Registration Dossier

Toxicological information

Repeated dose toxicity: inhalation

Currently viewing:

Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP and guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report Date:
1995

Materials and methods

Test guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
GLP compliance:
yes (incl. certificate)
Remarks:
testing lab.
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Pentacarbonyliron, according to the authors, iron content
was 28.3% (cerimetrical titration) which is nearly
theoretical Fe contents for Fe(CO)5

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Male and female SPF-Wistar rats/Chbb :THOM, supplied by Dr. K. Thomae GmbH, Biberach, Germany, were used at an age of about 7 weeks (on delivery). They were clinically free from any signs of disease. The animals of test groups 0, 1, 2 and 3 only were allocated to the groups at random (WTALOC randomization program supplied by Instem). The purpose of this was to obtain test groups of equal weight.
During the period when the rats were not exposed they were housed singly in wire cages (type OK III of Becker, Castrop-Rauxel, FRG) .
The animals were kept in fully air-conditioned rooms in which a temperature in the range of 20 - 24°C and relative humidity in the range of 30 - 70% were ensured by means of a central air-conditioning system. A light/dark rhythm of 12 hours was maintained (06.00 - 18.00 hours light; 18.00 - 06.00 hours dark).
The animals were offered KLIBA rat/mouse laboratory diet 24-343-4 10 mm pellets, Klingentalmühle AG, Kaiseraugst, Switzerland, and tap water ad libitum. During exposure food and water were withdrawn.
The animals were identified by ear tattoo.

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Details on inhalation exposure:
Special safety instructions had to be respected because of the explosivity of the material in presence of oxygen.
Inhalation atmospheres were generated by passing nitrogen through a thermostated steel cylinder filled with liquid FEC. The nitrogen iron pentacarbonyl vapors were then diluted with compressed air, mixed by passing through a glass mixing stage, and distributed after further dilution with blast air to the inhalation chambers at the appropriate concentration ratios.
The animals were kept singly in wire cages that were located in a glass-steel inhalation chamber, volume V = 1400 l.
In order to accustom the animals to the exposure conditions they were exposed to supply air in whole-body exposure systems on 5 days before the exposure period (preflow period). Then all test groups were exposed for 6 hours on workdays.
The animals did not have access to water or feed during the exposure.
Duration of treatment / exposure:
up to 28 days
Frequency of treatment:
5 days per week; 6 hours per day (totally up to 20 exposures)
Doses / concentrations
Remarks:
Doses / Concentrations:
0.1 ppm = ca. 0.0008 mg/l = test group 4; 0.3 ppm = ca. 0.002 mg/l = test group E; 1 ppm = ca. 0.008 mg/l = test group 1; 3 ppm = ca. 0.024 mg/l = test group 2; 10 ppm = ca. 0.081 mg/l = test group 3
Basis:
analytical conc.
No. of animals per sex per dose:
5
Control animals:
other: clean air
Details on study design:
Rats (Gage et al ., 1970) died after up to 18 exposures over 5 .5 hour exposures to 15 ppm FEC. Clinical examination revealed particularly lethargy and respiratory symptoms. The lung was found to be the target organ (lung edemas and congestions). At a concentration of 7 ppm and under the same exposure conditions no organ changes were described. Based on these findings, the following concentrations were selected:
- high concentration : 10 ppm
- intermediate concentration : 3 ppm
- low concentration: 1 ppm
A NOEL was expected with the low concentration, which is equivalent to 10 times the MAK value.
Because of severe toxic effects (lethality) at 10 ppm during the first and at 3 ppm during the second exposure, treatment was discontinued for these groups and the surviving animals were observed without further exposure. Two additional groups were exposed to lower concentrations.

Examinations

Observations and examinations performed and frequency:
The body weight of the animals of the test groups 0, 1, 2 and 3 was checked at the beginning of the preflow period, one day before beginning of the exposure period (day -1), at the beginning of the exposure period (day 0) and then, as a rule, once a week. The body weight of the animals of the test groups 4 and E was checked at the beginning of the exposure period (day 0) and then, as a rule, once a week.
The difference between the body weight on the day of weighing and the body weight at the beginning of exposure period was calculated as a group mean. This value was defined as body weight change.
Behavior and state of health of the test animals were checked, as a rule, 3 times on exposure days during exposure period, once on exposure days during preflow period and once on working days during post-exposure observation period.
A check for dead animals was made daily.
HAEMATOLOGY: Yes
CLINICAL CHEMISTRY: Yes
URINALYSIS: Yes
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
The statistical evaluation of the data was carried out on the computer systems of the Department of Toxicology.

Results and discussion

Results of examinations

Details on results:
One exposure to 10 ppm (test group 3) caused 100% lethality and 2 exposures to 3 ppm (test group 2) 50% lethality (3 male and 2 female animals) during a period of 4 days.
In test group 3 (10 ppm) the animals showed symptoms of respiratory distress and irritation as well as reduced general state. Pathological examinations revealed signs of irritation in the upper respiration tract and severe lung damage. In some animals lymphocyte depletion of the spleen occurred.
In test group 2 (3 ppm) the surviving animals showed accelerated respiration up to study day 9. No influence on body weight development was seen in the post-exposure observation period. No substance-related changes in hematological or clinico-chemical parameters occurred.
The same kind of lung damage as in test group 3 was found during pathological examination in the animal that died or were sacrificed prematurely. The surviving animals still showed increased absolute and relative lung weights and some histopathologic changes in the lungs at the end of the study period.
No substance related clinical signs and findings or influence on body weight development was seen in test groups 4, E and 1. No substance induced effects on hematological and clinicochemical parameters occurred besides a slight but mostly statistically significant elevation of CO-hemoglobin levels which is not considered as of toxicologial relevance. Pathological evaluation also did not reveal any morphological alterations besides a slight but statistically significant increase in absolute and relative lung weights of the male animals of test group 1 ppm.

Effect levels

open allclose all
Dose descriptor:
NOAEC
Effect level:
0.002 mg/L air
Sex:
male/female
Basis for effect level:
other: overall effects
Dose descriptor:
LOAEC
Effect level:
0.008 mg/L air
Sex:
male/female
Basis for effect level:
other: overall effects

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Concentrations of 10 and 3 ppm of FEC vapours inhaled 6 hours per working day in this 28-day study caused considerable lethality probably by severe damage to the lungs already after 1 or 2 exposures. At 1 ppm the only effect that might possibly be related to the substance exposure was an increase in absolute and relative lung weights of male animals at the end of the study period.
Concentrations of 0 .3 ppm or below did not cause toxic effects.