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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: 2b The study was conducted according to an appropriate OECD test guideline, with acceptable restrictions. The restrictions were that no urinalysis was conducted. There was also no information on the GLP status of the study.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Lack of Carcinogenicity of Ferric Chloride in F344 Rats.
Author:
Sato M, Furukawa F, Toyoda K, Mitsumori K, Nishikawa A, Takahashi M
Year:
1992
Bibliographic source:
DOI 10.1016/0278-6915(92)90048-P PMID 1427505 Food and Chemical Toxicology 30(10):837-42.
Reference Type:
publication
Title:
Oral subchronic toxicity studies of ferric chloride in F344 rat.
Author:
Sato H, Toyoda K, Furukawa F, Kokubo T, Takahashi M, Hayashi Y
Year:
1985
Bibliographic source:
Bull Natl Inst Hyg Sci (Tokyo) 0(103):21-8.

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
No information on GLP, limited details on environmental conditions, limited details on examinations conducted, and no urinalysis.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Iron trichloride
EC Number:
231-729-4
EC Name:
Iron trichloride
Cas Number:
7705-08-0
Molecular formula:
FeCl3
IUPAC Name:
iron(3+) trichloride
Details on test material:
- Name of test material (as cited in study report): Ferric chloride hexahydrate- Substance type: Iron salt- Physical state: Solid- Analytical purity: 98.5%- Impurities (identity and concentrations): No data- Composition of test material, percentage of components: No data- Purity test date: No data- Lot/batch No.: No data- Expiration date of the lot/batch: No data- Stability under test conditions: It was confirmed that a 2% solution of ferric chloride in distilled water was stable for one week at room temperature.- Storage condition of test material: No data

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS- Source: Charles River Japan Inc- Age at study initiation: Six weeks- Weight at study initiation: No data- Fasting period before study: No data- Housing: No data- Diet (e.g. ad libitum): Ad libitum- Water (e.g. ad libitum): Ad libitum- Acclimation period: One weekENVIRONMENTAL CONDITIONS- Temperature (°C): No data- Humidity (%): No data- Air changes (per hr): No data- Photoperiod (hrs dark / hrs light): No dataIN-LIFE DATES: No data

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Ferric chloride was dissolved in distilled water at concentrations of 0 (control), 0.12, 0.25, 0.5, 1.0 or 2.0 % (w/v).
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
14 weeks
Frequency of treatment:
Continuous
Doses / concentrations
Remarks:
Doses / Concentrations:0.12, 0.25, 0.5, 1.0 and 2.0% w/v FeCl3, equivalent to approximately 80, 154, 277, 550 and 1231 mg/kg bw/day in male rats, 88, 176, 314, 571 and 1034 mg/kg bw/day in female rats. Doses derived from information presented in graphs in Sato 1985Basis:nominal in water
No. of animals per sex per dose:
Ten
Control animals:
other: Drinking water only
Details on study design:
- Dose selection rationale: This is a dose-range finding study to determine doses for a two-year carcinogenicity study.- Rationale for animal assignment (if not random): No data- Rationale for selecting satellite groups: No satellite group- Post-exposure recovery period in satellite groups: None- Section schedule rationale (if not random): No data

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes - Time schedule: DailyDETAILED CLINICAL OBSERVATIONS: No dataBODY WEIGHT: Yes - Time schedule for examinations: WeeklyFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): - Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No - Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No FOOD EFFICIENCY:- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): YesOPHTHALMOSCOPIC EXAMINATION: No HAEMATOLOGY: Yes - Time schedule for collection of blood: At the end of the exposure period- Anaesthetic used for blood collection: No data- Animals fasted: No data- How many animals: All survivors- Parameters examined: no dataCLINICAL CHEMISTRY: Yes - Time schedule for collection of blood: At the end of the exposure period- Animals fasted: No data- How many animals: All survivors- Parameters examined: no dataURINALYSIS: No NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, for all survivors. No further details.HISTOPATHOLOGY: Yes, all major organs and tissues. No further details.
Statistics:
Body weight and the daily water intake data were analysed statistically using Student's t-test.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: No deaths or clinical signs of toxicity were observed. BODY WEIGHT AND WEIGHT GAIN: In the 1.0 and 2.0% groups there was a reduced body weight gain of at least 10% compared with the controls at the termination of treatment. WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): There was a significant suppression in the intake of drinking water observed in groups given concentrations of 0.5% or more (no further detail). HAEMATOLOGY: Males of the treated groups had significantly increased red blood cell counts (no further details). CLINICAL CHEMISTRY: Higher levels of serum iron were observed in males (control: 102±5 g/dl; 0.12%: 107±11 g/dl; 0.25%: 109±8  g/dl; 0.5%: 129±22  g/dl; 1.0%: 139±10  g/dl; 2.0%: 156 g/dl). GROSS PATHOLOGY: No findings reported.HISTOPATHOLOGY: NON-NEOPLASTIC: In examinations of sections stained with haematoxylin and eosin, brown pigment deposition was observed only in the keratin layers of the oesophageal mucosa in the groups given concentrations of 0.25% or higher, and in the laminae propriae of the large intestine in the 2.0% group. In sections stained with Berlin blue, increased numbers of positive pigments were also observed in the hepatocytes and Kupffer cells of the liver, the cartilage of the trachea and bronchus, the keratin mucosal layers of the tongue, the forestomach, the mucous layers of the small intestines, the white pulp of the spleen, the tubular epithelium of the kidney and the adipose tissues of the groups given 0.25% and higher. The intensity of the staining was marked in the intestine and liver. HISTOPATHOLOGY: NEOPLASTIC: not investigated in this range-finding study.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
0.5 other: %
Based on:
test mat. (total fraction)
Remarks:
FeCl3 solution in drinking water
Sex:
male/female
Basis for effect level:
other: Equivalent to 0.277 and 0.314 mg/kg bw/day in males and females, respectively.
Key result
Dose descriptor:
NOAEL
Effect level:
277 mg/kg bw/day (nominal)
Based on:
test mat. (total fraction)
Remarks:
FeCl3
Sex:
male
Basis for effect level:
body weight and weight gain
Dose descriptor:
NOAEL
Effect level:
314 mg/kg bw/day (nominal)
Based on:
test mat. (total fraction)
Remarks:
FeCl3
Sex:
female
Basis for effect level:
body weight and weight gain
Key result
Dose descriptor:
NOAEL
Effect level:
95 mg/kg bw/day (nominal)
Based on:
element (total fraction)
Remarks:
Fe
Sex:
male
Basis for effect level:
other: recalculated value from the FeCl3 level
Dose descriptor:
NOAEL
Effect level:
108 mg/kg bw/day (nominal)
Based on:
element (total fraction)
Remarks:
Fe
Sex:
female
Basis for effect level:
other: recalculated value from the FeCl3 level

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In a good quality dose range-finding study (reliability score 2) in which ferric chloride hexahydrate was administered to rats in their drinking water for 14 weeks, the NOAEL was 0.5% (equivalent to 277 and 314 mg/kg bw/day in males and females, respectively).
Executive summary:

In a good quality dose range-finding study (reliability score 2) in which ferric chloride hexahydrate was administered to Fischer 344 rats (10/sex/dose) in their drinking water for 14 weeks, at concentrations of 0.12, 0.25, 0.5, 1.0 and 2.0 % FeCl3 (equivalent to approximately 80, 154, 277, 550 and 1231 mg/kg bw/day in male rats, 88, 176, 314, 571 and 1034 mg/kg bw/day in female rats). All deaths and clinical signs of toxicity were recorded. Body weights were measured weekly. At the end of the dosing period, all survivors were killed for haematological, clinical chemistry and pathological exminations. All major organs and tissues were examined microscopically. There were no deaths or clinical signs of toxicity. There was a significant reduction in body weight gains at the two highest doses at the end of the treatment period. Treated males had increased levels of serum iron and higher red blood cell counts compared with controls. In microscopic examinations of sections stained with haematoxylin and eosin, brown pigment deposition was observed only in the keratin layers of the oesophageal mucosa in the groups given concentrations of 0.25 % or higher, and in the laminae propriae of the large intestine in the 2.0 % group. In sections stained with Berlin blue, increased numbers of positive pigments (an indication of iron overload) were also observed in the hepatocytes and Kupffer cells of the liver, the cartilage of the trachea and bronchus, the keratin mucosal layers of the tongue, the forestomach, the mucous layers of the small intestines, the white pulp of the spleen, the tubular epithelium of the kidney and the adipose tissues of the groups given 0.25% and higher. The intensity of the staining was marked in the intestine and liver. The NOAEL was 0.5 % (equivalent to 277 and 314 mg/kg bw/day in males and females, respectively) based on the reduced body weight gain.