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Basic toxicokinetics

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basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1991-06-24 to 1991-09-10
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented (GLP, but no control)

Data source

Reference Type:
study report
Report date:

Materials and methods

Objective of study:
Test guideline
no guideline available
GLP compliance:
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

Test material

Constituent 1
Reference substance name:
C.I. Pigment yellow 53
C.I. Pigment yellow 53
Constituent 2
Reference substance name:
Antimony nickel titanium oxide yellow
EC Number:
EC Name:
Antimony nickel titanium oxide yellow
Cas Number:
Constituent 3
Reference substance name:
Lichtgelb 8G
Lichtgelb 8G
Details on test material:
- Physical state: yellow powder
- 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

other: Wistar/Chbb:THOM
Details on test animals or test system and environmental conditions:
- 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 additional set of animals 304 g ± 1.7 g)
- Housing: Single 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; Klingentalmuehle AG, Kaiseraugst, Switzerland
- Water: during exposure withdrawn

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

Administration / exposure

Route of administration:
unchanged (no vehicle)
Details on exposure:
- Exposure apparatus: aerodynamic exposure apparatus (INA 60, volume V 90 L, BASF AG)
- 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 1500, blast air 4500; Exhaust air (L/h): 5400
- 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

- Samples taken from breathing zone: yes
Duration and frequency of treatment / exposure:
5 days
Doses / concentrations
Doses / Concentrations:
60 mg/m3
No. of animals per sex per dose / concentration:
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
Details on dosing and sampling:
Monitoring of the inhalation atmosphere
Sampling: apparatus and conditions
- Vacuum compressed air pump (Millipore)
- Sampling equipment with probe (Millipore)
- Internal diameter: 7 mm for test groups 1 to 5
- Filter: MN 85/90 Bf (d = 4.7 cm)
- Sampling velocity: 1.25 m/s
- Sampling amount: 45 L
- Sampling site: immediately adjacent to the animals' noses
- Sampling frequency: as a rule, one sample per concentration group about hourly.
No statistical evaluation was performed because no concurrent control was available.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
LUNG: Immediate post-exposure concentrations of Ni and Sb were 79 and 202 µg/lung, respectively (corresponding to 2 mg of pigment/lung). The concentrations declined during the post-exposure period, following first order kinetics; the clearance half-life was 50 days.

LIVER: Mean Sb concentration (quantification limit 0.2 ng/g of liver) in unexposed animals was 1.1 ng/g; immediate post-exposure and day 3 post-exposure concentrations were about 4-fold higher in exposed animals. During further observations the concentrations were 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 to 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, when 94 ng/g were determined (10-fold more than in other exposure groups. Presumably due to contamination of the sample.

Any other information on results incl. tables

The exposure level was set to a ten fold higher level than the limit level for inert dusts set at that time by the German MAK Commission and to ensure a sufficient measureable Ni-deposition in the lung. Though a control group was not studied through the course of the experiment, the results obtained appear internally consistent and interpretable in relation to toxicity for the following reasons:

- mortality: no deaths were observed during the exposure and post exposure periods

- clinical examination: no clinical signs were observed which were different from normal

- body weight: weight gains were not affected compared with historical controls.

With respect to the observed levels of Ni and Sb in liver, kidneys and lung the non-bioavailability of the pigment has been clearly demonstrated. Both metals were present in liver and kidneys in the range of the limit of quantitation or below, with the exception of a clear Ni peak in the kidneys on day 3 of the post-exposure period. This peak can hardly be explained physiologically and a contamination with Ni during the processing steps by an unknown Ni source cannot be excluded. In conclusion, this study demonstrates the non-bioavailability of Ni and Sb after inhalation of the test substance.

Applicant's summary and conclusion