Tungsten trioxide

Developmental toxicity / teratogenicity

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 trioxide
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

Test material information

Constituent 1

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 / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day

Remarks:

Vehicle control

Doses / concentrations 2

Dose / conc.:

40 mg/kg bw/day (actual dose received)

Doses / concentrations 3

Dose / conc.:

80 mg/kg bw/day (actual dose received)

Doses / concentrations 4

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)

1

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

2

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)

1

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

2

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 trioxide (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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