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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

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.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report date:
2012

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
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1,3-dioxolane
EC Number:
211-463-5
EC Name:
1,3-dioxolane
Cas Number:
646-06-0
Molecular formula:
C3H6O2
IUPAC Name:
1,3-dioxolane
Details on test material:
Source chemicals: methylal and dioxolane
Target chemicals: ethylal, propylal, butylal, TOU and 2-ethylhexylal

Test animals

Species:
rat

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
195 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: Developmental toxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

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.

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