Benzyldimethylamine

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: guideline study under GLP conditions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Benzyldimethylamine

EC Number:

203-149-1

EC Name:

Benzyldimethylamine

Cas Number:

103-83-3

Molecular formula:

C9H13N

IUPAC Name:

benzyldimethylamine

Test material form:

other: liquid

Details on test material:

content: > 99 %

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: young-adult (no further data)
- Weight at study initiation: 197-318 g
- Housing: individually
- Diet ad libitum
- Water ad libitum
- Acclimation period: 1 day

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 30 to 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

arachis oil

Details on exposure:

The test item was administered by gavage to three groups of twenty-four time mated rats between days 5 and 19 of gestation . A further group of twenty-fourtime mated females was exposed to the vehicle only to serve as a control. All females were terminated on day 20 of gestation.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The test item formulations were analyzed for concentration, stability (days 1, 4,and 10) and homogenicity by the test facility

Details on mating procedure:

no data

Duration of treatment / exposure:

gestation day 5 to gestation day 19 (14 days)

Frequency of treatment:

once daily

Duration of test:

gestation day 5 to gestation day 20

No. of animals per sex per dose:

24 females/dose

Control animals:

yes, concurrent vehicle

Details on study design:

Dose selection is based on the results of the preliminary study:
8 time mated females received 0, 50, 100 and 200 mg/kg bw/day test item diluted in arachis oil between gestation day 5 and day 19. Due to early termination of one female , clinical signs of toxicity and actual body weight loss the highest dose was reduced to 150 mg/kg bw on day 5 or day 6 of gestation. The NOAEL in this preliminary study was considered to be 100 mg/kg bw/day.
For the main developmental study a dosage sequence of 0, 35, 75 and 150 mg/kg bw/dy was recommended.

Examinations

Maternal examinations:

mortality: twice daily
clinical observations: once daily
body weight determination on day 3, 5, 6, 7, 8, 11, 14, 17, and 20 of gestation
food consuption determination on day 3, 5, 8, 11, 14, 17 and 20 of gestation
water consumption daily inspected

Ovaries and uterine content:

uterine / implantation data:
pregnancy status, number of corpora lutea, gravid uterus weight
number, status and intra-uterine position of implantations

Fetal examinations:

external foetal abnormalities, foetal weight foetal sex, placental weight, skeletal and visceral foetal abnormalities

Statistics:

parametric analysis of variance followed by pairwise comparison or non parametirc methods were used

Indices:

pre-implantation loss, post-implantation loss, % male foetuses for determination of sex ratio, fertility index, gestation index

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
----Mortality
There were no unsheduled deaths
----Clinical signs:
from 35 mg/kg bw/day unspecific signs:
-some females showed increased salivation from day 13 earliest
-some females showed noisy respiration or decreased respiration
----Body weight
--at 35 and 75 mg/kg bw/day:
Body weight development was comparable to control animals
-- at 150 mg/kg bw/day
Females showed a marked reduction in body weight gain throughout the the treatment period
Compared to the control animals body weight gain was reduced by 41 %
----Food consumption
at 150 mg/kg bw/day
females showed a reduction (-13 %) in overall food consumption
----Water consumption
No adverse effects were detected
----Post mortem studies
No treatment related macroscopic abnormalities were detected.


----Fertility index and gestation index
was about 100 % in all dose groups including controls
----Number of corpora lutea and gravid uterus weight
at 150 mg/kg bw/day significantly reduced .
Group mean litter value:
number of corpora lutea
at 150 mg/kg bw/day: 12.2 (p<0.01); at 75 mg/kg bw/day: 14.5; at 35 mg/kg/bw/day: 14.9 versus control: 14.7
This intergroup difference was considered to be incidental and unrelatated to treatment due to ovulation and mating occuring prior to the administration of the test substance

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

75 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOEL

Effect level:

150 mg/kg bw/day

Basis for effect level:

other: developmental toxicity

3

Dose descriptor:

NOEL

Effect level:

150 mg/kg bw/day

Basis for effect level:

other: other:

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No treatment related effects were detected in
----foetal viability (male and female), or in
----foetal weights (male and females), or in
----growth and development.
Sex ratio was in the normal range

Fetal examination:
No treatment related effects were detected on fetal external findings.
No treatment-related effects were detected on skeletal development (including osseous and cartilaginous tissue) amd
none in the type and incidence of skeletal or visceral findings in fetuses from females treated with 150, 75 or 35 mg/kg bw/day.

A teratogenic effect of treatment was not evident up to and including the highest dose level (150 mg/kg bw/day)

Effect levels (fetuses)

1

Dose descriptor:

NOEL

Effect level:

150 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: developmental toxicity

2

Dose descriptor:

NOEL

Effect level:

150 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: other:

Fetal abnormalities

Abnormalities:

no effects observed

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

In conclusion, despite general toxicity (body weight reduction) in female rats at 150 mg/kg bw/day there is no evidence that the substance shows developmental toxicity.

Executive summary:

According to OECD TG 414 and under GLP conditions pregnant female rats received orally 0, 35, 75 and 150 mg/kg bw/day by gavage on gestation day 5 -19. All females were terminated on gestation day 20 and cesarian section was performed to evaluate the developing organism.

At the highest dose of 150 mg/kg bw/day females gained markedly less body weight (by 41 % compared to control) and a reduction (-13 %) in overall food consumption. Fertility index and gestation index was calculated to be 100 % in all treated animals including control animals. Post mortem, no macroscopic abnormalities were observed. Thus, due to the reduced weight gain at 150 mg/kg bw/day the NOAEL (maternal toxicity) is considered 75 mg/kg bw/day.

No treatment related effects were detected in foetal viability (male and female), or in foetal weights (male and females), or in growth and development. Sex ratio was in the normal range. No treatment related effects were detected on fetal external findings.

No treatment-related effects were detected on skeletal development (including osseous and cartilaginous tissue) and none in the type and incidence of skeletal or visceral findings in fetuses from females treated with 150, 75 or 35 mg/kg bw/day.

A teratogenic effect of treatment was not evident up to and including the highest dose level (150 mg/kg bw/day)

Thus, the NOEL (No Adverse Effect Level) for reproductive and developmental toxicity isconsidered to be 150 mg/kg bw/day

In conclusion, despite general toxicity (body weight reduction) in female rats at 150 mg/kg bw/day there is no evidence that the substance shows developmental toxicity.