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Administrative data

Description of key information

Acute toxicity, oral: LD50 > 2000 mg Pyrochlore/kg b.w.

Acute toxicity, inhalation: LC50  >5.11 mg/L air. (MMAD: 2.860 µm (GSD: 2.62))

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:
2000-11-22 to 2000-12-06
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
signed 2000-08-02
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland GmbH, Sandhofer Weg 7, D-97633 Sulzfeld
- Age at study initiation: males: 34 days; females: 43 days
- Weight at study initiation: mean weight males: 185.2 g (173 g- 192 g); mean weight females: 174.8 g (170 g - 183 g)
- Fasting period before study: Feeding was discontinued approx. 16 hours before administration; only tap water was then available ad libitum.
- Housing: During the observation period the animals are kept in groups of 2-3 animals in MAKROLON cages (type III); Granulated textured wood (Granulate A2, J. Brandenburg, D-49424 Goldenstedt) was used as bedding material for the cages.
- Diet (ad libitum): Altromin 1324 (ALTROMIN GmbH, D-32791 Lage / Lippe)
- Water (ad libitum): Drinking water
- Acclimation period: At least 5 adaptation days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 °C +/- 3 °C (maximum range)
- Relative humidity: 55 % +/- 15 % (maximum range)
- Photoperiod (hrs dark / hrs light): 12/12
No further information on the test animals was stated.
Route of administration:
oral: gavage
Vehicle:
other: 0.8 % hydroxypropyl-methylcellulose gel
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 20 ml/kg b.w.
no further information on the oral exposure was stated.



Doses:
2000 mg/kg b.w.
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 before and immediately, 5, 15, 30 and 60 min, as well as 3, 6 and 24 hours after administration. During the follow-up period, changes of skin and fur, eyes and mucous membranes, respiratory and the 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, 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 admininstration of the substance and thereafter in weekly intervals up to the end of the study, and at death.
- 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 showed evident lesions was performed, if necessary. Autopsy and macroscopic inspection of animals which died prematurely were carried out as soon as possible after exitus.
No further information on the study design was stated.
Statistics:
The LD50 could not be calculated because no lethality occurred in this Limit test.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred.
Clinical signs:
Under the present test conditions a single oral administration of 2000 mg Pyrochlore/kg b.w. to rats reveal no toxic symptoms.
Body weight:
The animals gained the expected weight through the test exposure period.
Gross pathology:
No abnormalities were noted at necropsy.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the present test conditions a single oral administration of 2000 mg Pyrochlore/kg b.w. to rats revealed no toxic symptoms. The animals gained the expected weight through the test exposure period. No abnormalities were noted at necrospy.
According to the criteria specified by Directive 67/548/EEC and subsequent regulations, the test item is not classified as acute toxic by the oral route.
According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is not classified as acute toxic by the oral route.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

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:
2010-07-01 to 2010-08-16
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study reliable without restrictions
Qualifier:
according to
Guideline:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Version / remarks:
2009-09-07
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
signed 2009-11-12
Test type:
acute toxic class method
Limit test:
yes
Specific details on test material used for the study:
- Particle size parameter (determined with a CILAS 715 (Non-GLP determination)): d(0.1) = 0.70 µm; d(0.5) = 5.13 µm (median); d(0.9) = 17.96 µm
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: Males: 49 days; Females: 63 days
- Weight at study initiation: Males: 223 - 226 g; Females: 201 - 209 g
- Fasting period before study: Feeding was discontinued approx. 16 hours before exposure
- Housing: During the 14-day observation period the animals are kept by sex in groups of 3 animals in MAKROLON cages (type III plus); Granulated textured wood (Granulat A2, J. Brandenburg, 49424 Goldenstedt, Germany) was used as bedding material for the cages.
- Diet: Commercial diet, ssniff® R/M-H V1534 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany)
- Water (ad libitum): Drinking water
- Acclimation period: At least 5 adaptation days; The animals were acclimatised to the test apparatus for approx. 1 hour on 2 days prior to testing. The restraining tubes did not impose undue physical, thermal or immobilization stress on the animals.

ENVIRONMENTAL CONDITIONS
- Temperature: 22°C±3°C (maximum range)
- Relative humidity: 55%±15% (maximum range)
- Photoperiod (hrs dark / hrs light): 12/12
No further information on the test animals was stated.
Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The study was carried out using a dynamic inhalation apparatus (RHEMA-LABORTECHNIK, 65719 Hofheim/Taunus, Germany) (air changes/h (≥ 12 times)) with a nose-only exposure of the animals according to KIMMERLE & TEPPER. The apparatus consists of a cylindrical exposure chamber (volume 40 L) which holds the animals in pyrex tubes at the edge of the chamber in a radial position.

- System of generating particulates/aerosols: The dust of the test material was generated with a rotating brush dust generator (RBG 1000, PALAS GmbH Partikel und Lasermesstechnik,76229 Karlsruhe, Germany).
The generator was fed with compressed air (5.0 bar) from a compressor (ALUP Kompressorenfabrik, 73257 Köngen, Germany) (air was taken from the surrounding atmosphere of the laboratory room and filtered using an in-line disposable gas-filter).
At the bottom of the exposure chamber, the air was sucked off at a lower flow rate than it was created by the dust generator in order to produce a homogenous distribution and a positive pressure in the exposure chamber (inflow 900 L/h, outflow 800 L/h).

Before initiating the study with the animals, a pre-test was carried out with the exposure system in order to verify that under the experimental settings chosen, the limit concentration of 5 mg/L air could be achieved by gravimetric analysis.

- Method of particle size determination: An analysis of the particulate size distribution was carried out twice during the exposure period using a cascade impactor according to MAY (MAY, K.R. Aerosol impaction jets, J.Aerosol Sci. 6, 403 (1975), RESEARCH ENGINEERS Ltd., London N1 5RD, UK
).
The dust from the exposure chamber was drawn through the cascade impactor for 5 minutes at a constant flow rate of 5 L/min. The slides were removed from the impactor and weighed on an analytical balance (SARTORIUS, type 1601 004, precision 0.1 mg).
The MMAD was estimated by means of non-linear regression analysis. The 32 µm particle size range and the filter (particle size range < 0.5 µm) were not included in the determination of the MMAD in order not to give undue weight to these values.
The GSD of the MMAD was calculated from the quotient of the 84.1%- and the 50%-mass fractions, both obtained from the above mentioned non-linear regression analysis.

- Treatment of exhaust air: The exhaust air was drawn through gas wash-bottles.

- Temperature, humidity, oxygen, carbon dioxide, air flow: A manometer and an air-flow meter (ROTA Yokogawa GmbH & Co. KG, 79664 Wehr/Baden, Germany) were used to control the constant supply of compressed air and the exhaust, respectively. Flow rates were checked hourly and corrected if necessary.
The oxygen content in the inhalation chamber was 21%. It was determined at the beginning and at the end of the exposure with a DRÄGER Oxygen-analysis test set (DRÄGER Tube Oxygen 67 28 081). Carbon dioxide concentration did not exceed 1%.
Temperature (22.2°C ± 0.4°C) and humidity (63.6% ± 0.3%) were measured once every hour with a climate control monitor (testo 175-HZ data logger).

TEST ATMOSPHERE - The inhalation chamber was equilibrated for at least 15 minutes (t95 approximately 8 minutes).
- Brief description of analytical method used: The actual dust concentration in the inhalation chamber was measured gravimetrically with an air sample filter (Minisart SM 17598 0.45 µm) and pump (Vacuubrand, MZ 2C (Membrane Pump,Vacuubrand GmbH + Co. KG, 97877 Wertheim/Main, Germany)) controlled by a rotameter. Dust samples were taken once every hour during the exposure. For that purpose, a probe was placed close to the animals' noses and air was drawn through the air sample filter at a constant flow of air of 5 L/min for 1 minute. The filters were weighed before and after sampling (accuracy 0.1 mg). The correct loading of the filter was checked by the airflow via the rotameter and by a positive weight increase of the filter after the sampling period of 1 minute.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE (if not tabulated)
- MMAD: 2.860 µm (GSD: 2.62)
No further information on the inhalation exposure was stated.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
see above ("Details on inhalation exposure")
Duration of exposure:
4 h
Remarks on duration:
Exposition started by locating the animals’ noses into the exposure chamber after equilibration of the chamber concentration for at least 15 minutes.
Concentrations:
5.11±0.08 mg pyrochlore/L air (actual concentration)
5.00 mg/L air (nominal concentration)
No. of animals per sex per dose:
3 male rats / 3 female rats
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. Careful clinical examinations were made at least twice daily until all symptoms subsided, thereafter each working day. Observations on mortality were made at least once daily (in the morning starting on test day 2). Individual weights of animals were determined once during the acclimatisation period, before and after the exposure on test day 1, on test days 3, 8 and 15.
- Necropsy of survivors performed: Yes
Necropsy of all animals was carried out and all gross pathological changes were recorded.
- 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, as well as somatomotor activity and behaviour pattern.
Particular attention was directed to observation of tremor, convulsions, salivation, diarrhoea, lethargy, sleep and coma. The animals were also observed for possible indications of respiratory irritation such as dyspnoea, rhinitis etc..
Changes in weight were calculated and recorded when survival exceeded one day.
No further information on the study design was stated.

Statistics:
not applicable
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.11 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: Standard deviation: 0.08 mg/L air; The LC50 cut-off value is 'unclassified'.
Mortality:
No mortality occurred.
Clinical signs:
other: Slight ataxia (0 - 60 min), slight tremor (0 - 60 min) and slight dyspnoea (0 min - 3 h) were observed in all 3 male and 3 female rats.
Body weight:
All animals gained the expected body weight throughout the study period.
Gross pathology:
No pathological findings were made.
Other findings:
No data
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of this study, the 4-hour inhalation LC50 of Pyrochlore is >5.11 mg/L air, and hence, the LC50 cut-off value 'unclassified'.
According to the EC Regulation 1272/2008 and subsequent regulations, the test material is not classified for acute inhalation toxicity.
According to the EC-Commission directive 67/548/EEC and subsequent regulations, the test material is not classified for acute inhalation toxicity.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

One acute oral toxicity study according to OECD guideline 401 has been performed that will be used for classification. This study indicates that oral LD50 is >2000 mg/Kg bw in rats.

For acute inhalation toxicity there is one animal study which will be used for classification and that has been performed according to OECD TG 436 and which shows no signs of acute toxicity after inhalation exposure to pyrochlore, indicating a LC50 > 5.11 mg/L.

Slight ataxia (0 - 60 min), slight tremor (0 - 60 min) and slight dyspnoea (0 min - 3 h) were observed in all 3 male and 3 female rats.

No mortality occured.

There are no reliable reports whatsoever on acute dermal toxicity in the public domain. However, the conduct of an acute dermal toxicity study is unjustified as inhalation of the substance is considered as major route of exposure and physicochemical properties and dermal absorption data of the substance do not suggest a significant rate of absorption through the skin (cf. Annex VIII section 8.5 Column 2 of regulation (EC) 1907/2006).

Justification for classification or non-classification

Acute toxicity oral:

Under the present test conditions a single oral administration of 2000 mg Pyrochlore/kg b.w. to rats revealed no toxic symptoms. The animals gained the expected weight through the test exposure period. No abnormalities were noted at necrospy. According to the criteria specified by Directive 67/548/EEC and subsequent regulations, the test item is not classified as acute toxic by the oral route. According to the EC Regulation No. 1272/2008 and subsequent regulations, the test item is not classified as acute toxic by the oral route.

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

The classification criteria acc. to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value, oral for a Category 1 classification of 300 mg/kg bw and at the guidance value, oral for a Category 2 classification of 2000 mg/kg bw. No classification required.

Acute inhalation toxicity:

The reference Haferkorn, J. is considered as key study for the endpoint acute inhalation toxicity and will be used for classification.

Under the conditions of this study, the 4-hour inhalation LC50 of Pyrochlore is >5.11 mg/L air. According to the EC Regulation 1272/2008 and subsequent regulations, the test material is not classified for acute inhalation toxicity. According to the EC-Commission directive 67/548/EEC and subsequent regulations, the test material is not classified for acute inhalation toxicity.

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

The classification criteria acc. to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – single exposure, inhalation dust/mist/fume are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value, inhalation dust/mist/fume for a Category 1 classification of 1.0 mg/L/4h and at the guidance value, inhalation dust/mist/fume for a Category 2 classification of 5.0 mg/L/4h. Therefore, no classification is required.

Finally, any category 3 classification should primarily be based on human data. However, such classification is also not warranted, since observations on respiratory irritation in test animals (rats) were not observed.