4-(2-aminoethyl)phenol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL was estimated to be 390.5 mg/kg bw when Sprague-Dawley male and female rats were orally exposed with 4-(2-Aminoethyl)phenol. 

Thus, as per criteria of CLP regulation, 4-(2-Aminoethyl)phenol can be not classified for reproductive toxicity.    

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

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:

other: as below

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.4

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

ethanol

Details on exposure:

not specified

Details on mating procedure:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

56 days for F0 and 98 days for F1

Frequency of treatment:

Daily

Details on study schedule:

not specified

Dose / conc.:

390.5 mg/kg bw/day

No. of animals per sex per dose:

26 rats/sex/dose

Control animals:

yes, concurrent no treatment

Details on study design:

not specified

Positive control:

not specified

Parental animals: Observations and examinations:

not specified

Oestrous cyclicity (parental animals):

not specified

Sperm parameters (parental animals):

not specified

Litter observations:

not specified

Postmortem examinations (parental animals):

not specified

Postmortem examinations (offspring):

not specified

Statistics:

not specified

Reproductive indices:

not specified

Offspring viability indices:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

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

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Dose descriptor:

NOAEL

Effect level:

390.5 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Remarks on result:

other: No effect on reproduction

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

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

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

other: not specified

Generation:

other: not specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

Remarks on result:

other: not specified

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Reproductive effects observed:

not specified

Treatment related:

not specified

Relation to other toxic effects:

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 "q" )  and "r" )  and "s" )  and ("t" and "u" )  )

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 Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Non binder, non cyclic structure by Estrogen Receptor Binding

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 Non binder, without OH or NH2 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 Very strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Arylethanamine-like derivatives (11a) AND Known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Non-steroid nucleus derived estrogen receptor (ER) and androgen receptor (AR) by DART scheme v.1.0

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Arylethanamine-like derivatives (11a) AND Known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Toluene and small alkyl toluene derivatives (8a) by DART scheme v.1.0

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as No superfragment by Superfragments ONLY

Domain logical expression index: "q"

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

Domain logical expression index: "r"

Similarity boundary:Target: NCCc1ccc(O)cc1
Threshold=50%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "s"

Similarity boundary:Target: NCCc1ccc(O)cc1
Threshold=60%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "t"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.0859

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.18

Conclusions:

NOAEL was estimated to be 390.5 mg/kg bw when Sprague-Dawley male and female rats were orally exposed with 4-(2-Aminoethyl)phenol.

Executive summary:

In a prediction done by SSS (2018) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for 4-(2-Aminoethyl)phenol. The NOAEL was estimated to be 390.5 mg/kg bw when Sprague-Dawley male and female rats were orally exposed with 4-(2-Aminoethyl)phenol.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

309.5 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimisch 2 and from OECD QSAR toolbox (2018)

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproductive toxicity:

In different studies, 4-(2-Aminoethyl)phenol has been investigated for reproductive toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimation in rodents, i.e. most commonly in rats for 4-(2-Aminoethyl)phenol along with the study available on structurally similar read across substance (4-methoxyphenyl)acetic acid (CAS no 104-01-8) and (4-methoxyphenyl)acetic acid (CAS no 104-01-8). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies. 

In a prediction done by SSS (2018) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for 4-(2-Aminoethyl)phenol. The NOAEL was estimated to be 390.5 mg/kg bw when Sprague-Dawley male and female rats were orally exposed with 4-(2-Aminoethyl)phenol. 

In another experimental study conducted by Hagan et al (Food Cosmetic Toxicology, Vol 5, pp. 141-157. 1967) on structurally similar read across phenethyl phenylacetate (CAS 102-20-5), 10 male and female Osborne-Mendel rats were treated with phenethyl phenylacetate in the concentration 0 and 500 mg/kg bw/day orally by gavage from 17 weeks. No treatment-related clinical signs and premature deaths were observed. No relevant necropsy findings were noted. No effects on reproductive organ i.e testes was noted in treated rats at 500 mg/kg bw. Hence Now Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to 500 mg/kg/day, when male and female Osborne-Mendel rats were treated with phenethyl phenylacetate (102-20-5) orally for 17 weeks.

Further supported by experimental study conducted by Kotin wt al (National Cancer Institute Division of Cancer Cause &Prevention Carcinogenesis Program Bethesda,Maryland,1968) on structurally similar read across (4-methoxyphenyl)acetic acid (CAS no 104-01-8), B6C3F1 female mice were treated with (4-methoxyphenyl)acetic acid in the concentration of 0 and 215 mg/kg bw/day in 0.5% gelatin for 7 to 28 day and after dose is administer through diet at 560 ppm for 18 months. Body weight gain was observed with the increase in duration of treatment. No gross pathological changes were observed in treated female mice. In addition, no fibroadenoma and carcinoma mammary gland were observed in treated female mice as compared to control. Therefore, NOAEL was considered to be > 215 mg/kg bw when B6C3F1 female mice by using (4-methoxyphenyl) acetic acid for 18 months.

Thus, based on the above study and predictions on 4-(2-Aminoethyl)phenol and its read across substances, it can be concluded that NOAEL value is 309.5 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, 4-(2-Aminoethyl)phenol can be not classified for reproductive toxicity.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the above study and predictions on 4-(2-Aminoethyl)phenol and its read across substances, it can be concluded that NOAEL value is 309.5 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, 4-(2-Aminoethyl)phenol can be not classified for reproductive toxicity.