3,4-dimethoxyphenethylamine

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL was estimated to be 313 mg/kg bw when Crj: CD(SD) male and female rats were orally exposed with 2-(3,4-dimethoxyphenyl)ethanamine.

Thus, as per criteria of CLP regulation, 2-(3,4-dimethoxyphenyl)ethanamine 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 3.3 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 3.3

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

- Name: 2-(3,4-dimethoxyphenyl)ethan-1-amine
- InChI:1S/C10H15NO2/c1-12-9-4-3-8(5-6-11)7-10(9)13-2/h3-4,7H,5-6,11H2,1-2H3
- Smiles:COc1ccc(CCN)cc1OC
- Name of test material: Homoveratrylamine
- Molecular formula :C10H15NO2
- Molecular weight :181.2335 g/mol
- Substance type:organic

Species:

rat

Strain:

Crj: CD(SD)

Details on species / strain selection:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

propylene glycol

Details on exposure:

not specified

Details on mating procedure:

not specified

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

not specified

Frequency of treatment:

Daily

Details on study schedule:

not specified

Dose / conc.:

313 mg/kg bw/day

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

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:

no effects observed

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive function (oestrous cycle)

Remarks on result:

other: No effect observed

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 ("g" and ( not "h") )  )  and ("i" and ( not "j") )  )  and ("k" and ( not "l") )  )  and "m" )  and "n" )  and "o" )  and "p" )  and ("q" and "r" )  )

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 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 >> Hydroquinones by DNA binding by OECD

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Narcotic Amine by Acute aquatic toxicity MOA by OASIS

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Aliphatic Amines by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as H-acceptor-path3-H-acceptor by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Aliphatic N-nitro group OR No alert found by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "i"

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: "j"

Referential boundary: The target chemical should be classified as Piperazine-, dioxane-, morpholine-, tetrahydrothiopyran-like derivatives and cyclohexanamine (17c) by DART scheme v.1.0

Domain logical expression index: "k"

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

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Aliphatic Amine, primary AND Aryl AND Ether by Organic Functional groups ONLY

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Aliphatic Amine, primary AND Aryl AND Ether by Organic Functional groups ONLY

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Aliphatic Amine, primary AND Aryl AND Ether by Organic Functional groups ONLY

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Alkylarylether AND Amine AND Aromatic compound AND Ether AND Primary aliphatic amine AND Primary amine by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.247

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.8

Conclusions:

NOAEL was estimated to be 313 mg/kg bw when Crj: CD(SD) male and female rats were orally exposed with 2-(3,4-dimethoxyphenyl)ethanamine.

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 2-(3,4-dimethoxyphenyl)ethanamine. The NOAEL was estimated to be 313 mg/kg bw when Crj: CD(SD) male and female rats were orally exposed with 2-(3,4-dimethoxyphenyl)ethanamine.  

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

313 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, 2-(3,4-dimethoxyphenyl)ethanamine 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 2-(3,4-dimethoxyphenyl)ethanamine along with the study available on structurally similar read across substance 1,3-Bis (aminomethyl) benzene (CAs no1477-55-0) 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 2-(3,4-dimethoxyphenyl)ethanamine. The NOAEL was estimated to be 313 mg/kg bw when Crj: CD(SD) male and female rats were orally exposed with 2-(3,4-dimethoxyphenyl)ethanamine.  

In another experimental study conducted by J-check (Ministry of Health, Labour and Welfare", "Ministry of the Environment" and "National Institute of Technology and Evaluation, 2010) on structurally similar read across substance 1,3-Bis (aminomethyl) benzene (CAs no1477-55-0), Crj:CD(SD) male and female rats were treated with D-Camphor in the concentration of 0 (vehicle), 50, 150, 450 mg/kg/day orally by gavage for 45 -48 days. Three males and one female died at 450 mg/kg bw and one male died at 150 mg/kg bw as compared to control. Salivation, nasal, rattle, irregular respiration, abdominal distension and nasal discharge were observed at 450 mg/kg bw. Salivation were observed in male rats at 150 mg/kg bw as compared to control. Decreased in body weight and food consumption was observed in treated male and female rats as compared to control. Similarly, No effect on estrous cycle, copulation index, fertility index, gestation length, number of corpora lutea or implantations, implantation index, gestation index, delivery index and, parturition or maternal behavior was observed in treated rats as compared to control. Significant increase in absolute and relative thymus weight and decrease in adrenal gland were observed at 450 mg/kg bw and Significant increase in relative weight of the testes were observed in male rats, but not statistically significant as compared to control. No effect on reproductive organ weight was observed as compared to control. Ulceration of the stomach and squamous hyperplasia of the forestomach were observed in male and female at 450 mg/kg bw as compared to control. In addition, No effect on viability and body weight of pups on day 0 and 4 were observed as compared to control. No external abnormalities were observed in pups as compared to control. Therefore, NOAEL was considered to be 450 mg/kg bw for P and F1 generation when Crj:CD(SD) male and female rats were treated with 1,3-Bis (aminomethyl) benzene orally by gavage for 45 -48 days.

Further supported by experimental study conducted by Kotinet al(National Cancer Institute Division of Cancer Cause &Prevention Carcinogenesis Program Bethesda, Maryland, 1968) on structurally similar read across substance 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 2-(3,4-dimethoxyphenyl)ethanamine and its read across substances, it can be concluded that NOAEL value is 313 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, 2-(3,4-dimethoxyphenyl)ethanamine 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 2-(3,4-dimethoxyphenyl)ethanamine and its read across substances, it can be concluded that NOAEL value is 313 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, 2-(3,4-dimethoxyphenyl)ethanamine can be not classified for reproductive toxicity.