Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity via oral application: NOAEL=1686mg/kg bw/day. Result will be read-across to diantimony tris(ethylene glycolate).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 686 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
One key study available (90-day repeated dose toxicity study in rats according to OECD 407, under GLP) which is reliable with minor restrictions (RL=2). The overall quality of the database is therefore high.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The is no indication for systemic toxicity in several repeated dose toxicity studies via oral and inhalation route, thus a NOAEC for inhalation, systemic toxicity is not identified.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
0.51 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
One key study available (chronic repeated dose toxicity study in rats according) which is reliable with minor restrictions (RL=2). The overall quality of the database is therefore high.

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Upon dissolution in aqueous media at physiologically relevant concentrations and pH conditions, the only aqueous antimony species emerging from all considered trivalent antimony substances is the trivalent antimony cation. In vitro bioaccessibility testing in various artificial body fluids (Hedberg et al., 2010) has shown that diantimony tris(ethylene glycolate) compared to diantimony trioxide has a lower release rate of antimony ions, thus read-across warrants an intrinsic conservatism.

With respect to systemic toxicity, read-across from diantimony trioxide toward diantimony tris(ethylene glycolate) is justified.

Please also refer to the study results presented in section 4.8 and 7.1.1 of the technical dossier (IUCLID) and in section 1.3 and 5.1.1 of the CSR.

The following conclusions can be drawn for diantimony trioxide and by read across, also for diantimony tris(ethylene glycolate):

Inhalation:

The majority of the repeated dose studies in animals cited above is considered inconclusive because they do not comply with current test guidelines, they lack essential information regarding exposure conditions and statistical evaluations of the results or both control and exposed animals showing signs of non-treatment related illness. Still, there are inhalation studies indicating that diantimony trioxide  can contribute to what is described as impairment of lung clearance (Newton et al., 1994; Watt, 1983; Groth et al., 1986a; MPI, 2003). A NOAEC of 0.51 mg/m³ is derived from the study by Newton et al., 1994 and brought forward to the risk characterisation. The NOAEC is based on impaired lung clearance that was observed at 4.50 mg/m³.

 

Oral:

Two repeated dose oral studies (Sunagawa, 1981; Hext et al., 1999) suggest that diantimony trioxide may be toxic to the liver. This being based on a 10 % increase in liver weight. In addition, one study (Hext et al.,1999) exhibited significantly elevated ASAT values and significantly decreased ALP values. The other study (Sunagawa, 1981) revealed both ASAT and ALP levels to be significantly elevated. However, in the absence of histological change or any clinical signs of antimony intoxication to support liver adversity, the differences are regarded as adaptive or incidental to treatment with diantimony trioxide. A NOAEL of 1686 mg/kg/d for liver toxicity is suggested.

 

Dermal:

Studies on repeated dermal exposure are not available. Given the experimentally verified negligible percutaneous absorption, this route of entry into the body is not considered relevant for risk assessment.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

Key study

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

Weight of evidence information

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:

Key study

Justification for classification or non-classification

Repeated dose toxicity, oral:

 

The reference Hext P.M., Pinot P.J. and Rimmel B.A. (1999) is considered as the key study for repeated dose toxicity via oral application and will be used for classification. Rats were dosed at 20,000 ppm/day orally via feed for 90 days. Based on the lack of any adverse effects, the no observed adverse effect level (NOAEL) via oral application for diantimony trioxide was established at 1686 mg/kg bw/day.

The classification criteria according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – repeated exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and the no observed adverse effect level (NOAEL) via oral application is above the guidance value for a Category 1 classification of 10 mg/kg bw/day and above the guidance value for a Category 2 classification of 100 mg/kg bw/day. For the reasons presented above, no classification for specific target organ toxicant (STOT) – repeated exposure, oral is required.

Repeated dose toxicity, dermal:

Diantimony trioxide was tested in a percutaneous absorption test indicating that absorption does not occur. The toxicological profile of this material does not give rise to concern in human use, since the substance is not absorbed through the skin. In view, also, of the lack of percutaneous absorption, a calculation of the margin of safety has not been carried out.

 

For the reasons presented above, no classification for specific target organ toxicant (STOT) – repeated exposure, dermal is required.

 

Repeated dose toxicity, inhalation:

The rat is uniquely sensitive to changes within the lung when exposed under conditions of particle overload to poorly soluble low-toxicity particles such as diantimony trioxide. Although particle overload is observed in other experimental species such as the mouse, it is only in the rat that a sequence of events is initiated that leads to fibroproliferative disease, septal fibrosis, hyperplasia and eventually lung tumours. However, similar pathological changes are not observed in other common laboratory rodents, non-human primates or in exposed humans. Detailed epidemiological investigations have shown no causative link between titanium dioxide (stated as a surrogate for poorly soluble particles such as diantimony trioxide) exposure and the risk of non-malignant respiratory disease in humans.

According to regulation (EC) 1272/2008, a classification for specific target organ toxicity – repeated exposure shall be taken into account only when reliable evidence associating repeated exposure to the substance with a consistent and identifiable toxic effect demonstrates support for the classification. These adverse health effects include consistent and identifiable toxic effects in humans, or, in experimental animals, toxicologically significant changes which have affected the function or morphology of a tissue/organ, or have produced serious changes to the biochemistry or haematology of the organism and these changes are relevant for human health.

The following observations have been made in experimental animals and in human epidemiological studies:

(i) No systemic toxicity was shown to result from chronic inhalation exposure in rats to high concentrations of diantimony trioxide

(ii) Particle overload is observed for insoluble particles such as diantimony trioxide, whereby the rat is the most sensitive species studied, and species-specific differences are demonstrated in various mechanistic animal studies (Oberdörster, 1996). It has been demonstrated with reasonable certainty that lung overload conditions are not relevant for human health and, therefore, results based on these data do not justify classification.

The high level of fibrotic changes in control rats clearly suggests that the test system/species is of rather limited value for the desired study objective. It is important to note that granuloma or granulomatous inflammation are not reported either by Watt (at exposures roughly equivalent to the Newton study) or by Groth (at exposure sup to 45 mg/m³). By weight-of-evidence, the indications of granulomatous changes suggested by Newton in particular because of the “high background” are hardly convincing. Out of the extensive catalogue of effects that trigger STOT classification, only the issue of granuloma remains. However, in the light of our comments above, by applying a weight-of-evidence approach, there is no consistent reporting of these effects. In accordance with guidance for STOT classification, there is an absence of consistent identifiable toxic effects other than the non-specific PSP overload, which is an adaptive response not triggering a STOT classification.