Antimony pentachloride

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

For fertility there are three non-standard studies in animals, one on female rats (Belyaeva, 1967) and one on male rats and mice (Omura et al., 2002), and one human occupational report study (Belyaeva, 1967). At a first glance, the inhalation study in female rats by Belyaeva (1967) appears to suggest that diantimony trioxide might have an adverse effect on fertility after repeated exposure to 250 mg/ m³. However, the results must be regarded as inconclusive and cannot be used for risk assessment, since the study report does not provide a valid description of the overall experimental conditions and the purity of the test substance. Furthermore, since it is well-established that rats are particularly sensitive to inert particle overload (in contrast to humans) which occurs in sub-chronic studies at levels approximately 50-fold below the level in Belyaeva (1967), it can reasonably be assumed that the rats in this study suffered from a massive, non-substance-specific impairment of their respiratorsystem by overload of lung macrophages and breakdown of their lung clearance, so that any adverse effects can easily be explained as of secondary nature. Significant pulmonary damage, impaired pulmonary function (hypoxia) and secondary changes related to hypoxia (e.g. renal lesions, erythroid hyperplasia) have subsequently been noted in recent chronic inhalation studies with rats and mice at exposure levels ranging from 3 0 30 mg/m³ (NTP, 2017).

 

The gavage study on male rats and mice (Omura, 2002) showed no testicular toxicity after 4 weeks repeated exposure up to 1200 mg/ kg bw. The human case report study on women occupationally exposed to diantimony trioxide indicates that diantimony trioxide might affect the fertility of female workers. However, this study is inconclusive due to the lack of information on the control group, the exposure situation and the overall workplace environment. Based on these fertility studies in animals and humans, no conclusion on female fertility can be derived. However, a 90-day oral feeding study in male and female rats, of diantimony trioxide reported no effects on reproductive organs up to a dose of 1686 mg/kg in males and 1879 mg/kg in females. The effects of antimony trioxide, potassium antimony tartrate and sodium hexahydroxoantimonate upon the fertility of rats and/or mice have been evaluated after oral exposure (Hext, et. al., 1999; Omura et al. 2002; Hansen, 2014a), and i.p. injection (Dieter, 1992), No significant adverse functional or structural impacts upon the reproductive systems of male or female animals have been observed. The NOAEL for effects upon fertility via oral exposure (adjusted for the antimony content of compounds evaluated) is in excess of 1000 mg/kg bw/day.

 

Data evaluating fertility impacts after inhalation exposure are lacking, but the overall profile of antimony compounds indicates low potential for reproductive toxicity. Fertility effects via inhalation exposure would not be expected given the high oral NOAEL for fertility impacts, coupled with the lack of developmental impacts from high (6.3 mg/m³) inhalation exposure to antimony trioxide (Schroeder, 2003).  

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

There are three possible values to be considered for the chemical safety assessment:

• NOAEL oral for Antimony trioxide: 1686 mg/kg bw/d) (subchronic; rat)
• NOAEL oral for Sodium hexahydroxoantimonate: 1000 mg/kg bw/d) (subchronic; rat)
• NOEC inhalation for Antimony trioxide: 6.3 mg/m³ (chronic; rat)

 

Among these values, the NOAEL oral for Antimony trioxide will be selected for use in the chemical assessment. The NOAEL for Sodium hexahydroxoantimonate appears to be conservative but this is the result of testing artifacts (lower doses of sodium hewahydroxoantimonate were administered in the study) and is not truly representative of a worst-case situation. Furthermore, starting from an oral NOAEL will enable a more robust calculation and extrapolation of DNELs.

Effects on developmental toxicity

Description of key information

The developmental toxicity of oral exposure of rabbits to antimony metal powder (Leuschner, 2017) and inhalation exposure of rats and mice to antimony trioxide (Schroeder, 2003) has been studied with little evidence of significant developmental deficits. Oral exposure studies of rabbits to antimony metal powder were complicated by maternal toxicity at the higher levels of antimony exposure. These exposures were associated with lethality, gastric irritation and reductions in maternal food intake and maternal body weight gain. Reductions in fetal weights, increased post-implantation losses and delayed vertebral ossification were observed in parallel to this maternal toxicity and have been documented to result from reduced maternal food intake and growth in the rabbit (Cappon et al., 2005). No impacts of antimony independent of maternal toxicity were observed.

Hansen (2014) evaluated the effects of oral gavage with 100, 300 and 1000 mg/kg bw/d sodium hexahydroantimonate upon developmental toxicity in Sprague Dawley rats. No evidence of maternal toxicity was evident up to 1000 mg/kg bw/d of sodium hexahydroantimonate (Sb V) although slight retardation of fetal skeletal ossification was observed at 300 and 1000 mg/kg bw/d. The significance of this mild effect is difficult to assess, particularly when contrasted with the observations from injection studies with other Sb (V) compounds projected to yield systemic Sb (V) concentrations approximately 10 - 100-fold higher than those achieved via oral gavage. This observed delayed ossification can be dismissed as not relevant as per Carney and Kimmel (2007).

 

A separate but growing body of literature has focused upon the therapeutic intravenous administration of Sb (V) compounds such as meglumine antimoniate for the treatment of leishmaniasis - a parasitic disease state endemic in tropical countries that in and of itself poses health risk to pregnant women and their fetuses. After more than 5 decades of therapeutic use of pentavalent antimonials, a small number of anecdotal case studies have suggested embryotoxicity during treatment for leishmaniasis.

 

Rodent studies have thus evaluated the developmental toxicity of meglumine antimoniate administered to the rat by injection (Miranda et al., 2006; Coelho et al, 2014):

 

Miranda et al. (2006) evaluated the developmental toxicity of daily subcutaneous injections of 75 – 300 mg Sb(V) /kg bw/day throughout gestation. Reductions in fetal weight and some skeletal and soft tissue abnormalities were evident at 300 mg/kg bw/day and attenuated at 150 mg/kg bw/day, yielding a NOAEL of 75 mg/kg bw/day. The authors suggest that maternal toxicity was not evident in the study but reductions in maternal weight gain during gestation were evident at the highest dose tested, and do indicate the presence of maternal toxicity.

 

Coelho et al. (2014) expanded upon the work of Miranda et al (2006), essentially conducting an extended one-generation reproductive test study (EOGRTS). Subcutaneous injection of 75 – 300 mg Sb(V)/kg bw/day to pregnant rats was conducted from day 0 to 20 of gestation and through parturition and lactation to post-natal day 21. Embryotoxicity, manifesting as decreases in pup weight and reductions in litter size, were noted to have occurred in the absence of maternal toxicity. However, suppression of maternal weight gain (minus the weight of the uterus) was observed and indicates the subtle onset of maternal toxicity at 300 mg/kg bw/day. Impacts upon pregnancy outcome had an apparent NOAEL of 150 mg Sb (V)/kg bw/d. Post-natal developmental impacts were present but minor. Other than modest decrements in female pup weight gain and exploratory behavior in female pups, no detrimental impacts of treatment were observed on neurobehavioural development, sexual maturation, male fertility or female reproductive performance. The authors concluded that meglumine antimoniate was a weak developmental toxicant and further postulated that the minor effects seen in offspring were potentially the result of decrements in maternal weight gain during gestation that had subsequent negative impacts upon lactation and pup nutrition.

 

The subcutaneous injection studies with meglumine antimoniate are relevant to pharmacological applications in the treatment of leishmaniasis. Coelho et al. (2014) further note that the injection doses used in the rat reproduction studies are much higher than those employed therapeutically in the treatment of leishmaniasis in humans– typically on the order of 20 mg Sb (V)/kg bw/d – and yield rat blood antimony levels approximately 100-fold higher than therapeutic human blood antimony levels. The systemic antimony levels achieved via s.c. injection are also strikingly higher than systemic levels that will result from physiological routes of exposure. For example, blood antimony levels of 160 µg/g result one hour after s.c. injection of 300 mg/kg bw meglumine antimoniate in the rat (Miranda et al., 2006). In contrast, oral administration of rodents at similar dosing rates is indicated to yield no detectable increases in antimony levels in blood (Coelho et al., 2014). Rodent blood antimony levels after injection are also approximately 10,000-fold higher than the blood antimony levels of humans occupationally exposed to antimony compounds (Wu and Chen, 2017). The mild developmental impacts observed after administration of antimony compounds by injection are thus elicited by systemic antimony levels many-fold higher than can conceivably be produced via physiological routes of exposure due to a combination of extremely limited uptake and/or irritating and emetic effects of highly soluble compounds (Dieter et al., 1991).  

 

Antimony compounds administered via physiological exposure routes do not produce developmental toxicity independent of maternal toxicity. The NOEC for effects from inhalation exposure is in excess of 6.3 mg/m³ for antimony trioxide.

 

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

6.46 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

One key study available (prenatal developmental toxicity study in rats according to OERCD 414) which is reliable with minor restrictions (RL=2). The overall quality of the database is therefore high.

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

For developmental toxicity there is one acceptable animal study available (Schroeder, 2003), albeit with dose intervals which were not strictly according to guidelines. Whereas the high dose did not give rise to any relevant systemic maternal toxicity, there were in fact signs of local inflammatory effects in the lung at mid and high dose groups, which is in line with other studies on diantimony trioxide showing an absence of systemic effects even at very high oral doses contrasting with adverse local lung effects via inhalation. With respect to developmental toxicity, this rat inhalation study with exposure 6 h/day throughout gestation showed no statistically significant effect whatsoever at 2.6, 4.4 or 6.3 mg diantimony trioxide /m³. Although a slight increase of resorptions and postimplantation loss was observed in the highest dose group, these values did not differ statistically from controls (p = 0.11) and were within the range of recent historical control data (4-8 %, mean 6 %). This study therefore allows derivation of an NOEC for developmental toxicity of > 6.46 mg antimony pentachloride/m³ (molecular weight conversion). Based on these studies there is no concern for reproductive toxicity and thus no quantitative risk characterisation will be made for the fertility or developmental toxicity.

Justification for selection of Effect on developmental toxicity: via inhalation route:

Key study

Toxicity to reproduction: other studies

Additional information

Antimony pentachloride hydrates in the presence of water/moisture, and then decomposes to either antimony trichloride and chlorine, antimony pentoxide and chlorine, or H₃SbO₄and hydrochloric acid. Conditions under which these various reactions occur are not clear, but require each different pressure and moisture. Assuming that antimony pentachloride can yield both Sb³⁺ ions and Sb⁵⁺ ions, it is proposed to read-across long-term effects of antimony pentachloride from long-term effects data available from trivalent and pentavalent antimony substances. This is a worst-case approach which enables a conservative assessment of antimony pentachloride, which is extremely difficult to test due to its chemical instability. 

Justification for classification or non-classification

Based on the weight of evidence from the available long-term toxicity studies in rodents and the relevant information on the toxicokinetic behaviour in rats, it was concluded that antimony substances do not present a reproductive toxicity hazard. There were no associated adverse effects on reproductive organs of rats and mice from chronic toxicity studies whereby exposures were either oral to high levels or inhalation to high concentrations of diantimony trioxide or other compounds.

 

At the moment, for the reasons presented above, no classification for reproductive toxicity according to regulation (EC) 1272/2008 is required for antimony pentachloride.