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Toxicological information

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
Study period:
Experiment start date (Animal Arrival) - 30 July 2015 to Completion date of experimental phase (Foetal pathology): 09 October 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
1. HYPOTHESIS FOR THE CATEGORY 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 dioxide
3. CATEGORY APPROACH JUSTIFICATION: See Annex 3 in CSR
4. DATA MATRIX: See Annex 3 in CSR
Cross-reference
Reason / purpose for cross-reference:
read-across: supporting information

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report date:
2016

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
ICH Harmonised Tripartite Guideline: Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility S5 (R2): finalised (Step 4) November 2005.
Deviations:
no
Principles of method if other than guideline:
ICH Harmonised Tripartite Guideline: Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility S5 (R2): finalised (Step 4) November 2005.
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Disodium wolframate
EC Number:
236-743-4
EC Name:
Disodium wolframate
Cas Number:
13472-45-2
Molecular formula:
Na2O4W
IUPAC Name:
Disodium dioxido(dioxo)tungsten
Test material form:
solid: crystalline
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 1504246000
- Purity test date: 93.1%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: The test item will be stored at room temperature, protected from light.
- Stability under test conditions: Test item formulations at concentrations of 0.5 mg/mL to 50 mg/mL in vehicle have been shown to be stable for up to 14 days at room temperature, when stored refrigerated and when frozen (approximately -80 ºC) (Kymos Reference S15/341-KE). On this basis, formulations, including Control, were stored refrigerated prior to use.

Test animals

Species:
rat
Strain:
other: Crl:CD (SD
Remarks:
Charles River (UK) Limited, Margate, Kent, CT9 4LT, England.
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent, CT9 4LT, England.
- Age at study initiation: 9 to 10 weeks
- Housing: Females were housed individually in grid-floor cages over paper lined trays.
- Diet and water (eg ad libitum): A pelleted rodent diet, VRF1 (manufactured by SDS) supplied by Charles River (UK) Limited, Margate, Kent, CT9 4LT, England, and mains tap water (in bottles) will be freely available.
- Acclimation period: The animals were acclimatised within the study room for at least two days after arrival. Towards the end of this period the animals were re-examined to confirm their suitability for use.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Target ranges 19 °C to 23 °C
- Humidity (%): Target ranges 40 % to 70 %,
- Air changes (per hr): Room was air-conditioned
- Photoperiod (hrs dark / hrs light): The room was illuminated by fluorescent light set to give a cycle of 12 hours light and 12 hours dark.

IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test item was formulated for dosing as a solution in the vehicle (purified water). Separate formulations were prepared for each dose level. The weighed quantity of test item was mixed in the appropriate quantity of vehicle. The formulations were prepared within the known stability period (14 days).
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Formulations for use on the first day and towards the end of dosing was analysed to determine their achieved concentrations. Vehicle (for Controls) was also be analysed on these occasions to confirm the absence of the test item. Analysis was conducted at Kymos Pharma Services using a validated method (code C003-MP0023).
Details on mating procedure:
The females were obtained from the supplier timed-mated and were by Day 1 to Day 4 of gestation on arrival. For mating, each female were paired with a sexually mature male of the same strain. The day on which mating is detected was designated Day 0 of gestation.
Duration of treatment / exposure:
Animals wiere dosed once daily, from Day 6 of gestation to Day 17 of gestation inclusive. Control animals received the vehicle only, following the same regimen as the other groups.
Frequency of treatment:
Animals were dosed once daily
Duration of test:
From Day 6 of gestation to Day 17 of gestation inclusive
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Remarks:
Vehicle control
Dose / conc.:
40 mg/kg bw/day (actual dose received)
Dose / conc.:
80 mg/kg bw/day (actual dose received)
Dose / conc.:
160 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
20 females per group per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels have been selected after examining existing toxicity data and on the basis of results from a preliminary dose range finding study (Sequani Study Number: OHS0004).
- Rationale for animal assignment (if not random): Allocation to groups wiere performed using a stratified randomisation procedure based on body weight ranges recorded on arrival.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
Animals will be examined twice daily for mortality and morbidity. During the treatment period each animal was routinely checked pre-dose and soon after completion of dosing. On week days, additional observations were made approximately 1 hour after dosing and approximately 4 hours after dosing or at the end of the working day (whichever is sooner).

DETAILED CLINICAL OBSERVATIONS: Yes
All animals will be examined daily for clinical signs of toxicity or changes in behaviour and appearance from the start of treatment.

BODY WEIGHT: Yes
Day 0 of gestation body weight will be recorded by the supplier. At Sequani, body weights will be recorded daily from Day 5 to 18 of gestation, inclusive, then again on Day 20 of gestation.

FOOD CONSUMPTION: Yes
The amount of food consumed by each animal will be recorded over Days 6 to 9, 9 to 12, 12 to 15, 15 to 18, and 18 to 20 of gestation.


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #: Females were killed on Day 20 of gestation
- Organs examined: The animals were weighed, the thoracic and abdominal cavities were opened by a ventral mid-line incision and the major organs were examined. Gravid uterus and placenta weights were recorded and organs or tissues showing any macroscopic abnormalities were removed and retained in fixative

Ovaries and uterine content:
For pregnant females the following observations will be made: 1. Number of corpora lutea 2. Number and distribution of implantations in each uterine horn, classified as early intrauterine deaths, late intrauterine deaths, dead foetuses or live foetuses 3. Gravid uterus weight 4. Placental weight
The implantations are numbered separately for the right and left horns. Numbering is sequential, commencing at the ovarian end through to the cervix. The live foetuses and their placentae will be removed and the uterus and ovaries will be retained in neutral buffered formaldehyde. Gravid uterus and placenta weights will be recorded for pregnant females killed on Day 20 of gestation only.
Fetal examinations:
Live foetuses will be killed by rapid cooling followed by immersion in fixative. The following observations will be made for live foetuses killed on Day 20 of gestation: 1. Foetal weights; 2. Foetal sexes, and 3. Foetal abnormalities (to include external, fresh visceral, fixed visceral and/or skeletal examinations)
Statistics:
Comparisons: Group 1 against Groups 2, 3 and 4.

Statistical tests and parameters: Data was processed to give group mean values and standard deviations, where appropriate. Where the data allow, the following methods wiere used for statistical analysis. Depending on the nature of the data set to be analysed, appropriate tests were applied. Where parametric tests may be appropriate they preceded by a check for homogeneity of variance using the Levene test and, where available, the Shapiro-Wilks test for normality. If either of these two assumptions fails a log transformation was applied before retesting. If the transformation fails, appropriate non-parametric tests was applied.

Proportions of foetuses affected were treated as continuous nonparametric data, using one-sided step-wise Jonckheere Tests. Probability values of less than 5 % were regarded as providing sufficient evidence to reject the null hypothesis and therefore statistical significance was identified at the p<0.05 level. For illustrative purposes, significance levels of p<0.01 and p<0.001 also were noted.
Indices:
1) Pre-implantation loss (%) = [(no. corpora lutea – no. implantation sites)/ number of corpora lutea] x 100
2) Post-implantation loss (%) = [(no. implantation sites – no. live foetuses)/no. of implantation sites] x 100

Mean foetal body weights will be calculated separately by sex for each litter; group mean body weights will be calculated (separately by sex) from the litter means. The percentage of foetuses in each litter exhibiting each classification of abnormality was calculated; group mean percentages was calculated from the litter percentages. The percentage of male foetuses, out of the total number of foetuses, was calculated for each litter.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
There was no clinical signs associated with sodium tungstate.
Mortality:
no mortality observed
Description (incidence):
There was no moratlity associated with sodium tungstate.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Females given 160 mg/kg/day gained less weight up to Day 15 of gestation but thereafter, mean . See Tables 1a, 1b and 2 on "Any other information on results incl. tables" section below.weight gain was similar to, or greater than, Controls. Whilst this initial body weight effect resulted in a statistically significantly lower body weight gain over the dosing period (p<0.05), absolute body weight on Day 20 of gestation was comparable with Controls, including that corrected for the gravid uterus weight. Body weight was unaffected in the groups given 40 or 80 mg/kg/day. See Tables 1a, 1b and 2 on "Any other information on results incl. tables" section below.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There was no effect of sodium tungstate on food intake.
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):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no macroscopic abnormalities associated with sodium tungstate
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
See Table 3 on "Any other information on results incl. tables" section below.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
There was no adverse effect of sodium tungstate on the uterine/implantation data. See Tables 4a and Table 4b on "Any other information on results incl. tables" section below.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
See Table 3 on "Any other information on results incl. tables" section below.
Early or late resorptions:
no effects observed
Description (incidence and severity):
See Table 3 on "Any other information on results incl. tables" section below.
Dead fetuses:
no effects observed
Description (incidence and severity):
See Table 4b on "Any other information on results incl. tables" section below.
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
All females were pregnant with the exception of Animal 53 given 80 mg/kg/day. There was no adverse effect of Sodium Tungstate on the uterine/implantation data. See Table 3 on "Any other information on results incl. tables" section below.

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOEL
Effect level:
ca. 80 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
Key result
Dose descriptor:
LOAEL
Effect level:
ca. 160 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
body weight and weight gain

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
No changes on group mean values of Litter weights (g) / foetal data . See Table 5 on "Any other information on results incl. tables" section below.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
See Table 3 on "Any other information on results incl. tables" section below.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
There was no effect of sodium tungstate on the sex ratio. See Table 5 on "Any other information on results incl. tables" section below.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
No changes on group mean values of Litter weights (g) / foetal data . See Table 5 on "Any other information on results incl. tables" section below.
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Description (incidence and severity):
See Table 6 on "Any other information on results incl. tables" section below.
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
The overall incidence of minor foetal abnormalities was significantly higher than Controls in litters given 160 mg/kg/day (p<0.05). This was largely attributable to an increase in the number of foetuses which showed irregular palate ridging and incomplete nasal ossification; both incidences were above the background data ranges. Foetuses from litters given 80 mg/kg/day also showed slightly higher incidences of these abnormalities, although these did not achieve statistical significance and were only marginally higher than the background data ranges.

Changes in the palate rugae seen on this study are considered likely to be related to Sodium Tungstate given the dose response and increase in litter incidence (25 foetuses from 16 litters in the group given 160 mg/kg/day compared with 7 foetuses from 6 litters in the Control group). However, in the absence of any attendant major abnormalities, or other signs of generalised disturbance in foetal development, the changes seen at the dose levels on this study are considered not adverse. In addition to the changes in the extent of nasal ossification, there was also a slight increase in the number of foetuses from litters given 160 mg/kg/day which showed the minor defects of incomplete ossification of the caudal vertebral centra and/or hyoid bone of the skull. These incidences however, were either within, or only just outside, the background data ranges. Foetuses from litters given 80 or 160 mg/kg/day also had an increase in the variant finding of ossified cervical vertebral centra. Whilst changes in the extent of ossification typically reflect a slight developmental delay, due to the propensity for repairing by postnatal skeletal remodelling, these changes are considered not adverse. See Table 6 on "Any other information on results incl. tables" section below.
Visceral malformations:
no effects observed
Description (incidence and severity):
See Table 6 on "Any other information on results incl. tables" section below.

Effect levels (fetuses)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
160 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
skeletal malformations
Key result
Dose descriptor:
NOEL
Effect level:
ca. 40 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
skeletal malformations

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

Table 1a. Body weight gains (g) - group mean values


 



































































































































Sex: Female



Body Weight Gain (Day of Gestation)



Group



0 to 5#



5 to 6#



6 to 7#



7 to 8#



8 to 9#



 



Group: 1


Control


0 mg/kg/day



Mean



22.4 I1



3.9 I1



2.0 R2



3.7 I1



4.1 I1



 



SD



11.0



3.8



6.6



4.8



7.7



 



N



20



20



20



20



20



 



Group: 2


Sodium Tungstate


40 mg/kg/day



Mean



22.2



4.1



1.4



4.6



4.0



 



SD



7.8



3.6



6.1



5.5



4.9



 



N



20



20



20



20



20



 



Group: 3


Sodium Tungstate


80 mg/kg/day



Mean



20.7



3.8



1.2



1.6



4.7



 



SD



9.6



4.7



6.9



4.6



4.2



 



N



19



19



19



19



19



 



Group: 4


Sodium Tungstate


160 mg/kg/day



Mean



20.4



4.8



0.3



2.7



2.8



 



SD



10.3



5.1



6.9



3.8



4.3



 



N



20



20



20



20



20



 



# [Statistically Analysed]


1 [I - Automatic Transformation: No Transformation]                                         


2 [R - Automatic Transformation: Rank]


 


Table 1b. Body weight gains (g) - group mean values


 



































































































































Sex: Female



Body Weight Gain (Day of Gestation)



Group



9 to 12#



12 to 15#



15 to 18#



6 to 18#



18 to 20#



 



Group: 1


Control


0 mg/kg/day



Mean



18.7 R1



18.4 I2



29.4 I2



76.2 I2



31.6 I2



 



SD



7.0



8.1



12.6



14.1



8.1



 



N



20



20



20



20



20



 



Group: 2


Sodium Tungstate


40 mg/kg/day



Mean



20.5



18.6



33.8



82.7



32.9



 



SD



6.0



6.3



7.0



10.2



4.7



 



N



20



20



20



20



20



 



Group: 3


Sodium Tungstate


80 mg/kg/day



Mean



18.4



18.2



32.6



76.8



36.5



 



SD



5.6



5.6



7.2



15.8



7.7



 



N



19



19



19



19



19



 



Group: 4


Sodium Tungstate


160 mg/kg/day



Mean



15.4



15.6



29.9



66.6 W3



34.8



 



SD



11.0



6.6



8.9



16.2



6.5



 



N



20



20



20



20



20



 



# [Statistically Analysed]


1 [R - Automatic Transformation: Rank]                                                           


2 [I - Automatic Transformation: No Transformation]


3 [W - Test: Williams 2 Sided p < 0.05]


 


Table 2. Terminal body weight (g) adjusted for gravid uterus weight (g) - group mean values


 












































































































Sex: Female



Dead Body Weight



Gravid Uterus Wt



BWt Adjusted for GUWt



Adjusted BWt Gain



Group



#



#



#



6 to 20#



Group: 1


Control


0 mg/kg/day



Mean



349.27 I1



71.1 R2



278.17 I1



32.42 I1



SD



30.15



23.0



17.85



10.75



N



20



20



20



20



Group: 2


Sodium Tungstate


40 mg/kg/day



Mean



359.18



73.4



285.83



39.03



SD



25.70



10.9



17.50



9.25



N



20



20



20



20



Group: 3


Sodium Tungstate


80 mg/kg/day



Mean



357.06



77.4



279.69



31.12



SD



32.53



13.9



24.31



14.85



N



19



19



19



19



Group: 4


Sodium Tungstate


160 mg/kg/day



Mean



346.06



69.3



276.81



29.71



SD



31.40



13.0



26.66



13.77



N



20



20



20



20



# [Statistically Analysed]


1 [I - Automatic Transformation: No Transformation]


2 [R - Automatic Transformation: Rank]


 


Table 3. Pregnancy data - summary


 





























































































Sex: Female



Group: 1
Control


0 mg/kg/day



Group: 2
Sodium Tungstate
40 mg/kg/day



Group: 3
Sodium Tungstate
80 mg/kg/day



Group: 4


Sodium Tungstate
160 mg/kg/day



Group Size



 



20



20



20



20



Not Pregnant



 



0



0



1



0



Not Pregnant %



 



0.0



0.0



5.0



0.0



Not Pregnant Died/Killed



Sum



0



0



0



0



Not Pregnant Schedule Kill



Sum



0



0



1



0



Pregnant



 



20



20



19



20



Pregnant %



 



100.0



100.0



95.0



100.0



Pregnant Died/Killed/Aborted



Sum



0



0



0



0



Pregnant with Total Resorption



Sum



0



0



0



0



Number with Live Foetuses



Sum



20



20



19



20



 


Table 4a. Uterine and implantation data - group mean values


 





















































































































Sex: Female



Group: 1
Control


0 mg/kg/day



Group: 2
Sodium Tungstate
40 mg/kg/day



Group: 3
Sodium Tungstate
80 mg/kg/day



Group: 4


Sodium Tungstate
160 mg/kg/day



Number with Foetuses



 



20



20



19



20



Number of Corpora Lutea#



Sum



275  R1



279



283



284



Mean



13.8  R1



14.0



14.9



14.2



SD



3.7



2.1



2.8



2.0



Number of Implantations#



Sum



259   R1



270



268



265



Mean



13.0  R1



13.5



14.1



13.3



SD



4.1



1.6



2.0



2.0



% Pre-implantation Loss #



Mean



6.1  R1



2.6



4.5



6.3



Number of Early Deaths



Sum



13



18



9



16



Mean



0.7



0.9



0.5



0.8



SD



1.0



0.7



0.7



1.1



Number of Late Deaths



Sum



0



0



0



0



Mean



0.0



0.0



0.0



0.0



SD



0.0



0.0



0.0



0.0



# [Statistically Analysed]


1 [R - Automatic Transformation: Rank]


 


Table 4b. Uterine and implantation data - group mean values (Continued)


 









































































Sex: Female



Group: 1
Control


0 mg/kg/day



Group: 2
Sodium Tungstate
40 mg/kg/day



Group: 3
Sodium Tungstate
80 mg/kg/day



Group: 4


Sodium Tungstate
160 mg/kg/day



Number of Dead Foetuses



Sum



0



0



0



0



Mean



0.0



0.0



0.0



0.0



SD



0.0



0.0



0.0



0.0



Number of Live Foetuses#



Sum



246   R1



252



259



249



Mean



12.3  R1



12.6



13.6



12.5



SD



4.0



1.8



2.3



2.2



% Post-implantation Loss #



Mean



4.6  R1



6.8



3.6



6.1



Mean % of Implantations



Mean



95.4



93.2



96.4



93.9



# [Statistically Analysed]


1 [R - Automatic Transformation: Rank]


 


Table 5. Litter weights (g) / foetal data - group mean values


 





























































































Sex: Female



Group: 1
Control


0 mg/kg/day



Group: 2
Sodium Tungstate
40 mg/kg/day



Group: 3
Sodium Tungstate
80 mg/kg/day



Group: 4


Sodium Tungstate
160 mg/kg/day



Number with Live Foetuses



 



20



20



19



20



No of Live Foetuses



Sum



246



252



259



249



No of Male Foetuses



Sum



133



145



141



114



No of Female Foetuses



Sum



113



107



118



135



% of Male Foetuses#



Mean



56.3 I1



57.3



54.8



44.3 W2



Litter Weight (g)#



Mean



46.66 R3     



47.85



51.40



46.15



Foetal Weight (M+F) (g)#



Mean



3.83 I1



3.80



3.77



3.70



Foetal Weight (M) (g)



Mean



3.93



3.88



3.88



3.82



Foetal Weight (F) (g)



Mean



3.65



3.68



3.67



3.60



Placental Weight (g)#



Mean



0.58 R3       



0.55



0.52



0.52



# [Statistically Analysed]


1 [I - Automatic Transformation: No Transformation]                                                


2 [W - Test: Williams 2 Sided p < 0.05]
3 [R - Automatic Transformation: Rank]


 


Table 6. Examination of foetuses - summary of group mean values



























































































Combined examination


(external/visceral/skeletal)



Group: 1 Control


0 mg/kg/day



Group: 2
Sodium Tungstate
40 mg/kg/day



Group: 3
Sodium Tungstate
80 mg/kg/day



Group: 4


Sodium Tungstate
160 mg/kg/day



 



Total number of litters examined



20



20



19



20



Total number of foetuses examined



246



252



259



249



Number with major abnormalities



1



1



1



0



Mean % of foetuses examined



0.4



0.5



0.5



0.5


 



Number of litters affected#



1



1



1



0



Number with minor abnormalities



56



74



75



81



Mean % of foetuses examined



23.2



30.1



28.4



33.1



Number of litters affected



19



20



19



20J



Number with variations



136



129



136



150



Mean % of foetuses examine



58.1



51.5



52.4



60.2



Number of litters affected#



20



20



19



20


Applicant's summary and conclusion

Conclusions:
Administration of sodium tungstate by oral gavage, once daily from Days 6 to 17 of gestation to Crl:CD(SD) rats at 40, 80 or 160 mg/kg/day was generally well tolerated. Maternal effects (initial body weight change) were evident at 160 mg/kg/day and minor foetal abnormalities were apparent at 80 or 160 mg/kg/day; however, these changes were considered not adverse.
Executive summary:

No fertility, reproductive, or developmental toxicity data of sufficient quality are available for tungsten dioxide (target substance). However, developmental toxicity data are available for sodium tungstate (source substance), which are used for read-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 in the Category section of this IUCLID submission or Annex 3 in the CSR.

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