Dimethoxymethane

Toxicity to reproduction

Administrative data

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Remarks:

The endpoint has evolved from EOGRT - basic test design (Cohorts 1A, and 1B without extension) to screening for reproductive / developmental toxicity (read-across using the data on Ethylal and Butylal to generate data on Methylal)

Type of information:

experimental study planned

Remarks:

The type of information has now evolved from an experimental study plan to a read-across approach to fulfill the requirement of section 7.8.1 as requested in communication number: SUB-C-2114374307-46-04/F of 28 September 2017.

Justification for type of information:

LAMBIOTTE & Cie received a notification dated 2 October 2018 of a draft decision on testing proposal on Dimethoxymethane (EC number 203-714-2; CAS number 109-87-5) (Communication number: TPE-D-2114445851-47-01/D; Registration number: 01-2119664781-31-0000; Submission number: YQ429271-14; Submission date: 15/01/2018).
justif
The information referring to this initial testing proposal is quoted as ‘Initial testing proposal (January 2018)’ in the current endpoint study record.

LAMBIOTTE & Cie comments as below.

Since the submission date of what has been assessed by ECHA as a Testing Proposal for an OECD TG 443, i.e. 15/01/2018, the situation has evolved in the sense that new data are available or will soon be available as a result of ECHA’s information requests on analogue substances Ethylal and Butylal. The Registrant now intends to fulfil the requirement of section 7.8.1 Toxicity to reproduction for the Substance by mean of read-across to those analogue substances.
For reasons of clarity and accuracy of information, the current endpoint study record related to testing proposal has been updated with the new strategy (quoted as ‘Comments to draft decision on testing proposal (December 2018)’)

--> Comments to draft decision on testing proposal (December 2018)

As a matter of facts, Lambiotte & Cie produces an homolog series of Acetals, namely Methylal (Dimethoxymethane), Ethylal (Diethoxymethane; EC number 207-330-6; CAS number 462-95-3; Registration number: 01-2119947549-21-0000; Submission number: DP356050-43; Submission date: 23/11/2012) and Butylal (Dibutoxymethane, 1,1’-[methylenebis(oxy)]dibutane; EC number 219-909-0; CAS number 2568-90-3; Registration number: 01-2119973500-41-0000; Submission number: TW485518-85; Submission date: 11/04/2014).

Several ECHA’s information requests related to reproductive toxicity are pending on those analogue substances, and more precisely:

A. On Ethylal, ECHA’s decision on a compliance check (Decision number: CCH-D-2114348443-50-01/F) dated 30 November 2016 requests the registrant to submit by 8 June 2020
A.i. A reproductive/developmental toxicity screening study in the Sprague Dawley rat by oral gavage administration (OECD TG 421).
An audited draft report of the OECD TG 421 study is already available. The results allow to draw the conclusion that in the absence of any evidence for general systemic toxicity or effects on reproductive performance/offspring development the no-observed-adverse-effect-level is 1000 mg/kg/day (the highest dose tested). The report will be finalized soon.
A.ii. An OECD 414 study by oral administration.
The draft report of the preliminary study will be issued on 16 November 2018, and the audited draft report on the main study will be available on 1 April 2019. The main study is ordered and will follow.

B. On Butylal, ECHA’s decision on a compliance check (Decision number CCH-D-2114348441-54-01/F) dated 30 November 2016 requests the registrant to submit by 9 December 2019 :
B.i. A reproductive/developmental toxicity screening study in the Sprague Dawley rat by oral gavage administration (OECD TG 421).
The QA audited draft report will be issued on 08 March 2019.
B.ii. An OECD 414 study by oral administration.
The draft report of the preliminary study will be issued on 13 December 2018. The main study is ordered and will follow.

Lambiotte proposes to make a read-across using the data on Ethylal and Butylal to generate data on Methylal and to fulfil the requirement of section 7.8.1 (OECD TG 421). The information gathered for Ethylal and Butylal would evidence that the conduct of an OECD TG 443 is not necessary, avoiding unjustified Vertebrate Animal Testing.

To support this proposal, Lambiotte submits here a read-across justification in the form of an update of the registration dossier of the Substance by the deadline of 10 December. This justification is provided in “Justification for type of information”.
In case the read-across to the analogue substances could not be accepted by ECHA, an experimental study (OECD TG 421) on Methylal could be proposed by the Registrant to confirm the prediction of the read-across.
Also, a correlation between the data of the three OECD 414 studies on Methylal, Ethylal and Butylal could be realized to support their validity.
Moreover, a study for effects on embryofoetal development by inhalation administration of Methylal in the rat (OECD TG 414) performed in 1997 concludes that the maternal NOEL is 1954 ppm, corresponding to 6080 mg/m³, and that the developmental NOEL is 10068 ppm or 31328 mg/m³ (the highest dose tested).
In any case, given the pending timing to obtain the final information on the analogue substances, as described above, and in order to ensure that Vertebrate Animal Testing will only be conducted as a last resort, the registrant requests a time limit longer than 24 months (e.g. 36 months) to update the registration dossier with the requested information.
The scientific justification supporting the read-across using the data on Ethylal and Butylal to generate data on Methylal and to fulfill the requirement of section 7.8.1 (OECDTG 421) is provided under ‘Attached justification’. Conclusions of this report are as follows:

“The data presented herein provide sufficient evidence that the Lambiotte linear alkyl acetal compounds described herein (methylal, ethylal, propylal and butylal) constitute a valid cluster based on cogent analyses of their physicochemical and biological properties (toxicological and metabolic data).
The Lambiotte linear alkyl acetal database of acute toxicity, mutagenicity and repeat-dose toxicology testing results is sufficiently robust to represent the overall toxicological properties of methylal and the linear alkyl acetal cluster described herein.
The cluster analysis presented herein demonstrates that it is valid and scientifically defensible to read-across the Lambiotte linear alkyl acetal cluster and to bridge the ethylal and butylal OECD 421 Reproductive and Developmental Toxicology Screening Data to methylal.”

--> Initial testing proposal (January 2018)
At REACH Annex X, EOGRTS is the standard information requirement to address reproductive toxicity.

TESTING PROPOSAL ON VERTEBRATE ANIMALS

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out: dimethoxymethane

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: : none to fulfil this requirement
- Available non-GLP studies: : none to fulfil this requirement
- Historical human data: no data available
- (Q)SAR: There is no reliable QSAR models addressing this requirement
- In vitro methods: tThere is no reliable in vitro methods addressing this requirement
- Weight of evidence: in absence of information (i.e., in vivo and/or in vitro studies, QSAR and read-across), weight of evidence approach is not possible
- Grouping and read-across: Since none of the potential candidates has been tested for reproductive toxicity in an extended one-generation study, read-across is not possible.
- Substance-tailored exposure driven testing [if applicable]: not applicable
- Approaches in addition to above [if applicable]: not applicable
- Other reasons [if applicable]: not applicable

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:
- Based on the existing data, adaptation options as defined in Annexes VI to X were not applicable for this substance and this requirement.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Details on study design / methodology proposed [if relevant]: The intention of the registrant is to follow the basic study that does not include mating of F1 animals (extension of Cohort 1B) or cohorts for developmental neurotoxicity (Cohorts 2A and 2B) or developmental immunotoxicity (Cohort 3) by oral administration.

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other: Read across approach

Version / remarks:

Comments to draft decision on testing proposal (December 2018)

Test guideline 2

Qualifier:

according to guideline

Guideline:

OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)

Version / remarks:

Initial testing proposal (January 2018)

Justification for study design:

--> Comments to draft decision on testing proposal (December 2018)
Study design is no longer relevant based on the read-across approach using the data on Ethylal and Butylal to generate data on Methylal and to fulfil the requirement of section 7.8.1 (OECD TG 421). The approach is fully described in “Justification for type of information”.

--> Initial testing proposal (January 2018)
- Premating exposure duration for parental (P0) animals: a ten weeks premating exposure duration
- Basis for dose level selection: based on the relevant existing data* and on a dose range-finding test
- Inclusion/exclusion of extension of Cohort 1B: based on the existing toxicological data*, there are no trigger for inclusion of extension of Cohort 1B to include the F2 generation
- Termination time for F2: No F2 generation as extension of Cohort 1B is considered
- Inclusion/exclusion of developmental neurotoxicity Cohorts 2A and 2B: based on the existing toxicological data*, there are no trigger for inclusion of developmental neurotoxicity Cohorts 2A and 2B
- Inclusion/exclusion of developmental immunotoxicity Cohort 3: based on the existing toxicological data*, there are no trigger for inclusion of developmental immunotoxicity Cohort 3
- Route of administration: oral
- Other considerations (e.g. on choice of species, strain, vehicle and number of animals): choice of species: rat; vehicle: water ; Number of animals: each test and control group should contain a sufficient number of mating pairs to yield at least 20 pregnant females per dose group

*An OECD 414 study in rabbit (performed following decision number CCH-D-2114343381-57-01/F)) is being finalized. The result could influence the design of the OECD 443 study. Taking into account the principle of minimizing the number of used animals to perform studies, the final design proposal of the OECD 443 study will be developed after finalization of the OECD 414 Study in rabbit.”

Test material

Test material information

Constituent 1

Reference substance name:

Dimethoxymethane

EC Number:

203-714-2

EC Name:

Dimethoxymethane

Cas Number:

109-87-5

Molecular formula:

C3H8O2

IUPAC Name:

dimethoxymethane

Test material form:

liquid

Details on test material:

- Name of test material (as cited in study report): Dimethoxymetane
- Physical state: colorless volatile liquid
- Storage condition of test material: at room temperature

Applicant's summary and conclusion

Conclusions:

As discussed above, it is scientifically justified to propose a read-across using data on Ethylal and Butylal to generate data on Methylal in order to fulfill the requirement of section 7.8.1 (OECD TG 421).

Executive summary:

Comments to draft decision on testing proposal (December 2018)

LAMBIOTTE & Cie received a notification dated 2 October 2018 of a draft decision on testing proposal on Dimethoxymethane (EC number 203-714-2; CAS number 109-87-5) (Communication number:  TPE-D-2114445851-47-01/D; Registration number:  01-2119664781-31-0000; Submission number:  YQ429271-14; Submission date: 15/01/2018).

LAMBIOTTE & Cie comments as below.

Since the submission date of what has been assessed by ECHA as a Testing Proposal for an OECD TG 443, i.e. 15/01/2018, the situation has evolved in the sense that new data are available or will soon be available as a result of ECHA’s information requests on analogue substances Ethylal and Butylal. The Registrant now intends to fulfil the requirement of section 7.8.1 Toxicity to reproduction for the Substance by mean of read-across to those analogue substances.

As a matter of facts, Lambiotte & Cie produces an homolog series of Acetals, namely Methylal (Dimethoxymethane), Ethylal (Diethoxymethane; EC number 207-330-6; CAS number 462-95-3; Registration number: 01-2119947549-21-0000; Submission number: DP356050-43; Submission date: 23/11/2012) and Butylal (Dibutoxymethane, 1,1’-[methylenebis(oxy)]dibutane; EC number 219-909-0; CAS number 2568-90-3; Registration number: 01-2119973500-41-0000; Submission number: TW485518-85; Submission date: 11/04/2014).

Several ECHA’s information requests related to reproductive toxicity are pending on those analogue substances, and more precisely:

A. On Ethylal, ECHA’s decision on a compliance check (Decision number: CCH-D-2114348443-50-01/F) dated 30 November 2016 requests the registrant to submit by 8 June 2020

A.i. A reproductive/developmental toxicity screening study in the Sprague Dawley rat by oral gavage administration (OECD TG 421).

An audited draft report of the OECD TG 421 study is already available. The results allow to draw the conclusion that in the absence of any evidence for general systemic toxicity or effects on reproductive performance/offspring development the no-observed-adverse-effect-level is 1000 mg/kg/day (the highest dose tested). The report will be finalized soon.

A.ii. An OECD 414 study by oral administration.

The draft report of the preliminary study will be issued on 16 November 2018, and the audited draft report on the main study will be available on 1 April 2019. The main study is ordered and will follow.

B. On Butylal, ECHA’s decision on a compliance check (Decision number CCH-D-2114348441-54-01/F) dated 30 November 2016 requests the registrant to submit by 9 December 2019 :

B.i. A reproductive/developmental toxicity screening study in the Sprague Dawley rat by oral gavage administration (OECD TG 421).

The QA audited draft report will be issued on 08 March 2019.

B.ii. An OECD 414 study by oral administration.

The draft report of the preliminary study will be issued on 13 December 2018. The main study is ordered and will follow.

Lambiotte proposes to make a read-across using the data on Ethylal and Butylal to generate data on Methylal and to fulfil the requirement of section 7.8.1 (OECD TG 421). The information gathered for Ethylal and Butylal would evidence that the conduct of an OECD TG 443 is not necessary, avoiding unjustified Vertebrate Animal Testing.

To support this proposal, Lambiotte submits here a read-across justification in the form of an update of the registration dossier of the Substance by the deadline of 10 December. This justification is provided in “Justification for type of information”.

In case the read-across to the analogue substances could not be accepted by ECHA, an experimental study (OECD TG 421) on Methylal could be proposed by the Registrant to confirm the prediction of the read-across.

Also, a correlation between the data of the three OECD 414 studies on Methylal, Ethylal and Butylal could be realized to support their validity.

Moreover, a study for effects on embryofoetal development by inhalation administration of Methylal in the rat (OECD TG 414) performed in 1997 concludes that the maternal NOEL is 1954 ppm, corresponding to 6080 mg/m³, and that the developmental NOEL is 10068 ppm or 31328 mg/m³ (the highest dose tested).

In any case, given the pending timing to obtain the final information on the analogue substances, as described above, and in order to ensure that Vertebrate Animal Testing will only be conducted as a last resort, the registrant requests a time limit longer than 24  months (e.g. 36 months) to update the registration dossier with the requested information.

The scientific justification supporting the read-across using the data on Ethylal and Butylal to generate data on Methylal and to fulfill the requirement of section 7.8.1 (OECDTG 421) is provided under ‘Attached justification’. Conclusions of this report are as follows:

“The data presented herein provide sufficient evidence that the Lambiotte linear alkyl acetal compounds described herein (methylal, ethylal, propylal and butylal) constitute a valid cluster based on cogent analyses of their physicochemical and biological properties (toxicological and metabolic data).

The Lambiotte linear alkyl acetal database of acute toxicity, mutagenicity and repeat-dose toxicology testing results is sufficiently robust to represent the overall toxicological properties of methylal and the linear alkyl acetal cluster described herein.

The cluster analysis presented herein demonstrates that it is valid and scientifically defensible to read-across the Lambiotte linear alkyl acetal cluster and to bridge the ethylal and butylal OECD 421 Reproductive and Developmental Toxicology Screening Data to methylal.”