Reaction products of 4,4'-methylenebis(cyclohexylamine) and 2,2'-[(1-methylethylidene)bis(4,1-phenyleneoxymethylene)]bisoxirane

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

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)

b. Model version: February 2, 2016 (QMRF 2.6)

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

PACM
NC1CCC(CC2CCC(N)CC2)CC1

PACM-BADGE-PACM (PACM-BP)
CC(C)(C1=CC=C(OCC(O)CNC2CCC(CC3CCC(N)CC3)CC2)C=C1)C1=CC=C(OCC(O)CNC2CCC(CC3CCC(N)CC3)CC2)C=C1

PACM-BADGE-BADGE-PACM (PACM-BBP)
CC(C)(C1=CC=C(OCC(O)CNC2CCC(CC3CCC(N)CC3)CC2)C=C1)C1=CC=C(OCC(O)COC2=CC=C(C=C2)C(C)(C)C2=CC=C(OCC(O)CNC3CCC(CC4CCC(N)CC4)CC3)C=C2)C=C1

PACM-BADGE-PACM-BADGE-PACM (PACM-BPBP)
CC(C)(C1=CC=C(OCC(O)CNC2CCC(CC3CCC(N)CC3)CC2)C=C1)C1=CC=C(OCC(O)CNC2CCC(CC3CCC(CC3)NCC(O)COC3=CC=C(C=C3)C(C)(C)C3=CC=C(OCC(O)CNC4CCC(CC5CCC(N)CC5)CC4)C=C3)CC2)C=C1

PACM-BADGE-BADGE-PACM-BADGE-BADGE-PACM (PACM-BBPBBP)
CC(C)(C1=CC=C(OCC(O)CNC2CCC(CC3CCC(N)CC3)CC2)C=C1)C1=CC=C(OCC(O)COC2=CC=C(C=C2)C(C)(C)C2=CC=C(OCC(O)CNC3CCC(CC4CCC(CC4)NCC(O)COC4=CC=C(C=C4)C(C)(C)C4=CC=C(OCC(O)COC5=CC=C(C=C5)C(C)(C)C5=CC=C(OCC(O)CNC6CCC(CC7CCC(N)CC7)CC6)C=C5)C=C4)CC3)C=C2)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 compound PACM-BP was based on 34 fragments that individually related back to 599 compounds in the Human Developmental Toxicity Mattison learning set with 84 of the 599 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).

Overall, the prediction of “inactive” for compound PACM-BBP was based on 35 fragments that individually related back to 604 compounds in the NCTR ER learning set with 84 of the 604 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).

Overall, the prediction of “inactive” for compound PACM-BPBP was based on 37 fragments that individually related back to 633 compounds in the Human Developmental Toxicity Mattison learning set with 88 of the 833 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).

Overall, the prediction of “inactive” for compound PACM-BBPBBP was based on 34 fragments that individually related back to 599 compounds in the Human Developmental Toxicity Mattison learning set with 84 of the 599 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

Qualifier:

no guideline required

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

Test material information

Constituent 1

Reference substance name:

4,4'-methylenebis(cyclohexylamine)

EC Number:

217-168-8

EC Name:

4,4'-methylenebis(cyclohexylamine)

Cas Number:

1761-71-3

Molecular formula:

C13H26N2

IUPAC Name:

4,4'-methylenedicyclohexanamine

Constituent 2

Reference substance name:

4,4'-Isopropylidenediphenol, oligomeric reaction products with 1-chloro-2,3-epoxypropane, reaction products with 4,4'-methylenebis(cyclohexylamine)

EC Number:

500-103-5

EC Name:

4,4'-Isopropylidenediphenol, oligomeric reaction products with 1-chloro-2,3-epoxypropane, reaction products with 4,4'-methylenebis(cyclohexylamine)

Cas Number:

38294-67-6

Molecular formula:

C

IUPAC Name:

Reaction products of 4,4'-methylenebis(cyclohexylamine) and 2,2'-[(1-methylethylidene)bis(4,1-phenyleneoxymethylene)]bisoxirane

Test material form:

liquid: viscous

Specific details on test material used for the study:

PACM-BADGE covers a series of polymers with repeating PACM and BADGE monomers as follows with additional abbreviated names:

PACM
PACM-BADGE-PACM (PACM-BP)
PACM-BADGE-BADGE-PACM (PACM-BBP)
PACM-BADGE-PACM-BADGE-PACM (PACM-BPBP)
PACM-BADGE-BADGE-PACM-BADGE-BADGE-PACM (PACM-BBPBBP)

Test animals

Species:

other: QSAR prediction

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Remarks on result:

other: QSAR Predicition

Results (fetuses)

Effect levels (fetuses)

Remarks on result:

other: QSAR Prediction

Overall developmental toxicity

Developmental effects observed:

not specified

Treatment related:

not specified

Applicant's summary and conclusion

Conclusions:

The Cat-SAR Human Developmental Toxicity - Mattison QSAR Model is derived from a dataset of compounds analyzed for potential human teratogenicity. The model contains developmental toxicity calls for 323 chemicals, 130 of which are classified as human teratogens and 193 as non-teratogens. The assessed PACM-BADGE adduct structures are a series of polymers with repeating PACM and BADGE monomers, as well as PACM.

For PACM, no prediction indicates there were no structural analogs associated with Human Developmental Toxicity
All other structures show no activity based on analysis of structural fragments.