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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Study period:
2016
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read accross following OECD guidelines

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: OECD Joint meeting of the chemicals committee and the working party on chemical, pesticides and biotechnology, Guidance on grouping of chemicals, ENV/JM/MONO(2007)28
Principles of method if other than guideline:
Several computational tools are nowadays available for applying in silico methods. The employed tools were selected according to the OECD Guidance Document on the validation of (Q)SAR models5 that describes generally accepted guidelines to evaluate if an in silico data is suitable for regulatory use.
In particular, these tools: 1) provide predictions for a defined endpoint; 2) are based on well defined algorithm; 3) assess the prediction in terms of applicability domain; 4) provide models internally and externally validated; 5) provide a mechanistic interpretation of the prediction, when possible. Additionally, these tools allows the user to inspect similar structures from the training set along with experimental results.
While this information does not take part to the prediction, it provides the user a complementary means to see how similar compounds are predicted and what the experimental values of similar compounds are. Look at analogues is useful to further assess the reliability of the prediction and also an initial, less-sophisticated easy way to understand estimate of toxicity.
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Dimethoxymethane
EC Number:
203-714-2
EC Name:
Dimethoxymethane
Cas Number:
109-87-5
Molecular formula:
C3H8O2
IUPAC Name:
dimethoxymethane
Constituent 2
Chemical structure
Reference substance name:
1,1'-[methylenebis(oxy)]dibutane
EC Number:
219-909-0
EC Name:
1,1'-[methylenebis(oxy)]dibutane
Cas Number:
2568-90-3
Molecular formula:
C9H20O2
IUPAC Name:
1,1'-[methylenebis(oxy)]dibutane

Results and discussion

Effect levels

Dose descriptor:
NOAEC
Effect level:
6 300 mg/m³ air
Based on:
test mat.
Sex:
not specified

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Source chemical: Methylal

Target chemicals: Ethylal, Butylal

Read-across predictions: NOAEC (13-week) = 6300 mg/m3

Experimental data for subchronic inhalation toxicity are available for the source compound Methylal based on a OECD 413 study conducted in rat under 90-days exposure period (GLP study). The available data refer to two different measurements, the NOEL, which is the no observed effect level, and the NOAEC, which is the no observed adverse effect concentration. The commissioner analysed in more details the study report of the source substance Methylal. No NOAEC is defined in the report but a NOAEC value could be defined at 6300 mg/m3 as a worst case value (=NOEL value). It has to be taken into account that the determination of the

NOAEC is highly toxicological evaluation-dependent, since the determination of an adverse effect is not as theoretical as the determination of an LC50 in an acute toxicity test.

In the current read-across analysis, the available experimental toxicity data of Methylal (i.e., NOAEC value of 6300 mg/m3) was used for the read-across prediction of the sub-chronic inhalation toxicity of the target compounds Ethylal and Butylal. However, since inhalation toxicity is strongly influenced by the vapor pressure, the experimental inhalation toxicity data of the source Methylal is expected to be higher than the inhalation toxicity of Ethylal Butylal because of their lower volatility with respect to the source Methylal.

Therefore, it was concluded that for the target compounds Ethylal and Butylal the read-across approach provided a conservative sub-chronic inhalation toxicity prediction of NOAEC = 6300 mg/m3.

Applicant's summary and conclusion

Conclusions:
The subchronic inhalation toxicity of the target 2-ethylhexylal provided by the weighted mean mathematical formalism is a NOAEC (13-week) = 3127.89 mg/m3
Executive summary:

The read-across analysis was performed for the toxicity super endpoint, including five endpoints, i.e. acute oral toxicity, acute dermal toxicity, acute inhalation toxicity, subchronic inhalation toxicity (90 days, rat) and prenatal developmental toxicity study, that were treated with the same reasoning in terms of mechanism action and for which the read-across follow a similar justification.

In the current study, methylal and dioxolane were selected by the commissioner as source chemicals or analogs, to predict the same endpoints for the target chemicals, i.e. ethylal, 2,5,7,10-tetraoxaundecane, 2-ethylhexylal, propylal, butylal, however, in the case experimental toxicity data of ethylal, 2,5,7,10-tetraoxaundecane, 2-ethylhexylal, propylal, butylal were already available from the commissioner for some of the toxicity endpoints, these data were also employed for the read-across predictions of the remaining target chemicals. Thus, depending on the availability of their experimental toxicity data, the five acetals (ethylal, propylal, butylal, 2,5,7,10-tetraoxaundecane, 2-ethylhexylal) were employed as source chemicals or target chemicals.

A many-to-many read-across was performed since the endpoint information for many chemicals, methylal and dioxolane, was used to estimate the same toxicity endpoints for the target chemicals, i.e. ethylal, propylal, butylal, 2,5,7,10-tetraoxaundecane and 2-ethylhexylal, which were considered to be “similar” enough according to their structural, mechanistic and physicochemical/reactivity property profiles to justify the read-across approach. Figure 4 (see full report attached below) shows an example of a many-to-many read-across approach.

Subchronic inhalation toxicity

Source chemicals: methylal and dioxolane

Target chemical(s): ethylal, propylal, butylal, 2,5,7,10-tetraoxaundecane and 2-ethylhexylal

Read-across predictions: NOAEC (13-week) = 3127.89 mg/m3

In the current read-across analysis, the available experimental toxicity data of methylal and dioxolane were used for the read-across prediction of the subchronic inhalation toxicity of the targets ethylal, propylal, butylal, 2,5,7,10-tetraoxaundecane and 2-ethylhexylal. The available data refer to two different measurements, the NOEL, which is the no observed effect level, and the NOAEC, which is the no observed adverse effect concentration.

The commissioner analysed in more details the study reports of the two source substances. For methylal, no NOAEC is defined in the report but a NOAEC value could be defined at 6300 mg/m3 as a worst case value (=NOEL value). Thus, the read-across prediction was performed employing the NOAEC values of 6300 mg/m3 for methylal and of 903 mg/m3 for dioxolane. It has to be taken into account that the determination of the NOAEC is highly toxicological evaluation-dependent, since the determination of an adverse effect is not as theoretical as the determination of an LC50 in an acute toxicity test. Tests are available for methylal and dioxolane and have been performed by different labs with different sensitivity to define an adverse effect which is the basis of the NOAEC. This difference of sensitivity could explain the disparity between NOAEC of methylal and dioxolane.

Since inhalation toxicity is strongly influenced by the vapor pressure, the experimental inhalation toxicity data of the source methylal was weighted less than the one of dioxolane, because of its much higher vapor pressure than the targets.

The subchronic inhalation toxicity of the targets ethylal, propylal, butylal, 2,5,7,10-tetraoxaundecane and 2-ethylhexylal would be predicted of NOAEC (13-week) = 903 mg/m3 in the worst case scenario. However, a more consistent prediction is considered the one provided by the weighted mean mathematical formalism which led to prediction of NOAEC (13-week) = 3127.89 mg/m3.

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