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Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June 24 - Sept 10, 1991
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented (GLP, but no real control))
Cross-reference
Reason / purpose for cross-reference:
read-across: supporting information
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
June 24 - Sept 10, 1991
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented (GLP, but no real control))
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Further information is included under ‘Attached justification’ in Section 13 of IUCLID and under ‘Cross-reference’ in the IUCLID Robust Study Summary.
Reason / purpose for cross-reference:
read-across source
Qualifier:
no guideline available
Principles of method if other than guideline:
Study of the bioavailability of metal ions from the substance after inhalation as a dust aerosol in rats
GLP compliance:
yes
Remarks:
Deviations: Analysis of Ni and Sb content in organs of test animals was performed in a laboratory without the ability of quality assurance checking; the stability of the test substance has not been proven by recharacterisation
Limit test:
yes
Species:
rat
Strain:
other: Wistar/Chbb:THOM
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach, Germany
- Age at study initiation: 7 weeks
- Weight at study initiation: 230 - 232 g ( the average weight of the addtional set of animals 304 g ± 1.7 g)
- Housing: Singly in Makrolon/wire cages (type MD III of Becker, Castrop-Rauxel, Germany)
- Diet: KLIBA rat/mouse/hamster laboratory diet 24-343-4 10 mm pellets; Klingentalmühle AG, Kaiseraugst, Switzerland
- Water: during exposure withdrawn


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose/head only
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: 0.6 - 1.0 µm/ 2.8 - 4.1 (measurements on d 3 and d 5
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: aerodynamic exposure apparatus (INA 60, volume V 90 l, BASF Aktiengesellschaft)
- Method of fixing animals in test chamber: exposure tubes; animal snouts projecting into the inhalation chamber
- Rate of air: Supply air (l/h): compressed air 1,500, blast air 4,500; Exhause air (l/h): 5,400
- System of generating particulates/aerosols: dust generator
- Temperature, humidity: 23.3-23.6 °C , 50.6-54.0 %
- Method of particle size determination: Gravimetrical determination

TEST ATMOSPHERE
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
5 days
Frequency of treatment:
6 hours/day, daily
Remarks:
Doses / Concentrations:
60 mg/m3 (0.06 mg/l)
Basis:
nominal conc.
No. of animals per sex per dose:
50 (divided into 5 groups with differing post-exposure periods)
Control animals:
other: During analyses of livers and kidneys of the first test groups the need occurred to analyse kidneys of untreated animals (blank values), therefore another set of animals was delivered age-matched to the test animals of test group 1 at sacrifice.
Details on study design:
Post-exposure period: 0, 3, 10, 31, 60 days
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least 3 times on exposure days and, as a rule, once during the preflow period and the post-exposure observation period.
BODY WEIGHT: Yes
- Time schedule for examinations: at the beginning of preflow, at the beginning of exposure period and then once a week
Sacrifice and pathology:
Control group was sacrificed on day of arrival
Group 1 on test day four (after the last exposure)
Group 2 at day 7 (post-exposure day 3)
Group 3 at day 14 (post-exposure day 10)
Group 4 at day 35 (post-exposure day 31)
Group 5 at day 64 (post-exposure day 60)
Other examinations:
ANALYSIS: Ni and Sb concentrations in lung, liver and kidneys were determined by ICP-MS; Food analysis: contaminations in the used commercial feed were 1.42 mg Ni/kg and 13 µg Sb/kg.
Statistics:
no statistical evaluation because no concurrent control.
Details on results:
No effects on mortality, clinical signs, body weights and body weight gains
Dose descriptor:
NOAEC
Effect level:
60 mg/L air
Remarks on result:
not determinable
Remarks:
no NOAEC identified
Critical effects observed:
not specified
CONTENT OF Ni AND Sb in:
LIVER: 
Mean Sb concentration (quantification limit 0.2 ng/g) in unexposed animals was 1.1 ng/g; directly post-exposure
and on day 3-post-exposure the concentration was about 4-fold higher in exposed animals, during further observation
the concentration was similar to unexposed animals (1.3 ng/g on day 10).
Mean Ni-concentration was in the same range in exposed and unexposed animals (however, below the quantification limit
of 10 ng/g; outliers not considered). 

KIDNEYS: 
Mean Sb concentration in unexposed animals was below the detection limit (1 ng/g), in exposed animals it was above the 
detection limit but below the quantification limit (3 ng/g), only the day 3 post exposure group reached a value of 5.6 
ng/g (2-3-fold increase compared with other observation days).
Mean Ni concentration was below the detection limit (1 ng/g) in unexposed animals and above detection limit but below
quantification limit (25 ng/g) in exposed animals, except on day 3 post-exposure 94 ng/g were determined (10-fold more
than in other exposure groups. Authors comment: presumably due to contamination of the sample). 

LUNG: 
Directly post-exposure the mean Ni and Sb concentration was 79 and 202 µg/lung , respectively (corresponding to 2 mg of
pigment/lung). The concentration declined during the post-exposure period, following first order kinetics; the clearance 
half-life was 50 days.


Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1994
Report date:
1994
Reference Type:
secondary source
Title:
SIDS Initial assessment report for SIAM 15
Author:
OECD
Year:
2002
Bibliographic source:
SIDS C.I. Pigment Yellow 53, CAS no. 8007-18-9

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Study of the bioavailability of metal ions from the substance after inhalation as a dust aerosol in rats
GLP compliance:
yes
Remarks:
Deviations: The analysis of Ni and Sb content in the organs of the test animals was performed in a laboratory without quality assurance unit. Therefore, the report was not audited by QAU; the stability of the test substance has not been proven by recharac
Limit test:
yes

Test material

Constituent 1
Reference substance name:
Lichtgelb 8G
IUPAC Name:
Lichtgelb 8G
Constituent 2
Chemical structure
Reference substance name:
Antimony nickel titanium oxide yellow
EC Number:
232-353-3
EC Name:
Antimony nickel titanium oxide yellow
Cas Number:
8007-18-9
Molecular formula:
(Ti, Sb, Ni) O2
IUPAC Name:
antimony nickel titanium oxide yellow
Details on test material:

- Batch No.: Pt 8817;
- Composition of test material, percentage of components: weight based: TiO2 76.8%, Sb2O5 13.6%, NiO 5% , SiO2 2.4%, Pb 31 ppm, As 16 ppm, other heavy metals < 5 ppm; Ni, soluble in 0.1 N HCl 46 ppm

Test animals

Species:
rat
Strain:
other: Wistar/Chbb:THOM
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach, Germany
- Age at study initiation: 7 weeks
- Weight at study initiation: 230 - 232 g ( the average weight of the addtional set of animals 304 g ± 1.7 g)
- Housing: Singly in Makrolon/wire cages (type MD III of Becker, Castrop-Rauxel, Germany)
- Diet: KLIBA rat/mouse/hamster laboratory diet 24-343-4 10 mm pellets; Klingentalmühle AG, Kaiseraugst, Switzerland
- Water: during exposure withdrawn


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose/head only
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: 0.6 - 1.0 µm/ 2.8 - 4.1 (measurements on d 3 and d 5
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: aerodynamic exposure apparatus (INA 60, volume V 90 l, BASF Aktiengesellschaft)
- Method of fixing animals in test chamber: exposure tubes; animal snouts projecting into the inhalation chamber
- Rate of air: Supply air (l/h): compressed air 1,500, blast air 4,500; Exhause air (l/h): 5,400
- System of generating particulates/aerosols: dust generator
- Temperature, humidity: 23.3-23.6 °C , 50.6-54.0 %
- Method of particle size determination: Gravimetrical determination

TEST ATMOSPHERE
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
5 days
Frequency of treatment:
6 hours/day, daily
Doses / concentrations
Remarks:
Doses / Concentrations:
60 mg/m3 (0.06 mg/l)
Basis:
nominal conc.
No. of animals per sex per dose:
50 (divided into 5 groups with differing post-exposure periods)
Control animals:
other: During analyses of livers and kidneys of the first test groups the need occurred to analyse kidneys of untreated animals (blank values), therefore another set of animals was delivered age-matched to the test animals of test group 1 at sacrifice.
Details on study design:
Post-exposure period: 0, 3, 10, 31, 60 days

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least 3 times on exposure days and, as a rule, once during the preflow period and the post-exposure observation period.
BODY WEIGHT: Yes
- Time schedule for examinations: at the beginning of preflow, at the beginning of exposure period and then once a week
Sacrifice and pathology:
Control group was sacrificed on day of arrival
Group 1 on test day four (after the last exposure)
Group 2 at day 7 (post-exposure day 3)
Group 3 at day 14 (post-exposure day 10)
Group 4 at day 35 (post-exposure day 31)
Group 5 at day 64 (post-exposure day 60)
Other examinations:
ANALYSIS: Ni and Sb concentrations in lung, liver and kidneys were determined by ICP-MS; Food analysis: contaminations in the used commercial feed were 1.42 mg Ni/kg and 13 µg Sb/kg.
Statistics:
no statistical evaluation because no concurrent control.

Results and discussion

Results of examinations

Details on results:
No effects on mortality, clinical signs, body weights and body weight gains

Effect levels

Dose descriptor:
NOAEC
Effect level:
60 mg/L air
Remarks on result:
not determinable
Remarks:
no NOAEC identified

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

CONTENT OF Ni AND Sb in:
LIVER: 
Mean Sb concentration (quantification limit 0.2 ng/g) in unexposed animals was 1.1 ng/g; directly post-exposure
and on day 3-post-exposure the concentration was about 4-fold higher in exposed animals, during further observation
the concentration was similar to unexposed animals (1.3 ng/g on day 10).
Mean Ni-concentration was in the same range in exposed and unexposed animals (however, below the quantification limit
of 10 ng/g; outliers not considered). 

KIDNEYS: 
Mean Sb concentration in unexposed animals was below the detection limit (1 ng/g), in exposed animals it was above the 
detection limit but below the quantification limit (3 ng/g), only the day 3 post exposure group reached a value of 5.6 
ng/g (2-3-fold increase compared with other observation days).
Mean Ni concentration was below the detection limit (1 ng/g) in unexposed animals and above detection limit but below
quantification limit (25 ng/g) in exposed animals, except on day 3 post-exposure 94 ng/g were determined (10-fold more
than in other exposure groups. Authors comment: presumably due to contamination of the sample). 

LUNG: 
Directly post-exposure the mean Ni and Sb concentration was 79 and 202 µg/lung , respectively (corresponding to 2 mg of
pigment/lung). The concentration declined during the post-exposure period, following first order kinetics; the clearance 
half-life was 50 days.


Applicant's summary and conclusion