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EC number: 231-146-5 | CAS number: 7440-36-0
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
![](https://poisoncentres.echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
Data source
Reference
- Reference Type:
- publication
- Title:
- Developmental toxicity of meglumine antimoniate and transplacental transfer of antimony in the rat
- Author:
- Elaine S. Miranda, Norbert Miekeley, Rosangel R. De-Carvalho, Francisco J.R. Paumgartten
- Year:
- 2 006
- Bibliographic source:
- Reproductive Toxicology 21 (2006) 292–300
Materials and methods
- Principles of method if other than guideline:
- The experimental setup is similar to the OECD 414, but no maternal toxicity at highest dose, proof of exposure by measurement of substance in blood mother and fetusses.
- GLP compliance:
- no
Test material
- Reference substance name:
- (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentol ; stiboric acid antimonic acid - 1-deoxy-1-(methylamino)-D-glucitol (1:1)
- Cas Number:
- 133-51-7
- Molecular formula:
- C7H18NO8Sb
- IUPAC Name:
- (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentol ; stiboric acid antimonic acid - 1-deoxy-1-(methylamino)-D-glucitol (1:1)
1
- Specific details on test material used for the study:
- Meglumine antimoniate (Glucantime®, Aventis Pharma, lot 104557)
The injected solution contained MA at 85mg SbV/mL
the injected volumes were adjusted to obtain the administered dose
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- Male and nulliparous female Wistar rats of the colony maintained by the
Centre for Breeding of Laboratory Animals of Oswaldo Cruz Foundation (CECAL-FIOCUZ), approximately 80 days old, were used in the experiments. The rats were individually housed in standard plastic cages with stainless steel coverlids and pinewood shavings as bedding, and kept in an animal room with controlled environmental conditions (12-h light:12-h dark cycle, lights
on from 8:00 to 20:00 h; temperature 22±1 ◦C; relative humidity approx- imately 70%). Animals were given free access to a pelleted diet for rats and mice (CR1 Nuvital, Nuvilab Ltd., Curitiba, PR, Brazil) and tap water.
Administration / exposure
- Route of administration:
- subcutaneous
- Vehicle:
- other: potassium metabisulfite 1.6mg/mL and sodium sulfite 0.18 mg/mL
- Details on exposure:
- injection on the back skin of the rats
daily from GD o till Gd 20. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Exposure was confirmed by measurement of the compound in the blood of Dam - every other day and in fetusses at day 21.
ICP-MS - the method was validated by analysis of certified reference materials. - Details on mating procedure:
- Mating was carried out by placing two females into the cage of one male for2 h (6:00–8:00 h) and confirmed by the presence of sperm in the vaginal smear. T
he day on which spermatozoa were detected in the smear was designated as day 0 of pregnancy - Duration of treatment / exposure:
- from GD 0 - GD 20
- Frequency of treatment:
- daily
- Duration of test:
- 21 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 other: untreated
- Remarks:
- untreated control
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Remarks:
- vehicle control
- Dose / conc.:
- 75 mg/kg bw/day (actual dose received)
- Remarks:
- Sb V
- Dose / conc.:
- 150 mg/kg bw/day (actual dose received)
- Remarks:
- SbV
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Remarks:
- SbV
- No. of animals per sex per dose:
- untreated controles: 21
vechilce control :20
75 mg Sb V : 19
150 mgSb V: 21
300mg Sb V: 20 - Control animals:
- yes
- yes, concurrent no treatment
- yes, concurrent vehicle
- Details on study design:
- standard experimental design - cfr OECD 414
extra animals were included to perform toxicokinetics during Day 1 of treatment
Examinations
- Statistics:
- Data were evaluated either by one-way analysis of variance (ANOVA)and the Duncan post hoc test, or by the Kruskal–Wallis test followed by the Mann–Whitney U-test whenever the data did not fit a normal distribution. Pro- portions were analysed either by the Chi-square test, or by the Fisher exact test if any expected frequencywas smaller than 5. Statistical analysiswas performed using MINITAB Software (MTB, University of Pennsylvania, 1984) and a difference was considered as statistically significan t at P<0.05.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- the reduction in weight gain of the dams at the higest concentration seemed to be, at least in part, due to embryotoxicity.
- Food efficiency:
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- effects observed, treatment-related
- Description (incidence and severity):
-
litter median (87,5%) significantly different from non-treated, vecicle control and 75mg dose groups. - Early or late resorptions:
- effects observed, treatment-related
- Description (incidence and severity):
- reduced number of resorptions in the highest test group (12,5%) --different from untreated control
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed - Changes in number of pregnant:
- no effects observed
- Other effects:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- the fetal body weight was only reduced in the highest dose group (P < 0.05 compared to all other groups).
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined - Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- liter mean was not different in the different groups.
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- not examined
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- differencesin the range of historical controles
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- differences were in the range of historical controles.
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- dose related reduction in both the absolute and relative liver weights.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- >= 75 - < 150 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- reduction in number of live offspring
Applicant's summary and conclusion
- Conclusions:
- Embryotoxicity, reductions in fetal weight and some skeletal and soft tissue abnormalities at 300 mg/kg/bw Sb(V). NOAEL for embryotoxicity set at 75 mg/kg bw Sb(V) due to observation of minor effects at 150 mg/kg bw/day. No maternal toxicity said to be present, but significant reductions in maternal weight gain were evident at highest dose tested and indicate onset of maternal toxicity.
- Executive summary:
Meglumine antimoniate (MA), a pentavalent antimonial (SbV) drug, has been used for the treatment of leishmaniases for over half a century
but there is almost no data on its safety and kinetics during pregnancy. This study was undertaken to investigate the developmental toxicity ofMA as well as the transplacental transfer of antimony (Sb) in rats. Wistar rats (approximately 20 per group) were treated subcutaneously (s.c.) with MA (0, 75, 150, 300mgSbV/(kgBWday)) during pregnancy (days 1–20). An untreated control group was evaluated as well. Caesarean sections were performed on day 21 and implantations, living and dead fetuses, and resorptions were recorded. Fetuses were weighed and fixed in Bouin’s solution and one-third of each litterwas examined for soft-tissue anomalies. The remaining fetuses were cleared and stained with Alizarin red S for skeleton evaluation. No adverse effect ofMAon the mothers was noted at any dose level. No embryotoxicity was observed at the lowest dose but, at the highest dose,MAincreased embryolethality, reduced fetal weight and augmented the occurrence of some soft-tissue and skeleton variations. Therefore, the no-observed-adverse-effect level for MA-induced embryotoxicity was 75mgSbV/(kgBWday). In a separate group of rats treated with 300mgSbV/(kgBWday) s.c. during whole pregnancy, blood (0.2mL) was taken from the tail vein 1, 2, 4, 6, 12 and 24 h after treatment on day 1 and thereafter every other day immediately before drug injection. Blood was also taken from fetuses removed on day 21, 24 h after the last injection of MA. Blood levels of Sb were determined by ICP-MS and results showed that most of administered Sb was eliminated rapidly (in less than 6 h), but nadir blood concentrations increased gradually during treatment from 1 to 2?g/g, 24 h after the first dose, up to approximately 38?g/g after the 20th dose. Levels of Sb in fetal blood were as high as 10–15?g/g, i.e. approximately 30% their mothers’ nadir levels near term. These findings indicated that repeated administration of MA during gestation led to an accumulation of Sb in mothers and fetuses.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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