4,4'-carbonimidoylbis[N,N-diethylaniline] monohydrochloride

Endpoint summary

Description of key information

Skin sensitisation:

The prediction done using the OECD QSAR toolbox version 3.4 with log kow as the primary descriptor and considering the five closest read across substances, the skin sensitization in Dunkin-Hartley male and female guinea pig was predicted for 4,4'-carbonimidoylbis(N,N-diethylaniline) hydrochloride ( 6358-36 -7). The test substance caused no sensitizing reaction in Dunkin-Hartley male and female guinea pig. Therefore 4,4'-carbonimidoylbis(N,N-diethylaniline) hydrochloride ( 6358-36 -7) was considered to be not sensitizing in guinea pig.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

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 limited documentation / justification

Justification for type of information:

Data is predicted using OECD QSAR toolbox version 3.4 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Principles of method if other than guideline:

Prediction of Skin Sensitisation by using QSAR Toolbox 3.4.0.17 version.

GLP compliance:

not specified

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

Not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): 4,4'-carbonimidoylbis(N,N-diethylaniline) hydrochloride
- Molecular formula: C21H29N3.ClH
- Molecular weight: 359.936 g/mol
- Substance type: Organic
- Physical state: solid

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

male/female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: BRL, Biological Research Laboratories Ltd.
- Age at study initiation: 7 to 8 weeks
- Weight at study initiation: 359 to 454 g
- Housing: individually in Makrolon type-3 cages
- Diet (e.g. ad libitum): pelleted standard Kliba 342 (ad libitum)
- Water (e.g. ad libitum): community tap water (ad libitum)
- Acclimation period: one week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 40 to 70
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12/12

Route:

intradermal and epicutaneous

Vehicle:

petrolatum

Concentration / amount:

Intradermal injection of test article diluted to 1%, dermal application of 15%,

Route:

epicutaneous, occlusive

Vehicle:

petrolatum

Concentration / amount:

10%

Day(s)/duration:

24 and 48 hour

No. of animals per dose:

10 animals/sex in treatment group;
5 animals/sex in control group

Details on study design:

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 3
- Site: dorsal skin from the scapular region
- Frequency of applications: single
- Concentrations: diluted to 1%


B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: 24 hours
- Exposure period: 24 hours
- Test groups:
- Control group:
- Site: left and right flank
- Concentrations: 10% in petrolatum oil
- Evaluation (hr after challenge): 24 and 48 hours

Challenge controls:

No data available.

Positive control substance(s):

yes

Remarks:

formaldehyde solution

Statistics:

Mean values with standard deviations. Fisher-Test (The Exact Fisher Test for comparison of the basic proability of two binominal distributions. L. Sachs, Statistische Auswertungsmethoden, Georg Thieme Verlag, Stuttgart . For calculation of p-values the 24 hours reading of the animals from the control and test groups was used.

Reading:

rechallenge

Hours after challenge:

24

Group:

test chemical

Dose level:

10%

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

No sensitization observed .

Remarks on result:

no indication of skin sensitisation

The prediction was based on dataset comprised from the following descriptors: "Skin Sensitisation"
Estimation method: Takes mode value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

((((("a" or "b" )  and ("c" and ( not "d") )  )  and ("e" and ( not "f") )  )  and ("g" and ( not "h") )  )  and ("i" and "j" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine by DNA binding by OECD

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as AN2 AND AN2 >> Michael-type addition to quinoid structures  AND AN2 >> Michael-type addition to quinoid structures  >> N-Substituted Aromatic Amines by Protein binding by OASIS v1.4

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.4

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >>  Michael-type addition, quinoid structures OR AN2 >>  Michael-type addition, quinoid structures >> Quinones and Trihydroxybenzenes OR AN2 >> Schiff base formation OR AN2 >> Schiff base formation >> Polarized Haloalkene Derivatives OR AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation OR AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation >> Haloalkenes with Electron-Withdrawing Groups OR AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation >> Polarized Haloalkene Derivatives OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Amino Anthraquinones OR Non-covalent interaction >> DNA intercalation >> Fused-Ring Primary Aromatic Amines OR Non-covalent interaction >> DNA intercalation >> Quinones and Trihydroxybenzenes OR Non-specific OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    >> Specific Imine and Thione Derivatives OR Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Amino Anthraquinones OR Radical >> Radical mechanism via ROS formation (indirect) >> Fused-Ring Primary Aromatic Amines OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitro Azoarenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroaniline Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR Radical >> Radical mechanism via ROS formation (indirect) >> Quinones and Trihydroxybenzenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives OR SN1 OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Amino Anthraquinones OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Fused-Ring Primary Aromatic Amines OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitro Azoarenes OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroaniline Derivatives OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR SN1 >> Nucleophilic substitution on diazonium ion OR SN1 >> Nucleophilic substitution on diazonium ion >> Specific Imine and Thione Derivatives OR SN2 OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Haloalkenes with Electron-Withdrawing Groups OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polarized Haloalkene Derivatives OR SN2 >> SN2 at sp3 and activated sp2 carbon atom OR SN2 >> SN2 at sp3 and activated sp2 carbon atom >> Polarized Haloalkene Derivatives by DNA binding by OASIS v.1.4

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine by DNA binding by OECD

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates >> Thioureas OR Michael addition OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR No alert found OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Aromatic nitro OR SN1 >> Nitrenium Ion formation >> Aromatic phenylureas OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine OR SN1 >> Nitrenium Ion formation >> Secondary aromatic amine OR SN2 OR SN2 >> P450 Mediated Sulfoxidation OR SN2 >> P450 Mediated Sulfoxidation >> Thioureas-SN2 by DNA binding by OECD

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OECD

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Acylation Involving a Leaving group OR Acylation >> Direct Acylation Involving a Leaving group >> Acetates OR SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Halo-triazines by Protein binding by OECD

Domain logical expression index: "i"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.948

Domain logical expression index: "j"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.37

Interpretation of results:

other: not sensitising

Conclusions:

The skin sensitization potential of 4,4'-carbonimidoylbis(N,N-diethylaniline) hydrochloride ( 6358-36 -7) was estimated by using OECD QSAR toolbox v3.4 with log kow as the primary descriptor and considering the six closest read across substances. 4,4'-carbonimidoylbis(N,N-diethylaniline) hydrochloride ( 6358-36 -7)was predicted to be non sensitizing to the skin of Dunkin-Hartley male and female guinea pig.

Executive summary:

The skin sensitization potential of 4,4'-carbonimidoylbis(N,N-diethylaniline) hydrochloride ( 6358-36 -7) was estimated by using OECD QSAR toolbox v3.4 with log kow as the primary descriptor and considering the six closest read across substances. 4,4'-carbonimidoylbis(N,N-diethylaniline) hydrochloride ( 6358-36 -7)was predicted to be non sensitizing to the skin of Dunkin-Hartley male and female guinea pig.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Skin sensitization 

In different studies, 4,4'-carbonimidoylbis(N,N-diethylaniline) hydrochloride has been investigated for potential for skin sensitization to a greater or lesser extent. The studies are based on in vivo experiments in guinea pig for target chemical 4,4'-carbonimidoylbis(N,N-diethylaniline) and its structurally similar read across substances Disodium 4,4'-bis [(4-anilino-6-morpholino-1,3,5-triazin-2-yl)amino]stilbene-2,2'-disulphonate(CAS:16090-02-1)andSodium4-[3,6-bis(diethylamino)-2,7-dimethylxanthenium-9-yl]benzene-1,3-disulfonate (CAS: 3520-42-1). The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

The prediction done using the OECD QSAR toolbox version 3.4 with log kow as the primary descriptor and considering the five closest read across substances, the skin sensitization in Dunkin-Hartley male and female guinea pig was predicted for 4,4'-carbonimidoylbis(N,N-diethylaniline) hydrochloride ( 6358-36 -7). The test substance caused no sensitizing reaction in Dunkin-Hartley male and female guinea pig. Therefore 4,4'-carbonimidoylbis(N,N-diethylaniline) hydrochloride ( 6358-36 -7) was considered to be not sensitizing in guinea pig.

It is supported by the experimental data conducted by John F. Griffith, PhD, Cincinnati (Archives of Dermatology, 1973)on structurally similar read across substance Disodium 4,4'-bis[(4-anilino-6-morpholino-1,3,5-triazin-2-yl)amino]stilbene-2,2'-disulphonate(CAS:16-90-02-1)in human.The sensitization test was performed on 70 human by repeated insult patch test.10% of disodium 4,4'-bis[(4-anilino-6-morpholino-1,3,5-triazin-2-yl)amino]stilbene-2,2'-disulphonate in 0.5% vehicle was applied to 70 human subjects.For this test, the materials were applied under occlusive patches in a series of nine applications, each of 24 hours' duration, during a three-week period. Challenge applications were made two weeks later.Disodium 4,4'-bis[(4-anilino-6-morpholino-1,3,5-triazin-2-yl)amino]stilbene-2,2'-disulphonate tested did not reveal any tendency to produce skin sensitization among the human subjects who were exposed to the test material. Therefore Disodium 4,4'-bis [(4-anilino-6-morpholino- 1,3,5-triazin-2-yl) amino]stilbene-2,2'-disulphonate was considered to be non sensitizing to the human .

It is further supported by experimental data conducted by THE SCIENTIFIC COMMITTEE ON COSMETIC PRODUCTS AND NON-FOOD PRODUCTS (SCCNFP,2004) on another structurally similar read across substance Sodium4-[3,6-bis(diethylamino)-2,7-dimethylxanthenium-9-yl]benzene-1,3-disulfonate (CAS: 3520-42-1) inguinea pigs. The skin sensitization study of sodium 4-[3,6-bis(diethylamino)-2,7-dimethylxanthenium-9-yl]benzene-1,3-disulfonatewas performed in Himalayan spotted albino guinea pigs to observe its sensitizing efficacy for the period of 25 days. In induction treatment 10 females were used. Animals were induced with intradermal induction and epidermal induction.  The challenge was performed for test substance with 10 % in 1 % CMC under occlusive patch for 24 h at a different part of the skin. Observations were made at 24 and 48 hours removal of the dressings After challenge no skin reactions were observed. Hence the test chemicalsodium 4-[3,6-bis(diethylamino)-2,7-dimethylxanthenium-9-yl]benzene-1,3-disulfonate was considered to be non sensitizing to the Himalayan spotted albino guinea pigs.

 

Thus based on the above predictions on 4,4'-carbonimidoylbis(N,N-diethylaniline) hydrochloride as well as its read across substances and applying weight of evidence , it can be concluded that 4,4'-carbonimidoylbis(N,N-diethylaniline) hydrochloride is not a skin sensitizer. Thus comparing the above annotations with the criteria of CLP regulation, 4,4'-carbonimidoylbis(N,N-diethylaniline) hydrochloride can be considered as not classified for skin sensitization effect.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the above predictions on 4,4'-carbonimidoylbis(N,N-diethylaniline) hydrochloride as well as its read across substances and applying weight of evidence , it can be concluded that 4,4'-carbonimidoylbis(N,N-diethylaniline) hydrochloride is not a skin sensitizer. Thus comparing the above annotations with the criteria of CLP regulation, 4,4'-carbonimidoylbis(N,N-diethylaniline) hydrochloride can be considered as not classified for skin sensitization effect.