Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Jun 24 - Sep 10, 1991
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented (GLP, but no real control)

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

Objective of study:
distribution
Test guideline
Qualifier:
no guideline available
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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
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 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 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- Water: during exposure withdrawn


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

Administration / exposure

Route of administration:
inhalation
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- 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 1,500, blast air 4,500; Exhaust 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
Duration and frequency of treatment / exposure:
5 day(s)
Doses / concentrations
Remarks:
Doses / Concentrations:
60 mg/m3
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
Details on dosing and sampling:
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
ANALYSES: Ni and Sb concentrations in lung, liver and kidneys determined by ICP-MS (Inductively coupled plasma – mass spectrometry); Food analysis: contamination in the commercial feed was 1.42 mg Ni/kg and 13 µg Sb/kg.
Statistics:
no statistical evaluation because no concurrent control.

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 (2-3-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. Authors´ comment: Presumably due to contamination of the sample).

Applicant's summary and conclusion