Ammonium trioxovanadate

Endpoint summary

Description of key information

Ammonium trioxovanadate is toxic via ingestion and harmful by inhalation, but not via the dermal route.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1991-12-11 to 1992-01-27

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

signed 1991-07-25

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS - Sprague-Dawley, Tif:RAI f (SPF)
- Source: Lippische Versuchstierzucht, HAGEMANN GmbH, D-4923 Extertal 1
- Age at study initiation: approximately. 40 - 60 days
- Weight at study initiation: 159 - 199 g
- Fasting period before study: feeding was discontinued approximately 16 hours before administration. Only tap water was offered ad libitum.
- Housing: granulated textured wood was used as bedding material for the cages (Granulat Typ A2, supplier: Messrs. BRANDENBURG, Inh. H. Brandenburg, D-2849 Goldenstedt). During the observation period, surviving animals were kept in groups of 2 - 3 animals in MAKROLON cages (type III).
- Diet: standardized diet for rats and mice ALTROMIN 1324 (supplied by: ALTROMIN GmbH, D-4937 Lage/Lippe)
- Water (ad libitum): tap water
- Quarantine period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22°C ± 3°C (maximum range)
- Relative humidity: 60% ± 20% (maximum range)
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

other: 0.8% aqueous hydroxypropyl-methylcellulose gel

Details on oral exposure:

VEHICLE
- Batch no.: MM 84097413B

MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg bw (dose interval factor: 2.15)

DOSAGE PREPARATION: Ammonium metavanadate was suspended in 0.8% aqueous hydroxypropyl-methylcellulose gel.

Doses:

male and female rats: 100, 215, and 464 mg/kg bw
female rats only: 46.4 mg/kg bw

No. of animals per sex per dose:

5 males / 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations were performed immediately, 5, 15, 30 and 60 minutes, as well as 3 hours, 6 hours and 24 hours after administration. During the follow-up period, changes of skin and fur, eyes and mucous membranes, respiratory and circulatory, autonomic and central nervous system and somatomotor activity as well as behaviour pattern were observed at least once a day until all symptoms subsided, and thereafter each working day. Attention was also paid to possible tremor, convulsions, salivation, diarrhoea, lethargy, sleep and coma. Observations on mortality were made at least once daily with appropriate actions taken to minimise loss of animals during the study. Individual body weights were recorded before administration of the substance, thereafter in weekly intervals up to the end of the study, and at death. Changes in weight were calculated and recorded when survival exceeds one day.
- Necropsy of survivors performed: yes; at the end of the experiments all surviving animals were sacrificed dissected and inspected macroscopically. All gross pathological changes were recorded. from animals which survived 24 hours or longer a microscopic examination of all organs which show evident lesions is performed. Autopsy and macroscopic inspection of rats which died prematurely were carried out as soon as possible after exitus.

Statistics:

The LD50 was calculated by regression analysis and probit analysis (FINNEY). The mortality rates at 24 hours ad at 14 days were used.

Sex:

male

Dose descriptor:

LD50

Effect level:

218.1 mg/kg bw

Based on:

test mat.

Remarks on result:

other: LD50 after 14 days; Slope: 14.98

Sex:

female

Dose descriptor:

LD50

Effect level:

141.4 mg/kg bw

Based on:

test mat.

Remarks on result:

other: LD50 after 14 days; Slope: 9.32

Sex:

male/female

Dose descriptor:

LD50

Effect level:

169.33 mg/kg bw

Based on:

test mat.

95% CL:

126.86 - 226.03

Remarks on result:

other: LD50 after 14 days; Slope: 4.52

Sex:

male

Dose descriptor:

LD50

Effect level:

371.1 mg/kg bw

Based on:

test mat.

Remarks on result:

other: LD50 after 24 hours; Slope: 7.86

Sex:

female

Dose descriptor:

LD50

Effect level:

212.48 mg/kg bw

Based on:

test mat.

Remarks on result:

other: LD50 after 24 hours: Slope: 14.98

Sex:

male/female

Dose descriptor:

LD50

Effect level:

275.87 mg/kg bw

Based on:

test mat.

95% CL:

203.71 - 373.57

Remarks on result:

other: LD50 after 24 hours; Slope: 4.36

Mortality:

46.4 mg/kg bw: none
100 mg/kg bw: 2 females (day 3)
215 mg/kg bw: 2 males (24 hours - day 4)/ 4 females (24 hours - day 3)
464 mg/kg bw: 5 males (4 hours - day 4) / 5 females (70 minutes - 24 hours)

Clinical signs:

other: Male rats: 46.4 mg/kg bw: none 100 mg/kg bw: none 215 mg/kg bw: slight/moderate reduced motility (3 hours - day 2; 5 males); slight/moderate ataxia (3 hours - day 2; 5 males); slight/moderate dyspnoea (3 hours - day 2; 5 males); moderate muscular hypotoni

Gross pathology:

Animals that died prematurely:
215 mg/kg bw: 1/2 males and 3/4 females had reddened intestinal mucosa
464 mg/kg bw: 4/5 males had (severely) dark liver and reddened intestinal mucosa; 5/5 females had severely dark liver and (severely) reddened intestinal mucosa
All further deceased animals showed no pathological findings.
Surviving animals (sacrificed) (male and female):
no pathological findings

Interpretation of results:

Toxicity Category III

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

LD50 (male rats) = 218.07 mg/kg bw
LD50 (female rats) = 141.43 mg/kg bw
LD50 (male and female rats) = 169.33 mg/kg bw (CL: 126.86 - 226.03 mg/kg bw)
The lowest lethal dose was 215 mg/kg bw (males) and 100 mg/kg bw (females), the no-effect level was 100 mg/kg bw (males) and 46.4 mg/kg bw (females).
According to the EC-Commission directive 67/548/EEC and its subsequent amendments, the test substance is classified as toxic if swallowed.
According to the EC-Regulation 1272/2008 and subsequent regulations, the test item is classified as Category 3.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

141.4 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1992-01-13 to 1992-02-11

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

signed 1991-07-25

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS - Sprague-Dawley/ Tif:RAI f (SPF)
- Source: Lippische Versuchstierzucht, HAGEMANN GmbH, D-4923 Extertal 1
- Age at study initiation: approximately. 40 - 60 days
- Weight at study initiation: males: 186 - 313 g; females: 175 - 215 g
- Fasting period before study: food was discontinued approximately 16 hours before exposition.
- Housing: granulated textured wood (type 2, supplied by: Johannes Brandenburg, D-2849 Goldenstedt) was used as bedding material. During the 14- day observation period, the animals were kept in groups of two or three in MAKROLON cages (type III).
- Diet (ad libitum): standardized diet for rats ALTROMIN 1324 (supplied by: ALTROMIN GmbH, D-4937 Lage/Lippe)
- Water (ad libitum): tap water
- Quarantine period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22°C ± 3°C (maximum range)
- Relative humidity: 60% ± 20% (maximum range)
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

clean air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus/Exposure chamber volume/Method of holding animals in test chamber: the study was carried out using a dynamic inhalation apparatus with a nose only exposure of the animals according to KIMMERLE & TEPPER (RHEMA-LABORTECHNIK, D-6238 Hofheim/Taunus).
The apparatus consists of a cylindrical exposure chamber (volume 40 L) which holds a maximum of 20 animals in pyrex tubes at the edge of the chamber in a radial position.

- System of generating particulates/aerosols: the dust was generated with a dust generator and dosing apparatus (BURGHART, D-2000 Wedel/Holstein). The generator was fed with compressed air from a compressor. At the bottom of the exposure chamber the air was sucked off at a lower rate as created by the dust generator in order to produce a slight positive pressure in the exposure chamber.

- Method of particle size determination: an analysis of the particle size distribution was carried out twice during the exposure period using a cascade impactor according to MAY (1975) (MAY, K.R. 'Aerosol impaction jets', J. Aerosol Sci. 6, 403 (1975), RESEARCH ENGINEERS Ltd., (UK)-London N1 5RD).
The dust from the exposure chamber was sucked through the cascade impactor for 0.5 to 4 minutes at a constant flow rate of 5 L/min.The slides were removed from the impactor and were weighed on an analytical balance (SARTORIUS, type 1601 004, precision 10 µg).
The mass median aerodynamic diameter (MMAD) was estimated by means of nonlinear regression analysis (LITCHFIELD & WILCOXON). The 32 µm particle size range was not included in the determination of the MMAD in order not to give undue weight to this value.

- Temperature, humidity, air flow: air-flow meters (Rotameter, ROTA Apparate- und Maschinenbau, D-7867 Wehr 2/Baden) were used to control the constant supply of compressed air and vaccum. Flow rats were checked at least once/hour and corrected if necessary. Air changes per hour were 25.5.
The temperature (GTH 1200 Digital Thermometer, Fa. Greisinger Electronic GmbH, D-8413 Regenstauf) and humidity (Sekunden-Hygrometer Typ 6100, Testoterm) were continuously monitored close to the nose of the animals in the inhalation chamber. The temperature was 22°C ± 3°C and the relative humidity was 60% ± 20%.

Exposition started by locating the rats into the exposure chamber.

TEST ATMOSPHERE
- Brief description of analytical method used: the dust concentration in the inhalation chamber was measured with an air sample filter (Minisart N SM 17598; 0.45 µm) and pump (water jet air pump controlled by a rotameter). Dust samples were taken during the first half and during the second half of the exposure. Air was sucked through at the constant flow of air of 5 L/min for 1 to 4 minutes. The filters were weighed before and after sampling (accuracy 0.01 mg). Concentration of the test substance in the air was calculated as mg/L.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE
- MMAD (Mass median aerodynamic diameter):
0.72 mg/L air: 7.22 µm
1.21 mg/L air: 8.21 µm
1.54 mg/L air: 10.78 µm
2.20 mg/L air: 9.94 µm
3.49 mg/L air: 13.26 µm
- Respirable amount (particle size ≤4 µm):
0.72 mg/L air: 0.19 mg/L air
1.21 mg/L air: 0.26 mg/L air
1.54 mg/L air: 0.21 mg/L air
2.20 mg/L air: 0.35 mg/L air
3.49 mg/L air: 0.36 mg/L air

Analytical verification of test atmosphere concentrations:

yes

Remarks:

please refer to "Details on inhalation exposure" above

Duration of exposure:

4 h

Concentrations:

Nominal concentration:
males and females: 1.2, 1.5, 2.5 and 3.5 mg/L air
males only: 0.7 mg/L air
Actual concentrations:
male and female rats: 1.21 ± 0.09 , 1.54 ± 0.38, 2.20 ± 0.32 and 3.49 ± 0.91 mg/L air
male rats only: 0.72 ± 0.13 mg/L air
3.49 mg/L air was the highest amount of the test substance that could be generated in the inhalation chamber.

No. of animals per sex per dose:

5 males / 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: during and following exposure, observations were made and recorded systematically; individual records were maintained for each animal. A careful clinical examination was made at least once each day until all symptoms subsided, thereafter each working day.
Observations on mortality were made at least once daily with appropriate actions taken to minimize loss of animals to the study, e.g. necropsy or refrigeration of those animals found dead and isolation or sacrifice of weak or moribund animals.
Individual body weights of the animals were determined before the exposure, after 1 week and at study termination.
- Necropsy of survivors performed: yes; necropsy of all animals was carried out and all gross pathological changes were recorded. From animals which survived 24 hours or longer a microscopic examination of all organs which showed evident lesions was performed.

Statistics:

The LC50 (14 days) was calculated by regression analysis according to FINNEY.

Sex:

male

Dose descriptor:

LC50

Effect level:

2.61 mg/L air (analytical)

Based on:

test mat.

95% CL:

1.69 - 4.03

Exp. duration:

4 h

Remarks on result:

other: Slope: 3.754

Sex:

female

Dose descriptor:

LC50

Effect level:

2.43 mg/L air (analytical)

Based on:

test mat.

95% CL:

1.82 - 3.24

Exp. duration:

4 h

Remarks on result:

other: Slope: 5.668

Sex:

male/female

Dose descriptor:

LC50

Effect level:

2.51 mg/L air (analytical)

Based on:

test mat.

95% CL:

1.95 - 3.23

Exp. duration:

4 h

Remarks on result:

other: Slope: 4.479

Sex:

male

Dose descriptor:

LC0

Effect level:

0.72 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Sex:

female

Dose descriptor:

LC0

Effect level:

1.21 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

0.72 mg/L air: no mortality
1.21 mg/L air: one male died 6 days after start of exposure
1.54 mg/L air: one female died 24 hours after start of exposure
2.20 mg/L air: three males and 2 females died between 2 and 3 days after start of exposure
3.49 mg/L air: three males and 4 females died between 24 hours and 7 days after start of exposure.

Clinical signs:

other: 0.72 mg/L air: no signs of systemic intolerance 1.21 mg/L air: piloerection (and lacrimation in 1 male) in 3 male animals on the first to third day of recovery 1.54 mg/L air: dyspnoea in 1 female animal on the first day of recovery 2.20 mg/L air: apathy,

Body weight:

No inhibition of body weight gain was observed.

Gross pathology:

0.72, 1.21 and 1.54 mg/L air: no pathological findings
Animals that died prematurely:
2.20 mg/L air: 2/2 females had noses with haemorrhagic incrustation
3.49 mg/L air: 1/3 male had a nose with haemorrhagic incrustation; 2/4 females had lungs with dark-red foci
These changes can be regarded as unspecific effects which usually occur after the inhalation exposure to a dust.
All further deceased animals showed no pathological findings.
Surviving animals (sacrificed (males and females):
no pathological findings

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

LC50 (male rats): 2.61 mg/L air (analytical)
LC50 (female rats): 2.43 mg/L air (analytical)
LC50 (male and female rats): 2.51 mg/L air (analytical)
The no-effect-level was 0.72 mg/L air for 4 hours for males and 1.21 mg/L air for females.
According to the EC-Commission directive 67/548/EEC and its subsequent amendments, the test substance is classified as harmful by inhalation.
According to the EC-Regulation 1272/2008 and subsequent regulations, the test item is classified as Category 4.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

2 430 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1992-01-14 to 1992-01-28

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

signed 1991-07-25

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS - Sprague-Dawley, Tif:RAI f (SPF)
- Source: Lippische Versuchstierzucht, HAGEMANN GmbH, D-4923 Extertal 1
- Age at study initiation: approximately. 40 - 60 days
- Weight at study initiation: 160 - 182 g
- Fasting period before study: feeding was discontinued approximately 16 hours before administration. Only tap water was offered ad libitum.
- Housing: granulated textured wood was used as bedding material for the cages (Granulat Typ A2, supplier: Messrs. BRANDENBURG, Inh. H. Brandenburg, D-2849 Goldenstedt). On the day of treatment and during the observation period, the animals were kept in groups of 2 - 3 animals in MAKROLON cages (type III).
- Diet: standardized diet for rats ALTROMIN 1324 (supplied by: ALTROMIN GmbH, D-4937 Lage/Lippe)
- Water (ad libitum): tap water
- Quarantine period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22°C ± 3°C (maximum range)
- Relative humidity: 60% ± 20% (maximum range)
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

occlusive

Vehicle:

other: 0.8% aqueous hydroxypropyl-methylcellulose gel

Details on dermal exposure:

TEST SITE
- Area of exposure: the hair on the site of application was clipped with hair-clippers without causing injury approximately 24 hours before application. The site was situated on the animal's back between the fore and hind extremities and had an area of at least 5 x 6 cm (1/10 of body surface).
- Type of wrap if used: the test substance was applied to 8 layers of gauze and then to the application site. The patch was covered with a plastic sheet and secured with adhesive plaster.

REMOVAL OF TEST SUBSTANCE
- Washing: residual substance was removed by using lukewarm tap water.
- Time after start of exposure: at the end of the exposure period

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): the volume of application was 20 mL/kg bw. The dose interval factor was 1.25.

VEHICLE
- Ammonium metavanadate was suspended in 0.8% aqueous hydroxypropyl-methylcellulose gel.
- Batch no.: MM 84097413B

Duration of exposure:

24 hours

Doses:

2000 and 2500 mg/kg bw

No. of animals per sex per dose:

5 males / 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations were performed immediately, 5, 15, 30 and 60 minutes, as well as 3 hours, 6 hours and 24 hours after administration. During the follow-up period (at least 2 weeks) changes in skin and fur, eyes and mucous membranes, respiratory and circulatory, autonomic and central nervous system and somatomotor activity and behaviour pattern were observed at least once a day until all symptoms subsided, thereafter each working day. Attention was also paid to possible tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma. Observations on mortality were made at least once daily with appropriate actions taken to minimise loss of animals during the study. Individual body weights were recorded before administration of the substance, thereafter in weekly intervals up to the end of the study, and at death. Changes in weight were calculated and recorded when survival exceeds one day.
- Necropsy of survivors performed: yes; at the end of the experiments all surviving animals were sacrificed dissected and inspected macroscopically. All gross pathological changes were recorded. From animals which survive 24 hours or longer a microscopic examination of all organs which show evident lesions was performed. Autopsy and macroscopic inspection of the animals which died prematurely were carried out as soon as possible after exitus.
- Other examinations performed: the skin was observed for the development of erythema and oedema and was rated according to the Draize scale.

Statistics:

The LD50 could not be calculated because no mortality occurred.

Sex:

male

Dose descriptor:

LD50

Effect level:

> 2 500 mg/kg bw

Based on:

test mat.

Remarks on result:

other: LD50 after 24 hours and 14 days.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 500 mg/kg bw

Based on:

test mat.

Remarks on result:

other: LD50 after 24 hours and 14 days.

Mortality:

None of the animals died prematurely.

Clinical signs:

other: Under the present test conditions no local or systemic intolerance reactions were observed up to the highest tested dose-level of 2500 mg/kg bw by dermal administration to rats.

Gross pathology:

No pathological findings.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

LD50 (male rats) > 2500 mg/kg bw
LD50 (female rats) > 2500 mg/kg bw
According to the EC-Commission directive 67/548/EEC and its subsequent amendments, the test substance is not classified.
According to the EC-Regulation 1272/2008 and subsequent regulations, the test item is not classified.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 500 mg/kg bw

Additional information

Justification for selection of acute toxicity – oral endpoint
reliable GLP - study performed with ammonium trioxovanadate

Justification for selection of acute toxicity – inhalation endpoint
reliable GLP - study performed with ammonium trioxovanadate

Justification for selection of acute toxicity – dermal endpoint
reliable GLP - study performed with ammonium trioxovanadate

Justification for classification or non-classification

The available information indicates that ammonium trioxovanadate is acutely toxic via the oral route and harmful via the inhalation route, but not acutely toxic or harmful via the dermal route. Ammonium trioxovanadate requires classification as toxic if swallowed (R25) and harmful by inhalation (R20) according to Directive67/548/EEC. Furthermore, ammonium trioxovanadate requires classification as toxic if swallowed (Category 3) and harmful if inhaled (Category 4) according to Regulation (EC) 1272/2008. Classification of ammonium trioxovanadate for acute toxicity via the dermal route is not required according to Directive67/548/EEC and Regulation (EC) 1272/2008.

Specific target organ toxicant (STOT) – single exposure: oral and inhalation

The classification criteria according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral and inhalation are not met since reversible or irreversible adverse health effects (local or/and systemic) were not observed below lethal levels in addition to effects responsible for the death of the animals. Hence, classification i snot required.

Specific target organ toxicant (STOT) - single exposure: dermal

The classification criteria according to Regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – single exposure dermal are not met since adverse health effects, including reversible and irreversible, were not observed immediately or delayed after exposure.