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Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Short description of key information:

According to column 1 "Standard information required” in Annex IX of REACH, a 2-genreation reproduction toxicity test is needed if the 28-day or 90-day study indicates adverse effects on reproductive organs or tissues.

No adverse effects have been recorded in testes, epididymides, ovaries and uterus in rabbits exposed to 1000 mg/kg bw/d of 2,5,7,10-TETRAOXAUNDECANE in the 28-day dermal toxicity (Gillotin, 2012).

Effects on developmental toxicity

Description of key information

The pieces of information that build the weight of evidence are the following:

A) Read-across from dioxolane and dimethoxymethane (Pavan, 2012):

The following predictions were obtained for the prenatal developmental studies of propylal, TOU, 2-ethylhexylal and butylal: NOAEL (dev) of 195 mg/kg/bw/d (obtained as mean value of dioxolane NOAEL (dev) data) and NOAEL (mat) of 250 mg/kg/bw/d.

B) QSAR model predictions for structural dysmorphogensis developmental toxicity on mouse (Pavan, 2012)

Fully documented with QPRF and QMRF

Negative prediction considered little reliable (therefore it is suggested to be employed in a weight of evidence approach to support other experimental data or read-across studies).

C) QSAR model predictions for structural dysmorphogensis developmental toxicity on rabbit (Pavan, 2012)

Fully documented with QPRF and QMRF

Negative prediction considered reliable

D) QSAR model predictions for structural dysmorphogensis developmental toxicity on rat (Pavan, 2012)

Fully documented with QPRF and QMRF

Negative prediction considered little reliable (therefore it is suggested to be employed in a weight of evidence approach to support other experimental data or read-across studies).

E) QSAR model predictions for structural dysmorphogensis developmental toxicity on rodent (Pavan, 2012)

Fully documented with QPRF and QMRF

Negative prediction considered little reliable (therefore it is suggested to be employed in a weight of evidence approach to support other experimental data or read-across studies).

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
June 2012
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
As shown in the attached report, the suggested source chemicals , i.e. methylal and dioxolane, can be considered sufficient similar in relation to the toxicity super endpoint to the target chemicals, i.e. ethylal, propylal, butylal, 2,5,7,10-tetraoxaundecane and 2-ethylhexylal, to apply the read-across approach. Their structural similarity is also supported by a close similarity in terms of reactivity properties relevant for toxicity end points and in terms of physicochemical properties, although it was noted that 2-ethylhexylal shows some relevant physicochemical differences form the other acetals. Thus, it was concluded that the acetals are sufficiently similar to justify the experimental test results of the source chemicals to be read-across to target chemicals, although the 2-ethylhexylal predictions have to be considered of lower reliability than the other predictions because of its lower physicochemical similarity with the source chemicals.
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
GLP compliance:
no
Species:
rat
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
195 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: Developmental toxicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
The available experimental toxicity data of methylal and dioxolane were used for the read-across prediction of the prenatal developmental toxicity of the targets ethylal, propylal, butylal, 2,5,7,10-tetraoxaundecane and 2-ethylhexylal. The following predictions were obtained for the prenatal developmental studies of propylal, TOU, 2-ethylhexylal and butylal: NOAEL (dev) of 195 mg/kg/bw/d and NOAEL (mat) of 250 mg/kg/bw/d.

These results were further confirmed by the QSAR model predictions for structural dysmorphogensis developmental toxicity on rabbit, rat, rodent and mouse for ethylal, butylal, 2,5,7,10-tetraoxaundecane, 2-ethylhexylal, which resulted to be NEGATIVE, although the reliability of the QSAR predictions was often little because the chemical class of the acetals is poorly represented in the employed Leadscope model.
Executive summary:

Prenatal developmental toxicity study

Source chemicals: methylal and dioxolane

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

Read-across predictions: NOAEL (dev) of 195 mg/kg/bw/d and NOAEL (mat) of 250 mg/kg/bw/d for propylal, TOU, 2-ethylhexylal and butylal.

NOAEL (dev) of 31814.88.3mg/m3 and NOAEL (mat) of 6174.64 mg/m3for ethylal.

In the current read-across analysis, the available experimental toxicity data of methylal and dioxolane were used for the read-across prediction of the prenatal developmental toxicity of the targets ethylal, propylal, butylal, 2,5,7,10-tetraoxaundecane and 2-ethylhexylal. The available developmental toxicity data were further analysed by the commissioner and it was highlighted that in the methylal inhalation study, NOEL (dev) and NOAEL (dev) can be considered equal (as the NOEL is the highest tested dose and no effect is observed in the test). Thus, in this study, NOAEL (dev) was considered as 31814.77 mg/m3.

In addition, in the dioxolane study, the NOAEL are defined by oral route and the adverse effect is a reduced ossification of the foetus. This kind of adverse effect is not observed with methylal. Thus, since the oral route is relevant for propylal, TOU, 2-ethylhexylal and butylal and the inhalation route is relevant for ethylal, the dioxolane data were read-across to propylal, butylal, 2,5,7,10-tetraoxaundecane and 2-ethylhexylal, while the methylal data were read-across to ethylal.

Thus, the following predictions were obtained for the prenatal developmental studies of propylal, TOU, 2-ethylhexylal and butylal: NOAEL (dev) of 195 mg/kg/bw/d, obtained as mean value of dioxolane NOAEL (dev) data, and NOAEL (mat) of 250 mg/kg/bw/d. The prediction for 2-ethylhexylal acute has to be considered of lower reliability than the other predictions because of its lower similarity with the source chemicals.

While, the following predictions were obtained for the prenatal developmental studies of ethylal: NOAEL (dev) of 31814.88.3mg/m3 and NOAEL (mat) of 6174.64 mg/m3.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
195 mg/kg bw/day
Study duration:
subacute
Species:
other: Rat, mouse, rabbit, rodent
Quality of whole database:
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.
Endpoints from two tests equivalent or similar to OECD Guideline 414 (Klimisch code 2) performed with dioxolane was read-across to the target substance TOU.
The read-across approach was confirmated with QSAR predictions.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

The weight of evidence approach is justified as determined from more than one piece of information (independent sources). We claim the reliability, relevance, adequacy and quality of the weight of evidence:

-     Reliability: Klimisch score of 2 is assigned to the pieces of information. 

-     Relevance:

o  Relevance of test material: the substance purity is not relevant regarding in-silico predictions (QSAR and read-accross) but the test material is equivalent to the submission substance identity. Relevance for QSAR is defined in QPRF and QMRF. The target Dimethoxymethane and the source 1,2-dimethoxyethane can be considered sufficiently structurally and mechanistically similar to apply the read-across approach. Relevance of the read-across approach is supported by structural similarity between the source and the target chemicals and is also supported by a close similarity in terms of mechanism of action, physicochemical and reactivity properties relevant for the taret endpoint.

o  Relevance of test method and conditions: Relevance for QSAR is defined in QPRF and QMRF. Relevance of the read-across is supported by the key study status of the source study.

o  Relevance of the endpoint: the values obtained extend over 2 different approaches and show a clear evidence of low developmental toxicity:

-> Read-across: NOAEL (dev) of 195 mg/kg/bw/d and NOAEL (mat) of 250 mg/kg/bw/d

-> QSAR prediction: negative in rat, rodent, rabbit and mouse

o  Relevance of alternative methods: relevance of QSAR is defined in QPRF and QMRF. Relevance of the read-across is supported by the clear analogy between the source and the target chemicals. 

-     Adequacy: the clear trend resulting from 2 different approaches allow a clear decision related to classification with absence of concern.

-     Quantity: five pieces of information are considered. 

Justification for selection of Effect on developmental toxicity: via oral route:

Read Accross following OECD guidelines with results confirmed by QSAR

Justification for classification or non-classification

The read across study as well as the QSAR predictions are considered as reliable enough and do not present any sufficient signs for classification as toxic to reproduction.

Additional information