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Key value for chemical safety assessment

Effects on fertility

Description of key information

The endpoint conclusion was derived after evaluation of all data available on analogues. The worst case was selected for the endpoint conclusion. A summary of the evaluation is included in Section 13.

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
The rationale to read across the data is attached in Section 13.
Reason / purpose:
read-across source
Specific details on test material used for the study:
BiOIxBr(1-x)
with x = 0.4 - 0.85
Typical x = 0.6; BiOI0.6Br0.4 (this distribution was used as the basis for calculations of doses)
Clinical signs:
no effects observed
Mortality:
not specified
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
not specified
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
KI produced no significant reductions in parental body weight or food consumption
Key result
Dose descriptor:
NOAEL
Effect level:
0.1 other: % in diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed at the highest tested dose
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 302 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks:
Recalculated dose based on iodide content (see Section "Any other information on results").
Sex:
male/female
Basis for effect level:
other: no adverse effects observed at the highest tested dose
Key result
Critical effects observed:
no
Clinical signs:
not specified
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
KI significantly increased offspring mortality at the highest dose.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
KI produced decreased weight gain at the two highest doses throughout the first 90 days after birth.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
In rats killed on day 90 after birth KI reduced brain and body weight at a dose of 0.1% of the diet, and reduced body but not brain weight at a dose of 0.05% of the diet. No significant effect was found on absolute or relative thyroid weight at 90 days of age.
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Functionally, KI delayed auditory startle at the two highest doses, delayed olfactory orientation to the home-cage scent at the middle dose and decreased female running-wheel activity at all dose levels.
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
Functionally, KI delayed auditory startle at the two highest doses, delayed olfactory orientation to the home-cage scent at the middle dose and decreased female running-wheel activity at all dose levels.
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
0.025 other: % in diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
mortality
body weight and weight gain
developmental neurotoxicity
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
ca. 77 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks:
Recalculated dose based on iodide content (see any other information on results").
Sex:
male/female
Basis for effect level:
mortality
body weight and weight gain
developmental neurotoxicity
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
0.05 other: % in diet
System:
nervous system
Organ:
other: olfactory neurons
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes
Key result
Reproductive effects observed:
yes
Lowest effective dose / conc.:
0.05 other: % in diet
Treatment related:
yes
Relation to other toxic effects:
reproductive effects in the absence of other toxic effects
Dose response relationship:
yes
Relevant for humans:
not specified
Conclusions:
In the study with rats, in which a read-across analogue potassium iodide was administered in diet at 0.025%, 0.05% and 0.1% to male and female rats before and during breeding, to females only during gestation and lactation, and to their offspring after weaning (day 21 after birth) through to day 90, the NOAEL for developmental toxicity was 0.025% in diet, based on decreased body weight and weight gain and delayed auditory startle at the two top dose levels. The NOAEL for parental toxicity was 0.1% in diet. The exposure to 0, 0.025, 0.05 or 0.1% (w/w) of the diet was calculated to correlate to appr. 0, 23, 45 and 90 mg KI/kg bw/day, based on default values reported in TNO report V98.390 (1998), or appr. 17.5, 39 and 69 mg I-/kg bw/day. These results can be read across to bismuth oxy-iodide bromide, applying a correction for molecular weight. The calculated NOAELs for developmental and parental toxicity correspond respectively to 77 and 302 mg BiOI0.6Br0.4/kg bw/day.
Executive summary:

A read-across analogue potassium iodide (KI) was fed to male and female rats before and during breeding, to females only during gestation and lactation, and to their offspring after weaning (day 21 after birth) through to day 90, at levels of 0, 0.025, 0.05 or 0.1% (w/w) of the diet. Dams in a fifth group (positive controls) were given 4 mg/kg bw ip of the anti-mitotic/cytotoxic drug 5-azacytidine on day 17 of gestation. All offspring were reared by their natural dams and were evaluated blind with respect to treatment in a battery of standardized behavioural tests between 3 and 90 days of age. KI produced no significant reductions in parental body weight or food consumption, though it significantly reduced litter size and increased offspring mortality at the highest dose, and decreased weight gain at the two highest doses throughout the first 90 days after birth. Functionally, KI delayed auditory startle at the two highest doses, delayed olfactory orientation to the home-cage scent at the middle dose and decreased female running-wheel activity at all dose levels. In rats killed on day 90 after birth KI reduced brain and body weight at a dose of 0.1% of the diet, and reduced body but not brain weight at a dose of 0.05% of the diet. No significant effect was found on absolute or relative thyroid weight at 90 days of age. Several additional behavioural effects were observed in the low-dose KI group, but because these effects were not dose-dependent, they were not regarded as reliable. 5-Azacytidine produced evidence of substantially greater developmental toxicity than KI. It was concluded that KI produced evidence of developmental toxicity consistent with a picture of impaired thyroid function. The parental NOEL value for potassium iodide in rats was 0.1% in diet, while the NOAEL for offspring was 0.025% in diet. The exposure to 0, 0.025, 0.05 or 0.1% (w/w) of the diet was calculated to correlate to appr. 0, 23, 45 and 90 mg KI/kg bw/day, based on default values reported in TNO report V98.390 (1998), or appr. 17.5, 39 and 69 mg I-/kg bw/day. These results can be read across to bismuth oxy-iodide bromide, applying a correction for molecular weight. The calculated NOAELs for developmental and parental toxicity correspond respectively to 77 and 302 mg BiOI0.6Br0.4/kg bw/day.


Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
302 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Sufficient data available on all analogues.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

The endpoint conclusion was derived after evaluation of all data available on analogues. The worst case was selected for the endpoint conclusion. A summary of the evaluation is included in Section 13.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
The rationale to read across the data is attached in Section 13.
Reason / purpose:
read-across source
Specific details on test material used for the study:
BiOIxBr(1-x)
with x = 0.4 - 0.85
Typical x = 0.6; BiOI0.6Br0.4 (this distribution was used as the basis for calculations of doses)
Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Number of abortions:
not specified
Pre- and post-implantation loss:
not specified
Early or late resorptions:
not specified
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
not specified
Other effects:
not specified
Key result
Dose descriptor:
NOAEL
Effect level:
302 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: no adverse effects on the highest tested dose
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 302 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks:
Recalculated dose based on iodide content (see any other information on results").
Basis for effect level:
other: no adverse effects at highest dose tested.
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
KI produced decreased weight gain at the two highest doses throughout the first 90 days after birth.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): KI produced decreased weight gain at the two highest doses throughout the first 90 days after birth.
Reduction in number of live offspring:
effects observed, treatment-related
Description (incidence and severity):
KI significantly increased offspring mortality at the highest dose.
Changes in sex ratio:
not specified
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
KI significantly reduced litter size at the highest dose.
Changes in postnatal survival:
effects observed, treatment-related
Description (incidence and severity):
KI significantly increased offspring mortality at the highest dose.
External malformations:
no effects observed
Skeletal malformations:
not specified
Visceral malformations:
not specified
Other effects:
effects observed, treatment-related
Description (incidence and severity):
In rats killed on day 90 after birth KI reduced brain and body weight at a dose of 0.1% of the diet, and reduced body but not brain weight at a dose of 0.05% of the diet. No significant effect was found on absolute or relative thyroid weight at 90 days of age.
Details on embryotoxic / teratogenic effects:
Functionally, KI delayed auditory startle at the two highest doses, delayed olfactory orientation to the home-cage scent at the middle dose and decreased female running-wheel activity at all dose levels. In rats killed on day 90 after birth KI reduced brain and body weight at a dose of 0.1% of the diet, and reduced body but not brain weight at a dose of 0.05% of the diet. No significant effect was found on absolute or relative thyroid weight at 90 days of age. Several additional behavioural effects were observed in the low-dose KI group, but because these effects were not dose-dependent, they were not regarded as reliable
Key result
Dose descriptor:
NOAEL
Effect level:
0.025 other: % in diet
Based on:
test mat.
Sex:
not specified
Basis for effect level:
reduction in number of live offspring
fetal/pup body weight changes
changes in litter size and weights
changes in postnatal survival
other: delayed auditory startle at the two highest doses, delayed olfactory orientation to the home-cage scent at the middle dose and decreased female running-wheel activity at all dose levels
Key result
Dose descriptor:
NOAEL
Effect level:
17.5 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks:
Recalculated dose based on iodide content (see any other information on results").
Sex:
not specified
Basis for effect level:
reduction in number of live offspring
changes in postnatal survival
other: delayed auditory startle at the two highest doses, delayed olfactory orientation to the home-cage scent at the middle dose and decreased female running-wheel activity at all dose levels
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
0.05 other: % in diet
Treatment related:
yes
Relation to maternal toxicity:
developmental effects in the absence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
yes

The exposure to 0, 0.025, 0.05 or 0.1% (w/w) of the diet was calculated to correlate to appr. 0, 23, 45 and 90 mg KI/kg bw /day. The calculation was based on default values reported in TNO report V98.390 (1998). These doses correlate to appr. 17.5, 39 and 69 mg I-/kg bw/ day. These doses correlate to approximately 77, 172 and 302 mg BiOI0.6Br0.4.

Conclusions:
In the study with rats, in which a read-across analogue potassium iodide was administered in diet at 0.025%, 0.05% and 0.1% to male and female rats before and during breeding, to females only during gestation and lactation, and to their offspring after weaning (day 21 after birth) through to day 90, the NOAEL for developmental toxicity was 0.025% in diet, based on decreased body weight and weight gain and delayed auditory startle at the two top dose levels. The NOAEL for parental toxicity was 0.1% in diet. The exposure to 0, 0.025, 0.05 or 0.1% (w/w) of the diet was calculated to correlate to appr. 0, 23, 45 and 90 mg KI/kg bw/day, based on default values reported in TNO report V98.390 (1998), or to appr. 17.5, 39 and 69 mg I-/kg bw/ day. These results can be read-across to bismuth oxy-iodide bromide, applying a correction for molecular weight. The NOAELs for developmental and parental toxicity correspond respectively to approximately 77 and 302 mg BiOI0.6Br0.4/kg bw/day.
Executive summary:

A read-across analogue potassium iodide (KI) was fed to male and female rats before and during breeding, to females only during gestation and lactation, and to their offspring after weaning (day 21 after birth) through to day 90, at levels of 0, 0.025, 0.05 or 0.1% (w/w) of the diet. Dams in a fifth group (positive controls) were given 4 mg/kg bw ip of the anti-mitotic/cytotoxic drug 5-azacytidine on day 17 of gestation. All offspring were reared by their natural dams and were evaluated blind with respect to treatment in a battery of standardized behavioural tests between 3 and 90 days of age. KI produced no significant reductions in parental body weight or food consumption, though it significantly reduced litter size and increased offspring mortality at the highest dose, and decreased weight gain at the two highest doses throughout the first 90 days after birth. Functionally, KI delayed auditory startle at the two highest doses, delayed olfactory orientation to the home-cage scent at the middle dose and decreased female running-wheel activity at all dose levels. In rats killed on day 90 after birth KI reduced brain and body weight at a dose of 0.1% of the diet, and reduced body but not brain weight at a dose of 0.05% of the diet. No significant effect was found on absolute or relative thyroid weight at 90 days of age. Several additional behavioural effects were observed in the low-dose KI group, but because these effects were not dose-dependent, they were not regarded as reliable. 5-Azacytidine produced evidence of substantially greater developmental toxicity than KI. It was concluded that KI produced evidence of developmental toxicity consistent with a picture of impaired thyroid function. The parental NOEL value for potassium iodide in rats was 0.1% in diet, while the NOAEL for offspring was 0.025% in diet. The exposure to 0, 0.025, 0.05 or 0.1% (w/w) of the diet was calculated to correlate to appr. 0, 23, 45 and 90 mg KI/kg bw/day, based on default values reported in TNO report V98.390 (1998), or to appr. 17.5, 39 and 69 mg I-/kg bw/ day. These results can be read-across to bismuth oxy-iodide bromide, applying a correction for molecular weight. The NOAELs for developmental and parental toxicity correspond respectively to approximately 77 and 302 mg BiOI0.6Br0.4/kg bw/day.


Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
77 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Sufficient data available on all analogues.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the available data, bismuth oxy-iodide bromide is not classified for toxicity to reproduction or to development according to Regulation (EC) No 1272/2008.