Bismuth bromide iodide oxide

Endpoint summary

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 for cross-reference:

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 for cross-reference:

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.