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Repeated dose toxicity: oral

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Endpoint:
repeated dose toxicity: oral, other
Remarks:
combined repeated dose and reproductive/developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
not specified
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Study summary available only. Original reference was not obtainable, but the study was approved by the OECD procedure on Mutual Acceptance of Data (MAD).
Cross-reference
Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
reproductive toxicity, other
Remarks:
combined repeated dose and reproductive/developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
not specified
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Study summary available only. Original reference was not obtainable, but the study was approved by the OECD procedure on Mutual Acceptance of Data (MAD).
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
not specified
Limit test:
no
Justification for study design:
not applicable
Specific details on test material used for the study:
not specified
Species:
rat
Strain:
not specified
Details on species / strain selection:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
not specified
Route of administration:
oral: gavage
Vehicle:
not specified
Details on exposure:
not specified
Details on mating procedure:
not specified
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
males: 42 days
females: 42 - 54 days
Frequency of treatment:
not specified
Details on study schedule:
not specified
Dose / conc.:
125 mg/kg bw/day (actual dose received)
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
not specified
Control animals:
yes
Details on study design:
not specified
Positive control:
not specified
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes, death

DETAILED CLINICAL OBSERVATIONS: Not specified

BODY WEIGHT: Yes

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Not specified
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not specified

WATER CONSUMPTION AND COMPOUND INTAKE: Not specified
Oestrous cyclicity (parental animals):
not specified
Sperm parameters (parental animals):
not specified
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number of neonates, survival rate, and sex ratio of live neonates



Postmortem examinations (parental animals):
ORGAN WEIGHTS: Yes
HISTOPATHOLOGY: Yes
Postmortem examinations (offspring):
not specified
Statistics:
not specified
Reproductive indices:
not specified
Offspring viability indices:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Description (incidence):
- there were female deaths in the 500 mg/kg bw/day group only.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
- body weight gain was reduced in males by 21% in the 250 mg/kg bw/day group and by 37% in the 500 mg/kg bw/day group, and in females by 17% in the 250 and by 15% in the 500 mg/kg bw/day groups.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
- mean cell volume was increased by 7% in the 500 mg/kg bw/day male treatment group, and metheamoglobin decreased by up to 78% for females in the 125, 250 and 500 mg/kg bw/day treatment groups.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
- cholinesterase was decreased in males by up to 41% at doses of 250 and 500 mg/kg bw/day.
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathological examination showed hemosiderin deposits in the hepatocytes, hyperplasia of the adrenals and zona fasciculata, hyperkeratosis of forestomach, hemosiderin deposits in the stomach, and neutrophil infiltration of submusoca in both sexes of the animals, at 500 mg/kg bw/day. In the case of decedent animals, severe villous atrophy of forestomach was observed; abnormalities of gastric function were detected. Therefore, it is concluded that deaths in female rats were caused by physical irritancy of the test substance.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
GROSS PATHOLOGICAL FINDINGS
Following necropsy, there were no pathological changes of ovaries, testes and epididymides in treated animals.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
- there were no differences in mating rate between control and tested groups (93.3 % in control group, 86.7 % in 125 mg/kg bw/day group, 100 % in 250 mg/kg bw/day and 100 % in 500 mg/kg bw/day group).
- birth rate showed no difference between the treated and the control groups.
- there were no differences in fertility index (73.3%, 80.0%, 93.3%, and 66.7% for male rats, and 78.6%, 85.7%, 93.35, and 66.7% for female rats in control, 125 mg bw/kg/day, 250 mg/kg bw/day and 500 mg/kg bw/day groups), and gestation periods (23.6 d in control group, 22.1 d in 125 mg/kg bw/day group, 22.3 d in 250 mg/kg bw/day group and 22.1 d in 500 mg/kg bw/day group) between control and treated groups.
- pre-implantation loss rates (14.4 %, 9.4 %, 14.3 % and 9.8 % for the control, low, intermediate and high dose groups, respectively) and post-implantation loss (6.0 %, 6.0 %, 3.1 % and 7.0 %, respectively) were unaffected by treatment.
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
haematology
clinical biochemistry
organ weights and organ / body weight ratios
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
55 mg/kg bw/day (actual dose received)
Based on:
element
Remarks:
Fe
Sex:
male/female
Basis for effect level:
body weight and weight gain
haematology
clinical biochemistry
organ weights and organ / body weight ratios
Dose descriptor:
NOAEL
Remarks:
reproduction
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: based on no significant difference in mating data and pre- and post-implantation loss rate.
Dose descriptor:
NOAEL
Remarks:
reproduction
Effect level:
220 mg/kg bw/day (actual dose received)
Based on:
element
Remarks:
Fe
Sex:
male/female
Remarks on result:
other: based on no significant difference in mating data and pre- and post-implantation loss rate.
Critical effects observed:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
no effects observed
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
MORTALITY / VIABILITY
The survival rate at postpartum day 0, and survival rate at postpartum day 4 showed no difference between the treated and the control groups.

OTHER FINDINGS
The number of neonates showed no difference between the treated and the control groups.
The sex ratio of live neonates was not affected by ferrous chloride.
A single case of acaudia and decreased crown rump length on postpartum day 4 in 125 mg/kg/day group (i.e. no dose response relationship) were the only findings of note.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
220 mg/kg bw/day (actual dose received)
Based on:
element
Remarks:
Fe
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Critical effects observed:
not specified
Reproductive effects observed:
no
Conclusions:
This study found no indication of any reproductive toxicity in parent animals at the maximum tested dose of 500 mg/kg bw/day (equivalent to 220 mg Fe /kg bw/day). Therefore, the NOAEL for reproductive toxicity was 500 mg/kg bw/day.

The original reference could not be obtained and this study entry is based on an available study summary, but the study was approved by the OECD procedure on Mutual Acceptance of Data (MAD).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report date:
2004

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
Iron dichloride
EC Number:
231-843-4
EC Name:
Iron dichloride
Cas Number:
7758-94-3
Molecular formula:
Cl2Fe
Test material form:
not specified
Details on test material:
not specified
Specific details on test material used for the study:
not specified

Test animals

Species:
rat
Strain:
not specified
Details on species / strain selection:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
not specified

Administration / exposure

Route of administration:
oral: gavage
Details on route of administration:
not specified
Vehicle:
not specified
Details on oral exposure:
not specified
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
males: 42 days
females: 42 - 54 days
Frequency of treatment:
not specified
Doses / concentrationsopen allclose all
Dose / conc.:
125 mg/kg bw/day (actual dose received)
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
not specified
Control animals:
yes
Details on study design:
not specified
Positive control:
not specified

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes, death

DETAILED CLINICAL OBSERVATIONS: Not specified

BODY WEIGHT: Yes

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Not specified
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not specified

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: Not specified

WATER CONSUMPTION AND COMPOUND INTAKE: Not specified
OPHTHALMOSCOPIC EXAMINATION: Not specified

HAEMATOLOGY: Yes
CLINICAL CHEMISTRY: Yes
URINALYSIS: Yes

NEUROBEHAVIOURAL EXAMINATION: Not specified
IMMUNOLOGY: Not specified
Sacrifice and pathology:
ORGAN WEIGHTS: Yes
HISTOPATHOLOGY: Yes
Statistics:
not specified

Results and discussion

Results of examinations

Clinical signs:
not specified
Mortality:
mortality observed, treatment-related
Description (incidence):
- there were female deaths in the 500 mg/kg bw/day group only.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
- body weight gain was reduced in males by 21% in the 250 mg/kg bw/day group and by 37% in the 500 mg/kg bw/day group, and in females by 17% in the 250 and by 15% in the 500 mg/kg bw/day groups.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
- mean cell volume was increased by 7% in the 500 mg/kg bw/day male treatment group, and metheamoglobin decreased by up to 78% for females in the 125, 250 and 500 mg/kg bw/day treatment groups.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
- cholinesterase was decreased in males by up to 41% at doses of 250 and 500 mg/kg bw/day.
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Organ weight measurements showed that liver weights were increased by up to 24% absolute weight in intermediate and high dose animals of both sexes, with adrenal weights increased by up to 31% absolute weight, 61% relative weight in males and thymus weights decreased by up to 32% absolute weight, 27% relative weight in females from these same treatment groups (relative and absolute values altered in all instances).
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathological examination showed hemosiderin deposits in the hepatocytes, hyperplasia of the adrenals and zona fasciculata, hyperkeratosis of forestomach, hemosiderin deposits in the stomach, and neutrophil infiltration of submusoca in both sexes of the animals, at 500 mg/kg bw/day. In the case of decedent animals, severe villous atrophy of forestomach was observed; abnormalities of gastric function were detected. Therefore, it is concluded that deaths in female rats were caused by physical irritancy of the test substance.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
URINALYSIS
- urinalysis showed no difference between control and treated groups.

GROSS PATHOLOGICAL FINDINGS
Following necropsy, there were no pathological changes of ovaries, testes and epididymides in treated animals.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical biochemistry
haematology
organ weights and organ / body weight ratios
Dose descriptor:
NOAEL
Effect level:
55 mg/kg bw/day (actual dose received)
Based on:
element
Remarks:
Fe
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical biochemistry
haematology
organ weights and organ / body weight ratios

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The NOAEL was concluded to be 125 mg/kg/day for males and females, equivalent to 55 mg Fe/kg/day. This NOAEL is based on changes in body weight gain, liver and adrenal weight, mean cell volume and cholinesterase in males, and changes in body weight gain, liver and thymus weight and metheamoglobin in females.

The original reference could not be obtained and this study entry is based on an available study summary, but the study was approved by the OECD procedure on Mutual Acceptance of Data (MAD).