Indium trichloride

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Data source

Reference

Reference Type:

publication

Title:

Embryotoxic and teratogenic effects of indium chloride in rats and rabbits.

Author:

Ungváry G, Szakmáry E, Tátrai E, Hudák A, Náray M and Morvai V.

Year:

2000

Bibliographic source:

J Toxicol Environ Health A, 59(1):27-42

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Indium trichloride

EC Number:

233-043-0

EC Name:

Indium trichloride

Cas Number:

10025-82-8

Molecular formula:

Cl3In

IUPAC Name:

indium trichloride

Details on test material:

- Name of test material (as cited in study report): indium chloride
- Molecular formula (if other than submission substance): InCl3, CAS: 10025-82-8), Aldrich Chemical, Inc)

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: LATI, Gödöllö
- Weight at study initiation: 210-240g
- Housing: climatized animal house, plastic cages, on steam-sterilized, hardwood shavings
- Diet (ad libitum): standard rat pellets (LATI, Gödöllö)
- Water (ad libitum): tap water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 40-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): hours 06-08, dim light; 08-18, daylight; 18-20, dim light; 20-06, darkness

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

none

Details on mating procedure:

Rats were mated as follows: Males were placed among the females overnight. Vaginal smears were taken daily and stained with 1% methylene
blue solution. The day when sperm were found in the vaginal smear of the females in estrus was regarded as the first day of gestation.

Duration of treatment / exposure:

-rats treated with 0, 50, 100, 200 and 400 mg/kg bw on GD 6-15
-rats treated with 0, 400 mg/kg bw on one of GD 8, 9, 10, 11, 12, 13, 14 or 15

Frequency of treatment:

daily

Duration of test:

21 days

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

50 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

100 mg/kg bw/day

Doses / concentrations 3

Dose / conc.:

200 mg/kg bw/day

Doses / concentrations 4

Dose / conc.:

400 mg/kg bw/day

No. of animals per sex per dose:

No. of pregnant animals/group:
control: 33
Gestation days6-15 :
50 mg/kg: 20
100 mg/kg: 20
200 mg/kg: 20
400 mg/kg: 21

Control animals:

yes, concurrent no treatment

Details on study design:

none

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION: Yes

WATER CONSUMPTION : Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #21
- Organs examined: brain, hypophysis, thymus, lungs, heart, liver, spleen, kidneys, adrenals, and ovaries , stomach, and uterus

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes:
- Soft tissue examinations: Yes:
- Skeletal examinations: Yes
- Head examinations: No

Statistics:

Parametric data (maternal organ weights, clinical and biochemical parameters, food and fluid consumption, fetal and placental weights) of groups were compared using analysis of variance and Dunnett’s test, while nonparametric variables (maternal weight gain, frequencies of pre- and postimplantational lossess, frequencies of body weight, skeletal and internal organ retardations, minor and major anomalies) of groups were compared using a Kruskal–Wallis test. The level of significance was chosen at 5%.

Indices:

none

Historical control data:

none

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Mortality:

no mortality observed

Description (incidence):

no death occurred

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

dose-related inhibition of weight gain

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

significant decrease with increasing doses of InCl3; the greatest reduction in the group treated with 400 mg/kg

Food efficiency:

not specified

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

following parameters did not change markedly: red and white cell counts, hematocrit, MCV, MCH, and MCHC values, hemoglobin, serum total protein, albumin concentrations

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

bilirubin concentration, and AST and ALT acitiviets in serum significantly decreased

Urinalysis findings:

not examined

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

at the highest dosage (400mg/kg), the relative weights of liver, pancreas, and brain increased

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

hemorrhagic foci at the cortico-medullar border in the interstitium of the kidneys of dams treated with 400 mg/kg indium chloride

Histopathological findings: neoplastic:

no effects observed

Maternal developmental toxicity

Number of abortions:

no effects observed

Pre- and post-implantation loss:

effects observed, treatment-related

Dead fetuses:

effects observed, treatment-related

Details on maternal toxic effects:

Details on maternal toxic effects:
- Mortality and time to death: no death occurred
- Body weight gain: dose-related inhibition of weight gain
- Food consumption: significant decrease with increasing doses of InCl3; the greatest reduction in the group treated with 400 mg/kg
- organ weights: at the highest dosage (400mg/kg), the relative weights of liver, pancreas, and brain increased
- clinical parameters: bilirubin concentration, and AST and ALT acitiviets in serum significantly decreased

Effect levels (maternal animals)

1

Key result

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

body weight and weight gain

food consumption and compound intake

2

Key result

Dose descriptor:

LOAEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

body weight and weight gain

food consumption and compound intake

Results (fetuses)

Fetal body weight changes:

effects observed, treatment-related

Reduction in number of live offspring:

effects observed, treatment-related

External malformations:

effects observed, treatment-related

Skeletal malformations:

effects observed, treatment-related

Visceral malformations:

effects observed, treatment-related

Details on embryotoxic / teratogenic effects:

Details on embryotoxic / teratogenic effects:
-postimplantation loss, frequency of fetuses with retarded body weight, skeletal and visceral retardation: significantly increase with dose of InCl3
-gross external malformations, visceral anomalies, congenital major skeletal anomalies: significantly increase with dose of InCl3

Effect levels (fetuses)

1

Key result

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: % of malformed fetuses

2

Key result

Dose descriptor:

LOAEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: % of malformed fetuses

Fetal abnormalities

Abnormalities:

effects observed, treatment-related

Localisation:

external: tail

skeletal: forelimb

skeletal: sternum

skeletal: rib

skeletal: vertebra

skeletal: hindlimb

visceral/soft tissue: urinary

visceral/soft tissue: male reproductive system

Overall developmental toxicity

Developmental effects observed:

yes

Lowest effective dose / conc.:

100 mg/kg bw/day

Treatment related:

yes

Relation to maternal toxicity:

developmental effects as a secondary non-specific consequence of maternal toxicity effects

Dose response relationship:

yes

Relevant for humans:

no

Any other information on results incl. tables

Indium concentration in the maternal blood was increased dose-dependently 24 h after oral administration. Indium appeared also in the fetal blood in concentrations lower than that found in maternal blood. For the lowest and highest doses, indium concentrations in the fetal blood were 33% and 11% of those in maternal blood, respectively.

Applicant's summary and conclusion

Conclusions:

InCl3 was teratogenic and embryotoxic but only at maternally toxic doses

Executive summary:

Daily indium chloride doses of control ( 0) , 50, 100, 200, or 400 mg/ kg were administered orally to Sprague-Dawley rats by gavage, on d 6–15 of gestation, and daily metal doses of control ( 0) , 50, 100, or 200 mg/ kg were administered to New Zealand rabbits on d 6–20 of gestation. Further groups of pregnant rats were treated with control ( 0) or 400 mg/ kg indium chloride orally on one of d 8, 9, 10, 11, 12, 13, 14, or 15 of gestation. The dams and fetuses were examined on d 21 ( rats) and 30 ( rabbits) of gestation, using standard teratological methods. Indium concentrations in maternal and fetal blood of rats increased dose-dependently. Percentage bioavailability of indium in the dams increased with increasing dose. Indium concentration in fetal blood was lower than that of the dams being 33 and 11% of that of the dams at the lowest and highest doses, respectively.
The repeat oral administration of indium chloride to pregnant SD rats from GD 6 through 15 (positive for sperm presence = GD 1) induced rudimentary tail, anury, syndactyly, clubfoot, exencephaly, undescended testis, dilatation of the renal pelvis and ureter, and skeletal anomalies of the rib, vertebrae, and sternebrae in GD 21 fetuses at 100 mg/kg/day. The repeat oral administration of indium chloride to pregnant New Zealand rabbits from GD 6 through 20 (positive for sperm presence = GD 1) induced renal agenesia and ectopic kidney in GD 30 fetuses at 100 mg/kg/day or more. The maternal and fetal toxicity NOAEL for rats and rabbits was 50 mg/kg bw. The LOAEL (maternal and fetal toxicity) in rats was 100 mg/kg and in rabbits (maternal and fetal) was 200 mg/kg (except for the possibility of renal effects in the foetuses at the 100mg/kg level). Increasing dose above the NOAEL, increased post-implantation loss, reduced fetal body weight and increased skeletal and visceral retardation. Fetal retardation in rats was independent of exposure time (not tested in rabbits) occurring after oral administration of 400 mg/kg InCl3 on days 10, 11, 12, 14 or 15 of gestation. A single oral dose of 400 mg/kg InCl3 resulted in a maternal blood indium concentration of 1038 ug/l. Unlike continuous administration of InCl3 on GD 6-15, there were no major anomalies of the fetal urogenital system in rats following single day administrations. In rabbits there was a low overall malformation rate of 3.5 and 6.3% at 100 and 200mg/kg bw but this was considered positive when compared to the usual spontaneous malformation rate in rabbits of 0.7 – 4.2% and the malformations were renal which has a usual malformation rate of <1%. Decreased weight gain was seen in both rat and rabbit dams but decreased weight gain alone was not associated with teratogenic or embryolethal effects which were seen only when bilirubin concentration and AST and ALT activities were significantly decreased in dams (rats – no information on rabbits). The main target organ in the rat and rabbit dams was the kidney.