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Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
REPORTING FORMAT FOR THE CATEGORY APPROACH
1. HYPOTHESIS FOR THE ANALOGUE APPROACH: The hypothesis is that properties are likely to be similar or follow a similar pattern because of the presence of a common metal ion, in this case tungstate.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES):
Source: Sodium tungstate
Target: Tungsten Trioxide
3. CATEGORY APPROACH JUSTIFICATION: See Annex 1 in CSR
4. DATA MATRIX: See Annex 1 in CSR
Cross-referenceopen allclose all
Reason / purpose:
read-across: supporting information
Reason / purpose:
reference to same study
Reference
Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Well documented scientfically sound study similar to OECD guidelines with sufficient information provided on materials and methods to evaluate results. However as this study is used in the context of a read across, Klimisch 2 is assigned.
Justification for type of information:
REPORTING FORMAT FOR THE CATEGORY APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH: The hypothesis is that properties are likely to be similar or follow a similar pattern because of the presence of a common metal ion, in this case tungstate.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES):
Source: Sodium tungstate
Target: Tungsten trioxide

3. CATEGORY APPROACH JUSTIFICATION: See Annex 1 in CSR

4. DATA MATRIX: See Annex 1 in CSR
Reason / purpose:
read-across: supporting information
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
other: EPA OPPTS 870.3650 "Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Study
Deviations:
yes
Remarks:
The protocol was extended beyond the minimum 54 days of treatment to accomodate evaluation of the development of the offspring through postnatal day 20 as well as their dams following the last dose on day 70.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories (Wilmington, MA)
- Age at study initiation: 8 weeks
- Housing: The adults (e.g., P1) were singly housed (except during mating)
- Acclimation period: 14 days
Route of administration:
oral: gavage
Vehicle:
other: deionized water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The powder readily dissolved in a deionized water (diH2O) vehicle for the concentrations used in this study at 5, 62.5 and 125 mg/mL. The solution was concentrated to administer a volume of 1 mL/kg body weight not to exceed 2 mL. Fresh solution was made daily and administered via oral gavage


VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: no data
- Amount of vehicle (if gavage): no data
- Lot/batch no. (if required): no data
- Purity: no data
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: not specified
- Length of cohabitation: 14 days
- Verification of same strain and source of both sexes: not specified
- Proof of pregnancy: vaginal plug referred to as day 1 of pregnancy
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
70 days
Frequency of treatment:
Daily pre- and postnatal exposure
Details on study schedule:
Day 13: 24 hr usine/feces
Day 14: Mating begins
Day 28: Mating ends
Day 70: Last dosing
Dose / conc.:
5 mg/kg bw/day (actual dose received)
Dose / conc.:
62.5 mg/kg bw/day (actual dose received)
Dose / conc.:
125 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
40 rats per sex per treatment group
Control animals:
yes, concurrent vehicle
Details on study design:
Dosing continued for 70 days and encompassed mating following 14 days of treatment, that continued through the 14 day mating period, the 22 day gestational period, and through to postnatal day (PND)20. In order to ensure a total of 70 day exposure, adults were dosed for any additional days necessary following weaning. Prenatal pup exposure was from sodium tungstate crossing through the placenta and postnatal exposure was indirect via dams' milk. Offspring (F1 generation) were monitored until PND70. On PND1 (day of parturition=PND 0), the number of pups in each litter was recorded. Litters were culled on PND4 to eight pups, and litters were weighed. Selection of pups was pseudo-random to maintain a 4 male/4 female ratio whenever possible, and all pups remained with their biological mothers.
Parental animals: Observations and examinations:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Throughout the exposure period, dams and the males used for mating were observed for clinical signs of toxicity.

BODY WEIGHT: Yes
- Time schedule for examinations: Pregnant dams were weighed on gestation days (GD) 1, 10, 15 and 20, and gestational weight gain and gestation length were recorded.

Various organ tissues (heart, spleen, kidney, liver, lungs, brain, testes, ovaries, thymus, bone, gastrointestinal tract, etc,) were carefully removed and postfixed in 4% paraformaldehyde no longer than 24 h. After dehydration, tissues embedded in paraffin and 40 μm coronal sections were made on glass slides for histological evaluation using hematoxylin and eosin.
Litter observations:
PND 0-4: SIze of Litter (#males/#females), weight of litter, and gross abnormalities
PND 4: Liiter culled to 8 pups (4 males and 4 females)
PND 5: Individual pups weight starting on PND 5 and weekly therefe
Postmortem examinations (parental animals):
Tungsten concentrations in brain tissue were measured in adults and pups for the control and highest dose groups only. Ten male and female adults from each dose group were necropsied on the day of the last dose were necropsied on PND20 and PND70. For all necropsies, animals were anesthetized via CO2 overdose followed by exsanguination via the vena cava. Concentrations of the tungstate anion were determined using inductively coupled plasma mass spectrometry (ICP-MS).

Various organ tissues (heart, spleen, kidney, liver, lungs, brain, testes, ovaries, thymus, bone, gastrointestinal tract, etc,) were carefully removed and postfixed in 4% paraformaldehyde no longer than 24 h. After dehydration, tissues embedded in paraffin and 40 μm coronal sections were made on glass slides for histological evaluation using hematoxylin and eosin (H&E) stain.
Postmortem examinations (offspring):
Tungsten concentrations in brain tissue were measured in pups for the control and highest dose groups only. Ten male and female adults from each dose group were necropsied on the day of the last dose were necropsied on PND20 and PND70. For all necropsies, animals were anesthetized via CO2 overdose followed by exsanguination via the vena cava. Concentrations of the tungstate anion were determined using inductively coupled plasma mass spectrometry (ICP-MS).
Statistics:
All statistical testing was performed using ANOVA with repeated measures factors. Tukey'svHSD analysis was used to evaluate pair-wise comparisons.
Clinical signs:
no effects observed
Description (incidence and severity):
Animals were observed for clinical signs of toxicity throughout the exposure period, although none were noted. Additionally, no deaths were recorded for the adult females or males at the doses tested.
Mortality:
no mortality observed
Description (incidence):
No deaths were recorded for the adult females or males at the doses tested
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Sodium tungstate treatments did not have an effect on average gestational weight gain in adults
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Sodium tungstate treatments did not have an effect on average gestational weight gain in adults
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
1) A significant effect of tungstate exposure on spontaneous locomotor activity was detected especially with low dose treated dams. Compared to control and the high dose treated animals, the low dose treated dams spent more time on ambulatory time and distance traveled and less time in stereotypies. On the contrary, in high dose treated dams less time resting and more time in stereotypic movements than the controls or low dose group were markedly observed. Maternal retrieval test revealed that sodium tungstate exposure to dams had no effect on latency in both treatment groups. In the dams, opposing exposure effects were observed in the low and high dose groups related to locomotor activity and exploration.

2) On PND 20, the mean tungstate ion concentrations in males and females of the 125 mg/kg/day treatment group were 0.008 ± 0.006 ppm and 0.002±0.002 ppm, respectively. No tungstate ion was detected in the males or females of the control group. Furthermore, no tungstate ion was detected in the brains of males or females in the control or high dose group on PND 70.

3) Tungstate ion concentrations in dam milk secretions measured PND10–14 were significantly greater in the 125 mg/kg/day treatment group (0.45 ± 0.007 ppm) than in the low dose group (0.021 ± 0.001 ppm) or controls (0.005±0.0 ppm). Concentrations in the low dose group did not significantly differ from controls.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
The heart showed histological lesions, histiocytic inflammation from minimal to mild with cardiomyocyte degeneration and necrosis in several P0 animals of 125 mg NW dose group
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathological examination showed no severe chronic injury in the organs tested. However, the heart showed histological lesions, histiocytic inflammation from minimal to mild with cardiomyocyte degeneration and necrosis in several P0 animals of 125 mg NaW dose group.
Histopathological findings: neoplastic:
not specified
Other effects:
effects observed, treatment-related
Description (incidence and severity):
- The study results indicate that a significant difference was found for one of the treatment groups on measures of reproductive toxicity. In the dams, particularly 125 mg dose group animals showed longer gestational period when compared to control, 5 and 62.5 mg groups, but did not have an effect on average gestational weight gain in adults and offspring.
- Tungstate ion concentrations in the male and female adult and pup brains after sodium tungstate exposure were significantly greater in the high dose (125 mg) treated rats than control. Similarly, in dam milk secretions tungstate ion concentrations was significantly greater in the 125 mg treatment group than in the low dose group or controls. Further, we also observed increased concentration of tungstate ion distribution in other major organs like heart, spleen, kidney, thymus, testes, lungs, liver, femur bone and gastrointestinal regions in both male and female treated adult and pups.
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
Daily administration of sodium tungstate produced no overt evidence of toxicity and had no apparent effect on mating success
- Tungstate ion concentrations in the male and female adult rats after sodium tungstate exposure were significantly greater in the high dose (125 mg) treated rats than control
- Further, we also observed increased concentration of tungstate ion distribution in other major organs like heart, spleen, kidney, thymus, testes, lungs, liver, femur bone and gastrointestinal regions in both male and female treated adult rats.
- Histopathological examination showed no severe chronic injury in the organs tested.
Key result
Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
gross pathology
histopathology: non-neoplastic
reproductive performance
Key result
Dose descriptor:
LOEL
Effect level:
125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
Key result
Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Behaviour
Key result
Dose descriptor:
LOAEL
Effect level:
125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Critical effects observed:
yes
Lowest effective dose / conc.:
125 mg/kg bw/day (actual dose received)
System:
cardiovascular
Organ:
heart
Treatment related:
yes
Dose response relationship:
no
Relevant for humans:
not specified
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Sodium tungstate treatments did not have an effect on average gestational weight gain in adults and offspring
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
Daily administration of sodium tungstate produced no overt evidence of toxicity on offspring physical development.
Histopathological findings:
no effects observed
Description (incidence and severity):
Daily administration of sodium tungstate produced no overt evidence of toxicity on offspring physical development and no significant test article-related lesions
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Tungstate ion concentrations in the pup brains after sodium tungstate exposure were significantly greater in the high dose (125 mg) treated rats than control. Similarly, in dam milk secretions tungstate ion concentrations was significantly greater in the 125 mg treatment group than in the low dose group or controls. Further, we also observed increased concentration of tungstate ion distribution in other major organs like heart, spleen, kidney, thymus, testes, lungs, liver, femur bone and gastrointestinal regions in pups.
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
For righting reflex, a significant sex effect was found on male where males were faster than females. However, there was no dose related effect on this activity (Fig. 3). Further, on ultrasonic distress vocalization test, pups showed dose-related effects during 60 s time period. The high dose treated pups exhibited more vocalization than control and 5 mg groups
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
clinical signs
mortality
body weight and weight gain
gross pathology
histopathology: non-neoplastic
Key result
Generation:
F1
Based on:
test mat.
Sex:
male/female
Basis for effect level:
developmental neurotoxicity
Remarks on result:
not determinable because of methodological limitations
Key result
Reproductive effects observed:
no
Conclusions:
Daily administration of sodium tungstate produced no overt evidence of toxicity and had no apparent effect on mating success, and did not cause a change in gestation length and weight gain in adult females. No significant test article related histopathological findings were observed in the F1 treatment groups. The 2011 publication mentions the investigation of neurobehavioral findings only in the control, low and high dose groups but not from the mid dose (only body weight gain, tungsten organ distribution data and histopathology) for the mid dose group animals are reported. The neurobehavioral results in the 2008 publication resemble the results reported in the 2011 publication. However, the 2011 paper does not quote the 2008 publication of the same group. This causes some doubt on the study design.

Executive summary:

No fertility, reproductive, or developmental toxicity data of sufficient quality are available for tungsten trioxide (target substance). However, reproductive toxicity data are available for sodium tungstate (source substance), which will be used for reading across. Due to lower water solubility and lower toxicity for the target substance compared to the source substance, the resulting read across from the source substance to the target substance is appropriate as a conservative estimate of potential toxicity for this endpoint. In addition, read across is appropriate because the classification and labelling is more protective for the source substance than the target substance, the PBT/vPvB profile is the same, and the dose descriptors are, or are expected to be, lower for the source substance. For more details, refer to the read-across category approach included in the Category section of this IUCLID submission and/or as an Annex in the CSR.

Reason / purpose:
reference to same study
Reference
Endpoint:
developmental toxicity
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
REPORTING FORMAT FOR THE CATEGORY APPROACH
1. HYPOTHESIS FOR THE ANALOGUE APPROACH: The hypothesis is that properties are likely to be similar or follow a similar pattern because of the presence of a common metal ion, in this case tungstate.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES):
Source: Sodium tungstate
Target: Tungsten Trioxide
3. CATEGORY APPROACH JUSTIFICATION: See Annex 1 in CSR
4. DATA MATRIX: See Annex 1 in CSR
Reason / purpose:
read-across: supporting information
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
other: EPA OPPTS 870.3650 "Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Study
Deviations:
yes
Remarks:
The protocol was extended beyond the minimum 54 days of treatment to accomodate evaluation of the development of the offspring through postnatal day 20 as well as their dams following the last dose on day 70.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories (Wilmington, MA)
- Age at study initiation: 8 weeks
- Housing: The adults (e.g., P1) were singly housed (except during mating)
- Acclimation period: 14 days
Route of administration:
oral: gavage
Vehicle:
other: deionized water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The powder readily dissolved in a deionized water (diH2O) vehicle for the concentrations used in this study at 5 mg/mL and 125 mg/mL. The solution was concentrated to administer a volume of 1 mL/kg body weight not to exceed 2 mL. Fresh solution was made daily and administered via oral gavage

VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: no data
- Amount of vehicle (if gavage): no data
- Lot/batch no. (if required): no data
- Purity: no data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Concentrations of the tungstate anion were determined using inductively coupled plasma mass spectrometry (ICP-MS).
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: not specified
- Length of cohabitation: 14 days
- Verification of same strain and source of both sexes: not specified
- Proof of pregnancy: vaginal plug referred to as day 1 of pregnancy
Duration of treatment / exposure:
70 days
Frequency of treatment:
daily pre- and postnatal exposure
Dose / conc.:
5 mg/kg bw/day (actual dose received)
Dose / conc.:
62.5 mg/kg bw/day (actual dose received)
Dose / conc.:
125 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
40 rats per sex per treatment group
Control animals:
yes, concurrent vehicle
Details on study design:
In order to ensure a total of 70 days exposure, adults were dosed for any additional days necessary following weaning. Prenatal pup exposure was from sodium tungstate crossing through the placenta and postnatal exposure was indirect via dams' milk.
Maternal examinations:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Throughout the exposure period, dams and the males used for mating were observed for clinical signs of toxicity.

BODY WEIGHT: Yes
- Time schedule for examinations: Pregnant dams were weighed on gestation days (GD) 1, 10, 15 and 20, and gestational weight gain and gestation length were recorded.

OTHER: N/A



Ovaries and uterine content:
no data
Fetal examinations:
- External examinations: No data
- Soft tissue examinations: Yes: control and high dose pups
- Skeletal examinations: No data
- Head examinations: Yes
Statistics:
All measures were analyzed using ANOVA. Repeated measures ANOVA were used where appropriate. All animals in the pre-weanling litter were tested for righting reflex and separation distress so the litter was used as the unit of analysis for the ANOVA. The fiducial limit was pb 0.05 and post-hoc comparisons were performed using Tukey's HSD analysis for pair-wise comparisons as appropriate.
Clinical signs:
no effects observed
Description (incidence and severity):
Animals were observed for clinical signs of toxicity throughout the exposure period, although none were noted.
Mortality:
no mortality observed
Description (incidence):
No deaths were recorded for the adult females or males at the doses tested
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Sodium tungstate treatments did not have an effect on average gestational weight gain in adults.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
A significant effect of tungstate exposure on spontaneous locomotor activity was detected especially with low dose treated dams. Compared to control and the high dose treated animals, the low dose treated dams spent more time on ambulatory time and distance traveled and less time in stereotypies. On the contrary, in high dose treated dams less time resting and more time in stereotypic movements than the controls or low dose group were markedly observed.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathological examination showed no severe chronic injury in the organs tested. However, the heart showed histological lesions, histiocytic inflammation from minimal to mild with cardiomyocyte degeneration and necrosis in several P0 animals of 125 mg dose group
Histopathological findings: neoplastic:
not specified
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Tungstate ion concentrations in the male and female adult and pup brains after sodium tungstate exposure were significantly greater in the high dose (125 mg) treated rats than control (data not shown). Similarly, in dam milk secretions tungstate ion concentrations was significantly greater in the 125 mg treatment group than in the low dose group or controls. Increased concentration of tungstate ion distribution in other major organs like heart, spleen, kidney, thymus, testes, lungs, liver, femur
bone and gastrointestinal regions in both male and female treated adult.
Number of abortions:
not specified
Pre- and post-implantation loss:
not specified
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
not specified
Changes in pregnancy duration:
effects observed, treatment-related
Description (incidence and severity):
The study results indicate that a significant difference was found for one of the treatment groups on measures of reproductive toxicity. In the dams, particularly 125 mg dose group animals showed longer gestational period when compared to control, 5 and 62.5 mg groups.

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): The study results indicate that a significant difference was found for one of the treatment groups on measures of reproductive toxicity. In the dams, particularly 125 mg dose group animals
Changes in number of pregnant:
not specified
Other effects:
effects observed, treatment-related
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS):
Astatistically significant difference was found for one of the treatment groups on measures of reproductive toxicity. In the dams, average gestation duration was longer for the 125 mg/kg/day dose group than for the control and 5 mg/kg/day groups. Average gestational weight gain did not differ across treatments.

Key result
Dose descriptor:
NOAEL
Effect level:
> 125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
clinical signs
mortality
Key result
Dose descriptor:
LOEL
Remarks:
125 mg dose group animals showed longer gestational period when compared to control, 5 and 62.5 mg groups
Effect level:
125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
effects on pregnancy duration
Dose descriptor:
LOAEL
Effect level:
125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
histopathology: non-neoplastic
Key result
Abnormalities:
effects observed, treatment-related
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Sodium tungstate treatments did not have an effect on average gestational weight gain in offspring
Reduction in number of live offspring:
not specified
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
effects observed, treatment-related
Description (incidence and severity):
- Increased concentration of tungstate ion distribution in other major organs like heart, spleen, kidney, thymus, testes, lungs, liver, femur bone and gastrointestinal regions in both male and female treated pups
- On PND 20, the mean tungstate ion concentrations in males and females of the 125 mg/kg/day treatment group were 0.008 ± 0.006 ppm and 0.002±0.002 ppm, respectively. No tungstate ion was detected in the males or females of the control group. Furthermore, no tungstate ion was detected in the brains of males or females in the control or high dose group on PND 70.
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There were no differences in average number of pups born.
All pups were inspected for physical birth defects, including missing digits, however, none were found.
The high dose group demonstrated a greater number of ultrasonic distress vocalizations when separated from the dam and littermates.

Key result
Dose descriptor:
NOAEL
Effect level:
> 125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
changes in litter size and weights
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no

Tungstate ion concentrations in the male and female adult and pup brains after sodium tungstate exposure were significantly greater in the high dose (125 mg) treated rats than control. Similarly, in dam milk secretions tungstate ion concentrations was significantly greater in the 125 mg treatment group than in the low dose group or controls. Further, an increased concentration of tungstate ion distribution was observed in other major organs like heart, spleen, kidney, thymus, testes, lungs, liver, femur bone and gastrointestinal regions in both male and female treated adult and pups.

Conclusions:
This study evaluated the reproductive, systemic and developmental effects of sodium tungstate in rats following 70 days of daily pre-and postnatal exposurevia oral gavage to 5, 62.5 and 125 mg/kg/ day through mating, gestation and weaning (PND 0–20). Daily administration of sodium tungstate produced no overt evidence of toxicity and had no apparent effect on mating success or offspring physical development.
Executive summary:

No fertility, reproductive, or developmental toxicity data of sufficient quality are available for tungsten trioxide (target substance). However, developmental toxicity data are available for sodium tungstate (source substance), which will be used for reading across. Due to lower water solubility and lower toxicity for the target substance compared to the source substance, the resulting read across from the source substance to the target substance is appropriate as a conservative estimate of potential toxicity for this endpoint. In addition, read across is appropriate because the classification and labelling is more protective for the source substance than the target substance, the PBT/vPvB profile is the same, and the dose descriptors are, or are expected to be, lower for the source substance. For more details, refer to the read-across category approach included in the Category section of this IUCLID submission and/or as an Annex in the CSR.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Neurobehavioral effects of sodium tungstate exposure on rats and their progeny
Author:
McInturf SM, Bekkedal MY, Wilfong E, Arfsten D, Gunasekar PG, Chapman GD.
Year:
2008
Bibliographic source:
Neurotoxicol Teratol., 30(6): 455-61
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report Date:
2007

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: EPA OPPTS 870.3650 "Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Study
Deviations:
yes
Remarks:
The protocol was extended beyond the minimum 54 days of treatment to accomodate evaluation of the development of the offspring through postnatal day 20 as well as their dams following the last dose on day 70.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): Sodium tungstate dihydrate (Reported as 10213-10-2)
- Source: Fisher Scientific
- Analytical purity: >98%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories (Wilmington, MA)
- Age at study initiation: 8 weeks
- Housing: The adults (e.g., P1) were singly housed (except during mating)
- Acclimation period: 14 days

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: deionized water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The powder readily dissolved in a deionized water (diH2O) vehicle for the concentrations used in this study at 5 mg/mL and 125 mg/mL. The solution was concentrated to administer a volume of 1 mL/kg body weight not to exceed 2 mL. Fresh solution was made daily and administered via oral gavage

VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: no data
- Amount of vehicle (if gavage): no data
- Lot/batch no. (if required): no data
- Purity: no data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Concentrations of the tungstate anion were determined using inductively coupled plasma mass spectrometry (ICP-MS).
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: not specified
- Length of cohabitation: 14 days
- Verification of same strain and source of both sexes: not specified
- Proof of pregnancy: vaginal plug referred to as day 1 of pregnancy
Duration of treatment / exposure:
70 days
Frequency of treatment:
daily pre- and postnatal exposure
Doses / concentrationsopen allclose all
Dose / conc.:
5 mg/kg bw/day (actual dose received)
Dose / conc.:
125 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
40 rats per sex per treatment group
Control animals:
yes, concurrent vehicle
Details on study design:
In order to ensure a total of 70 days exposure, adults were dosed for any additional days necessary following weaning. Prenatal pup exposure was from sodium tungstate crossing through the placenta and postnatal exposure was indirect via dams' milk.

Examinations

Maternal examinations:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Throughout the exposure period, dams and the males used for mating were observed for clinical signs of toxicity.

BODY WEIGHT: Yes
- Time schedule for examinations: Pregnant dams were weighed on gestation days (GD) 1, 10, 15 and 20, and gestational weight gain and gestation length were recorded.

OTHER: N/A



Ovaries and uterine content:
no data
Fetal examinations:
- External examinations: No data
- Soft tissue examinations: Yes: control and high dose pups
- Skeletal examinations: No data
- Head examinations: Yes
Statistics:
All measures were analyzed using ANOVA. Repeated measures ANOVA were used where appropriate. All animals in the pre-weanling litter were tested for righting reflex and separation distress so the litter was used as the unit of analysis for the ANOVA. The fiducial limit was pb 0.05 and post-hoc comparisons were performed using Tukey's HSD analysis for pair-wise comparisons as appropriate.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
Animals were observed for clinical signs of toxicity throughout the exposure period, although none were noted.
Mortality:
no mortality observed
Description (incidence):
No deaths were recorded for the adult females or males at the doses tested
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Sodium tungstate treatments did not have an effect on average gestational weight gain in adults.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
A significant effect of tungstate exposure on spontaneous locomotor activity was detected especially with low dose treated dams. Compared to control and the high dose treated animals, the low dose treated dams spent more time on ambulatory time and distance traveled and less time in stereotypies. On the contrary, in high dose treated dams less time resting and more time in stereotypic movements than the controls or low dose group were markedly observed.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathological examination showed no severe chronic injury in the organs tested. However, the heart showed histological lesions, histiocytic inflammation from minimal to mild with cardiomyocyte degeneration and necrosis in several P0 animals of 125 mg dose group
Histopathological findings: neoplastic:
not specified
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Tungstate ion concentrations in the male and female adult and pup brains after sodium tungstate exposure were significantly greater in the high dose (125 mg) treated rats than control (data not shown). Similarly, in dam milk secretions tungstate ion concentrations was significantly greater in the 125 mg treatment group than in the low dose group or controls. Increased concentration of tungstate ion distribution in other major organs like heart, spleen, kidney, thymus, testes, lungs, liver, femur
bone and gastrointestinal regions in both male and female treated adult.

Maternal developmental toxicity

Number of abortions:
not specified
Pre- and post-implantation loss:
not specified
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
not specified
Changes in pregnancy duration:
effects observed, treatment-related
Description (incidence and severity):
The study results indicate that a significant difference was found for one of the treatment groups on measures of reproductive toxicity. In the dams, particularly 125 mg dose group animals showed longer gestational period when compared to control, 5 and 62.5 mg groups.

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): The study results indicate that a significant difference was found for one of the treatment groups on measures of reproductive toxicity. In the dams, particularly 125 mg dose group animals
Changes in number of pregnant:
not specified
Other effects:
effects observed, treatment-related
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS):
Astatistically significant difference was found for one of the treatment groups on measures of reproductive toxicity. In the dams, average gestation duration was longer for the 125 mg/kg/day dose group than for the control and 5 mg/kg/day groups. Average gestational weight gain did not differ across treatments.

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
> 125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
clinical signs
mortality
Key result
Dose descriptor:
LOEL
Remarks:
125 mg dose group animals showed longer gestational period when compared to control, 5 and 62.5 mg groups
Effect level:
125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
effects on pregnancy duration
Dose descriptor:
LOAEL
Effect level:
125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
histopathology: non-neoplastic

Maternal abnormalities

Key result
Abnormalities:
effects observed, treatment-related

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Sodium tungstate treatments did not have an effect on average gestational weight gain in offspring
Reduction in number of live offspring:
not specified
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
effects observed, treatment-related
Description (incidence and severity):
- Increased concentration of tungstate ion distribution in other major organs like heart, spleen, kidney, thymus, testes, lungs, liver, femur bone and gastrointestinal regions in both male and female treated pups
- On PND 20, the mean tungstate ion concentrations in males and females of the 125 mg/kg/day treatment group were 0.008 ± 0.006 ppm and 0.002±0.002 ppm, respectively. No tungstate ion was detected in the males or females of the control group. Furthermore, no tungstate ion was detected in the brains of males or females in the control or high dose group on PND 70.
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There were no differences in average number of pups born.
All pups were inspected for physical birth defects, including missing digits, however, none were found.
The high dose group demonstrated a greater number of ultrasonic distress vocalizations when separated from the dam and littermates.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
> 125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
changes in litter size and weights

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

Tungstate ion concentrations in the male and female adult and pup brains after sodium tungstate exposure were significantly greater in the high dose (125 mg) treated rats than control. Similarly, in dam milk secretions tungstate ion concentrations was significantly greater in the 125 mg treatment group than in the low dose group or controls. Further, an increased concentration of tungstate ion distribution was observed in other major organs like heart, spleen, kidney, thymus, testes, lungs, liver, femur bone and gastrointestinal regions in both male and female treated adult and pups.

Applicant's summary and conclusion

Conclusions:
This study evaluated the reproductive, systemic and developmental effects of sodium tungstate in rats following 70 days of daily pre-and postnatal exposurevia oral gavage to 5, 62.5 and 125 mg/kg/ day through mating, gestation and weaning (PND 0–20). Daily administration of sodium tungstate produced no overt evidence of toxicity and had no apparent effect on mating success or offspring physical development.
Executive summary:

No fertility, reproductive, or developmental toxicity data of sufficient quality are available for tungsten trioxide (target substance). However, developmental toxicity data are available for sodium tungstate (source substance), which will be used for reading across. Due to lower water solubility and lower toxicity for the target substance compared to the source substance, the resulting read across from the source substance to the target substance is appropriate as a conservative estimate of potential toxicity for this endpoint. In addition, read across is appropriate because the classification and labelling is more protective for the source substance than the target substance, the PBT/vPvB profile is the same, and the dose descriptors are, or are expected to be, lower for the source substance. For more details, refer to the read-across category approach included in the Category section of this IUCLID submission and/or as an Annex in the CSR.