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Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards, well documented and acceptable for assessment

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Inhalation Toxicity Study on Rats Exposed to Titanium Tetrachloride Atmospheric Hydrolysis Products for Two Years
Author:
Lee KP, Kelly DP, Schneider PW, Trochimowicz HJ
Year:
1986
Bibliographic source:
Toxicology and Applied Pharmacology 83: 30-45
Reference Type:
publication
Title:
Epidemiologic Study of Lung Cancer Mortality in Workers Exposed to Titanium Tetrachloride
Author:
Fayerweather WE, Karns ME, Gilby PG, Chen JL
Year:
1992
Bibliographic source:
J. Occup. Med. 34(2): 164-169

Materials and methods

Principles of method if other than guideline:
Rats were exposed to TiCl4 hydrolysis products by inhalation exposure at aerosol concentrations of 0, 0.1, 1.0 and 10 mg/m3 for 6 h/day, 5 days/week for 2 years.
GLP compliance:
not specified

Test material

Constituent 1
Reference substance name:
titanium chloride
IUPAC Name:
titanium chloride

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Weight at study initiation: 240 +- 10 g
- Housing: individually
- Diet: ad libitum
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23+-2 °C
- Humidity (%): 50+-10 %
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: air
Remarks on MMAD:
MMAD / GSD: The aerodynamic diameter (AD) of the chamber particulate was determined twice at the 10 mg/m3 concentration with a Brink cascade impactor. Virtually all the particles were less than 1.6 µm AD, and the mass median diameter was about
0.5 µm with geometric standard deviation of about 2.
Details on inhalation exposure:
Inhalation Chambers
Special chambers were constructed of Hastelloy, a high-nickel stainless-steel which was found to withstand the corrosive effects of TiCl4 vapor. The
chambers were of conventional shape and had a volume of 4.0 m3, with a special vertical-opening, hydraulically operated door.

Atmosphere Generation and Analysis
TiCI4 vapors were generated by passing nitrogen over liquid TiCl4 in a glass vessel situated in a 20°C constant-temperature
bath. TiCI4 vapors were mixed with the 1000 liters/min chamber air supply at the chamber top. TiCl4 hydrolysis occurs so rapidly in air that a second
nitrogen stream was required to shield the vapor delivery tube to avoid build up of solid hydrolysis products on the delivery
tube tip. Chamber atmospheres were monitored by trapping the solid TiCl4 hydrolysis products on cellulose acetate filters which were then analyzed
for titanium content by a calorimetric method. Chamber concentrations were reported as mg/m3 of TiCI4 as calculated
from the titanium concentration. The aerodynamic diameter (AD) of the chamber particulate was determined twice at the 10 mg/m3 concentration with a Brink cascade impactor. Virtually all the particles were less than 1.6 µm AD, and the mass median diameter was about
0.5 µm with geometric standard deviation of about 2. There was essentially no unhydrolyzed TiCI4 in the chamber atmosphere.
This was determined by drawing chamber air through a filter in tandem with a water-filled impinger. If unhydrolyzed TiCI4 vapors were present, they
would have passed through the filter and titanium would have been found in the impinger water.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chamber atmospheres were monitored by trapping the solid TiCl4 hydrolysis products on cellulose acetate filters which were then analyzed
for titanium content by a calorimetric method. Chamber concentrations were reported as mg/m3 of TiCI4 as calculated
from the titanium concentration.
Duration of treatment / exposure:
24 months
Frequency of treatment:
6 hours/day, 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.1, 1.0 and 10 mg/m3
Basis:
nominal conc.
No. of animals per sex per dose:
100
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
Five males and five females from each group were killed after 3 and 6 months of exposure and, subsequently, 10 males and 10 females were
killed after 1 year of exposure. All surviving rats were killed at the end of the 2-year exposure.
Sacrifice and pathology:
All rats killed by design, found dead, or killed in extremis were subjected to gross
and microscopic evaluation. All surviving rats were killed at the end of the 2-year exposure and their tissues were
examined grossly and microscopically.

Results and discussion

Effect levels

Dose descriptor:
LOAEL
Effect level:
0.1 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
other: mild rhinitis

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

There were no abnormal clinical signs, body weight changes, or excess mortality in any exposed groups. No pathological changes other than a mild rhinitis were observed at 0.1 mg/m3. At 1.0 mg/m3, the incidence of mild rhinitis and tracheitis was increased. The lungs showed a minute dust-laden macrophage (dust cell) reaction with slight Type II pneumocyte hyperplasia in alveoli adjacent to the alveolar ducts. The pulmonary response at the 1.0 mg/m3 satisfied the biological criteria for a nuisance dust. At 10 mg/m3, extrapulmonary particle deposition occurred in the tracheobronchial lymph nodes, liver, and spleen without any tissue response. An increased incidence of rhinitis, tracheitis and dust cell response with Type II pneumocyte hyperplasia, alveolar bronchiolarization, foamy dust cell accumulation, alveolar proteinosis, cholesterol granuloma, and focal pleurisy was also observed. The pulmonary lesions developed in the alveolar duct region where dust cells had accumulated and had provoked a chronic tissue response. In addition, a few well-differentiated, cystic keratinizing squamous carcinomas were developed from alveoli showing bronchiolarization with squamous metaplasia in the alveolar duct region. No tumor metastasis was found in other organs. The lung tumors were a unique type of experimentally induced tumor and have not been seen usually in man or animals. Therefore, the relevance to man of this type of lung tumor is highly questionable.

Applicant's summary and conclusion