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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
reproductive toxicity, other
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
2016
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
1. SOFTWARE

Gnarus systems CAT-SAR system (http://www.gnarus-systems.com/how-it-works/cat-sar-overview/)

2. MODEL (incl. version number)

Cat-SAR Human Developmental Toxicity - Mattison (QMRF 1.1)
February 2, 2016 (QMRF 2.6)

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL

ME-CGE-DETA structures with same molecular formula (C14 H25 N3 O2) and molecular weight (267.37)

2-ME-CGE-DETA
CC1=CC=CC=C1OCC(O)CNCCNCCN

3-ME-CGE-DETA
CC1=CC(OCC(O)CNCCNCCN)=CC=C1

4-ME-CGE-DETA
CC1=CC=C(OCC(O)CNCCNCCN)C=C1


4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODELS

Human Teratogenicity (i.e., developmental toxicity): This model is derived from a dataset of compounds analyzed for potential human teratogenicity developed by Dr. Donald Mattison. The model contains developmental toxicity calls for 323 chemicals, 130 of which are classified as human teratogens and 193 as non-teratogens.

Ghanooni, M., D.R. Mattison, Y.P. Zhang, O.T. Macina, H.S. Rosenkranz, and G. Klopman (1997) Structural determinants associated with risk of human developmental toxicity. American Journal of Obstetrics and Gynecology, 176: 799-806.

5. APPLICABILITY DOMAIN

Generally--the applicable domain of this model is small organic molecules that would fit the general attributes of compounds contained the Human Developmental Toxicity database

Cat-SAR, unlike some other SAR expert systems, does not use default predictions. Chemicals have to be either predicted as active or inactive on account of fragments contained in their structure. If no identical fragment is found in an unknown chemical that meets rules 1-3 in section 4.4 of this QMRF, no prediction is made. In this fashion, the applicable domain is determined on a one-by-one basis.


6. ADEQUACY OF THE RESULT

Overall, the prediction of “inactive” for structural analogues of DIME-CGE-DETA were based on 17 fragments that individually related back to 263 compounds in the Human Developmental Toxicity Mattison learning set with 80 of the 739 compounds being classified as human developmental toxicants (noting redundancy wherein individual chemicals may relate to more than one fragment and cut-point value to separate active from inactive calls).

Data source

Reference
Reference Type:
other: QSAR Software
Title:
Gnarus Systems cat-SAR structure-activity relationship (SAR) program
Year:
2016
Bibliographic source:
Ghanooni, M., D.R. Mattison, Y.P. Zhang, O.T. Macina, H.S. Rosenkranz, and G. Klopman (1997) Structural determinants associated with risk of human developmental toxicity. American Journal of Obstetrics and Gynecology, 176: 799-806.

Materials and methods

Test guideline
Guideline:
other: REACH Guidance on QSARS R.6
Principles of method if other than guideline:
Ghanooni, M., D.R. Mattison, Y.P. Zhang, O.T. Macina, H.S. Rosenkranz, and G. Klopman (1997) Structural determinants associated with risk of human developmental toxicity. American Journal of Obstetrics and Gynecology, 176: 799-806.

Test material

Constituent 1
Chemical structure
Reference substance name:
1,2-Ethanediamine, N-(2-aminoethyl)-, reaction products with glycidyl tolyl ether
EC Number:
282-199-6
EC Name:
1,2-Ethanediamine, N-(2-aminoethyl)-, reaction products with glycidyl tolyl ether
Cas Number:
84144-79-6
Molecular formula:
C14H26N3O2
IUPAC Name:
1,2-Ethanediamine, N-(2-aminoethyl)-, reaction products with glycidyl tolyl ether
Test material form:
liquid: viscous
Specific details on test material used for the study:
CGE-DIMER
CC1=CC=C(OCC(O)COC2=CC=C(C)C=C2)C=C1

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

Remarks on result:
other: QSAR Predictied Value

Results: P1 (second parental generation)

Effect levels (P1)

Remarks on result:
other: QSAR Predictied Value

Results: F1 generation

Effect levels (F1)

Remarks on result:
other: QSAR Predictied Value

Results: F2 generation

Effect levels (F2)

Remarks on result:
other: QSAR Predictied Value

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Overall, the prediction of “inactive” for structural analogues of DIME-CGE-DETA were based on 31 fragments that individually related back to 739 compounds in the Human Developmental Toxicity Mattison learning set with 80 of the 739 compounds being classified as human developmental toxicants (noting redundancy wherein individual chemicals may relate to more than one fragment and cut-point value to separate active from inactive calls).  

Applicant's summary and conclusion

Conclusions:
Overall, the prediction of “equivocal” for compound CGE-DIMER was based on 17 fragments that individually related back to 263 compounds in the Human Developmental Toxicity Mattison learning set with 39 of the 263 compounds being classified as human developmental toxicants (noting redundancy wherein individual chemicals may relate to more than one fragment and cut-point value to separate active from inactive calls).

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