Registration Dossier

Administrative data

Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
According to Annex VIII (8.5.), for nanoforms, a study by the oral route shall be replaced by a study by the inhalation route (8.5.2), unless exposure of humans via inhalation is unlikely, taking into account the possibility of exposure to aerosols, particles or droplets of an inhalable size.

Iron oxide isostearate is produced and used in a solvent, and is never isolated as such during the whole life cycle. When the substance was isolated from its solvent to do the studies for the registration purpose, it has formed a sticky powder, preventing the realisation of an inhalation study.
The manufacturing stage of the substance is performed in a closed batch process. The effluents are collected and calcined. The uses occur also in closed systems.
During the final use as additive in motors, the substance is completely trapped into the device and is consumed during the combustion in the motor (see VSET certification - DPX13, 2007 attached in IUCLID section 13.2). It is the end of the life cycle of the substance.
For all these reasons, exposure of humans via inhalation is unlikely; handling of the registered substance does not produce vapour, aerosols or droplets.. Therefore, for acute toxicity, the oral route exposure is considered as a worst case.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From July 2001 to 21 Dec 2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
room temperature sometimes out of the target (minor deviation)
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, L'Arbresle, France.
- Age at study initiation: on the day of treatment, the animals were approximately 6 weeks old.
- Weight at study initiation: 178 ± 6 g for the males and 132 ± 12 g for the females (on the day of treatment)
- Fasting period before study: approximately 18 hours
- Housing: in polycarbonate cages with stainless steel lid (48 cm x 27 cm x 20 cm), 1 to 7 animals/sex during the acclimation period and 3 rats/sex/group during the treatment period
- Diet: free access to A04 C pelleted diet
- Water: drinking water filtered by a FG Millipore membrane (0.22 micron), provided ad libitum
- Acclimation period: at least 5 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 2°C
- Humidity: 30 to 70%
- Air changes: approximately 12 cycles/hour
- Photoperiod: 12 h light/12 h dark

IN-LIFE DATES: From 18 July 2001 (first treatment) to 8 August 2001 (necropsy of the last animal)
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/ml
- Amount of vehicle: 10 mL/kg
- Justification for choice of vehicle: data not available
- Lot/batch no.: 70K0127
- Purity: data not available

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION: The test substance was mixed with the required quantity of vehicle, using an ultra-turrax (freshly on the morning of administration).

CLASS METHOD
- Rationale for the selection of the starting dose: the information on the toxic potential of the test substance suggested that mortality was unlikely at the highest dose-level (2000 mg/kg bw).
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
3 males and 3 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
> Clinical signs and mortality: frequently during the hours following administration of the test substance, and at least once a day thereafter.
> Body weight: just before administration of the test substance on day 1 and then on days 8 and 15.
- Necropsy of survivors performed: yes
Statistics:
not applicable
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No signs of toxicity were observed at this dose-level
Mortality:
No deaths were observed at 2000 mg/kg bw during the study.
Clinical signs:
No clinical signs were observed at 2000 mg/kg bw during the study.
Body weight:
The body weight gain of the treated animals was similar to that of the historical control animals.
Gross pathology:
Macroscopic examination of the main organs of the animals revealed no apparent abnormalities.
Interpretation of results:
GHS criteria not met
Conclusions:
The oral LD50 of the test substance is > 2000 mg/kg bw (with no signs of toxicity at the dose level).
Executive summary:

In an acute oral toxicity study according to OECD TG 423 and GLP (CIT report 22316 TAR), scored as validity 1 according to Klimisch criteria, groups of fasted 6-week old Sprague-Dawley rats (3/sex) were given a single oral dose of cerium and iron oxide isostearate in corn oil at the dose of 2000 mg/kg bw (limit test) and observed for 14 days. Clinical signs and mortality were checked frequently during the hours following administration of the test substance, and at least once a day thereafter. Body weight was measured just before administration of the test substance on day 1 and then on days 8 and 15.

 

Under the experimental conditions, the oral LD50 of the test substance cerium and iron oxide isostearate is higher than 2000 mg/kg in rats.

No effects were observed during the observation period (no clinical signs no mortality and no effect on body weight) and at necropsy.

 

No classification for acute oral toxicity is warranted based on the absence of mortality up to a limit dose level, according to the criteria of EU GHS.

This study is classified as acceptable, as it is performed according to OECD guideline and GLP.

Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
from 21 June to 22 October 2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Janvier, Le Genest-saint-Isle, France
- Age at study initiation: on the day of treatment, the animals were approximately 8 weeks old.
- Weight at study initiation: 202 ± 9 g (on the day of treatment)
- Fasting period before study: approximately 18 hours
- Housing: in polycarbonate cages with stainless steel lid (48 cm x 27 cm x 20 cm), 1 to 7 animals/sex during the acclimation period and 3 rats/sex/group during the treatment period
- Diet: free access to adapted pelleted diet (SSNIFF Spezialdiäten GmbH, Soest, Germany)
- Water: drinking water filtered by a FG Millipore membrane (0.22 micron), provided ad libitum
- Acclimation period: at least 5 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 2°C
- Humidity: 30 to 70%
- Air changes: approximately 12 cycles/hour
- Photoperiod: 12 h light/12 h dark

IN-LIFE DATES: From 29 June 2004 (first treatment) to 15 July 2004 (necropsy of the last animal)
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 100 mg/mL
- Amount of vehicle: 2 x 10 mL/kg
- Justification for choice of vehicle: data not available
- Lot/batch no.: 122K0131

MAXIMUM DOSE VOLUME APPLIED: 2 x 10 mL/kg

CLASS METHOD
- Rationale for the selection of the starting dose: as the information on the toxic potential of the test item suggested that mortality was unlikely at the highest dose-level, the starting dose-level of 2000 mg/kg was chosen.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
2 x 3 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
> Clinical signs and mortality: frequently during the hours following administration of the test substance, and at least once a day thereafter.
> Body weight: just before administration of the test substance on day 1 and then on days 8 and 15.
- Necropsy of survivors performed: yes
Statistics:
not applicable
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: no mortality and no systemic toxicity were observed.
Mortality:
No mortality occurred during the study.
Clinical signs:
Only hypoactivity, piloerection and dyspnea were observed on day 1 in all animals of the first treated group. No clinical signs were noted in the second treated group.
Body weight:
The body weight gain of 2/3 females of the second treated group was slightly reduced during the first or second week of the study when compared to lab historical control animals. The overall body weight of the other animals was not affected by treatment with the test item.
Gross pathology:
Macroscopic examination of the main organs of the animals revealed no apparent abnormalities.
Interpretation of results:
GHS criteria not met
Conclusions:
The oral LD50 of the test substance is > 2000 mg/kg bw (with no mortality at the dose level).
Executive summary:

In an acute oral toxicity study according to OECD TG 423 and GLP (CIT report 28266 TAR), scored as validity 1 according to Klimisch criteria, groups of fasted 8-week old Sprague-Dawley rats (2 x 3 females) were given a single oral dose of cerium and iron oxide isostearate (active matter of DPX11) in corn oil at the dose of 2000 mg/kg bw (limit test) and observed for 14 days. Clinical signs and mortality were checked frequently during the hours following administration of the test substance, and at least once a day thereafter. Body weight was measured just before administration of the test substance on day 1 and then on days 8 and 15.

 

Under the experimental conditions, the oral LD50 of the test substance cerium and iron oxide isostearate is higher than 2000 mg/kg in rats.

No mortality occurred during the study.

Only hypoactivity, piloerection and dyspnea were observed on day 1 in all animals of the first treated group. No clinical signs were noted in the second treated group.

The overall body weight of the other animals was not affected by treatment with the test item and no abnormalities were seen at the necropsy.

No classification for acute oral toxicity is warranted based on the absence of mortality up to a limit dose level, according to the criteria of EU GHS.

This study is classified as acceptable, as it is performed according to OECD guideline and GLP.

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion