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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 based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
other: Predicted data
Title:
10.11.2014 07:29 [R]: 61.875 mg/kg bw/day; Estimation for NOAEL for CAS 99-97-8
Author:
Sustainability Support Services (Europe) AB
Year:
2014
Bibliographic source:
QSAR toolbox version 3.1

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: estimated data
Principles of method if other than guideline:
Data is from QSAR toolbox version 3.1
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
SMILES:Cc1ccc(N(C)C)cc1

Test animals

Species:
rat
Strain:
Wistar

Administration / exposure

Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Duration of treatment / exposure:
10 days
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 75, 150, 300 mg/kg bw/day
Basis:
no data

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
61.875 mg/kg bw/day
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables






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

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

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 Acylation OR Acylation >> Isocyanates and Isothiocyanates OR Acylation >> Isocyanates and Isothiocyanates >> Isothiocyanates OR Acylation >> P450 Mediated Activation to Acyl Halides OR Acylation >> P450 Mediated Activation to Acyl Halides >> 1,1-Dihaloalkanes OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates >> Benzylamines-Acylation OR Michael addition OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems >> Furans OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems >> Thiophenes-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 >> Alkyl phenols OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Hydroquinones OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Methylenedioxyphenyl OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Polycyclic (PAHs) and heterocyclic (HACs) aromatic hydrocarbons-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated amides OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated ketones OR Michael addition >> Quinones and Quinone-type Chemicals OR Michael addition >> Quinones and Quinone-type Chemicals >> Quinones OR No alert found OR Schiff base formers OR Schiff base formers >> Chemicals Activated by P450 to Mono-aldehydes OR Schiff base formers >> Chemicals Activated by P450 to Mono-aldehydes >> Benzylamines-Schiff base OR Schiff base formers >> Chemicals Activated by P450 to Mono-aldehydes >> N-methylol derivates OR SN1 >> Carbenium Ion Formation OR SN1 >> Carbenium Ion Formation >> Allyl benzenes OR SN1 >> Carbenium Ion Formation >> Hydrazine OR SN1 >> Carbenium Ion Formation >> N-Nitroso (alkylation) OR SN1 >> Carbenium Ion Formation >> Polycyclic (PAHs) and heterocyclic (HACs) aromatic hydrocarbons-SN1 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 nitroso OR SN1 >> Nitrenium Ion formation >> Primary (unsaturated) heterocyclic amine OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine OR SN1 >> Nitrenium Ion formation >> Secondary aromatic amine OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic nitro OR SN2 OR SN2 >> Direct Acting Epoxides and related OR SN2 >> Direct Acting Epoxides and related >> Epoxides OR SN2 >> Episulfonium Ion Formation OR SN2 >> Episulfonium Ion Formation >> Mustards OR SN2 >> Epoxidation of Aliphatic Alkenes OR SN2 >> Epoxidation of Aliphatic Alkenes >> Phenoxy polarised alkenes OR SN2 >> Nitrosation-SN2 OR SN2 >> Nitrosation-SN2 >> Nitroso-SN2 OR SN2 >> P450 Mediated Epoxidation OR SN2 >> P450 Mediated Epoxidation >> Coumarins OR SN2 >> P450 Mediated Epoxidation >> Thiophenes-SN2 OR SN2 >> SN2 at an sp3 Carbon atom OR SN2 >> SN2 at an sp3 Carbon atom >> Aliphatic halides OR SN2 >> SN2 at an sp3 Carbon atom >> Alkyl carbamates by DNA binding by OECD

Domain logical expression index: "c"

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

Domain logical expression index: "d"

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 Acylation >> Direct Acylation Involving a Leaving group >> Sulphonyl halides OR Acylation >> Isocyanates and Related Chemicals OR Acylation >> Isocyanates and Related Chemicals >> Isothiocyanates OR Acylation >> Ring Opening Acylation OR Acylation >> Ring Opening Acylation >> alpha-Lactams OR Michael addition OR Michael addition >> Acid imides OR Michael addition >> Acid imides >> Acid imides-MA OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - aldehydes OR Michael addition >> Polarised Alkenes >> Polarised alkene - amides OR Michael addition >> Polarised Alkenes >> Polarised alkene - cyano OR Michael addition >> Polarised Alkenes >> Polarised alkene - esters OR Michael addition >> Polarised Alkenes >> Polarised alkene - ketones OR Michael addition >> Polarised Alkenes >> Polarised alkene - nitro OR Michael addition >> Polarised Alkenes >> Polarised alkene - pyridines OR Michael addition >> Quinones and Quinone-type Chemicals OR Michael addition >> Quinones and Quinone-type Chemicals >> Benzoquinones OR Michael addition >> Quinones and Quinone-type Chemicals >> Pyranones (and related nitrogen chemicals) OR Michael addition >> Quinones and Quinone-type Chemicals >> Quinone-diimine OR Michael addition >> Quinones and Quinone-type Chemicals >> Quinone-imine OR Schiff Base Formers OR Schiff Base Formers >> Direct Acting Schiff Base Formers OR Schiff Base Formers >> Direct Acting Schiff Base Formers >> Mono-carbonyls OR SN2 OR SN2 >> Episulfonium Ion Formation OR SN2 >> Episulfonium Ion Formation >> Mustards OR SN2 >> Epoxides and Related Chemicals OR SN2 >> Epoxides and Related Chemicals >> Epoxides OR SN2 >> SN2 reaction at a sulphur atom OR SN2 >> SN2 reaction at a sulphur atom >> Disulfides OR SN2 >> SN2 reaction at a sulphur atom >> Thiols OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl diazo OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl halides OR SN2 >> SN2 reaction at sp3 carbon atom >> Allyl acetates and related chemicals OR SN2 >> SN2 reaction at sp3 carbon atom >> alpha-Halobenzyls (and related cyano, sulfate and sulphonate subs. chem.) OR SN2 >> SN2 reaction at sp3 carbon atom >> Phosphonates OR SN2 >> SN2 reaction at sp3 carbon atom >> Thiophosphates OR SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Activated halo-benzenes by Protein binding by OECD

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 Moderate binder, NH2 group OR Moderate binder, OH grooup OR Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Strong binder, NH2 group OR Strong binder, OH group OR Weak binder, NH2 group OR Weak binder, OH group OR Very strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "g"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.234

Domain logical expression index: "h"

Parametric boundary:The target chemical should have a value of log Kow which is <= 5.93

Applicant's summary and conclusion

Conclusions:
The NOAEL for N,N-dimethyl-p-toluidine was estimated to be 185.875 mg/kg bw/day for rats for 10 days , this subacute value when converted to subchronic value is equivalent to 61.875 mg/kg bw/day for rats for 90 days duration using the toolbox version 3.2
Executive summary:

The NOAEL for N,N-dimethyl-p-toluidine was estimated to be 185.875 mg/kg bw/day for rats for 10 days, this subacute value when converted to subchronic value is equivalent to 61.875 mg/kg bw/day for rats for 90daysduration using the toolbox version 3.2. The data is estimated to be based on the data summarized below

CAS no.

End point

Value

Species

Doses

Duration

Effects

Remarks

121-69-7

NOAEL

365mg/kg bw/day

mice

365mg/kg bw/day

14 days

no adverse effects on survival or weight gain of the dams, or birth weight, weight gain, or viability of the F1 generation through the first three postpartum day

 

27311-52-0

NOAEL

90.0 mg/kg bw/day

Rat

60, 80, 120 mg/kg/d

10 days

no teratogenic effect observed

 

123-30-8

NOEL

100 mg/kg bw/day

Rat

0, 40, 200, 500 mg/kg

40 - 60 days

Decreased food consumption, and brown urine in females. No developmental effects observed

 

84852-15-3

NOAEL

188 mg/kg bw/day

Rat

0, 75, 150, 300 mg/kg bw/day

10 days

No significant effects were observed on no. of resorption, no of fetus, fetal body weight, sex ratio

 

 

All the values when equalized to 90 days duration by using conversion factor of 3 and, the values are summarized as follows

CAS no.

End point

Species

Value

Duration

121-69-7

NOAEL

Rat

212.90mg/kg bw/day

90 days

27311-52-0

NOAEL

Rat

30 mg/kg bw/day

90 days

123-30-8

NOEL

Rat

33.3 mg/kg bw/day

90 days

84852-15-3

NOAEL

Rat

62.66 mg/kg bw/day

90 days

 

 

Based on the above values it can be concluded that the estimated value for substance N,N-dimethyl-p-toluidine corresponds to NOEL value for the species rat with duration of 90 days. Thus the calculated NOEL values for 90 days may vary in the range of 30 – 212.90 mg/kg bw /day. Thus the predicted NOEL value is (calculated to be) 61.875 mg/kg bw/d with 90 days for rat (harmonized using assessment factors) falls within the domain using Log Kow as the descriptor and justified to be used as NOEL for further DNEL calculation for the purpose of risk assessment. Also it does not impact the classification of the substance thus the predicted value considered to be acceptable.

 

Justified to be used as NOEL for the purpose of weight of evidence