Indium trichloride

Endpoint summary

Description of key information

High quality repeat dose whole body inhalation studies, following OECD guidelines 412 (2 -week exposure) and 413 (13 -week exposure) were conducted on indium oxide (IO) and indium tin oxide (ITO) (Nagano et al 2011) in rats and mice. Specific effects included increased lung weights, alveolar proteinosis, increased inflammatory cell infliltration and hyperplasia of the alveolar epithelium. A further group of animals was used to set-up a 13 -week recovery group at the 0.1 mg/m3 ITO dose level. The comparable results in rats are shown below:

RATS 13 wk study	IO (mg/m^3)	IO (mg/m^3)	IO (mg/m^3)	ITO (mg/m^3)	ITO (mg/m^3)	ITO (mg/m^3)	ITO (mg/m^3)+13 wk recovery	ITO (mg/m^3)+13 wk recovery	ITO (mg/m^3)+13 wk recovery
	0	0.1	1	0	0.1	1	0	0.1	NA
Lung weight		↑	↑		↑	↑		↑
Alveolar proteinosis			+		+	+		+
AM infiltration		+ (slight)	+		+	+		+
Inflammatory cell infiltration			+			+		+
Hyperplasia alveolar epithelium			+					+
BALT granuloma
Alveolar wall fibrosis								+
Pleural thickening								+
LN granuloma			+		+	+		+
		NOAEL			LOAEL

AM: alveolar macrophages; LN: Lymph nodes

If the results of the studies are evaluated in context with the guidance produced by the SCOEL committee (Ref: European Commission Methodology for the derivation of occupational exposure limits. Scientific Committee on Occupational Exposure Limits (SCOEL). Key documentation (version 7), June 2013) on setting an OEL, where the objective of Council Directive 80/1107/EC is "The protection of workers against risks to their health and safety from exposure to chemical, physical and biological agents considered harmful" then the data used to derive an OEL should be separated into the 4 categories listed below:

The effects of increasing exposure to chemical substances may be viewed as a continuum:

(1) no effects observed

(2) compensatory effects or early effects of dubious significance without adverse health consequences

(3) early health impairement (clear adverse effects)

(4) overt disease, possibly death

Effects may be considered to become 'adverse' during the transition from (2) to (3) above

Using this guidance when interpreting the results of the 13 -week study in rat with IO it could be concluded that the 0.1 mg/m3 dose level is an NOAEL. The only effect observed at this dose level, infiltration of alveolar macrophage and neutrophils and increased lung weight, could be due to exposure to a relatively insoluble, high density metal salt. Without other clear adverse endpoints present, the 0.1mg/m3 dose level shows an adaptive resonse to the clearance of a relatively insoluble metallic salt and could therefore be defined as a NOAEL for the purpose of defining a DNEL or OEL.

For ITO, the adverse effects were more significant even at the lowest dose tested in the rat and all lung/lymph lesions persisted in the 13-week recovery period for ITO (not measured for IO) with progression to alveolar wall fibrosis, alveolar epithelial hyperplasia, infiltration of alveolar macrophages and inflammatory cells at 0.1 mg/m³.

 

In mice, similar results were observed to those described in the rat studies (lesions more severe with ITO than IO) but with overall lower severity scores compared to rats, particularly for alveolar proteinosis and alveolar macrophage infiltration. There was no recovery period included in the study.

In a further study, Nagano et al 2011, conducted a 2 -year carcinogenicity study on ITO in the rat and mouse to OECD Guideline 451 (see below in additional information).

The table below present the LOAEL and NOAEL's for the most sensitive respiratory effects observed in the sub-chronic inhalation animal studies conducted with respirable size aerosols of indium oxide and ITO in Fisher 344 rats and B6C3F1 mice. It also calculates an NOAEL for use in subsequent chronic DNEL derivation for IO and ITO. The toxic effects of both compounds in both species were typical of lung inflammation, with the overall response for both compounds being greater in rats and the response for ITO being greater than IO in both species.

MICE	IO (mg/m^3)	ITO (mg/m^3)
13 wk NOAEL	0.1	NA
13 wk LOAEL	1.0 (M/F)	0.1 (M/F)
RATS
13 wk NOAEL	0.1	NA
13 wk LOAEL	1 (M/F)	0.1 (M/F)
2 yr NOAEL		NA
2 yr LOAEL		0.01
Choice of NOAEL/LOAEL for DNEL determination	0.1 mg/m^3	0.01 mg/m^3
Conversion factor from sub-chronic to chronic^a	2	1
Conversion factor for NOAEL determination from a LOAEL value^b	1	3
Comparable chronic NOAEL for DNEL derivation	0.05 mg/m^3	0.0033 mg/m^3

a –Conversion for difference in duration of exposure:2 (sub-chronic to chronic exposure)

b –To convert a LOAEL to a NOAEL, the REACH TGD (Chapter R.8 of the ‘Guidance on information requirements and chemical safety assessment’) suggests an assessment factor (AF) of 3 as minimum for the majority of cases and going up to a default of 10 for exceptional cases. An AF of 3 is applied to convert LOAEL to NOAEL.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

0.1 mg/m³

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

exposure considerations

Justification for data waiving:

a short-term toxicity study does not need to be conducted because exposure of humans via the dermal route in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

exposure considerations

Justification for data waiving:

a short-term toxicity study does not need to be conducted because exposure of humans via the dermal route in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Nagano et al 2011, conducted also a 2 -year carcinogenicity study on ITO in the rat and mouse to OECD Guideline 451. Fifty mice of both sexes were exposed to ITO at 0 (control), 0.01, 0.03 or 0.1 mg/m3 for 6h/day, 5day/wk for 104wk, and 50 rats of both sexes were exposed to 0, 0.01 or 0.03 mg/m3 ITO for the same time period. The repeated exposure of 50 rats of both sexes to 0.1 mg/m3 ITO was discontinued at the 26th week, followed by clean air exposure for the remaining 78wk. In rats, incidences of bronchiolo-alveolar adenomas and carcinomas, bronchiolo-alveolar hyperplasia, alveolar wall fibrosis and thickened pleural wall, alveolar proteinosis and infiltrations of alveolar macrophages and inflammatory cells were significantly increased. Combined incidences of malignant lung tumours in male rats and total lung tumours in male and female rats were significantly increased at exposure to 0.01 mg/m3 ITO. In mice, no carcinogenic response occurred, but thickened pleural wall, alveolar proteinosis and alveolar macrophage infiltration were induced. Mice were less susceptible to ITO than rats. The lung content of indium was the greatest, followed by the spleen, kidney and liver. Increases in blood indium levels were dose-dependent. There was clear evidence that inhaled ITO was carcinogenic in male and female rats but no clear evidence in mice, together with occurence of chronic pulmonary lesions in both rats and mice.

Justification for classification or non-classification

The results of the repeat dose whole body inhalation studies indicate that both indium oxide and indium tin oxide would receive a specific target organ toxicity repeat exposure (STOT-RE) classification, category 1 according to the EU CLP criteria (EU 1272/2008) as 'significant' effects (those that clearly indicate functional disturbance or morphological changes) were observed at or < 0.02 mg/L/6h/d (20 mg/m3/6h/d)

Based upon read across to Indium oxide (In203) repeated dose toxicity inhalation data and according to Regulation (EC) No 1272/2008, Indium chloride would require a specific target organ toxicity repeat exposure (STOT-RE) classification, category 1