Antimony pentachloride

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Value:

0.042 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:

0.042 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

3

Dose descriptor:

LOAEC

Value:

3 mg/m³

AF for interspecies differences (allometric scaling):

3

Justification:

As per the ECHA Guidance R8, application of assessment factors needs be considered. In interspecies extrapolations for systemic effects, assessment factors of up to 10 can be appropriate to account for differences such as allometric factors that yield differences in metabolic rates or toxicokinetics. For local effects associated with inhalation exposure, an assessment factor of 2.5 is suggested.

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 differences to be addressed by assessment factors, the application of both a HEC and AFs would be redundant in an interspecies comparison. Indeed, the HEC correction lowers the expected human NOAEC by a factor of 16, much more than 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 0.051 mg/m3 after consideration of interspecies differences.

AF for intraspecies differences:

1

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) and Hattis et al. (1999) 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 is also derived from greater homogeneity of worker populations when occupational hygiene regimens and other risk management practices (Hoet, 2009; i2a, 2017) 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 0.017 mg/m3 based upon antimony content.

AF for remaining uncertainties:

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). Confidence in the dose-response for antimony induced inflammation is thus relatively high and additional assessment factors for data quality are not needed.

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:

138 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

Value:

1 686 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 409 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Selection of the relevant dose-descriptor

 

No studies evaluating the systemic toxicity resulting from dermal exposure to antimony pentachloride were found. Estimation of a long term systemic DNEL for the dermal exposure route was thus undertaken via oral to dermal route extrapolation. Further given that studies of oral toxicity have not been conducted for antimony pentachloride, studies with diantimony trioxide were selected on read across. Trivalent antimony compounds are generally more toxic than their pentavalent counterparts, making selection of diantimony trioxide for route to route extrapolation a conservative mode of DNEL calculation. Moreover, conversion of antimony from the pentavalent state to the trivalent state occurs in vivo. The NOAEL of 1686 mg/kg bw/d from a subchronic oral toxicity study of diantimony trioxide in rats (Hext et al., 1999) was selected as being the most relevant for estimating systemic effects that might be associated with dermal uptake of antimony pentachloride.

 

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. Since the effects of diantimony trioxide are mediated by release and subsequent dermal uptake of the Sb oxyanions, read across to other antimony compounds is possible. The NOAEL can thus be adjusted for the antimony content of diantimony trioxide [(243.6/291.5) x 1686 = 1409] 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 extrapolatio: 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

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

Two DNELs have been derived for antimony pentachloride:

• Long-term DNEL for workers – inhalation, local effects
• Long-term DNEL for workers – dermal, systemic effects