two different exposure routes. 

In the specific case of the antimony compounds under consideration, uptake rates after oral or dermal exposure are quite limited and can, for the purpose of DNEL derivation, be presumed to be the same: the absorption of antimony compounds such from the gastrointestinal tract after oral exposure is, based upon studies in rodents, very low and on the order of 0.05 to 0.3%. 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. Indeed, dermal uptake will likely be lower than oral uptake, building additional conservatism into calculated DNELs that impart an extra margin of safety. 

Since the effects of diantimony trioxide are presumed to be mediated by release and subsequent dermal uptake of the Sb (III) oxyanion, read across to other antimony (III) compounds is possible. The NOAEL can thus be adjusted for the antimony content of diantimony trioxide yielding a NOAEL indexed to antimony content of 1409 mg/kg bw/d.

AF for dose response relationship:
1
Justification:
Adequate vdata available
AF for differences in duration of exposure:
2
Justification:
Subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Correction for differences in metabolic rate (AS)
AF for other interspecies differences:
2.5
Justification:
Remaining differences (e.g. toxicokinetics/-dynamics)
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
AF for remaining uncertainties:
1
Justification:
Route extrapolation: oral to dermal
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:
48.8 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):
50
Dose descriptor starting point:
NOAEL
DNEL value:
1 686 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
1 409 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Selection of the relevant dose-descriptor

As noted by the EU RAR (2008) on diantimony trioxide"Two repeated dose oral studies suggest that diantimony trioxide may be toxic to the liver based on a 10% increase in liver weight, supported by significantly elevated ALP and ASAT levels(Sunagawa, 1981; Hext et al., 1999).However, in the absence of histological changes or any clinical signs of antimony intoxication to support that the liver findings are adverse, the findings are regarded as adaptive or incidental to treatment with diantimony trioxide and a NOAEL of 1686 mg/kg bw/d for repeated dose toxicity is derived from these studies.”

 

In accordance with the EU RAR, the NOAEL of 1686 mg/kg bw/dfrom a subchronic oral toxicity study in rats is used as starting point for DNEL derivation for antimony III compounds. The effects of diantimony trioxide are presumed to be mediated by release and subsequent uptake of the Sb (III) oxyanion, and read across to other antimony (III) compounds releasing such oxyanion, is thus assumed possible. The NOAEL can thus be adjusted for the antimony content of diantimony trioxide yielding a NOAEL indexed to antimony content of 1409 mg/kg bw/d

 

Modification of the dose descriptor to the correct starting point

Because the route of exposure is identical in animals and in humans, no correction of the starting point is necessary.

AF for dose response relationship:
1
Justification:
Adequate data available
AF for differences in duration of exposure:
2
Justification:
Subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Correction for differences in metabolic rate (AS)
AF for other interspecies differences:
2.5
Justification:
Remaining differences (e.g. toxicokinetics/-dynamics)
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