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Endpoint:
toxicity to birds, other
Remarks:
dietary toxicity test
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Remarks:
Not enough information to assess the quality of the study. Lacking detail on husbandry, housing, dosing accuracy, and statistical analysis. Due to similar or lower transformation/dissolution results for the target substance than the source substance, the resulting toxicity potential would also be expected to be similar or lower, so read-across is appropriate. In addition, read-across is justified because the classification and labelling is the same or less severe for the target substance PBT/vPvB profile is the same. Finally, the dose descriptors are, or are expected to be, sufficiently similar or higher for the target substance, and read-across to the source chemical is adequately protective. For more details refer to the attached description of the read across approach.
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 Dioxide
3. CATEGORY APPROACH JUSTIFICATION: See Annex 1 in CSR
4. DATA MATRIX: See Annex 1 in CSR
Reason / purpose:
read-across: supporting information
Qualifier:
no guideline followed
Principles of method if other than guideline:
Hens were fed the test substance, and xanthine dehydrogenase levels were monitored in the tissues. Chicks from eggs laid by these birds were then used in growth tests where they were fed additional test substance or not. These chicks were compared to chicks whose hens had not been fed the test substance. Xanthine dehydrogenase levels were monitored in the tissues of the chicks as well.
GLP compliance:
no
Dose method:
feed
Analytical monitoring:
no
Vehicle:
not specified
Details on preparation and analysis of diet:
Breeder ration supplement with 250 ppm tungsten, as sodium tungstate.
Test organisms (species):
other: Breeder hens, (WPC)
Details on test organisms:
TEST ORGANISM
- Common name: Breeder hens
- Sexes used: Females, with adequate males to ensure maximum fertility
Limit test:
no
Total exposure duration (if not bolus):
4 wk
Remarks:
Hens fed tungsten for 30 days prior to setting and hatching eggs.
Post exposure observation period:
None
No. of animals per sex per dose and/or stage:
Experiment 1- Controls-65 hens, Treated-95 hens
Experiment 2, Trial 1- 40 chicks treated, (20 from treated hens, 20 from control); 40 chicks not treated (20 from treated hens, 20 from control)
Experiment 2, Trial 2- 52 chicks treated (26 from treated hens, 26 from control) 40 chicks not treated (26 from treated hens, 26 from control)
Control animals:
yes, plain diet
Nominal and measured doses / concentrations:
Experiment 1-Hens-First 10 days, 250 ppm test substance, the next 20 days, 500 ppm test substance.
Experiment 2, Trial 1 -Chicks, 500 ppm test substance, 4 weeks (breeder ration)
Experiment 2, Trial 2-Chicks, 500 ppm test substance, 24 days (broiler ration)
Details on test conditions:
-No information on adult hen conditions.
-Chicks were reared in starter-type battery brooders equipped with wire screen floors.
-Chicks were fed food and water ad libitum.
-Weekly chick weights and individual gain and feed conversion data were collected.
Details on examinations and observations:
n/a
Details on reproductive parameters:
n/a
Reference substance (positive control):
no
Duration (if not bolus):
30 d
Dose descriptor:
LOEC
Effect level:
500 mg/kg diet
Conc. / dose based on:
test mat.
Basis for effect:
other: decline in xanthine dehydrogenase activity
Duration (if not bolus):
10 d
Dose descriptor:
NOEC
Effect level:
250 mg/kg diet
Conc. / dose based on:
test mat.
Basis for effect:
other: decline in xanthine dehydrogenase activity
Duration (if not bolus):
30 d
Dose descriptor:
NOEC
Effect level:
500 mg/kg diet
Conc. / dose based on:
test mat.
Basis for effect:
other: egg production and hatchability
Duration (if not bolus):
4 wk
Dose descriptor:
LOEC
Effect level:
500 mg/kg diet
Conc. / dose based on:
test mat.
Basis for effect:
other: feed conversion and growth depression
Mortality and sub-lethal effects:
No mortality was reported
Reported statistics and error estimates:
Analysis of variance was used to compare results within the same experiment.

Test Results:

Experiment 1

- The addition of 250 ppm sodium tungstate had little or no effect on the xanthine dehydrogenase activity of the hen tissues tested.

- 500 ppm tungsten caused a steady decline in xanthine dehydrogenase activity, which appeared to stabilize around 30 days.

- Neither level of sodium tungstate had an apparent effect on the rate of egg production or hatchability.

Experiment 2, Trial 1 and Trial 2

-Day old chicks from hens fed tungstate had significantly higher amounts of xanthine dehydrogenase in the liver and intestine than did chicks from hens receiving no tungstate.

- Chicks from hens fed the tungsten-supplemented ration grew at a significantly slower rate than did the control chicks on both the breeder ration and the broiler ration.

- When the chick ration was supplemented with 500 ppm tungsten, a slower rate of gain was observed when compared to rations containing no supplementation.

- At four weeks of age, there appeared to be no difference in the xanthine dehydrogenase activities between the chicks, regardless of the ration fed or the hen treatment

-The variation that occurred in the enzyme determinations was large, and the sample size relatively small. This may have accounted for there being no statistical differences.

Conclusions:
Chicks from hens fed a sodium tungstate supplemented ration grew at a significantly slower rate than controls. Chicks fed sodium tungstate grew at a slower rate than chicks who were not fed the test substance. 500 ppm test substance did not apear to effect egg production or hatchability.
Executive summary:

No toxicity to birds data of sufficient quality were available specifically on tungsten dioxide (target substance). However, toxicity to birds data is available on sodium tungstate (source substance), which will be used for reading across. Due to similar 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, conservative for the target 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.

Endpoint:
toxicity to birds, other
Remarks:
dietary toxicity test
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Study period:
N/A
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Remarks:
Non-standard study with insufficient information provided on methods to adequately evaluate data. Due to similar or lower transformation/dissolution results for the target substance than the source substance, the resulting toxicity potential would also be expected to be similar or lower, so read-across is appropriate. In addition, read-across is justified because the classification and labelling is the same or less severe for the target substance PBT/vPvB profile is the same. Finally, the dose descriptors are, or are expected to be, sufficiently similar or higher for the target substance, and read-across to the source chemical is adequately protective. For more details refer to the attached description of the read across approach.
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 DIoxide
3. CATEGORY APPROACH JUSTIFICATION: See Annex 1 in CSR
4. DATA MATRIX: See Annex 1 in CSR
Reason / purpose:
read-across: supporting information
Qualifier:
no guideline available
Principles of method if other than guideline:
Chicks were fed varying amount of tungsten as sodium tungstate in the diet. Growth effects and xanthine dehydrogenase activity were monitored over 6 weeks.
GLP compliance:
no
Specific details on test material used for the study:
Details on properties of test surrogate or analogue material (migrated information):
N/A
Dose method:
feed
Analytical monitoring:
no
Vehicle:
no
Details on preparation and analysis of diet:
DIET PREPARATION
- Description and nutrient analysis of basal diet provided in study report: yes
- Preparation of doses: No details
Test organisms (species):
other: White Leghorn Chicks (Genus and species not provided)
Details on test organisms:
TEST ORGANISM
- Common name: White Leghorns
- Age at test initiation (mean and range, SD): 1 day old
- Weight at test initiation (mean and range, SD): 40-44 g average
- Sexes used: mixed
Limit test:
no
Total exposure duration (if not bolus):
6 wk
Post exposure observation period:
None
No. of animals per sex per dose and/or stage:
9 groups total, 29 chicks each in groups 4 and 8; 22 chicks each in all other groups. Group 1 is the control. See Table 1, below
Control animals:
yes, plain diet
Nominal and measured doses / concentrations:
Groups 1, 2- no tungsten. Group 1 starter mash diet
Groups 4- 45mg/kg tungsten.
Groups 8 - 94 mg/kg tungsten; See Table 1, below.
Details on test conditions:
NO. OF BIRDS PER REPLICATE
- For negative control: 22 or 29
- For treated: 22 or 29


NO. OF REPLICATES PER GROUP
- For negative control: 1
- For treated: 1


Details on examinations and observations:
N/A
Details on reproductive parameters:
N/A
Reference substance (positive control):
no
Key result
Duration (if not bolus):
5 wk
Dose descriptor:
LOEC
Effect level:
45 mg/kg diet
Conc. / dose based on:
test mat.
Basis for effect:
other: decrease in xanthine dehydrogenase and molybdenum concentrations; body weight
Repellency factors (if applicable):
N/A
Mortality and sub-lethal effects:
Mortality- 3 weeks
Group 4-14%
Group 8-24%


Mortality- 5 weeks
Group 4-24%
Group 8-28%
Effects on reproduction:
N/A
Results with reference substance (positive control):
N/A
Further details on results:
See below

Results

Table 2. Effects of diets containing W on growth and xanthine dehydrogenase activities of chicks.

Xanthine dehydrogenase activity (mm302/20 min/flask), week 6

 Group Body wt. 3 wks (g)  Body wt. 5 wks (g)  intestine  liver  kidney  pancreas
 1  218 343   8  32  11  6
 2  217  311  8  32  12  4
 4  169  311  1  4  1  1
 8  149  274  1  3  2  2

XD levels measured after 6 weeks on the diets, using 28.3 mg liver or kidney, and 84.9 mg intestine or pancreas per flask.

- After 3 weeks, 6 chicks from Groups 8 (94 mg/kg W) were sacrificed, and analyzed for Xanthine dehydrogenase and Mo.

- The mean values for intestine, liver, kidney, and pancreas were 0.4, 2.2, 0.2, and 0.8 mm3O2/20 min. respectively for Group 8 (avg Mo 0.20 ug/g dry wt)

- Therefore, within 3 weeks, the addition of 94 mg/kg to the diet markedly depressed tissue Mo and XD activities.

- After 6 weeks, half of the uric acid normally produced by chicks was replaced by a mixture of xanthine and hypoxanthine in Group 8.

Conclusions:
Molybdenum deficiency in chicks can be induced by the addition of tungsten to the diet. At high levels, this can reduce growth rate, and markedly depletes tissue xanthine dehydrogenase and molybdenum levels.
Executive summary:

No toxicity to birds data of sufficient quality were available specifically on tungsten dioxide (target substance). However, toxicity to birds data is available on sodium tungstate (source substance), which will be used for reading across. Due to similar 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, conservative for the target 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.

Endpoint:
toxicity to birds, other
Remarks:
dietary toxicity test
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Remarks:
Insufficient information provided on methods to accurately evaluate the study. Due to similar or lower transformation/dissolution results for the target substance than the source substance, the resulting toxicity potential would also be expected to be similar or lower, so read-across is appropriate. In addition, read-across is justified because the classification and labelling is the same or less severe for the target substance PBT/vPvB profile is the same. Finally, the dose descriptors are, or are expected to be, sufficiently similar or higher for the target substance, and read-across to the source chemical is adequately protective. For more details refer to the attached description of the read across approach.
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 Dioxide
3. CATEGORY APPROACH JUSTIFICATION: See Annex 1 in CSR
4. DATA MATRIX: See Annex 1 in CSR
Reason / purpose:
read-across: supporting information
Principles of method if other than guideline:
Enzymatic liver enzyme activity was measured after feeding the birds a tungsten supplemented diet.
GLP compliance:
not specified
Specific details on test material used for the study:
Details on properties of test surrogate or analogue material (migrated information):
no data
Dose method:
feed
Analytical monitoring:
not specified
Vehicle:
not specified
Details on preparation and analysis of diet:
Experiment 1: Proprietary diet containing (per kg): 218 g protein, 0.5 mg molybdenum and 0.6 mg tungsten without addition, or with supplements of either 500 or 1000 mg tungsten/kg.
Experiment 2: Fed on a glucose-casein diet of low molybdenum content (<0.02 mg/kg) for 15 d. Then allocated to one of two dietary treatments: 1. low molybdenum control diet, 2. control diet supplemented with 150 mg tungsten/kg from day 1 and 600 mg tungsten mg tungsten/kg from day 22
Test organisms (species):
other: Broiler cockerels
Details on test organisms:
TEST ORGANISM
- Common name: Broiler cockerels (chicken)
- Source: commercial hatchery
- Age at test initiation (mean and range, SD): obtained at 1 d of age

Limit test:
no
Total exposure duration (if not bolus):
35 d
Remarks:
several studies were conducted with varying exposure times, one at least 35 days
No. of animals per sex per dose and/or stage:
Experiment 2: Sixty broiler cockerels
Experiment 3: One hundred and twenty broiler cockerels
Control animals:
other: low molybdenum control diet
Nominal and measured doses / concentrations:
No data
Details on test conditions:
Experiment 1:
Sixty broiler cockerels were randomly distributed into three groups which were fed on a proprietary diet containing (per kg): 218 g protein, 0.5 mg molybdenum and 0.6 mg tungsten without addition, or with supplements of either 500 or 1000 mg tungsten/kg. The birds in each treatment were randomly subdivided into two groups and fed on the respective diets with or without a supplement of 4.0 mg molybdenum/kg diet.

Experiment 2:
One hundred and twenty broiler cockerels were fed on a glucose-casein diet of low molybdenum content (<0.02 mg/kg) for 15 d. The chicks were then allocated randomly to one of two dietary treatments:
1. the low-molybdenum control diet fed throughout the experiment.
2. the control diet supplemented with 150 mg tungsten/kg from day 1 and 600 mg tungsten/kg from day 22.
Details on examinations and observations:
Experiment 1:
At 28 d of age four birds were randomly selected from each treatment and killed.

The livers were rapidly excised and analysed for tungsten, molybdenum and xanthine dehydrogenase activity.

Experiment 2:
Four chickens from each treatment were randomly selected and killed on days 1, 2, 4, 7, 11, 16, 21, 28 and 35. After killing, the intestines and livers were rapidly removed. The intestines were extruded and washed and samples from the upper jejunum taken for further analyses. The liver samples were analysed for tungsten, molybdenum and xanthine dehydrogenase activity and the intestinal samples were analysed for xanthine dehydrogenase activity. Blood samples were also taken from the chickens of the control and supplementary dietary tungsten treatments killed on day 35. These were analysed for tungsten, molybdenum, hemoglobin, uric acid and xanthine plus hypoxanthine.
Details on reproductive parameters:
no data
Reference substance (positive control):
no
Key result
Duration (if not bolus):
28 d
Dose descriptor:
LOEC
Effect level:
1 000 mg/kg diet
Conc. / dose based on:
act. ingr.
Basis for effect:
other: reduced liver xanthine dehydrogenase activities
Key result
Duration (if not bolus):
28 d
Dose descriptor:
NOEC
Effect level:
ca. 500 mg/kg diet
Conc. / dose based on:
act. ingr.
Basis for effect:
other: reduced liver xanthine dehydrogenase activities
Mortality and sub-lethal effects:
Experiment 1:
No birds died during this experiment. There was no mortality in this experiment. Supplementation of the diet with 1 g tungsten/kg significantly (P<0.01) increased liver tungsten concentrations in birds receiving no additional molybdenum. Liver xanthine dehydrogenase activities were significantly (P< 0.001) reduced in birds receiving the high dietary concentration of tungsten with no molybdenum supplement but the effect was abolished when additional molybdenum was fed.

Experiment 2:
No birds died form either dietary treatment during this experiment. By day 28 the mean body-weight gains of the eight birds remaining on the control and dietary tungsten tungsten treatments were respectively 1 000 and 864 g.

Both liver and intestinal xanthine dehydrogenase activities decreased with increasing liver tungsten concentrations. This decline in enzyme activity occurred at approximately the same rate in both tungsten treatments. Extrapolation of the data indicated that zero activity occurred in both tissues at a
tungsten concentration of approximately 25 ug/g liver.

The blood molybdenum concentrations of the control and tungsten-fed birds on day 35 were respectively 0.06 and 0.02 ug/mL, but this difference did not attain statistical significance. The blood tungsten concentrations of these groups of birds at this time were 0.1 and 15.4 ug/mL respectively and these were significantly different (P< 0.001). The plasma xanthine plus hypoxanthine concentrations in the birds on the
control and supplementary dietary tungsten treatments on day 35 were 0.5 and 12.9 mg/100 mL respectively (P<0.01). The plasma uric acid concentrations were 2.0 and 6.2 mg/100 mL respectively (P< 0.001). The mean hemoglobin concentrations of birds on these treatments were similar at 9.4 and 9.6 mg/100 mL blood respectively.
Effects on reproduction:
no data
Results with reference substance (positive control):
n/a
Reported statistics and error estimates:
Experiment 1:
The data were analysed by analysis of variance.

Experiment 2:
The data were analysed by analysis of variance. Each day's data were analysed separately because of the changes in the doses of tungsten administered to the birds. Regression analyses relating intestinal and hepatic xanthine dehydrogenase activities to liver tungsten concentrations were also conducted.

Liver molybdenum concentrations and the activity of liver xanthine dehydrogenase were markedly reduced only when the tungsten concentration of tissues approached this high concentration.

The proportion of the liver molybdenum contributing to the xanthine dehydrogenase enzyme was calculated for experiment 2 from the known specific activity of highly purified extracts of this enzyme from chicken and turkey liver These calculations indicated that at normal liver molybdenum concentrations approximately 37% of the liver molybdenum was bound to xanthine dehydrogenase, while at the lowest molybdenum concentrations observed prior to death (seen in injection groups only) only approximately 7% of the liver molybdenum was bound to the enzyme. This would suggest that these chicks were affected primarily by a tungsten toxicity rather than by a simple molybdenum deficiency.

Conclusions:
Liver xanthine dehydrogenase activities were significantly (P< 0.001) reduced in birds receiving the high dietary concentration (1000 mg/kg diet) of tungsten
Executive summary:

No toxicity to birds data of sufficient quality were available specifically on tungtsen dioxide (target substance). However, toxicity to birds data is available on sodium tungstate (source substance), which will be used for reading across. Due to similar 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, conservative for the target 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.

Description of key information

Several older studies on chicken species were identified in which the birds were fed varying amounts of tungsten, in the form of sodium tungstate in their diets.  The NOAELs identified from these studies ranged from approximately 45-500 mg tungsten/kg, depending on which endpoints were examined in each study.  However, none of these studies were conducted with standard methodology and they were deemed to be less than reliable.

Key value for chemical safety assessment

Short-term EC50 or LC50 for birds:
45 mg/kg food

Additional information

Due to similar or lower transformation/dissolution results for tungsten dioxide (the target substance) than sodium tungstate (the source substance), the resulting toxicity potential would also be expected to be similar or lower, so read-across is appropriate. Therefore, the dose descriptors are expected to be sufficiently similar or higher for the target substance, and read-across to the source chemical is adequately protective. For more details refer to the attached description of the read-across approach.