Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study planned (based on read-across)
Study period:
Subject to decision on testing proposal
Justification for type of information:
A read-across approach is applied between Reaction products of monoethanolamine and boric acid (1:1) and Reaction products of monoethanolamine and boric acid (1:3) for the human health endpoints due to the structural similarity of the two reaction products (Scenario 6 in ECHA’s RAAF document), both resulting from the same starting materials (only the ratio is different), and through the same manufacturing process.
Commercial MEA Polyborate products are commonly formulated at either 1:1 or 1:3 mole ratios of MEA to boric acid, or sometimes at ratios in between. All compositions in this range contain equilibrium mixtures of the exact same chemical species, but with somewhat different population distributions.
The existing physico-chemical, toxicological, environmental fate and ecotoxicological data already showed good correlation with no significant differences between the two ratios.

The results of the newly commissioned, additional anchoring studies (water solubility, vapour pressure and octanol-water coefficient, Salmonella typhimurium reverse mutation assay and in the Escherichia coli reverse mutation assays, acute toxicity studies via dermal route and oral route) showed good correlation between Reaction products of monoethanolamine and boric acid (1:1) and Reaction products of monoethanolamine and boric acid (1:3), and therefore further supported our category hypothesis.

However, no toxicokinetic (absorption, metabolism, distribution, elimination) data is available for MEA-Polyborate. Available data is primarily physico-chemical properties that influence the absorption and distribution of the substance in the body. This data provides limited information indicating a read-across approach between the reaction products of MEA Polyborate 1:1 and 1:3 for the human health endpoints is likely justified for repeated dose studies including 90-day toxicity studies. However, since no data is available on the metabolism of MEA Polyborate, additional data is needed to inform if read across is justified for repeated dose studies. In this case data from dose range finding studies for the proposed developmental toxicity and 90-day toxicity studies will provide the requisite information to determine if read-across is justified for repeated dose toxicity studies.
Category: MEA Polyborates

TESTING PROPOSAL ON VERTEBRATE ANIMALS
Sub-chronic toxicity study (90-day), oral route (Annex IX, Section 8.6.2.; Test method: EU B.26/OECD TG 408) in rats

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out : Reaction products of monoethanolamine and boric acid (1:3)
- Name of the substance for which the testing proposal will be used [if different from tested substance] : Reaction products of monoethanolamine and boric acid (1:1)

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION [please address all points below]:
- Available GLP studies and non-GLP studies
There is no existing reliable (GLP or non-GLP) data on the sub-chronic toxicity to rats in a 90-day study (via the oral route) with Reaction products of monoethanolamine and boric acid (1:1) / Reaction products of monoethanolamine and boric acid (1:3). Therefore this is a standard information requirement for which data must be provided. The information on this endpoint is not available for the registered substance, but needs to be present in the registration dossier to meet the information requirements.
No 28-day repeated dose toxicity test are available on either ratios as these are waived due to higher-tier studies are proposed.
In both acute dermal toxicity study (Klimisch Category 1) and acute oral toxicity studies (Klimisch Category 1), Reaction products of monoethanolamine and boric acid (1:1) / Reaction products of monoethanolamine and boric acid (1:3) showed low acute dermal toxicity.

- Historical human data: A literature search and SIEF survey has not identified historical data on human exposure to Reaction products of monoethanolamine and boric acid 1:1/ 1:3 and its toxicological effects. Adaptation based on historical human data, therefore, is not possible.

- (Q)SAR
Due to the presence of inorganics and the complex chemistry, the substance falls outside of the applicability domain of the globally recognized (Q)SAR models. Therefore, no (Q)SAR modelling has been carried out on Reaction products of monoethanolamine and boric acid (1:1) / Reaction products of monoethanolamine and boric acid (1:3)

- In vitro methods
The application of in vitro methods is not relevant to the assessment of the effects of Reaction products of monoethanolamine and boric acid (1:1) / Reaction products of monoethanolamine and boric acid (1:3) on the sub-chronic toxicity to rats in a 90-day study (via the oral route) given the biological complexity of the endpoint.

- Weight of evidence: Upon reviewing all available information, including GLP and non-GLP studies, in vitro and QSAR methods, and based on our category approach, a tiered testing approach is proposed. A weight of evidence based adaptation, however, is not considered to be applicable.

- Substance-tailored exposure driven testing: Considering the intended uses of the substance, exposure-driven adaptation is not applicable.


- Grouping and read-across

A read-across approach is proposed between of Reaction products of monoethanolamine and boric acid (1:1) and Reaction products of monoethanolamine and boric acid (1:3), with the the sub-chronic toxicity to rats in a 90-day study (via the oral route) only to be conducted on the 1:3 ratio.
The justification for the read-across approach results from the structural similarity of the two reaction products, same manufacturing process from the same starting materials (only the ratio is different), existing physico-chemical, toxicological, environmental fate and ecotoxicological data which already showed good correlation with no significant differences between the two ratios, and additional anchoring studies generated to substantiate the category approach.
The conclusions discussed above suggest similar local and systemic toxicity profiles for the two substances. The use of data from MEA Polyborate 1:3 to read-across to MEA Polyborate 1:1 for the repeated dose toxicity (oral) endpoint is considered to provide sufficient confidence.

Category name: MEA Polyborates

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
The adaptations in column 2 of Annexes VI to X have been considered in the development of the testing proposal for sub-chronic toxicity to rats in a 90-day study (via the oral route) to provide data to address the data gap.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Details on study design / methodology proposed

It is proposed that Reaction products of monoethanolamine and boric acid (1:3) will be tested for sub-chronic oral toxicity in an OECD Guideline for testing of chemicals 408 “Subchronic Oral Toxicity – Rodent: 90-day study” and under GLP.

We propose a tiered testing strategy: where additional tests are required under Annexes IX and X; it is proposed that these tests be conducted sequentially where relevant (e.g. to address the same endpoint), for the reasons outlined below. As part of this tiered strategy the developmental study (EU B.31/OECD TG414) will be conducted prior the 90-day study (OECD TG 408).
i. Results from one test may render a subsequent test unnecessary, as appropriate classification and labelling information and risk management measures may be able to be derived from these without other tests.
ii. Results from one test may help as range finders for subsequent tests and/or may help in refining the protocol.
iii. On the grounds of animal welfare (as outlined in REACH recitals 13, 33, 37, 40, 49, 50, 64 and especially 47), and Article 13(1) and (2)), in vivo tests on vertebrate animals are to be minimised and avoided where possible. Utilisation of a tiered testing strategy, in which additional tests are potentially avoided dependent on the results of preceding tests, is desirable and consistent with the aims and objectives of REACH.

Data source

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)

Test material

Reference
Name:
Unnamed
Test material form:
liquid
Details on test material:
Appearance: Clear colourless liquid
Purity/Composition: UVCB
Test item storage: At room temperature protected from light
Stable under storage conditions until: 31 March 2018 (expiry date)

Test animals

Species:
rat

Administration / exposure

Details on route of administration:
Oral administration of the test item is relevant because physicochemical properties mean systemic uptake via the oral route is more likely than via the dermal or inhalation routes.
Details on study design:
Physicochemical properties mean that category substances are predicted to be absorbed very slowly via the dermal route and no significant uptake is expected. With respect to the inhalation route, the substances have a vapour pressure of < 0.01 Pa at 25 °C and, under normal conditions of handling and use, absorption of test material in the form of vapours, gases or mists via the respiratory tract is not expected to be relevant or significant.

Results and discussion

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion