4-(2-aminoethyl)phenol

Endpoint summary

Description of key information

Based on 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, repeated dose oral toxicity was predicted for the test compound 4-(2-aminoethyl)phenol ( 51-67-2). The study assumed the use of male and female Osborne-Mendel strain in chronic study of 17 weeks. No significant alterations were noted at the dose level of 712.75 mg/Kg bw/day. The predicted No Observed Adverse Effect Level (NOAEL) for compound 4-(2-aminoethyl)phenol is considered to be 712.75mg/Kg bw/day. Based on this value it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral

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:

Prediction is done using OECD QSAR Toolbox version 3.4 and the supporting QMRF report has been attached.

Qualifier:

according to guideline

Guideline:

other: As mention below

Principles of method if other than guideline:

Prediction is done using OECD QSAR Toolbox version 3.4, 2018.

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

Name: 4-(2-Aminoethyl)phenol
SMILES:NCCc1ccc(O)cc1
InChI:1S/C8H11NO/c9-6-5-7-1-3-8(10)4-2-7/h1-4,10H,5-6,9H2
Mol. formula: C8H11NO
Molecular Weight: 137.1809 g/mole

Species:

rat

Strain:

Osborne-Mendel

Sex:

male/female

Details on test animals or test system and environmental conditions:

Not specified

Route of administration:

oral: feed

Details on route of administration:

Not specified

Vehicle:

not specified

Details on oral exposure:

Not specified

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

Not specified

Duration of treatment / exposure:

17 weeks

Frequency of treatment:

Not specified

Remarks:

Not specified

No. of animals per sex per dose:

Not specified

Control animals:

not specified

Details on study design:

Not specified

Positive control:

Not specified

Observations and examinations performed and frequency:

Not specified

Sacrifice and pathology:

Not specified

Other examinations:

Not specified

Statistics:

Not specified

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

712.75 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant effect were observed at this dose

Remarks on result:

other: No toxic effect were observed

Critical effects observed:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Primary amines by OECD HPV Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Aliphatic Amines AND Phenols (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Michael addition AND Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals AND Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Alkyl phenols by DNA binding by OECD

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "e"

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  >> Substituted Phenols by Protein binding by OASIS v1.4

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >>  Michael-type addition, quinoid structures OR AN2 >>  Michael-type addition, quinoid structures >> Quinoneimines OR AN2 >> Nucleophilic addition reaction with cycloisomerization OR AN2 >> Nucleophilic addition reaction with cycloisomerization >> Hydrazine Derivatives OR Radical OR Radical >> Generation of ROS by glutathione depletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >> Haloalkanes Containing Heteroatom OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Hydrazine Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR Radical >> ROS formation after GSH depletion (indirect) OR Radical >> ROS formation after GSH depletion (indirect) >> Quinoneimines OR SN1 OR SN1 >> Nucleophilic attack after nitrenium ion formation OR SN1 >> Nucleophilic attack after nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines OR SN2 OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> Direct nucleophilic attack on diazonium cation OR SN2 >> Direct nucleophilic attack on diazonium cation >> Hydrazine Derivatives OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom by DNA binding by OASIS v.1.4

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Strong binder, OH group OR Very strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Moderate binder, NH2 group OR Moderate binder, OH grooup by Estrogen Receptor Binding

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules (GSH) by Protein binding potency

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Extremely reactive (GSH) OR Extremely reactive (GSH) >> Phenyl acrylate (MA) by Protein binding potency

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Non-Metals by Groups of elements

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Alkali Earth OR Halogens OR Metalloids OR Transition Metals by Groups of elements

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Aliphatic Amine, primary AND Aryl AND Phenol AND Precursors quinoid compounds by Organic Functional groups

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Alcohol OR Aldehyde by Organic Functional groups

Domain logical expression index: "u"

Similarity boundary:Target: NCCc1ccc(O)cc1
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "v"

Similarity boundary:Target: NCCc1ccc(O)cc1
Threshold=80%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "w"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.289

Domain logical expression index: "x"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.34

Conclusions:

The predicted No Observed Adverse Effect Level (NOAEL) for 4-(2-aminoethyl)phenol ( 51-67-2) is considered to be 712.75 mg/Kg bw/day.

Executive summary:

Based on 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, repeated dose oral toxicity was predicted for the test compound 4-(2-aminoethyl)phenol ( 51-67-2). The study assumed the use of male and female Osborne-Mendel strain in chronic study of 17 weeks. No significant alterations were noted at the dose level of 712.75 mg/Kg bw/day. The predicted No Observed Adverse Effect Level (NOAEL) for compound 4-(2-aminoethyl)phenol is considered to be 712.75mg/Kg bw/day. Based on this value it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

712.75 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

K2 data from prediction OECD QSAR 3.4

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity: via oral route;

 Prediction and experimental studies were reviewed to determine the toxic nature of target substance Tyramine, 4-(2-aminoethyl)phenol ( 51-67-2) upon repeated exposure by oral route. The studies are as mentioned below:

Based on 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, repeated dose oral toxicity was predicted for the test compound 4-(2-aminoethyl)phenol ( 51-67-2). The study assumed the use of male and female Osborne-Mendel strain in chronic study of 17 weeks. No significant alterations were noted at the dose level of 712.75 mg/Kg bw/day. The predicted No Observed Adverse Effect Level (NOAEL) for compound 4-(2-aminoethyl)phenol is considered to be 712.75mg/Kg bw/day. Based on this value it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Another chronic toxicity study for Read across was performed by E. C. Hagan et al.( Food and cosmetics toxicology,1967) to determine the oral toxic nature of Phenethyl phenyl acetate; IUPAC name ; 2-phenylethyl phenylacetate (102-20-5). The read across substances share high similarity in structure and log kow .Therefore, it is acceptable to derive information on toxicity from the analogue substance. Repeated dose oral study for Phenethyl phenylacetate was assessed for its possible toxic potential. For this purpose Subchronic study for 17 weeks was conducted on Osborne-Mendel male and female rats. The test material was exposed at the concentration of 0, 50, 250 and 500 mg/kg bw (1000.2500 and 10000ppm)by oral feed. The animal’s weight, food intake and general condition were recorded every week. Haematological examinations were made at termination of the subacute studies. These examinations included white cell counts, red cell counts, haemoglobins and haematocrits. At the termination of the experiments the rats were sacrificed and exsanguinated. The tissues of all the rats were examined macroscopically at the time of sacrifice. The viscera were removed and the liver, kidneys, spleen, heart, and testes were weighed. These organs, the remaining abdominal and thoracic viscera, and one hind leg, for bone, bone marrow, and muscle, were preserved in 10 ~o buffered formalin-saline solution for histopathological examination. For routine histopathology, sections were embedded in paraffin wax and stained with haematoxylin and eosin. No mortality observed. No significant effect were observed at doses 0, 50, 250 or 500 mg/kg bw in treated group compare to control in clinical sign, Body weight, Food intake , Haematology, organ weight ,gross and histopathology . Hence the NOAEL was considered to be 500 mg/kg bw for Phenethyl phenylacetate in male and female rats by oral feed for 17 weeks study.

Repeated inhalation study:

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance 4-(2-aminoethyl)phenol ( 51-67-2) ,which is reported as 0.0031697607mmHg at 25 C. Also considering the particle size distribution of the substance the majority of the particles was found to be in the size of 150 micron to 53 micron which is much larger size range compared to the inhalable particulate matter. Thus, exposure to inhalable dust, mist and vapour of the chemical 4-(2-aminoethyl)phenol is highly unlikely. Therefore this study is considered for waiver.

 

Repeated dermal study;

The acute toxicity value for 4-(2-aminoethyl)phenol ( 51-67-2) (as provided in section 7.2.3) is 3044 mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that 4-(2-aminoethyl) phenol shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that 4-(2-aminoethyl) phenol exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

 

Based on the data available for the target chemical and its prediction, Tyramine, 4-(2-aminoethyl)phenol does not exhibit toxic nature upon repeated exposure by oral, inhalation and dermal route of exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

Based on the data available for the target chemical Tyramine, 4-(2-aminoethyl)phenol does not exhibit toxic nature upon repeated exposure by oral, inhalation and dermal route of exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation.