Creating sets of similar nanoforms with the ECETOC NanoApp: real-life case studies

Figures & data

Figure 1. Tiered approach for building and justification of sets of nanoforms. Properties considered in different Tiers are listed. The expected association between Tier 2/3 properties and exposure, fate, toxicokinetics, toxicity and ecotoxicity is indicated in dark gray (strong/direct), and light gray (for weaker/indirect).

Table 1. Overview of the case studies and nanoforms included.

Substance (CAS number)	Nanoform code in this manuscript	Codes used earlier for nanoform identification	Relevant published data
Barium sulfate (7727-43-7)	NF1	NM-220	Landsiedel et al. (2014), Klein et al. (2012)
	NF2	NM-220 reproduced batch	Konduru et al. (2014), Schwotzer et al. (2017)
Colloidal silica (7631-86-9)	NF3	55 nm-SiO2	Maser et al. (2015), Wiemann et al. (2018)
	NF4	30 nm-SiO2	Maser et al. (2015), Wiemann et al. (2018)
	NF5	15 nm-SiO2	Maser et al. (2015), Wiemann et al. (2018)
	NF6	9 nm-SiO2	Maser et al. (2015), Wiemann et al. (2018)
Cerium oxide (1306-38-3)	NF7	nCeO2	Stueckle et al. (2017), Demokritou et al. (2013)
	NF8	CeO2	Landsiedel et al. (2014), NanoCare Final Scientific Report (2009)
	NF9	CeO2-A	Schaefer et al. (2012), NanoCare Final Scientific Report (2009)
	NF10	CeO2-B	Schaefer et al. (2012), NanoCare Final Scientific Report (2009)
	NF11	CeO2-D	Schaefer et al. (2012), NanoCare Final Scientific Report (2009)
	NF12	CeO2-NM212	Singh et al. (2014), Gosens et al. (2014), Keller et al. (2014), Geraets et al. (2012), Hund-Rinke et al. (2018)
	NF13	CeO2-NM211	Singh et al. (2014), Gosens et al. (2014), Keller et al. (2014), Geraets et al. (2012), Hund-Rinke et al. (2018)
	NF14	CeO2-Al	Landsiedel et al. (2014), NanoCare Final Scientific Report (2009)
Pigment Blue 15:3 (147-14-8)	NF15	–	–
	NF16	–	–
	NF17	–	–
	NF18	–	–

Table 2. Tier 1 similarity conclusions for BaSO₄ nanoforms.

	NF1	NF2	Tier 1 Rule	Outcome
Main constituents^a	BaSO4 (96.9%)	BaSO4 (98.2%)	-Ratio of content for each constituent between the two nanoforms <1.5
Crystallinity (%)	Barite (100%)		-Ratio of each of the crystalline forms between the two nanoforms <1.5. -OR data showing that the toxicological profile of crystalline forms present in the nanoforms are similar.
Impurities/additives (%)	Polyacrylic acid (3.1%)	Polyacrylic acid (1.8%)	-Total impurities/additives <3% in both NFs -OR ratio of each of the individual impurities/additives (above 2% in any of the two NFs) <2.
Surface treatments	None		-Surface treatment agents are identical between the two nanoforms. -The ratio of the surface treatment agents between the two nanoforms <1.5.
CLP-based on composition	Not classified		-The content of each constituent triggers the same CLP classification for the two NFs.
Shape	Spheroidal		-Platelets cannot be part of a set with other shape categories. -For mixed-shape category NFs that contain platelets, the ratio of % of platelets between the two NFs <3.
AR	1.22	1.41	-Ratio of aspect ratios <2.
Assembly structure	NO	NO	-None of the nanoforms has an assembly structure. -OR both of the nanoforms have the same assembly structure.
D50-d1 (nm)	17.5	25	-Ratio of each of these percentiles (d50, d90 for dimension 1 and dimension 3) between the two nanoforms <1.5
D90-d1 (nm)	31.7	40
D50-d3 (nm)	17.5^b	25^b	-d90 value for the largest dimension of all NFs <5 µm.
D90-d3 (nm)	31.7 ^b	40^b
SSA (m^2/g)	33	38	-Ratio of SSA between two nanoforms <1.5.
Production process	Same synthesis protocol		-Production processes for the two NFs under comparison are not expected to lead to different aggregation states.

Green cells in the ‘outcome’ column indicate that each of the Tier 1 Rules was fulfilled.

^aMain constituents refer to all particle constituents, except for additives, impurities, and surface treatment agents.

^bThe available TEM reports only provided size percentiles for one dimension. Considering that the particles are spheroidal, with relatively low aspect ratios (<1.5 in both cases), we approximated the size percentiles for the third dimension to be equal to those of the first dimension.

Figure 2. Overall conclusions for barium sulfate nanoforms. The green thumb indicates that a match was possible based on limited differences in intrinsic properties. If a Tier 2 justification had been needed, a ‘J’ would be present in the green thumb, as indicated in the legend for a justified match.

Table 3. Tier 1 similarity conclusions for colloidal silica nanoforms.

	NF3	NF4	NF5	NF6	Tier 1 Rule	3 vs. 4	3 vs. 5	3 vs. 6	4 vs. 5	4 vs. 6	5 vs. 6
Main constituents^a	Silica (>99%)				-Ratio of constituent content <1.5
Crystallinity (%)	Amorphous (100%)				-Ratio of each of the crystalline forms <1.5. -OR data showing similar toxicological profile.
Impurities /additives (%)	<1%				-Total impurities/additives <3% -OR ratio of individual impurities/additives (>2% in any of the two NFs) <2.
Surface treatments	None				-Surface treatment agents are identical. -The ratio of the surface treatment agents between the two nanoforms <1.5.
CLP-based on composition	No classified constituent				-Constituent content triggers the same CLP classification for the two NFs.
Shape	Spheroidal				-Platelets cannot be part of a set with other shape categories. -For mixed-shape category, the ratio of % of platelets between the two NFs <3.
AR	1.25				-Ratio of aspect ratios <2.
Assembly structure	NO				-None of the nanoforms has an assembly structure. -OR both of the nanoforms have the same assembly structure.
D50-d1 (nm)	67	21	13	3.4	-Ratio d50 for dimension 1 < 1.5
D90-d1 (nm)	93	39	22	8.9	-Ratio d90 for dimension 1 < 1.5
D50-d3 (nm)	67	21	13	3.4	-Ratio d50 for dimension 3 < 1.5
D90-d3 (nm)	93	39	22	8.9	-Ratio d90 for dimension 3 < 1.5
					-d90 value for the largest dimension of all NFs <5 µm.
SSA (m^2/g)	50	100	200	300	-Ratio of SSA between two nanoforms <1.5.
Production process	Stober process				-Production processes for the two NFs under comparison are not expected to lead to different aggregation states.

For each pairwise combination of nanoforms, green cells indicate Tier 1 rules that were fulfilled, while orange cells indicate Tier 1 rules that were not fulfilled.

Table 4. Tier 2 similarity conclusions in relation to size and specific surface area for colloidal silica nanoforms.

	NF3	NF4	NF5	NF6	Tier 2 rule	3 vs. 4	3 vs. 5	3 vs. 6	4 vs. 5	4 vs. 6	5 vs. 6
D50-d1 (nm)	67	21	13	3.4	Ratio dXX for dimension Y < 3 (as long as both NFs are >10 nm, the threshold is increased to <5 if a worst-case NF is selected for testing)	*
D90-d1 (nm)	93	39	22	8.9			*
D50-d3 (nm)	67	21	13	3.4		*
D90-d3 (nm)	93	39	22	8.9			*
SSA (m^2/g)	50	100	200	300	-Ratio of SSA <3 (or <5 if a worst-case nanoform is selected for testing)		*			*
Dissolution in lysosomal simulated fluid (half time, days)	656	438	328	283	-Ratio of dissolution half-times <3. Except in the following two scenarios: -A worst-case nanoform is selected for testing (threshold for dissolution is <5). -Dissolution half-times higher >1 year in the two nanoforms, are always considered similar.
Dissolution in freshwater (half time, days)	2.76	0.88	0.55	0.59		*	*	*
Reactivity – FRAS assay (nmol/mg; % positive control)	0.4; 0.11%	1.3; 0.40%	2.8; 0.86%	4.2; 1.28%	-Reactivity (as % of positive control) of the two nanoforms differs in <10%. -In assays with wide dynamic ranges (>100): ratio of each of the crystalline forms between the two nanoforms <5.
In vitro toxicity in macrophages (LDH, Glucuronidase, TNFα in NR8383 cells; NOAEC)	45	22	22	11	-Ratio of the selected dose descriptor for each of the in vitro toxicity assays between the two nanoforms <3.
In vitro toxicity in a second mammalian cell line (LDH and ATP in Calu-3; NOAEC)	100	100	100	100
Dispersion stability (in Daphnia medium ADaM)	96	99	100	100	-Percentage (of initially dispersed particles) stable in suspension of the two nanoforms differs in <40%

Only intrinsic properties that did not match Tier 1 conditions are included in the table. The color code for intrinsic properties for each pairwise combination of nanoforms is: yellow, when Tier 2 rules are fulfilled (i.e., similarity is sufficient provided that it will be supported by the triggered functional assays); an asterisk denotes that, for that combination, a worst-case NF would need to be used for regulatory testing; red, when Tier 2 rules are not fulfilled (i.e., similarity is too low and grouping into a set cannot be justified regardless of the results of the functional assays). The color code for the functional assays for each pairwise combination of nanoforms is: green, when Tier 2 rules are fulfilled; an asterisk denotes that Tier 2 rules are fulfilled provided that a worst-case nanoform is selected for regulatory testing; red, when Tier 2 rules are not fulfilled.

Figure 3. Overall conclusions for silica nanoforms. Left: allowing worst-case NF for grouping; Right: not allowing worst-case NF for grouping. Red thumbs indicate a definite no-match. In this case, this is due to differences in size descriptors and SSA. Green thumbs with a ‘J’ indicate that a match is possible, due to the moderate differences in intrinsic properties, which do not result on relevant differences in functional properties.

Table 5. Tier 1 similarity conclusions for ceria nanoforms.

	NF7	NF8	NF9	NF10	NF11	NF12	NF13	NF14	7 vs. 8	7 vs. 9	7 vs. 10	7 vs. 11	7 vs. 12	7 vs. 13	7 vs. 14	8 vs. 9	8 vs. 10	8 vs. 11	8 vs. 12	8 vs. 13	8 vs. 14	9 vs. 10	9 vs. 11	9 vs. 12	9 vs. 13	9 vs. 14	10 vs. 11	10 vs. 12	10 vs. 13	10 vs. 14	11 vs. 12	11 vs. 13	11 vs. 14	12 vs. 13	12 vs. 14	13 vs. 14
Main constituents^a	Cerium oxide (>99%)							CeO2 (86.8%)
Crystallinity (%)	Cerianite (100%)
Impurities /additives (%)	None identified (purity >99% in all cases)							Al (3.4%), Zr (9.8%)
Surface treatments	None
CLP-based on composition	No classified constituent
Shape	Spheroidal
AR	1.2	1.4	1.6	1.3	1.4	1.3	1.3	1.2
Assembly structure	None
D50-d1 (nm)	35	40	14	20	14	21	7.2	12
D90-d1 (nm)	60	65	20	29	20	41	12	25
D50-d3 (nm)	35	40	14	20	14	21	7.2	12
D90-d3 (nm)	60	65	20	29	20	41	12	25
SSA (m^2/g)	28	26	63	44	63	27	66	46
Production process	Pyrolysis					Precipitation		Pyr

For each pairwise combination of nanoforms, green cells indicate Tier 1 rules that were fulfilled, while orange cells indicate Tier 1 rules that were not fulfilled. For simplicity, the rules are not included (for details see Tables 2 and 3).

Table 6. Tier 2 similarity conclusions for ceria nanoforms.

	NF7	NF8	NF9	NF10	NF11	NF12	NF13	NF14	7 vs. 8	7 vs. 9	7 vs. 10	7 vs. 11	7 vs. 12	7 vs. 13	7 vs. 14	8 vs. 9	8 vs. 10	8 vs. 11	8 vs. 12	8 vs. 13	8 vs. 14	9 vs. 10	9 vs. 11	9 vs. 12	9 vs. 13	9 vs. 14	10 vs. 11	10 vs. 12	10 vs. 13	10 vs. 14	11 vs. 12	11 vs. 13	11 vs. 14	12 vs. 13	12 vs. 14	13 vs. 14
Impurities/additives (%)	None identified (purity > 99% in all cases)							Al (3.4%), Zr (9.8%)
D50-d1 (nm)	35	40	14	20	14	21	7.2	12													*				*				*			*		*		*
D90-d1 (nm)	60	65	20	29	20	41	12	25		*		*				*		*																		*
D50-d3 (nm)	35	40	14	20	14	21	7.2	12													*				*				*			*		*		*
D90-d3 (nm)	60	65	20	29	20	41	12	25		*		*				*		*																		*
SSA (m^2/g)	28	26	63	44	63	27	66	46
Dissolution in lysosomal simulated fluid (half-time, days)	>365
Dissolution in marine water (half-time, days)	>365
Reactivity – FRAS assay (nmol/mg; % positive control)	0.3; 0.1	1.1; 0.4	0.9; 0.3	0.4; 0.1	0.9; 0.3	0.5; 0.2	0.9; 0.3	2.8: 0.9
In vitro toxicity in macrophages (LDH, glucuronidase, TNFα in NR8383 cells, NOEC in µg/mL)		180				90	180	45
In vitro toxicity in a second mammalian cell line (LDH and ATP in Calu-3; NOEC in µg/cm^2)		100
Dispersion stability (in Daphnia medium ADaM)	82	61	2	3	2	75	91
Dustiness Index			9.7E + 05	9.2E + 0.5	1.0E + 06	1.3E + 05	1.5E + 05

Only intrinsic properties that did not match Tier 1 conditions are included in the table; the color code for intrinsic properties for each pairwise combination of nanoforms is: yellow, when Tier 2 rules are fulfilled (i.e., similarity is sufficient provided that it will be supported by the triggered functional assays); an asterisk denotes that, for that combination, a worst-case NF would need to be used for regulatory testing; red, when Tier 2 rules are not fulfilled (i.e., similarity is too low and grouping into a set cannot be justified regardless of the results of the functional assays). The color code for the functional assays for each pairwise combination of nanoforms is: green, when Tier 2 rules are fulfilled; red, when Tier 2 rules are not fulfilled. For simplicity the rules are not included (for details see Table 4).

Figure 4. Overall conclusions for ceria nanoforms. Red thumbs indicate a definite no-match. In this case, this is due to differences in size descriptors, or results of some of the functional assays (dispersion stability and dustiness). Green thumbs (without a ‘J’) indicate that a match is possible due because Tier 1 conditions are fulfilled. Yellow thumbs indicate that a definite conclusion still depends on the data that has not been provided (in this case from functional assays).

Figure 5. Illustrative screenshots on how the ECETOC NanoApp summarizes the reasons for the overall conclusions for some NF comparisons. Red thumbs on specific parameters indicate a definite no-match, whereas yellow thumbs on specific parameters indicate missing information. A) Impurities, size and specific surface area do not allow grouping of NF8 and NF14 (NFs identified in the table heading). B) Size and specific surface area do not allow grouping of NF8 and NF10, the panel on the right (blue oval) describes that environmental dispersion stability, needed to justify lack of impact of differences in size, resulted in excessive differences between NF8 and NF10. C) Size and aggregation state provisionally prevent grouping of NF7 and NF12. If missing data gaps would be addressed (i.e., dustiness for NF7, as indicated in the red box at the bottom with ‘Missing information’), such grouping might become possible.

Figure 6. Comparison of changes in BALF parameters after 5 days exposure to NF8, NF12, NF13 and NF14. Effects are shown as BMCs using a logarithmic scaling. BMCs were calculated using the benchmark dose software (PROAST, proastweb.rivm.nl, Slob, 2002). Critical effect concentrations correspond to the following predetermined changes in the responses over the controls: 400% for PMN, 100% for total protein, LDH, GGT and ALP, and 20% for alveolar macrophages and total cell count. Evaluations 3 days (A) and 24 days (B) after the end of exposure. Data on all parameters were available for all materials at both time points, n.r. denotes the lack of a significant trend in the dataset. Total cell counts and protein levels are not included in (B) as no significant trends were found, except for a slight increase in total protein levels for NF8.

Figure 7. Overall conclusions for Pigment Blue 15:3 nanoforms. Green thumbs indicate that a match is possible due because Tier 1 conditions are fulfilled. Yellow thumbs indicate that a definite conclusion still depends on data that has not been provided (in this case from functional assays in Tier 2).

Table 7. Tier 1 similarity conclusions for Pigment Blue 15:3 nanoforms.

Pig. Blue 15:3	NF15	NF16	NF17	NF18	15 vs. 16	15 vs. 17	15 vs. 18	16 vs. 17	16 vs. 18	17 vs. 18
Main constituents	29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32 copper (>98%)
Crystallinity (%)	Monoclinic; P21/c (Nr. 14) (= beta form)
Impurities /additives (%)	<2%
Surface treatments	None
CLP-based on composition	None
Shape	Spheroidal
AR	2	2.7	2.5	1.7
Assembly structure	None
D50-d1 (nm)	38	45	44	51
D90-d1 (nm)	56	67	71	80
D50-d3 (nm)	38	45	44	51
D90-d3 (nm)	56	67	71	80
SSA (m^2/g)	68	55	55	54
Production process	Phthalic anhydride–urea process

For each pairwise combination of nanoforms, green cells indicate Tier 1 rules that were fulfilled. For simplicity the rules are not included (for details see Tables 2 and 3).

Table 8. Tier 2 similarity conclusions for Pigment Blue 15:3 nanoforms.

Pig Blue 15:3	NF15	NF16	NF17	NF18	15 vs. 16	15 vs. 17	15 vs. 18	16 vs. 17	16 vs. 18	17 vs. 18
Static dissolution in phagolysosomal simulated fluid (% dissolved)	<0.05	<0.05	<0.05	<0.05
Reactivity – FRAS assay (nmol/mg; % positive control)	0.4; 0.1	0.5; 0.2	0.4;0.1	0.5;0.2
Dispersion stability (in OECD Medium GD318: with NOM, 1 mM Ca, pH7)	23	23	20	9

For each pairwise combination of nanoforms, green cells indicate Tier 1 rules that were fulfilled. For simplicity the rules are not included (for details see Table 4).

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