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Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

No in vitro L5178Y TK +/- mouse lymphoma forward mutation assay data are available for WC (target substance). However, in vitro L5178Y TK +/- mouse lymphoma forward mutation assay data are available for W (source substance), which will be used for read across. Due to similar water solubility, in vitro bioaccessibility in synthetic alveolar, lysosomal, and interstitial fluids simulating inhalation exposure, and available toxicity data for the target and source substances, the resulting toxicity potential would also be expected to be similar, so read-across is appropriate between these substances. In addition, read-across is appropriate for this endpoint because the classification and labelling is the same for the source and target substances, the PBT/vPvB profile is the same, and the dose descriptors are, or are expected to be, sufficiently similar. For more details, refer to the attached description of the read-across approach. In addition, although not required under REACH because of the lack of mutagenicity observed in the available in vitro mutagenicity assays, an in vivo micronucleus assay was also used for read across to support the weight of evidence that WC is not a mutagen.

Short description of key information:

In an in vitro bacterial gene mutation assay conducted according to OECD 471, two in vitro chromosome aberration assays conducted according to OECD 473, and an in vitro micronucleus assay, WC was deemed to be negative for mutagenicity. No in vitro L5178Y TK +/- mouse lymphoma forward mutation assay data of sufficient quality are available for WC. However, in vitro L5178Y TK +/- mouse lymphoma forward mutation assay data are available for W and were negative for mutagenicity.

Link to relevant study records

Referenceopen allclose all

Endpoint:
in vitro cytogenicity / chromosome aberration study in mammalian cells
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2007-02-27 to 2008-01-23
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
The study was performed according to OECD guideline 473 with minor deviations that did not impact the validity of the study. GLP study.
Qualifier:
according to
Guideline:
OECD Guideline 473 (In Vitro Mammalian Chromosome Aberration Test)
Deviations:
yes
Remarks:
however none that would affect the validity of the study.
GLP compliance:
yes
Type of assay:
in vitro mammalian chromosome aberration test
Species / strain / cell type:
other: Chinese hamster lung (CHL) cells
Details on mammalian cell type (if applicable):
- Type and identity of media: McCoy's 5A medium supplemented with 10 % heat inactivated foetal calf serum and 100 ug/mL gentamycin
Metabolic activation:
with and without
Metabolic activation system:
Aroclor induced rat liver S9
Test concentrations with justification for top dose:
Experiment 1
- 3-hour treatment without S9: 125.0, 250.0, 375.0, 500.0, 625.0, 750.0, 875.0, 1000, 1500, 2000, 2500, 3000, 3750, 4500 and 4997 ug/mL
- 3-hour treatment with S9: 125.0, 250.0, 500.0, 750.0, 1000, 1250, 1500, 1750, 2000, 2250, 2500 and 3000 ug/mL

Experiment 2, Trial 1
- 20-hour treatment in the absence of S9: 50.0, 100.0, 200.0, 300.0, 400.0, 500.0, 600.0, 750.0, 900.0, 1100, 1250, 1500 and 2000 ug/mL
- 3-hour treatment in the presence of S9: 250.0, 500.0, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750 and 3000 ug/mL

Experiment 2, Trial 2
- 3 hour treatment in the presence of S9: 250.0, 500.0, 750.0, 900.0, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1800, 2000 and 2500 ug/mL
Vehicle / solvent:
- Vehicle(s)/solvent(s) used: McCoy's 5A culture medium.
- Justification for choice of solvent/vehicle: Preliminary solubility data indicated that the test substance formed a homogeneous suspension in the medium which was considered suitable for dosing, at concentrations up to approximately 5.26 mg/mL.
Untreated negative controls:
no
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Positive control substance:
4-nitroquinoline-N-oxide
Remarks:
without metabolic activation Migrated to IUCLID6: 0.25 and 0.30 ug/mL
Untreated negative controls:
no
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Positive control substance:
methylmethanesulfonate
Remarks:
without metabolic activation Migrated to IUCLID6: 12.50 and 25.00 ug/mL
Untreated negative controls:
no
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Positive control substance:
cyclophosphamide
Remarks:
with metabolic activation Migrated to IUCLID6: 6.25 and 12.50 ug/mL
Details on test system and experimental conditions:
METHOD OF APPLICATION: In medium

DURATION
- Exposure duration and Expression time (cells in growth medium): Experiment 1 was comprised of a 3 hour treatment + and -S9 followed by a 17 hour recovery period. Experiment 2 was comprised of a 3 hour treatment +S9 followed by a 17 hour recovery period, together with a continuous 20 hour treatment in the absence of S9. Approximately 1.5 hours prior to harvest (20 hours), colchicine was added to give a final concentration of approximately 1 ug/mL to arrest dividing cells in metaphase.
- Fixation time (start of exposure up to fixation or harvest of cells): Cells were harvested 20 hours after the beginning of treatment.

SPINDLE INHIBITOR (cytogenetic assays): Colchicine
STAIN (for cytogenetic assays): Giemsa

NUMBER OF REPLICATIONS: Quadruplicate cultures were treated with the vehicle and duplicate cultures were treated with the test substance and positive controls.

NUMBER OF CELLS EVALUATED: 100 metaphase spreads per slide where appropriate.

DETERMINATION OF CYTOTOXICITY
- Method: Population doubling relative to controls.

OTHER EXAMINATIONS:
- Determination of polyploidy: Yes
- Determination of endoreplication: Yes

SLIDE PREPARATION: Cells were kept in fixative at 1-10 degrees C before slides were made, but slides were not made on the day of harvest to ensure that cells were adequately fixed. Cells were centrifuged and resuspended in a minimal amount of fresh fixative (if required) to give a milky suspension.Several drops of 45 % (v/v) aqueous acetic acid were added to each suspension to enhance chromosome spreading, and several drops of suspension were transferred to clean microscope slides labeled with the appropriate study details. After the slides had dried, the cells were stained for 5 minutes in filtered 4 % (v/v) Giemsa in pH 6.8 buffer. The slides were rinsed, dried and mounted with coverslips.

SLIDE ANALYSIS: Slides from the positive controls were checked to ensure that the system was operating satisfactorily. Where appropriate, one hundred metaphases from each slide were analyzed for chromosome aberrations. Where 10 cells with structural aberrations (excluding gaps) were noted on a slide, analysis was terminated. Only cells with 23 to 27 (modal number +/- 2) chromosomes were considered acceptable for analysis. Any cells with more than 27 chromosome (polyploid, hyperdiploid or endoreduplicated cells) observed during the evaluation were recorded separately.
After completion of scoring and decoding of slides, the numbers of aberrant cells in each culture were categorized as follows:
1. Cells with structural aberrations including gaps.
2. Cells with structural aberrations excluding gaps.
3. Polyploid, endoreduplicated or hyperdiploid cells.
The totals for category 2 in the vehicle control cultures were compared with the current laboratory historical negative control (normal) ranges to determine whether the assay was acceptable or not. The totals for category 2 in the test substance treated cultures were also compared with normal ranges.
Evaluation criteria:
Evaluation Criteria- For a valid test, the test substance was considered to induce clastogenic events if:
1. A proportion of cells with structural aberrations at one or more concentrations that exceeded the normal range were observed in both replicate cultures.
2. A statistically significant increase in the proportion of cells with structural aberrations (excluding gaps) was observed (p<= 0.05).
3. There was a concentration-related trend in the proportion of cells with structural aberrations (excluding gaps).
- The test substance was considered positive in the assay if all the above criteria were met.
- The test substance was considered negative in the assay if none of the above criteria were met.
- Results which only partially satisfied the above criteria were dealt with on a case-by-case basis. Evidence of a concentrated-related effect was considered useful but not essential in the evaluation of a positive result. Biological relevance was taken into account, for example consistency of response within and between concentrations and (where appropriate) between experiments, or effects occurring only at high or very toxic concentrations, and the types and distribution of aberrations.
Statistics:
The statistical significance of increases in the percentage of cells with structural aberrations for any data set was only taken into consideration if the frequency of aberrant cells in both replicate cultures at one or more concentrations exceeded the normal range. The statistical method used was the Fisher's exact test. Probability values of p <= 0.058 were accepted as significant. The proportions of cells in categories 1 and 3 were examined in relation to normal ranges and may have been analyzed by Fisher's exact test.
Species / strain:
other: Chinese hamster lung (CHL) cells
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
cytotoxicity
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Additional information on results:
TEST-SPECIFIC CONFOUNDING FACTORS
- Precipitation: Range-finding assay - Precipitation was observed in the 3 hour treatment assays in the absence and presence of S9 at concentrations of 388.6 ug/mL and above. In the 20 hour exposure assay in the absence of S9, precipitation was observed at concentrations of 647.6 ug/mL and above.
Chromosome aberration assay - Precipitation was observed at all concentrations in the 3 and 20 hour treatment in the presence or absence of metabolic activation, except at the 50 ug/mL dose level in the 20 hour treatment assay in the absence of metabolic activation.

RANGE-FINDING/SCREENING STUDIES: The test substance was evaluated for toxicity (population doubling relative to controls) in a range-finding experiment at concentrations ranging from 18.13-4997 ug/mL in the presence and absence of metabolic activation. Duplicate cultures were treated with the vehicle and single cultures were treated with the test substance. Positive controls were not included. The experiment was comprised of a 3 hour treatment + and -S9 followed by a 17 hour recovery period, together with a continuous 20 hour treatment in the absence of S9.
1. 3 hour treatment in the absence of S9- Cytotoxicity ranged from 0-3 % at concentrations ranging from 18.13-647.6 ug/mL, and from 71-90 % at concentrations of 1079 ug/mL and above.
2. 3 hour treatment in the presence of S9-Cytotoxicity ranged from 0-4 % at concentrations ranging from 18.13-1079 ug/mL, and from 44-100 % at concentrations of 1799 ug/mL and above.
3. 20 hour treatment in the absence of S9-Cytotoxicity ranged from 0-1 % at concentrations ranging from 18.13-647.6 ug/mL, and from 23-99 % at concentrations of 1079 ug/mL and above.

COMPARISON WITH HISTORICAL CONTROL DATA: The proportion of cells with structural aberrations (excluding gaps) in the vehicle control cultures fell within the normal historical range. Treatment of cultures with the test substance in the absence and presence of S9 resulted in frequencies of cells with structural aberrations (excluding gaps) which were similar to those in observed concurrent vehicle control cultures in all assays. The numbers of aberrant cells (excluding gaps) in all test substance treated cultures fell within normal ranges.
No increases in the frequency of cells with numerical aberrations, which exceeded the concurrent controls and the normal range, were observed in cultures treated with the test substance in the absence and presence of S9.

ADDITIONAL INFORMATION ON CYTOTOXICITY:
Experiment 1
- 3-hour treatment in the absence of S9: Cytotoxicity levels ranged from 20-100 % at the concentrations originally tested (125-4997 ug/mL). The 125, 500, and 625 ug/mL cultures were chosen for chromosomal aberration analysis. Cytotoxicity levels at 125, 500 and 625 ug/mL were 20, 42, and 53 %, respectively.
- 3-hour treatment in the presence of S9: Cytotoxicity levels ranged from 10-72 % at the concentrations originally tested (125-3000 ug/mL). The 500, 1500 and 2500 ug/mL cultures were chosen for chromosomal aberration analysis. Cytotoxicity levels at 500, 1500 and 2500 ug/mL were 16, 30, and 56 %, respectively.

Experiment 2, Trial 1
- 20-hour treatment in the absence of S9: Cytotoxicity levels ranged from 12-100 % at the concentrations originally tested (50-2000 ug/mL). The 50, 200 and 300 ug/mL cultures were chosen for chromosomal aberration analysis. Cytotoxicity levels at 50, 200 and 300 ug/mL were 12, 43 and 52 %, respectively.
- 3-hour treatment in the presence of S9: Cytotoxicity levels ranged from 5-100 % at the concentrations originally tested (250-3000 ug/mL). Based on the steep concentrated related toxicity a second trial was run under this treatment condition, using a narrower concentration range with more closely spaced concentrations. This trial was not included in chromosomal aberration analysis.

Experiment 2, Trial 2
- 3 hour treatment in the presence of S9: Cytotoxicity levels ranged from 8-69 % at the concentrations orginally tested (250-2500 ug/mL). The 500, 1000, 1500 and 2500 ug/mL cultures were chosen for chromosomal aberration analysis. Cytotoxicity levels at 500, 1000, 1500 and 2500 ug/mL were 26, 14, 13 and 69 %, respectively.
Remarks on result:
other: all strains/cell types tested
Remarks:
Migrated from field 'Test system'.
Conclusions:
The test substance did not induce chromosome aberrations in cultured Chinese hamster lung (CHL) cells when tested to the limit of cytotoxicity in both the absence and presence of rat liver metabolic activation system (S9).
Endpoint:
in vitro gene mutation study in bacteria
Remarks:
Type of genotoxicity: gene mutation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Reliability assigned by the secondary source. Only the secondary source reviewed.
Qualifier:
according to
Guideline:
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
GLP compliance:
yes
Type of assay:
bacterial reverse mutation assay
Species / strain / cell type:
S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
Species / strain / cell type:
E. coli WP2 uvr A pKM 101
Metabolic activation:
with and without
Metabolic activation system:
Aroclor induced rat liver S9 mix
Test concentrations with justification for top dose:
5, 15, 50, 150, 500, 1500, 5000 µg/plate
Untreated negative controls:
yes
Positive controls:
yes
Details on test system and experimental conditions:
Type: Ames test
METHOD OF APPLICATION: 2 independent assays were performed: range finding (standard plate incorporation) and repeat (including a pre-incubation stage)

Statistics:
no data
Species / strain:
S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Positive controls validity:
valid
Species / strain:
E. coli WP2 uvr A pKM 101
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Positive controls validity:
valid
Additional information on results:
No signs of toxicity were noted toward any of the tested strains at any dose. No substantial increase in revertant colony numbers over control counts were obtained with any of the tester strains at any tungsten carbide concentration in either the presence or the absence of S9 mix. The positive controls were functional.
Conclusions:
Interpretation of results (migrated information):
negative
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Genetic toxicity in vivo

Description of key information

In addition, sodium tungstate was negative for mutagenicity in an in vivo micronucleus assay conducted according to OECD 474. Based on the lack of mutagenicity reported in the overwhelming majority of in vitro assays, as well as in the in vivo micronucleus assay, WC is not considered a mutagen.

Link to relevant study records
Reference
Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
2003-07-16 to 2004-01-06
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
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 Carbide
3. CATEGORY APPROACH JUSTIFICATION: See Annex 1 in CSR
4. DATA MATRIX: See Annex 1 in CSR
Reason / purpose:
read-across: supporting information
Qualifier:
according to
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
Deviations:
no
GLP compliance:
yes
Type of assay:
micronucleus assay
Species:
mouse
Strain:
other: Crl:CD-1 (ICR)BR
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Portage MI
- Age at study initiation: 9 weeks at time of dosing
- Weight at study initiation: 30.3 to 37.9 grams at the time of dosing
- Assigned to test groups randomly: yes, by a computer program
- Housing: The animals were housed in sanitary polycarbonate cages containing Sani-Chips Hardwood Chip Laboratory bedding. The animals were housed, separated by gender, up to five animals per cage during acclimation, and by full dose group/harvest timepoint after randomization.
- Diet: PMI Feeds, Inc. Certified Rodent Diet #5002 ad libitum
- Water: tap water ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature: 64-79 degrees F
- Humidity: 30-70%
- Air changes: at least 10 per hour
- Photoperiod: 12 hours light/12 hours dark


IN-LIFE DATES: From: 2003-08-25 and 2003-08-26
Route of administration:
oral: gavage
Vehicle:
- Vehicle(s)/solvent(s) used: corn oil
- Concentration of test material in vehicle: 25, 50, and 100 mg/ml for initial test and 75 mg/ml for repeat test
- Amount of vehicle (if gavage or dermal): 10 ml/kg
- Lot/batch no. (if required): 12-406
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Prior to dosing, each concentration of the test substance was prepared by adding the appropriate volume of the vehicle to a pre-weighed quantity of the test substance and mixing, forming homogeneous suspensions. The formulations were held at room temperature prior to dosing and stirred during the dosing procedure.

Duration of treatment / exposure:
Animals received a single oral gavage dose of the test substance.
Frequency of treatment:
Animals received a single oral gavage dose of the test substance.
Post exposure period:
24 hours (all dose groups) and 48 hours (vehicle control, positive control, 750 mg/kg and 1000 mg/kg groups only)
Remarks:
Doses / Concentrations:
250, 500, and 1000 mg/kg
Basis:
actual ingested
initial assay
Remarks:
Doses / Concentrations:
750 mg/kg
Basis:
actual ingested
repeat assay
No. of animals per sex per dose:
6 male animals/dose/time point (only 5 animals/dose/time point were used for the actual analysis)
Control animals:
yes, concurrent vehicle
Positive control(s):
Cyclophosphamide
- Route of administration: oral gavage
- Doses / concentrations: 80 mg/kg
Tissues and cell types examined:
erythrocytes (bone marrow)
Details of tissue and slide preparation:
CRITERIA FOR DOSE SELECTION: The high dose in the micronucleus assay was the maximum tolerated dose determined by the range-finding study. This dose should have produced some indication of toxicity, e.g., toxic signs, death, or depression of the ratio of PCEs to normochromatic erythrocytes (NCEs).


TREATMENT AND SAMPLING TIMES: 24 and 48 hours (vehicle and high dose group only


DETAILS OF SLIDE PREPARATION: At the appropriate harvest timepoint, the animals were euthanized by CO2 inhalation followed by incision of the diaphragm. The hind limb bones (tibias) were removed from marrow extraction from five surviving animals in each treatment and control group. For each animal, the marrow flushed from the bones was combined in an individual centrifuge tube containing 3 to 5 ml fetal bovine serum.
Following centrifugation to pellet the tissue, the supernatant was removed by aspiration and portions of the pellet were spread on slides and air-dried. The slides were fixed in methanol, stained in May-Grunswald solution followed by Giemsa, and protected by permanently mounted coverslips.


METHOD OF ANALYSIS: The slides were scored for micronuclei and the PCE to NCE cell ratio. The micronucleus frequency (expressed as percent micronucleated cells) was determined by analyzing the number of micronucleated PCEs from at least 2000 PCEs per animal. The PCE:NCE ratio was determined by scoring the number of PCEs and NCEs observed while scoring at least the first 500 erythrocytes per animal.
Micronuclei were darkly stained and generally round, although almond and ring shaped micronuclei occasionally occurred. Micronuclei were sharp bordered and generally between one-twentieth and one-fifth the size of the PCEs. The unit of scoring was the micronucleated cell, not the micronucleus; thus, the occasional cells with more than one micronucleus was counted as one micronucleated PCE, not two (or more) micronuclei.
The staining procedure permitted the differentiation by color of PCEs and NCEs (bluish-gray and red, respectively).
The historical background frequency of micronucleated cells was expressed as the percentage of micronucleated cells based on the number of PCEs analyzed.


Evaluation criteria:
The criteria for a positive response were the detection of a statistically significant increase in micronucleated PCEs for at least one dose level, and a statistically significant dose-related response. If both of these were not present, than the result was negative. Statistical significance was not the only determinate of a positive response; the Study Director also considered the biological relevance of the results in the final evaluation.
Statistics:
Assay data analysis was performed using an analysis of variance on untransformed proportions of cells with micronuclei per animal and on untransformed PCE:NCE ratios when the variances were homogenous. Ranked proportions were used for heterogeneous variances. If the analysis of variance was statistically significant (p<=0.05), a Dunnett's t-test was used to determine which dose groups, if any, were statistically significantly different from the vehicle control. Analyses were performed separately for each sampling time.
Sex:
male
Genotoxicity:
negative
Toxicity:
yes
Vehicle controls validity:
valid
Negative controls validity:
not applicable
Positive controls validity:
valid
Additional information on results:
RESULTS OF RANGE-FINDING STUDY
- Dose range: 500-2000 mg/kg
- Clinical signs of toxicity in test animals: Clinical signs included slightly hypoactive, soft feces, rough haircoat, recumbent, cold to touch, opaque eyes, and hypoactive.
- Harvest times: Animals were analyzed at 1 hour, 4 hours, 6 hours, 1 day, and 2 days after dosing.
- High dose with and without activation: 2000 mg/kg
- Other: 3 males and 3 females per group were used in this study, but since no relevant differences in toxicity between the sexes were observed, only males were used in the micronucleus assay. Two males and 1 female died in the 1500 mg/kg group, and 3 males and 2 females in the 2000 mg/kg died. Based on these results, the maximum tolerated dose was estimated to be 1000 mg/kg.


RESULTS OF DEFINITIVE STUDY
- Induction of micronuclei (for Micronucleus assay): The test substance did not induce any statistically significant increases in micronucleated PCEs at any dose level examined (250, 500, and 750 mg/kg). The vehicle control group had less than approximately 0.4% micronucleated PCEs and the group mean was within the historical control range. The positive control induced a statistically significant increase in micronucleated PCEs as compared to that of the vehicle control, with means and standard errors of 3.95 +/- 0.33 % and 2.37 +/- 0.32 %, for the initial and repeat micronucleus assays, respectively.
- Ratio of PCE/NCE (for Micronucleus assay): The test substance was not cytotoxic to the bone marrow (i.e., no statistically significant decrease in the PCE:NCE ratio) at any dose level of the test substance.

Toxic Signs: Toxic signs were observed at the 1000 mg/kg dose level including soft feces, hypoactivity, rough haircoat and death at both the 24 and 48 hour timepoints (5 out of 12 died). Based on the high mortality rate, the rest of the animals in this group were euthanized and the bone marrow was not analyzed. One animal at the 500 mg/kg dose developed soft feces, and animals at the 750 mg/kg dose level developed soft feces, hypoactivity, rough haircoats, irregular respiration, and/or recumbency. In addition, one animal died in the 750 mg/kg group.

Conclusions:
The test substance was reported as negative in the mouse bone marrow micronucleus assay, under the conditions of this study.
Executive summary:

No genetic toxicity in vivo of sufficient quality are available for tungsten carbide (target substance). However, genetic toxicity in vivo 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..

Additional information

Justification for classification or non-classification

The in vitro bacterial reverse gene mutation assay, in vitro chromosome aberration assays, and in vitro micronucleus assay of sufficient quality on WC were negative for mutagenicity. In addition, an in vitro L5178Y TK +/- mouse lymphoma forward mutation assay conducted on W and an in vivo micronucleus assay conducted on sodium tungstate dihydrate, used for read across to WC, were negative for mutagenicity. Therefore, based on the weight-of-evidence (WoE) from the available data, WC does not warrant classification for mutagenicity.