Indium trihydroxide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.3 µg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor:

other: corrected NOAEC

Value:

63 µg/m³

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

Justification:

sub-chronic to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

1

Justification:

Rats considered more sensitive than humans for inhaled inorganic particles

AF for intraspecies differences:

5

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.12 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

300

Dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

70 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

AF for interspecies differences (allometric scaling):

4

AF for other interspecies differences:

2.5

AF for intraspecies differences:

5

AF for the quality of the whole database:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Additional information - workers

Derivation of respirable DNEL (local effects, long term, inhalation route)

1)      Define the most relevant dose descriptor:

The most relevant dose descriptor has been derived from a 3-Month whole body Inhalation Toxicity Study of indium oxide in Fischer 344 rats (Nagano et al 2011). The NOAEL was 0.1 mg/m³ In₂O₃. 

 

2)      Derive a corrected NOAEL, using the Multiple path particle deposition (MPPD) model

 

The European Chemical Agency guidance (described in ‘Chapter R.8: characterization of dose [concentration]-response for human health) on the DNEL/DMEL derivation for respiratory effects starting from animal inhalation studies does not address the issue of particle size differences between animals and workers or differences in dosimetry (ECHA, 2008). As a result, these DNEL/DMELs based on animal aerosols will not be directly comparable to the workplace exposures and may overestimate the risks associated with the coarser and more heterogeneous workplace indium exposures. Therefore, we can apply an approach to calculate the equivalent human concentrations (EHC) to the animal aerosols for local respiratory effects after inhalation (Oller and Oberdörster, 2010). The daily deposited dose can be calculated by using this MPPD model (Asgharian et al. 2009) and applying either rat or human parameters. The equivalent deposited dose per unit of surface area in the lungs of humans and rats are calculated. In practice this can be done by

·        Using the PSD of the rat aerosol to calculate daily deposited doses in rats and in humans. The MPPD model calculates the deposition fraction for both rat and human respiratory tract allowing for variations of PSD, breathing parameters, exposure parameters. With the particle deposition fraction, the daily deposited doses in rats and humans can be calculated by applying the formula:

a = deposition fraction x concentration (mg/m³) x tidal volume (m³) x length of exposure (min)  x respiratory frequency (min^-1)

·        Calculating the ratio of deposited doses (rat/human)

·        Multiplying this ratio by the rat NOAEC to get the respirable EHC corresponding to the rat NOAEC

 

 

The MPPD model was applied under the assumptions shown in Table below

 

Table-Assumptions used in applying the multiple path particle deposition model

Parameter	Rat	Human- Adult Worker	Human-Adult General Population
Particle Density (g/cm^3)
Indium oxide	7.16	7.16	7.16
MPPD Models (version 2.1.1)	asymmetric multiple path	5-Lobar Yeh-Schum	5-Lobar Yeh-Schum
Breathing Parameters
Type	nasal	oro-nasal normal augmenter	nasal
Functional Respiratory Capacity (cm^3)	4.0	3,300	3,300
Upper Respiratory Tract Volume (cm^3)	0.42	50	50
Respiratory Frequency (min^-1)	102	20	12
Tidal Volume (cm^3)	2.1	1,024	625
Inspiration fraction	0.5, no pause	0.5, no pause	0.5, no pause
Inhalability adjustment	yes	yes	yes
Surface Area at FRC^(a)
Tracheo-bronchiolar (cm^2)	24.2	4,149	4,149
Alveolar (cm^2)	2,422	634,620	634,620
Exposure Parameters
Daily (hr/day)	6	8	24

(a) Functional respiratory capacity (cm3)

 

Calculation of the ratio of deposited doses in the pulmonary (alveolar) region of the respiratory tract (rat/human):

Used parameters in MPPD model:

Density 7.16 g/cm3

MMAD = 2.1 µm

GSD = 1.7µm

Aerosol concentration: 0.1 mg/m3

Daily deposited dose (Alveolar)

 = deposition fraction x concentration (mg/m³) x tidal volume (m³) x length of exposure (min) x respiratory frequency (min^-1)

•         Deposition fraction rat: alveolar: 0.042

•         Deposition fraction human (workers): alveolar: 0.109

•         Daily deposited dose rat (6 h) =

0.042 x 0.1 x 2.1 10^-6 x 360 x 102 = 323.8704 10^-6mg    

•         Daily deposited dose human (workers) (8 h) =

0.109 x 0.1 x 1024 10^-6x 480 x 20 = 107151.36 10^-6mg

•         Daily deposited dose in rats per surface area: 0.13 ng/cm²  (SArat= 2422)

•         Daily deposited dose in humans per surface area: 0.17 ng/cm² (SAhuman= 634620)

•         Ratio of deposited doses rat/human: 0.76

 

Multiplying this ratio by the rat NOAEC to get the respirable EHC corresponding to the rat NOAEC:

 

0.1 mg In2O3/m³* 0,76 = 0,076 mg In2O3/m³* 0,83 = 63 µg In/m3

3)      Assessment factors: animal to human assessment factors for local respiratory effects after inhalation

 

The corrected NOAEL has to be corrected by assessment factors to account for the uncertainties of the database that led to the establishment of the DNEL.

The DNEL is calculated by dividing the corrected NOAEL of 63 µg/m3 (=calculated EHC corresponding to the rat NOAEC), see above) by an assessment factor. 

 

	Comment	ECHA default AF	Applied	Justification
Starting point 63 µg/m^3	Corrected NOAEL from 90days repeated dose inhalation toxicity study in rats
AF	Interspecies difference, allometric scaling rats                      - human	1 (local)	1	allometric scaling is usually not applied in the derivation of the inhalation DNEL. In that case, differences in the allometry are assumed to be compensated by differences in the respiration rate.
	Interspecies difference - remaining differences	2.5	1	Rats considered more sensitive than humans for inhaled inorganic particles
	Intraspecies variation, worker	5	5
	Exposure duration (90d to 2y)	2	2	subchronic to chronic
	Dose-response	1	1
	Quality of whole database	1	1
DNEL expressed as In			6.3 µg/m3

 

Interspecies difference- allometric scaling is usually not applied in the derivation of the inhalation DNEL. In that case, differences in the allometry are assumed to be compensated by differences in the respiration rate. (ECHA practical Guide 14, 2012). Allometric scaling in order to adjust for physiologically-based species differences is widely accepted for systemic toxicity after oral or dermal administration. However, it does not apply to local or systemic effects after inhalation because the inhalation rate in humans is 4-fold lower compared to rats according to the slower metabolic rate and thereby the allometric species difference is already implicitly taken into account (ECETOC 2010 TR No.110). 

Interspecies difference - remaining differences:

-         Interspecies Toxicokinetic differences. Toxicokinetic differences between rats and humans are mostly addressed by using the MPPD (Multiple Path Particle Deposition) model to calculate EHCs resulting in equivalent deposited (or retained doses) per unit of surface area of the lung. No additional factor for toxicokinetic differences needs to be applied.

-         Interspecies Toxicodynamic differences. For respiratory (local) toxicity effects after inhalation of particles of most metal-containing substances in the respirable range, 1-5 μm diameter, rats seem to be more susceptible to toxicity effects than primates or humans (Oberdörster, 1995; Mauderly, 1997; ILSI, 2000; Nikula et al., 2001; Greim and Ziegler-Skylakakis, 2007). Further, given that any toxicity to the lungs is anticipated to be a local effect and (as an underlying paradigm) that rats and humans are even equally susceptible then, therefore the toxicodynamic component of the interspecies AF for indium oxide can be set to 1.

 

Exposure duration (subchronic to chronic)
REACH Technical Guidance document (TGD) Chapter R.8 - ECHA -indicates an assessment factor of 2 needs to be applied for extrapolation from subchronic to chronic duration. Substance-specific information does not indicate the default value could be modified upwards or downwards

 

In conclusion, a DNEL (local) of 6.3µg In/m³) has been derived for the respirable fraction against which to judge the adequacy of workplace risk management measures (RMM) to control airborne exposure to indium compounds

Although there are several available studies on the exposure of workers to ITO, the data are not of EU origin and there is sufficient uncertainty in the data to suggest that they are not a suitable basis for deriving a DNEL or OEL for ITO. However, they could be used as supplementary information for setting e.g. recommended engineering controls or RPE at plant sites. Very limited data are available on IO in humans.

 

It is therefore considered that the high quality animal data should be used to set a DNEL for IO. It is recognised that the resulting inhalation DNEL will be conservative.

 

It is recommended that in cases of exposure to ITO or in mixed ITO/In compounds exposure, a specific ITO DNEL should be considered by the industry due to the significant difference in the level of toxicity observed with ITO in comparison to IO in animal studies and the confirmation from ITO production sites that a serious and potentially fatal inhalation disease has been observed in the workers.

 

Regarding the difference observed in toxicity of ITO and other in compounds, it appears that the sintering process by which SnO2 molecules are introduced into the crystal structure of In2O3, is critical for the unique toxicological properties of ITO (Lison et al 2009)

Derivation of dermal DNEL (systemic effects, long term, dermal route)

Oral systemic endpoint is used for the derivation of Dermal DNEL (systemic effects) by route to route extrapolation:

The study of Ungvary et al (2000) is used for the derivation of dermal DNEL, systemic effects, long term for the workers.

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 (OECD 414 - Prenatal Developmental Toxicity).

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

 

NOAEL= 50mg/kg/bw day

For the dermal systemic DNEL: (route to route extrapolation: oral to dermal):

Dermal NOAEL= oral NOAEL * (exp cond rat/exp cond human workers)* (ABS oral rat/ABS dermal rat) * ABS dermal rat/ABS dermal human

= 50mg/kg/bw day * (7days/5days) * 1/1

= 70mg/kg/bw day

DNEL derivation and applying AF

	Value	Comment
Starting point	70mg/kgbw/ day	NOAEL from an oral 21days developmental tox study in rats (Ungvary et al 2000) converted to corrected dermal NOAEL
Assessment factor	4	Interspecies difference, allometric scaling rat - human
	2.5	Interspecies difference - remaining differences
	5	Intraspecies variation, workers
	6	Exposure duration (subacute to chronic)
	1	Dose-response
	1	Quality of whole database
DNEL	0.23 mg InCl3/kgbw/ day = 0.12 mg In/kgbw/day

The derived dermal DNEL (systemic effects, long term) would only be applicable if the indium metal/compound was presented in an acidic or alkaline solution to the skin. Otherwise, in neutral conditions, no hazard would be identified as indium metal/compound is known to precipitate at neutral pH (ECTX 2014)

In cases where the metal/compound is solubilised, a dermal penetration value of 5% is chosen as a worst case as it is considered that the potential for a compound/metal to penetrate skin is rarely (if ever) higher than oral absorption.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Explanation for the modification of the dose descriptor starting point:

All uses ends up incorporated in articles with unintended release

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected