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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
reproductive toxicity, other
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
Justification for type of information:
Evaluates the effects upon exposure during gestation and PND on F1 (fertility and neurodevelopment).

Data source

Reference
Reference Type:
publication
Title:
Effects of in utero and lactational exposure to SbV on rat neurobehavioral development and fertility
Author:
Deise R. Coelho, Rosangela R. De-Carvalho, Rafael C.C. Rocha, Tatiana D. Saint’Pierre,
Francisco J.R. Paumgartten
Year:
2014
Bibliographic source:
Reproductive Toxicology 50 (2014) 98–107

Materials and methods

Principles of method if other than guideline:
only exposure of the dam (not the offsprings upon weaning)
GLP compliance:
no
Justification for study design:
evaluation of the offsprings (fertility and neurodevelopment) upon medical treatment of the mother during pregnancy and lactation.

Test material

Reference
Name:
Unnamed
Specific details on test material used for the study:
Meglumine antimoniate (MA; Glucantime®, Sanofi-Aventis Farmacêutica Ltd, Suzano, SP, Brazil).
The concentration of total Sb in the ampoules from the lot used in the experiments was 90.1 mg/mL, while the concentration of SbIII (determined by HG-ICP-MS, as described by Miekeley et al. [8]) was 3.2 mg/mL, or 3.5% of the total Sb. Therefore, the cal- culated concentration of SbV ([Sb-total]–[SbIII]) in the ampoules used in this investigation was 86.9 mg/mL. The injected volumes were adjusted to obtain the administered dose of MA (0, 75, 150, 300 mg SbV/kg body wt/d, sc). A vehicle-only control group (dose 0) received subcutaneous injections

Test animals

Species:
rat
Strain:
Wistar
Details on species / strain selection:
The animals were individually housed in standard plastic cages with stainless steel covers and pinewood shavings as bedding and maintained under controlled environmental con- ditions (12-h light:12-h dark photoperiod, lights on from 8:00 to
20:00 h; room temperature 21 ± 2◦C; relative air humidity approx- imately 70%). A commercial pellet diet for rats and mice (CR1 Nuvital, Nuvilab Ltd, Curitiba, PR, Brazil) and filtered tap water were available ad libitum throughout the experiment.
Sex:
male/female

Administration / exposure

Vehicle:
other: potassium metabisulfite 1.6 mg/mL and sodium sulfite 0.18 mg/mL
Details on exposure:
sc injection on the balk of the animal
Details on mating procedure:
2 females + one male /cage . Day of copulation was comfirmed by presence of spermatozoa in the vaginal smear ( = GD 0)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Total Sb and Sb III was quantified in the test substance MA by HG-ICP-MS. Sb V was calculated.
Duration of treatment / exposure:
42 days (from GD 0 until PND 21)
Frequency of treatment:
daily
Details on study schedule:
see table 1
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
SbV
Dose / conc.:
75 mg/kg bw/day (actual dose received)
Remarks:
SbV
Dose / conc.:
150 mg/kg bw/day (actual dose received)
Remarks:
SbV
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Remarks:
SbV
Details on study design:
see table 1
Positive control:
no

Examinations

Oestrous cyclicity (parental animals):
no
Sperm parameters (parental animals):
no (only used for copulation)
Litter observations:
F1:
somatic and neurobehaviour development, estrus cycle onset, open field test,
male: spermatid and sperm count
female : reproductive capacity, at C-section (liver weight, uterus, implantation sites, number live / dead fetusses
F2: ( fetal ): weight, sex and external morphological abnormalities
Postmortem examinations (parental animals):
at day PND 31 (10 days after weaning)
Statistics:
The data were analyzed by one-way analysis of variance (ANOVA) followed by Dunnett’s post hoc test. For data that were not normally distributed, the Kruskal–Wallis test was used, followed by the Mann–Whitney U test.
Proportions were compared using the chi-square test or Fisher’s exact test.
The statistical evaluations were performed using the SPSS® program, and differences were considered significant when P < 0.05. Data on the day of appearance of developmental landmarks are shown as the group median value and range (minimum–maximum), whereas other data are presented

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
no occurance of pre -and/or peri-implantation losses. 3
0% reduction of live newborns per litter on PND1
13% decreased BW at birth (on the account of females). No BW changes in male offsprings, while 17% decrease in female,
No effect on PND survival
At sexual maturity (PND 60) female BW was 10% lower for all treatment groups, but for the males.

Effect levels (P0)

Dose descriptor:
LOAEL
Effect level:
>= 150 - <= 300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
reproductive performance

Results: P1 (second parental generation)

General toxicity (P1)

Ophthalmological findings:
not examined
Haematological findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed

Results: F1 generation

General toxicity (F1)

Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Females reduced body weight at PND60 for all treatment groups
No effect on male BW.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Sexual maturation:
no effects observed
Description (incidence and severity):
females : during pregnacy (no extra treatment) a slight treatment related decrease in BWgain, accompanied by a reduction in liver weight.
males: no observed effects
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings:
not examined

Developmental neurotoxicity (F1)

Behaviour (functional findings):
no effects observed
Description (incidence and severity):
highest treatment group : Minor effect afor rearing up at PND 60 in female offspring.

Results: F2 generation

General toxicity (F2)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food efficiency:
not examined

Applicant's summary and conclusion

Conclusions:
Exposure of dams during pregnacy, causes 30% reduction of of the number of newborns and 17% bw reduction of the female pups ( no effect at male pups).
Exposure during pregnacy and lactation has no effect on reproductive capacity of the offsprings, and a minor effect on neurohavior of the females in highest treatment group (300 mg SbV).
Placental transfer of Sb to the fetus, and exposure of the offspring by the milk during lactation.
Sb in melk is easily absorbed by the offspring.
Executive summary:

a b s t r a c t

Meglumine antimoniate (MA) is a pentavalent antimony drug used to treat leishmaniases. We investigated the neurobehavioral development, sexual maturation and fertility of the offspring of MA-treated rats. Dams were administered MA (0, 75, 150, 300 mg SbV/kg body wt/d, sc) from gestation day 0, throughout parturition and lactation, until weaning. At the highest dose, MA reduced the birth weight and the number of viable newborns. In the male offspring, MA did not impair development (somatic, reflex mat- uration, weight gain, puberty onset, open field test), sperm count, or reproductive performance. Except for a minor effect on body weight gain and vertical exploration in the open field, MA also did not affect the development of female offspring. Measurements of the Sb levels (ICP-MS) in the blood of MA-treated female rats and their offspring demonstrated that Sb is transferred to the fetuses via the placenta and to the suckling pups via milk.