2-[(4-methyl-2-nitrophenyl)azo]-3-oxo-N-phenylbutyramide

Water solubility

Administrative data

Endpoint:

water solubility

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2011

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Test procedure according to method of Analytical Expert Group ETAD (Ecological and Toxicological Association of Dyes and Organic Pigment Manufacturer)

Justification for type of information:

This summary justification relates to organic pigments that (a) do not contain metals and do not represent salts, (b) are poorly soluble in water and n-octanol, (c) have a molecular weight > 200 g/mol and (d) have no surface modification that may change the properties of the substance (poorly soluble organic pigments (PSOPs) hereafter). The full justification, the sections referred to as well as the references are provided in the justification document attached in section 13.2.
1. The criteria of the nanomaterial definition have no scientific basis.
With respect to the upper limit of 100 nm, Commission Recommendation 2011/696/EU states that ‘there is no scientific evidence to support the appropriateness of this value’. With respect to the 50% threshold, a review of this Commission Recommendation states that ‘(s)ince the EC definition of nanomaterial should not be related to hazard or risk considerations, the selection of a threshold is essentially a policy choice and should be justified as such’ (Rauscher et al., 2015). Given the lack of a scientific basis of the criteria for the nanomaterial definition, it is inconceivable why the water solubility is considered an appropriate parameter for bulk forms of PSOPs, while it is not considered an appropriate parameter for nanoforms of PSOPs and why consideration of the effect of dispersion is of particular concern for nanoforms of PSOPs (see section 2.1 for more details).
2. The particle size of constituent particles used for classifying PSOPs as ‘nano’ or ‘bulk’ is irrelevant for their properties.
The particle size of constituent particles as determined by TEM image analysis for classification purposes according to the Commission Recommendation is of no relevance for the solubility or dissolution of PSOPs. Such particle size determinations (a) neglect the high degree of agglomeration/aggregation of the manufactured PSOP powders, (b) involve dispersion techniques that may not adequately reflect the dispersion of PSOPs in pigment preparations, test media or the environment and (c) do not address dynamic processes such as reagglomeration or Ostwald ripening taking place over time under real-world conditions (see section 2.2 for more details).
3. Bulk and nanoforms as well as different nanoforms of PSOPs both are poorly water soluble.
One of the concerns with respect to the water solubility of nanomaterials relates to the fact ‘that water solubility has the potential to increase for materials in the nano-size range due to their decreasing particle size and it may also be affected by their shape and surface coating’ (ECHA, 2017d). This effect is irrelevant for PSOPs. While OECD (2019) defines ‘poorly/sparingly water-soluble’ chemicals as those having a water solubility < 100 mg/L, ECHA (2017a) uses a stricter cut-off value of 1 mg/L. All PSOPs have water solubilities < 1 mg/L and most PSOPs have considerably lower water solubilities (< 0.05 mg/L). Importantly, the underlying evaluation by Stratmann et al. (2020) focussed on nanoforms of organic pigments covering different shapes and sizes. This finding demonstrates that nanoforms of PSOPs are also poorly water soluble despite a putatively higher specific surface area. Consequently, there is no relevant difference between bulk and nanoforms of PSOPs with all forms being poorly soluble in water. This observation can be explained by (a) the lacking scientific basis of the nanomaterial definition criteria (see above), (b) the fact that insolubility in water (as well as most solvents) is a functional requirement of organic pigments and (c) the fact that the PSOP definition excludes organic pigments with structural elements associated with a higher water solubility (see sections 1.1 and 1.2 for more details).
According to REACH Annex VII, 7.7, the potential confounding effect of dispersion shall be considered specifically for nanoforms while conducting a study. However, this issue is in fact not unique to nanoforms. This is also recognised in ECHA (2017d): ‘It is important to recognise that solubility and dispersibility are different and distinct phenomena (…) and it is important to differentiate between them. This situation is not unique to nanomaterials…’. The same document states that ‘this problem may be further amplified in the case of sparingly soluble nanomaterials’. While PSOPs are ‘sparingly soluble’, the differentiation between solubility and dispersibility is not a major issue due to the intrinsically high propensity of PSOPs to from aggregates and - particularly in aquatic media - to agglomerate (low dispersibility), allowing for reliable separation via filtration (also see section 2.2).
4. The low water solubility and expected low dissolution rate result in identical testing strategies. The considerations above demonstrate that bulk and nanoforms of PSOPs behave similarly and fast dissolution (see discussion below) can neither be expected for bulk nor nanoforms of an PSOP. The property is thus unrelated to the ‘nano character’ of PSOPs. More generally also ECHA (2017d) acknowledged: ‘Part of the advice provided is not strictly nano-specific and may for instance also be applicable to other particulate materials (e.g. relevance of dissolution rate)’. In consequence, the poor water solubility of (bulk and nanoform) PSOPs results in the same testing paradigm (focus on long-term ecotoxicity testing) as the low (or moderate) dissolution assumed (see discussion below).
5. The high relevance attributed to the dissolution rate applies to inorganic (and/or engineered) nanoparticles, but not to PSOPs. The suggestion that the dissolution rate is more relevant than the water solubility in the case of nanoforms is exclusively based on experience/data obtained for inorganic nanomaterials. The methods discussed in OECD (2020) are solely based on the ones developed for metals and metal compounds as described in OECD (2001). The OECD TG for the dissolution rate currently under development will also be based on OECD (2001), i.e. the one for the dissolution of metals/metal compounds. Overall, the issue of dissolution (rather than solubility) was originally identified as critical for metal compounds irrespective of ‘nano considerations’ (OECD, 2001) with questionable relevance for PSOPs. For metal compounds (and e.g. other materials with relevant surface functionalisation), dissolution (i.e. release of ions) may be of concern irrespective of a nano or bulk character. For example, both the nanoform and the bulk form of barium sulphate showed significant dissolution in a flow-through test (Koltermann-Jülly et al., 2018). The apparent applicability to metals/metal compounds is also evident in IUCLID (version 6.5) section 4.8, where the endpoints that can be entered are either ‘water solubility’ or ‘transformation/dissolution of metals and inorganic metal compounds’ (see section 2.3 for more details). Especially for PSOPs, the high propensity to form aggregates and agglomerates (increasing with decreasing particle size) compensates for the theoretical increase in specific surface area with decreasing particle size – the increase in specific surface area is, however, the scientific basis to assume a higher dissolution rate for nanomaterial compared to bulk.
6. No adopted test method exists for the determination of the dissolution rate. No adopted OECD Test Guideline (TG) or EU Test Method in Regulation (EC) No 440/2008 exists for the determination of the dissolution rate. As noted above, methods discussed in OECD (2020) were developed from the ones for metals and metal compounds described in OECD (2001). While ‘in principle’ the test procedures ‘may also be applicable for testing non-metal nanomaterials, (…) analytical possibilities still limit these options’ and that ‘the decision on an appropriate analytic method currently can only be done case-by-case’ (OECD, 2020). In the absence of an appropriate guideline for testing the dissolution of nanomaterials, the relevant ECHA Guidance (ECHA, 2017d) refers to two OECD documents, including OECD GD 29 (OECD, 2001; 2015). Again, these documents treat the release of ions from metals/metal compounds without relevance for PSOPs.
7. Analytical problems exist for PSOPs in determining the dissolution rate. For PSOPs, the analytical problems already recognised in OECD (2020) are indeed a major obstacle for testing the dissolution rate. The main problem is to establish reliable analytical methods with a sufficiently low limit of quantification to demonstrate very low dissolution (rates). For a comparatively small number of (both ‘fine’ and ‘coarse’) organic pigments testing the dissolution in water only resulted in values below the limit of detection (Hofmann et al., 2016).
8. The major aim of determining the dissolution rate can be achieved without testing. The results from testing the dissolution rate in water are primarily used to define the testing strategy for ecotoxicity testing. In this respect, the REACH Annexes suggest long-term testing ‘if the substance is poorly water soluble, or for nanoforms if they have low dissolution rate in the relevant test media’. Somewhat in contrast, ECHA (2017c) recommends long-term toxicity testing for nanomaterials that do ‘not dissolve fast’. This Guidance would therefore recommend long-term toxicity testing also for nanoforms showing moderate dissolution rates, while the REACH Annexes do not. Sticking to the recommendations in ECHA (2017c), long-term toxicity testing is recommended for bulk and nanoforms of PSOPs alike due to their poor water solubility and because fast dissolution is not expected.
Overall, the water solubility of PSOPs is low (<1 mg/L), irrespective of whether these exist in bulk or nanoform. Due to (a) the lack of an adopted test method, (b) the problems discussed above and (c) the fact that an adequate testing strategy can be defined without determining the dissolution rate, such testing is not required. The water solubility is therefore an adequate parameter for defining the fate and testing strategy for the submission substance.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2011

Report date:

2011

Materials and methods

Principles of method if other than guideline:

Determination of water solubility.
The analytical method for the determination is in agreement with the method that was agreed upon at the Analytical Experts Meeting of ETAD (Basel) on January 12, 2005.

Type of method:

other: ETAD method (see below)

Test material

Test material information

Constituent 1

Reference substance name:

2-[(4-methyl-2-nitrophenyl)azo]-3-oxo-N-phenylbutyramide

EC Number:

219-730-8

EC Name:

2-[(4-methyl-2-nitrophenyl)azo]-3-oxo-N-phenylbutyramide

Cas Number:

2512-29-0

Molecular formula:

C17H16N4O4

IUPAC Name:

2-[(4-methyl-2-nitrophenyl)diazenyl]-3-oxo-N-phenylbutanamide

Test material form:

solid: nanoform, no surface treatment

Results and discussion

Water solubility

Key result

Water solubility:

13 µg/L

Temp.:

22 °C

pH:

>= 5.8 - <= 6

Remarks on result:

other: The determination of water solubility was conducted at ambient temperature (22-23 °C)

Details on results:

The value above represents the mean from 3 determinations (sigma=2.8). See below for indidividual results.

Any other information on results incl. tables

Individual results:

	Absorption (d = 10 cm)	µg/L	pH
a1	0.00299	10.8	6.0
a2	0.00338	12.1	5.8
a3	0.00458	16.1	5.9

 

Applicant's summary and conclusion

Conclusions:

Interpretation of results: insoluble (< 0.1 mg/L).
The test substance has a water solubility of 13 µg/L.

Executive summary:

The water solubility was determined by UV-Vis analysis of the dissolved test substance amount in 30 mL water according to the method that was agreed upon at the Analytical Experts Meeting of ETAD (Basel) on January 12, 2005.

The test substance has a water solubility of 13 µg/L (22 -23 °C).