Registration Dossier

Administrative data

Description of key information

Acute Toxicity:

- oral: LD50 = 911 kg/kg bw (rat)

- inhalation: LC50 (4h) = 4.3 mg/L (rat)

- dermal: LD50: > 5000 mg/kg bw (rabbit)

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards, well documented and acceptable for assessment.
Qualifier:
according to
Guideline:
EPA OPP 81-1 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Inc. Wilmington, Massachusetts.
- Age at study initiation: young adults (9-12 weeks).
- Weight at study initiation: males: 256 - 339 g; females: 224 - 264 g;
- Fasting period before study: overnight (approximately 18 hours).
- Housing: individually.
- Diet: Purina Laboratory Chow , #5001, ad libitum.
- Water: tap water, ad libitum.
- Acclimation period: 10-21 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 24 °C
- Humidity (%): 30 - 70 %
- Photoperiod (hrs dark / hrs light): 12 h/ 12 h
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 10 ml

Doses:
600, 1200, 2500, 3500, 5000 mg/kg bw.
Initially 5000 mg/kg bw were dosed but due to mortality seen, additional levels were added.
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days;
- Frequency of observations: twice daily;
- Frequency of weighing: prefast, postfast (just prior to dosing), days 7 and 14;
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,
Statistics:
Lichfield and Wilcoxon method.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
911 mg/kg bw
Based on:
test mat.
95% CL:
728 - 1 140
Mortality:
600 mg/kg bw: 1 female died;
1200 mg/kg bw: 3 males and all females died;
2500, 3500 and 5000 mg/kg bw: all animals died;
Clinical signs:
Signs seen on the day of dosing in most groups included discharge, fecal staining, soft stool, and hypoactivity. On the day after dosing most animals in most groups showed urinary staining; a few animals had ataxia, hypothermia and prostration. Most surviving animals showed decreased food consumption on the day after dosing; this continued in some animals through day 3. Other signs occurred occasionally in a few animals. All surviving animals were free of significant abnormalities from day 6 through termination of the study (day 14).
Body weight:
All surviving animals gained weight.
Gross pathology:
Postmortem examinations of animals which were found dead revealed a variety of changes, primarily in the lungs and gastrointestinal tract. Some animals which were found dead exhibited changes in the stomach and intestine which were suggestive of an irritant effect (discoloration of walls), and most had apparent test material in the gastrointestinal tract. Several animals had accentuated lobular pattern of the liver. Other changes in animals found dead appeared to represent autolytic alterations or were the result of antemortem stress (testes in the body cavity). Changes in animals sacrificed after 14 days were similar to those seen in control animals.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
911 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:
1991-10-02 to 1991-11-13
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Guideline study without restrictions Minor deviations: - According to the guideline, the weight variation in animals or between groups used in a test should not exceed +/- 20 % of the mean weight. The males of the group with the 2.42 mg/l air concentration were slightly outside this weight range. - According to the guideline, the relative humidity should be between 30 - 70 % in the animal room. In this study the relative humidity was slightly higher (60 +/- 20 %). -According to the guideline, animals should be tested with inhalation equipment designed to sustain a dynamic air flow of 12 to 15 air changes per hour. In this study in the high concentration group the air flow was 29.4 changes per hour. - According to the guideline, the duration of exposure should be at least 4 hours after equilibration of the chamber concentration. It was not stated if the 4 hours started after equilibration of the chamber concentration. - According to the guideline, weight changes should be calculated and recorded when survival exceeds one days. This is missing in this study. -The GSD for the MMAD is missing. - The 95 % confidence level for the females is missing.
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
adopted 12 May 1981
Deviations:
yes
Remarks:
see "rational for reliability"
GLP compliance:
yes (incl. certificate)
Remarks:
The study report stated that the study was performed according to "Good Laboratory Practice" Regulations of the EEC enacted in Germany in the "Chemikaliengesetz" dated March 14th, 1990, BGBL I, pp. 521, 1990.
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Lippische Versuchstierzucht HAGEMANN GmbH, D-4923 Extertal 1
- Age at study initiation: 52-69 days
- Weight at study initiation: 188 - 270 g (males; 164 - 206 g (females)
- Fasting period before study: approx. 16 hours
- Housing: Animales were kept in groups of two or three in Makrolon cages (type III). Granulated textured wood (type 2, supplied by Johannes Brandenburg, D-4937 Goldenstedt) was used as bedding material.
- 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
No further significant information on test animals was stated.
Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
other: air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus & Exposure chamber volume: : The study was carried out using a dynamic inhalation apparatus with a nose only exposure of the animals according to KIMMERLE & TREPPER (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.

- Source and rate of air: At the bottom of the exposure chamber the air was sucked off at the similar rate as created by the dust generator in order to produce a homogenous distribution in the exposure chamber. Air-flow meters (Rotameter, ROTA Apparate- und Maschinenbau, D-7867 Wehr 2/Baden) were used to control the constant supply of compressed air and vacuum. Flow rates were checked at least once/hour and corrected if necessary. Air flow was 480 l/h for the low and medium concentration, and 1175 l/h for the high concentration. The air change was 12.0 changes per hour for the low and medium concentration, and 29.4 changes per hour for the high concentration.

- 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.

- 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).
The impactor is a device that classifies particles present in a sampleof air or gas into known size ranges. It does this by drawing the air sample through a cascade of progressively finer nozzles. The air jets from these impact on plane sampling surfaces (slides) covered with adhesive tape. Each stage represents an aerodynamic size range. The dust from the exposure chamber was sucked through the cascade impactor for 1.5 to 5 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 1601004, precision 10µg).
Respirable amount (particle size <= 4 µm)
Dose level 0.90 mg/l air:0.61 mg/l air
Dose level 2.42 mg/l air:2.01 mg/l air
Dose level 4.72 mg/l air: 3.52 mg/l air
The sample supplied had a particle size distribution of 55.9 % in the particle size range of 2.4 to 5.0 µm.

- Temperature, humidity: The temperature (GTH 1200 Digital Thermometer, Fa. Greisinger Electronic GmbH) and humidity (Sekunden-Hygrometer Typ 6100, Testoterm) was continuously monitored close to the nose of the animals in the inhalation chamber. The temperature was 19 °C - 21 °C and the relative humidity was 60 % - +/- 20 %.

TEST ATMOSPHERE (Test substance concentration)
- Brief description of analytical method used: The dust concentration in the inhalation chamber was measured with an air sample filter (Minisart SM 17598) 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. The Minisart SM 17598 filters were placed close to the animals' nose and sucked through with a constant flow of air of 300 l/h for 1 to 3 minutes. The filters were weighed before and after sampling (accuracy 0.01 mg).

TEST ATMOSPHERE
- Particle size distribution: The sample supplied had a particle size distribution of 55.9 % in the particle size range of 2.4 to 5.0 µm measured with a Malvern particle sizer.
Particle size (µm) and mean (concentration 0.90 mg/l air):
<0.5 µm: 1.33 %
0.5 µm: 12.80 %
1 µm: 22.25 %
2 µm: 52.36 %
4 µm: 68.25 %
8 µm: 75.84 %
16 µm: 90.17 %
>= 32 µm: 99.90 &
Particle size (µm) and mean (concentration 2.42 mg/l air):
<0.5 µm: 0.0 %
0.5 µm: 5.18 %
1 µm: 17.19 %
2 µm: 52.89 %
4 µm: 83.10 %
8 µm: 87.50 %
16 µm: 93.73 %
>= 32 µm: 100.01 %
Particle size (µm) and mean (concentration 4.72 mg/l air):
<0.5 µm: 1.87 %
0.5 µm: 8.85 %
1 µm: 31.02 %
2 µm: 69.52 %
4 µm: 74.59 %
8 µm: 78.18 %
16 µm: 91.77 %
>= 32 µm: 100.0 %
- MMAD:
Dose level 0.90 mg/l air: 2.44 µm
Dose level 2.42 mg/l air: 2.32 µm
Dose level 4.72 mg/l air: 2.01µm
No further significant information on inhalation exposure was stated.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
see "details on inhalation exposure" above.
Duration of exposure:
4 h
Remarks on duration:
Exposition started by locating the rats into the exposure chamber.
Concentrations:
mean actual concentration 0.90 +/- 0.39 (nominal concentration: 1.9 mg/l air), 2.42 +/- 0.38 (nominal concentration: 7.4 mg/l air), 4.72 +/- 1.45 (nominal concentration: 8.6 mg/l air) mg V2O5 analytical grade pulverised/l air. 4.72 mg/l air was the highest concentration that could be generated in the inhalation chamber.
No. of animals per sex per dose:
5 males /5 females
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: During and following espoxure, observations were made. 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. 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 after preparation of paraffin sections and HE-staining..
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: Cageside observations included, but were not limited to, changes in the skin and fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system, and somatomotor activity and behaviour pattern. Particluar attention was directed to observation of tremors, convulsions, salivation, diarrhoea. lethargy, sleep and coma.
No further significant information on study design was stated.
Statistics:
The mass median aerodynamic diameter (MMAD) was estimated by means of nonlinear regression analysis (LICHFIELD & WILCOXON). The 32 mm particle size range was not included in the determination of the MMAD in order not to give undue weight to this value.
The LC50 (24 hours/14days) was calculated by regression analysis (if possible according to FINNEY).
Sex:
male
Dose descriptor:
LC50
Effect level:
11.09 mg/L air
95% CL:
> 0.68 - < 180.68
Exp. duration:
4 h
Remarks on result:
other: Slope: 1.783; LC50 was calcualted according to Finney (probit analysis)
Sex:
female
Dose descriptor:
LC50
Effect level:
4.29 mg/L air
Exp. duration:
4 h
Remarks on result:
other: Slope: 20.14; LC50 was calculated by regressiong analysis.
Mortality:
Death at 2.42 mg/l in males and 4.72 mg/l in females.
At the dose-level of 2.42 mg/l prematurely deceased animal (1/5 males) died 4 days after start of exposure.
At the dose level of 4.72 mg/l prematurely deceased animals (1/5 males; 4/5 females) died 2 days after start of exposure.
Clinical signs:
Dose level and toxic signs:
0.90 mg/l: no signs of systemic intolerance (males and females)
2.42 mg/l: Except for mortality no signs of systemic intolerance (males and females)
4.72 mg/l: except for mortalitiy no signs of systemic intolerance (males and females)
Body weight:
There was no inhibition of body weight gain in males or females.
Gross pathology:
Autopsy of deceased animals:
lungs haemorrhagic: 4.72 mg/l (1/1 males; 3/4 females). All further deceased animals showed no pathological findings.
Autopsy of surviving animals:
lungs haemorrhagic: 2.42 mg/l air (2/4 males; 1/5 females)
Lungs haemorrhagic and light dark coloured: 4.72 mg/l air (1/4 males)
All further scarificed animals showed no pathological findings.
The histopathological changes found in the lungs were:
2.42 mg/l air: vascular congestion (2/2 males); oedema (1/2 males) and (inital) haemorrhagic bronchopneumonia (2/2 males)
4.72 mg/l air: vascular congestion (2/2 males; 3/3 females); oedema (1/2 males; 2/3 females) and (inital) haemorrhagic bronchopneumonia (2/2 males; 3/3 females)
These changes can be regarded as unspecific effects which can normally occur after the administration of a dust.
Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
According to the EEC-Commission directive of July 29th, 1983 on the approximation of the laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances (83/467/EEC) and the results obtained under the present test conditions V2O5 analytical grade pulverised can be classified as harmful in an acute inhalation toxicity test in the rat.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
4.3 mg/m³

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:
31.08.1988 - 14.09.1988
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards, well documented and acceptable for assessment.
Qualifier:
according to
Guideline:
EPA OPP 81-2 (Acute Dermal Toxicity)
GLP compliance:
yes
Test type:
other: Limit-test
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton-Dutchland Laboratory Animals, Denver, Pennsylvania.
- Age at study initiation: young adults (at least 8 weeks old).
- Weight at study initiation: males: 2,5 - 2,7 kg; females: 2,7 - 2,9 kg.
- Housing: individually.
- Diet: Lab Rabbit Chow HF (Purina #5326), 125 g/day while on test.
- Water: tap water, ad libitum.
- Acclimation period: 44 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16 - 21 °C
- Humidity (%): 30 - 70 %
- Photoperiod (hrs dark / hrs light): 12 h / 12 h

Type of coverage:
occlusive
Vehicle:
physiological saline
Details on dermal exposure:
TEST SITE
- Area of exposure: 4" x 12"
- Type of wrap if used: impervious plastic sheet

REMOVAL OF TEST SUBSTANCE
- Washing (if done): only wiped free of excess test material with dry paper towels.
- Time after start of exposure: 24 h

TEST MATERIAL
- For solids, paste formed: the dry material was placed direct on a gauze and moistened with 7 mls of saline

VEHICLE
- Amount(s) applied (volume or weight with unit): 7 ml
Duration of exposure:
24 h
Doses:
5000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days.
- Frequency of observations: twice daily.
- Frequency of weighing: pretest (time of clipping), predose, days 7 and 14.
- Necropsy of survivors performed: yes.
- Other examinations performed: clinical signs, body weight.
Statistics:
no statistics performed.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Mortality:
No mortality occured.
Clinical signs:
Local signs: Two males exhibited severe dermal effects at a small area of the dose site (necrosis followed by eschar formation, and exfoliation of the eschar tissue) which persisted throughout the study.

Systemic toxicity: All animals were free of significant signs of systemic toxicity; only single occurrences of nasal discharge, ocular discharge and fecal staining.
Body weight:
All animals exhibited a slight weight loss or no weight change by day 7, but most gained weight between day 7 and 14.
Gross pathology:
Gross postmortem observations confirmed the presence of dermal lesions. Other observations were similar to those seen in control animals or were considered to represent normal physiological variation.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
5 000 mg/kg bw

Additional information

Oral exposure route:

In the key study (BIO/DYNAMICS, 1989; Validity 2) performed according to EPA-guideline OPP 81-1 (Acute Oral Toxicity) and GLP, single doses of 600, 1200, 2500, 3500, and 5000 mg/kg bw of test material prepared with corn oil were given to groups of 5 animals per sex/dose by gavage. Above 2500 mg/kg bw all animals died and further three males and all females of the 1200 mg/kg bw group and one female of the 600 mg/kg bw group, died. Clinical signs included discharge, fecal staining, soft stool, and hypoactivity. On the day after dosing most animals showed urinary staining; a few animals showed ataxia, hypothermia and prostration. Most surviving animals showed decreased food consumption on the day after dosing. Postmortem examinations revealed a variety of alterations, primarily in the lungs and gastrointestinal tract. Some animals exhibited changes in the stomach and intestine which were suggestive of an irritant effect (discoloration of walls), and most had apparent test material in the gastrointestinal tract. Several animals had accentuated lobular pattern of the liver. Other changes in animals found dead appeared to represent autolytic changes or were the result of antemortem stress (testes in the body cavity).

 

Inhalation exposure route:

There are no substance specific information on divanadyl pyrophosphate for acute inhalation toxicity available. However, data from other vanadium compounds (divanadium pentoxide) were taken into account to access the respective endpoint.

In an acute inhalation toxicity test according to OECD 403 (Leuschner, 1991) divanadium pentoxide was harmful. At the dose level of 4.72 mg/l 1/5 males and 4/5 females died 2 days after start of exposure. At the dose level of 4.72 mg/l 1/5 males and 4/5 females died 2 days after start of exposure. The calculated LC50 is 11.09 mg/L for males and 4.29 mg/L for females.

Dermal exposure route:

The key study (BIO/DYANAMICS, 1989; Validity 2) is a test with rabbits performed according to EPA-guideline OPP 81-2 (Acute Dermal Toxicity). A single dose of 5000 mg/kg bw of the test material prepared with 0.9% saline was applied to five male and five female animals to the clipped skin and covered by a occlusive dressing for 24 hours. Two males exhibited severe dermal effects at a small area of the dose site (necrosis followed by eschar formation, and exfoliation of the eschar tissue) which persisted throughout the study. No mortality occurred and all animals were free of significant signs of systemic toxicity. Only single occurrences of nasal discharge, ocular discharge and fecal staining were observed. All animals exhibited a slight weight loss or no weight change in the first week after treatment, but most gained weight between days 7 and 14. Gross postmortem observations confirmed the presence of dermal lesions.

Justification for classification or non-classification

Based on the available data, Divanadyl pyrophosphate will be classified in accordance with regulation (EC) 1272/2008 as acute toxic category 4 (H302) after oral administration and as acute toxic category 4 (H332) after inhalation.