Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 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 408, under GLP) which is reliable without restrictions (RL=1). The overall quality of the database is therefore high.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Standard test data on potential effects of sodium hexahydroxoantimonate specifically on fertility are not available.

It should be noted, however, that based on the fact that diantimony pentoxide, sodium hexahydroxoantimonate and sodium antimonate contain antimony in the pentavalent oxidation state and that water solubility testing as well as transformation dissolution testing has shown similar dissolution pattern of pentavalent antimony cations form all three substances, read-across among the pentavalent antimony compounds (i.e. sodium hexahydroxoantimonate, sodium antimonate and diantimony pentoxide) is considered justified. In this context, a reported study according to OECD 408 (90-day repeated dose toxicity study via oral route) with sodium hexahydroxoantimonate should be considered.

The conduct of further testing of effects on fertility are not considered to be required, since in accordance with regulation (EC) 1907/2006, Annex IX, Section 8.7, Column 2, such studies do not need to be conducted if the substance is (i) of low toxicological activity (no evidence of toxicity seen in any of the tests available), (ii) it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma/blood concentrations below detection limit using a sensitive method and absence of the substance and of metabolites of the substance in urine, bile or exhaled air), and (iii) there is no or no significant human exposure. These conditions are considered to be fulfilled, since:

(i) a 90-day repeated dose toxicity study with sodium hexahydroxoantimonate indicated absolutely no effects whatsoever on reproduction up to the limit dose of 1000 mg/kg bw/day.

(ii) during the conduct of the 90-day repeated dose toxicity study, the 24-hour urine of all animals was collected after the last oral administration (day 90 of the study) and analysed for total antimony content. In all dose groups, the urine excretion was <<1% compared with the amount of antimony administered via gavage, indicating a minimal systemic bioavailability.

(iii) significant systemic exposure of humans to sodium hexahydroxoantimonate can be ruled out for REACH-related industrial and consumer uses.

Based on the overall toxicological profile of sodium hexahydroxoantimonate, their limited bioavailability and in particular the absence of any reports on any animal or human reproduction effects, there are no indications that such effects would be of concern. In consequence, for scientific and animal welfare reasons, the conduct of a study on fertility (i.e. a two-generation reproduction toxicity study) is not considered justified.

Short description of key information:

Based on the information from the available 90-day repeated dose toxicity study via gavage in rats (according to OECD 408, GLP) it is concluded that intake of high amounts of sodium hexahydroxoantimonate up to the limit dose of 1000 mg/kg bw/day is not associated with adverse effects on the reproductive organs of male and female animals.

Justification for selection of Effect on fertility via oral route:

Key study reported under IUCLID section 7.5.1 Repeated dose toxicity: oral

Effects on developmental toxicity

Description of key information

Based on the information from the available pre-natal developmental toxicity study via gavage in rats (according to OECD 414, GLP) it is concluded that maternal toxicity up to the highest dose level of 1000 mg/kg bw/d, and reproduction data of dams were not affected by treatment. There was no embryo-toxicity and no effect on the development of foetuses. No external visceral or skeletal malformations were observed and the incidence of variations was not different between treated and control groups. There were some incidences of skeletal retardations in the mid and high dose groups compared to the low dose group and the control. Most values were only slightly above historical control data, and when skeletal retardations were considered overall, the common finding of retardations were seen in about 99.3 to 100% of foetuses and 100% of litters including controls.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
One key study available (pre-natal developmental toxicity study in rats according to OECD 414, under GLP) which is reliable without restrictions (RL=1). The overall quality of the database is therefore high.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Based on the fact that diantimony pentoxide, sodium hexahydroxoantimonate and sodium antimonate contain antimony in the pentavalent oxidation state and that water solubility testing as well as transformation dissolution testing has shown similar dissolution pattern of pentavalent antimony cations form all three substances, read-across among the pentavalent antimony compounds (i.e. sodium hexahydroxoantimonate, sodium antimonate and diantimony pentoxide) is considered justified.

Three oral dose levels of sodium hexahydroxoantimonate were evaluated in a developmental toxicity study in rats. Four groups of 20 pregnant females were treated orally with dose levels of 0, 100, 300 and 1000 mg/kg bw/d in Methocel once daily from day 6 to 19 of gestation. Animals were sacrificed on day 20 of gestation and pups were evaluated for viability (number of alive and dead foetuses), sex distribution and body weights. Foetuses were inspected externally and subjected to skeletal and soft tissue examinations and evaluated for malformations, variations and retardations.

 

The results did not indicate any maternal toxicity up to the highest dose level of 1000 mg/kg bw/d, and reproduction data of dams were not affected by treatment. There was no embryo-toxicity and no effect on the development of foetuses. No external visceral or skeletal malformations were observed and the incidence of variations was not different between treated and control groups. However, there were some incidences of skeletal retardations in the mid and high dose groups compared to the low dose group and the control which were higher than historical control data as shown in the following table.

 

In the intermediate dose group (300 mg Sodium hexahydroxoantimonate/kg b.w./day) non-ossified caudal vertebral bodies were noted in 30.3% of the foetuses in comparison to only 17.8 % in the control group. The increase was statistically significant (p ≤ 0.01).

 

In the high dose group (1000 mg Sodium hexahydroxoantimonate/kg b.w./day) a statistically significant (p ≤ 0.01) increase was noted for the incidence of foetuses with dumbbell-shaped thoracic vertebral bodies, for the incidence of foetuses with less than 5 sacral vertebral bodies, for the incidence of foetuses with non-ossified caudal vertebral bodies and for the incidence of foetuses with non-ossified os ischiis.

 

It is of particular relevance in this context that most values were only slightly above historical control data, and when skeletal retardations were considered overall, the common finding of retardations were seen in about 99.3 to 100% of foetuses and 100% of litters including controls.

 

Table: Skeletal retardations

Number of foetuses with retardations

Group 1

Control

Group 2

100 mg / kg

NaSb(OH)6

Group 3

300 mg / kg

NaSb(OH)6

Group 4

1000 mg / kg

NaSb(OH)6

foetal incidence

N

%

 

146

100.0

 

142

99.3

 

142

100.0

 

138

99.3

litter incidence

N

%

 

20

100.0

 

20

100.0

 

20

100.0

 

20

100.0

 

 

In conclusion, slightly increased incidences of foetal retardations were seen mainly in the high dose group treated with 1000 mg/kg bw/d sodium hexahydroxoantimonate. However, statistically significant effects above the historical control data were restricted to only 4 locations and were generally only of slight incidence. Whereas a test item effect cannot be strictly ruled out, the nature of the compound with its poor oral bioavailability and its overall low to negligible systemic toxicity suggests that the mechanism may be related to an indirect effect: it may be speculated that the oral administration of antimony in such high doses may have resulted either in complex formation of antimony with calcium or perhaps even only an osmotic effect, which may have temporarily influenced calcium uptake in dams. The assumption of an indirect effect is supported by the absence of any other effects on foetal development like general growth retardation or effects on body weight or other developmental endpoints. In addition, published data indicate that only very small amounts of antimony can actually pass the placental barrier and become detectable in foetuses after dietary exposure of pregnant mice and rats (Gerber G.B. et al. 1982, Casals J.B. 1972).

 

The observed delayed ossification is a very common skeletal variation, which is however readily repairable during postnatal remodelling and is neither mechanistically linked to malformations, nor does it have general predictive value for teratogenesis. In consequence, this observation is not adverse in and of itself, and in a weight-of-evidence approach regarding the high prevalence also in controls and the absence of any other critical effects in foetuses is not considered indicative of an adverse effect on foetal development (Carney & Kimmel, 2007).

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

Key study

Justification for classification or non-classification

According to regulation (EC) 1272/2008 (CLP) the classification as a reproductive toxicant is intended for substances which have an intrinsic, specific property to produce an adverse effect on reproduction, and substances should not be classified if such an effect is produced solely as a non-specific secondary consequence of other toxic effects.

Effects on developmental toxicity:

Considering the nature and severity of effects as well as number of endpoints affected, which were observed in the pre-natal developmental toxicity study with sodium hexahydroxoantimonate, these are regarded to be of low or minimal toxicological significance. The observed effects on skeletal retardation are common findings and of spontaneous nature and were observed only in a small number and incidences were mostly only slightly above historical control levels.

In addition, there is evidence that the effects might be rather secondary related to disruption of calcium homoeostasis in mothers than a direct effect of the test item related to bone development in fetuses, although no maternal toxicity was evident in the study. 

In conclusion, based on the data observed for sodium hexahydroxoantimonate in a developmental toxicity study in rats, a classification as reproductive toxicant appears not adequate due to the nature and severity of the observed effects in fetuses.

Effects on fertility:

Based on the information from the available 90-day repeated dose toxicity study via gavage in rats (according to OECD 408, GLP) it is concluded that intake of high amounts of sodium hexahydroxoantimonate up to the limit dose of 1000 mg/kg bw/day is not associated with adverse effects on the reproductive organs of male and female animals. Thus, a classification for effects on fertility is not justified.

Additional information