3,4-dimethoxyphenethylamine

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from J-check

Data source

Reference

Reference Type:

review article or handbook

Title:

Preliminary Reproduction Toxicity Screening Test of 1,3-Bis (aminomethyl) benzene by Oral Administration in Rats

Author:

J-check

Year:

2010

Bibliographic source:

J-check, Ministry of Health, Labour and Welfare", "Ministry of the Environment" and "National Institute of Technology and Evaluation, 2010

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Principles of method if other than guideline:

Preliminary Reproduction Toxicity Screening Test of 1,3-Bis (aminomethyl) benzene in Rats

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1,3-Bis (aminomethyl) benzene

Cas Number:

1477-55-0

Molecular formula:

C8H12N2

IUPAC Name:

1,3-Bis (aminomethyl) benzene

Details on test material:

- Name of test material (as cited in study report): 1,3-Bis (aminomethyl) benzene
- Molecular formula (if other than submission substance): C8H12N2
- Molecular weight (if other than submission substance): 136.19 g/mole
- Substance type: Organic
- Physical state: colorless liquid
- Impurities (identity and concentrations): purity 99.8 wt%

Specific details on test material used for the study:

- Name of test material (as cited in study report): 1,3-Bis (aminomethyl) benzene
- Molecular formula (if other than submission substance): C8H12N2
- Molecular weight (if other than submission substance): 136.19 g/mole
- Substance type: Organic
- Physical state: colorless liquid
- Impurities (identity and concentrations): purity 99.8 wt%

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: Japan Charles River Co., Ltd. (Kanagawa)
- Age at study initiation: (P) x wks; (F1) x wks: 10 weeks
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g: Body weight during grouping ranged from 354 to 399 g for males and from 216 to 247 g for females.
- Fasting period before study:
- Housing: One animal was housed and housed in an aluminum front and floor stainless steel mesh breeding cage in a breeding room. Maternal animals after gestation day 18 were kept in aluminum front and floor stainless steel mesh breeding cages with nursery trays and nest making materials until nursing 4th.
- Diet (e.g. ad libitum): NMF solid feed (radiation sterilized feed) and was taken free during the breeding period.
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 2 ° C
- Humidity (%): 55 ± 10%
- Air changes (per hr): 15 times / hour, illuminance of 150 to 300 lux
- Photoperiod (hrs dark / hrs light): 12 hours (7 am lights, 7 pm off)

Administration / exposure

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

water

Remarks:

Purified

Details on exposure:

VEHICLE
- Justification for use and choice of vehicle (if other than water): Purified Water
- Concentration in vehicle: 0 (vehicle), 50, 150, 450 mg/kg/day
- Amount of vehicle (if gavage): 1 mL / 100 g body weight
- Lot/batch no. (if required):

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: 5 days
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy Sperm in vaginal plaque, and that day was taken as the 0th day of pregnancy.
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. Not specified
- Further matings after two unsuccessful attempts: [no / yes (explain)] Not specified
- After successful mating each pregnant female was caged (how): Individually

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

For the analysis of the concentration and homogeneity of the administration solution, samples were randomly extracted from batches of each group prepared at the start of preparation. As a result, the error with respect to the display density was in the range of -0.8 to + 6.9% and within the reference range (within ± 10%). Therefore, it was confirmed that a predetermined amount of 1,3-bis (aminomethyl) benzene was contained in the administration liquid used.

Duration of treatment / exposure:

Male : 48 days
Female : 41 to 45 days

Frequency of treatment:

Daily

Details on study schedule:

not specified

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

50 mg/kg bw/day

Doses / concentrations 3

Dose / conc.:

150 mg/kg bw/day

Doses / concentrations 4

Dose / conc.:

450 mg/kg bw/day

No. of animals per sex per dose:

Total: 96
0 (vehicle) mg/kg/day: 12 male, 12 female
50 mg/kg/day: 12 male, 12 female
150 mg/kg/day: 12 male, 12 female
450 mg/kg/day: 12 male, 12 female

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Dose was selected based on previous toxicity study, at 600 mg / kg group, salivation, decrease in locomotor activity, piloerection, abdominal distension Postmenopausal symptoms were observed in males and females, reduction in food intake and suppression of increase in body weight were observed in males, 1 in 12 males and 4 in females died. In the same group, epithelial hyperplasia accompanied by ulcer and hyperkeratosis in the mucous membrane of the forestomach of the stomach, an increase in granulocytic hematopoietic cells in the bone marrow, hypertrophy / vacuolation of the cortical cells in the adrenal glands and cecal enlargement in both sexes. Based on these results, preliminary study "1,3-bis (aminomethyl) benzene rats conducted at the same dose for 28-day repeated dose toxicity test, at 0, 10, 40, 150 and 600 mg / kg Oral administration simple oral reproductive toxicity test in 2 weeks preliminary test ", 2 out of 6 males in 600 mg / kg group and 1 in female died, salivation and the like were observed in males and females as symptoms after administration, the body weight gain was suppressed in males of the same group, and high levels of adrenal glands were observed in males and females.
Therefore, in this study, considering that dead animals were found in males and females at 600 mg / kg / day, in addition to considering that the administration period was extended to three times or more than the preliminary test, high doses of 450 mg / kg / day and was divided by the common ratio 3 below to 150 and 50 mg / kg / day.

Positive control:

not specified

Examinations

Parental animals: Observations and examinations:

Survival, Clinical sign, Body weight and weight gain, food consumption were examined.

Oestrous cyclicity (parental animals):

Any irregularity in estrous cyclicity was examined.

Sperm parameters (parental animals):

Not specified

Litter observations:

Numbers of offspring or live offspring, the sex ratio and Body weights sex were examined.

Postmortem examinations (parental animals):

Organ weight, gross pathology and histopathology was examined.

Postmortem examinations (offspring):

External, visceral and skeletal malformations were examined.

Statistics:

Weight, food consumption, number of corpus luteums, number of implantation traces, number of births, number of stillbirths, sex ratio, average sex, pregnancy period, implantation rate, delivery rate, birth rate, abnormal incidence of abnormal outer table, newborn 4th Multiple comparison test was performed on the survival rate, organ weight and relative weight of the mice .
For the birth rate, mating rate and conception rate, x 2 tests were used. The abnormal periodic incidence rate and the incidence of findings of pathological examination were tested using Fisher's exact test method 6). In addition, as for the results on newborns during the nursing period, the average per mother was taken as one sample. The significance level was carried out with 5 and 1% two-sided test.

Reproductive indices:

Copulation index, fertility index, gestation length, number of corpora lutea or implantations, implantation index, gestation index, delivery index and, parturition or maternal behavior were examined.

Offspring viability indices:

Viability index on day 0 and day 4 were examined.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

When treated wtih 450 mg/kg bw, Salivation, nasal, rattle, irregular respiration, abdominal distension and nasal discharge were observed.
When treated wtih 150 mg/kg bw, Salivation were observed in male rats as compared to control.

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, treatment-related

Description (incidence):

When treated wtih 450 mg/kg bw, three males and one female died.

When treated wtih 150 mg/kg bw, one male died as compared to control.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

When treated wtih 450 mg/kg bw, Decreased in body weight was observed in treated male and female rats as compared to control.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

When treated wtih 450 mg/kg bw, Decreased in food consumption was observed in treated male and female rats as compared to control.

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:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Ulceration and squamous hyperplasia of the forestomach were observed in male and female at 450 mg/kg bw

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

No effect on estrous cycle of treated rats were observed as compared to control.

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Description (incidence and severity):

No effect on 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.

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

450 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

organ weights and organ / body weight ratios

reproductive function (oestrous cycle)

reproductive performance

Remarks on result:

other: No effect observed

Target system / organ toxicity (P0)

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

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

no mortality observed

Description (incidence and severity):

No effect on viability of pups on day 0 and 4 were observed as compared to control.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No effect on body weight of pups on day 0 and 4 were observed as compared to control.

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:

no effects observed

Description (incidence and severity):

No external abnormality were observed in pups as compared to control.

Histopathological findings:

not specified

Other effects:

not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):

not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not specified

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

450 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

mortality

body weight and weight gain

gross pathology

Remarks on result:

other: No effect observed

Target system / organ toxicity (F1)

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

Overall reproductive toxicity

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

Applicant's summary and conclusion

Conclusions:

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.

Executive summary:

In a Preliminary Reproduction Toxicity Screening Test,  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.