4-methylpiperazin-1-amine

Endpoint summary

Description of key information

The skin sensitization potential of4-Methylpiperazin-1-amine (6928-85-4)was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across substances4-Methylpiperazin-1-amine was predicted to be not sensitizing to the skin of female Crl:HA guinea pig.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation

Remarks:

in vivo

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 from OECD QSAR toolbox v3.3 and the QMRF report has been attached.

Qualifier:

equivalent or similar to guideline

Guideline:

other: As mention below

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3, 2017

GLP compliance:

not specified

Type of study:

other: not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): 4-Methylpiperazin-1-amine
- Molecular formula: C5H13N3
- Molecular weight: 115.179 g/mol
- Substance type: organic
- Physical state: Liquid
- Smiles notation: N1(CCN(CC1)C)N
- InChl: 1S/C5H13N3/c1-7-2-4-8(6)5-3-7/h2-6H2,1H3

Species:

guinea pig

Strain:

other: Crl:HA

Sex:

female

Details on test animals and environmental conditions:

No data available

No. of animals per dose:

Total:30
test group:20
Control group:10

Details on study design:

No data available

Challenge controls:

No data available

Positive control substance(s):

not specified

Statistics:

No data available

Positive control results:

No data available

Reading:

1st reading

Group:

test chemical

Dose level:

3%

No. with + reactions:

0

Total no. in group:

20

Clinical observations:

No skin sensitization reaction was noted

Remarks on result:

no indication of skin sensitisation

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

((((((((((("a" or "b" or "c" )  and "d" )  and ("e" and ( not "f") )  )  and ("g" and ( not "h") )  )  and "i" )  and ("j" and ( not "k") )  )  and ("l" and ( not "m") )  )  and ("n" and ( not "o") )  )  and ("p" and ( not "q") )  )  and ("r" and ( not "s") )  )  and ("t" and "u" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Aliphatic Amines by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Hydrazine Derivatives by DNA binding by OASIS v.1.3 ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines by DNA binding by OECD ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Iminium Ion Formation AND SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines by DNA binding by OECD ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.3

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 >> Carbamates  OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis >> Dithiocarbamates OR Acylation >> Ring opening acylation OR Acylation >> Ring opening acylation >> beta-Lactams  OR SN2 OR SN2 >> Nucleophilic substitution at sp3 carbon atom OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> Sulfonates OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  by Protein binding by OASIS v1.3

Domain logical expression index: "i"

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

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CN Lipid Solubility < 0.4 g/kg by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as (!Undefined)Group CNHal Lipid Solubility < 400 g/kg OR Group All Aqueous Solubility < 0.00002 g/L OR Group All log Kow < -3.1 OR Group All Melting Point > 200 C OR Group CN Aqueous Solubility < 0.1 g/L OR Group CN log Kow > 4.5 OR Group CN Molecular Weight > 290 g/mol OR Group CNHal Aqueous Solubility < 0.1 g/L OR Group CNS Aqueous Solubility < 0.006 g/l OR Group CNS log Kow > 1.5 OR Group CNS Melting Point > 200 C OR Group CNS Melting Point > 50 C by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CN Lipid Solubility < 0.4 g/kg by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Group CN Vapour Pressure < 0.001 Pa by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Inclusion rules not met by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Ketones OR Tertiary aliphatic amine by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N by Chemical elements

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Group 14 - Metalloids Si,Ge OR Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Amino, aliphatic attach [-N<] AND Hydrazine [>N-N<] by Organic functional groups (US EPA)

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Amino, aliphatic attach [-NH-] OR Amino, aliphatic attach [-NH2] OR Aromatic Nitrogen, five-member ring OR Azomethine, aliphatic attach [-N=C] OR Nitrogen, two or tree olefinic attach [>N-] OR Olefinic carbon [=CH- or =C<] OR Olefinic carbon [=CH2] by Organic functional groups (US EPA)

Domain logical expression index: "t"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.15

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.89

Interpretation of results:

other: not sensitising

Conclusions:

The skin sensitization potential of 4-Methylpiperazin-1-amine (6928-85-4) was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across substances 4-Methylpiperazin-1-amine was predicted to be not sensitizing to the skin of female Crl:HA guinea pig.

Executive summary:

The skin sensitization potential of 4-Methylpiperazin-1-amine (6928-85-4) was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across substances4-Methylpiperazin-1-amine was predicted to be not sensitizing to the skin of female Crl:HA guinea pig.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

 

In different studies, 4-Methylpiperazin-1-amine (6928-85-4) has been investigated for potential of skin sensitization to a greater or lesser extent. The studies are based on in vivo experiments in guinea pig for target chemical, 4-Methylpiperazin-1-amine (6928-85-4) and its structurally similar read across substancesTriethylenediamine(280-57-9)and N-Methyldiethanolamine (105-59-9) the predicted data using the OECD QSAR toolbox has also been compared with the experimental data of read across.

The skin sensitization potential of 4-Methylpiperazin-1-amine (6928-85-4) was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across substances4-Methylpiperazin-1-amine was predicted to be not sensitizing to the skin of female Crl:HA guinea pig.

The experimental study conducted by OECD HPV SIDS (OECD HPV Chemical Programme, SIDS Dossier approved at SIAM 21, 2005) to evaluate the skin sensitizing potential of read across substanceTriethylenediamine(280-57-9). The skin sensitization study of Triethylenediamine(280-57-9)was performed by Guinea pig maximisation test in 20 Male and female Dunkin-Hartley albino guinea pigs. An additional 10 animals served as the vehicle control group; a positive control group was not included in the study.In induction phase,1^stinduction given using 0.1concentration in physiological saline by intradermal route while in 2ndinduction done by using 25% concentration by epidermal application. In challenge phase, test substance 10 % concentration in same vehicle used for first and second challenge dose. No skin sensitizing reaction observed after challenge application.2 Female showed emaciation at day 36 and37. One Female showed emaciation from day 36 to 39 of test. While 2 female showed diarrhea at day 37.The body weight gain of the animals was not affected during the test with the exception of 3 animal, 2 female died spontaneously at day 37 of the test study. No macroscopic findings were observed at necropsy for these animals had reddened abdominal wall, reddened diaphragm, and fluid in the myocardium were observed. Hence it is considered that Triethylenediamine(280-57-9)was not skin sensitizing in guinea pig by Guinea pig maximisation test.

 It is further supported by experimental study conducted by European Commission – European Chemicals Bureau(IUCLID Dataset-European Chemicals Bureau- 18–FEB–2000) to evaluate the skin sensitizing potential of read across substance N Methyldiethanolamine ( 105-59-9)The skin sensitization study of N Methyldiethanolamine was carried out in 20 guinea pigs by guinea pig maximization test. During induction animals were first induced intradermal with 5% test material in propylene glycol and dermally with 100%.following induction challenge was performed .since results at Challenge were equivocal a Re–Challenge was performed in the same manner as the Challenge, but at concentrations of 50% and 10% N–methyldiethanolamine. In order to differentiate dermal reactions produced by irritation from those produced by sensitization, 20 animals (5/sex/Challenge; treated concurrently during Induction with only vehicle or FCA/water emulsion) were subjected to the same Challenge or Re Challenge procedures as the animals which received test material during the Induction exposures. Fourteen days after the last induction exposure, the Challenge treatment was administered topically at 100%. Eighteen of the 20 animals challenged with 100% N–methyldiethanolamine exhibited clear dermal responses. Index of Sensitization at Challenge to N–methyldiethanolamine was 90%. The Severity Indices at Challenge for the test material group at 24 and 48 hours are 0.8 and 1.8, respectively, compared to 0.8 and 1.6, respectively, for the irritation control group (out of a maximum Index of 3.0). Due to the responses seen in the irritation controls, a Re–Challenge was performed at lower, less irritating concentrations. Animals were re–challenged with both 50% and 10% N–methyldiethanolamine at separate sites. Dermal evaluations were made approximately 24 and 48 hours after the removal of Challenge/Re–Challenge patches. It was observed that the test animals treated with re-challenged dose 50% and 10% N–methyldiethanolamine were free of dermal responses. The Severity indices at Re–Challenge at 24 and 48 hours were both 0.0 for both the test group and the irritation control group. Hence the test chemical N-Methyldiethanolamine (CAS No: 105-59-9) can be considered as non-sensitizing to guinea pigs at 50% and 10% concentration.

Thus based on the above predictions on4-Methylpiperazin-1-amine (6928-85-4) as well as its read across and applying weight of evidence, it can be concluded that 4-Methylpiperazin-1-amine (6928-85-4) is not a skin sensitizer. Thus comparing the above studies with the criteria of CLP regulation, 4-Methylpiperazin-1-amine (6928-85-4) can be considered as not classified for skin sensitization.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Thus comparing the above studies with the criteria of CLP regulation, 4-Methylpiperazin-1-amine (6928-85-4) can be considered as not classified for skin sensitization.