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Key value for chemical safety assessment

Effects on fertility

Description of key information
There are 2 subacute toxicity studies available in which N,N-dimethylbenzylamine is administered by gavage daily for up to 28 days. There were no effects on reproductive organs. 
Additional information

There is no 2-generation reproductive toxicity study available.

However , there are subacute toxicity studies available using the oral exposure route in which also the reproductive organs were considered histopathologically. Male and female rats were given N,N-dimethylbenzylamine daily up to doses of 400 mg/kg bw/day. No significant compound related effects on reproductive organs were reported

As confirmed by recent literature (Mangelsdorf et al 2003, Ulbrich & Palmer 1995, Janer et al 2007a, Dent 2007, Sanbuissho et al. 2009) in rodents histopathological examinations in repeated dose toxicity studies of reproductive tissues are of high value and high sensitivity for evaluation of reproductive toxicity in males and females. Histopathological changes on the reproductive organs in repeated dose toxicity studies are indicative of effects on fertility. With this respect repeated dose toxicity studies should be considered sensitive and sufficient information to evaluate toxicity on fertility if histological examination of the reproductive organs is covered.

Overall, based on the considerations above and the available data from repeated dose toxicity studies there is no reason to expect a specific reproductive toxicity of N,N-dimethylbenzylamine. Therefore, taking also into consideration the need to balance the value of information generation by animal testing with animal welfare performance of a 2-generation reproduction toxicity study is not necessary.

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Mangelsdorf. et al., 2003: Some aspects relating to the evaluation of the effects of chemicals on male fertility. Regulatory toxicology and Pharmacology 36, 69-98

Ulbrich & Palmer, 1995: Detection of effects on male reproduction ¿ a literature survey. J am. College of Toxicology 14, 293-327 Janer et al., 2007: A retrospective analysis of the added value of the rat two-generation reproductive toxicity study versus the rat subchronic toxicity study. Reproductive Toxicology 24, 103-113

Dent, 2007: Strength and limitations of using repeated-dose toxicity studies to predict effects on fertility. Regulatory Toxicology and Pharmacology 48, 241-258

Sanbuissho et al., 2009: Collaborative work on evaluation of ovarian toxicity by repeated-dose and fertility studies in female rats. J Tox. Sci. 34: Special Issue SP1-SP22


Short description of key information:
There is no 2-generation reproductive toxicity study available. Based on the availble data from repeated dose toxicity studies, there is no evidence of a specific reproductive toxicity of N,N-dimethylbenzylamine.

Effects on developmental toxicity

Description of key information
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. Despite maternal toxicity at 150 mg/kg bw/day (reduced weight gain) N,N-Dimethylbenzylamin did not reveal developmental toxicity.
Link to relevant study records
Reference
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
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals 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
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
Remarks:
Doses / Concentrations:
0, 35, 75, 150 mg/kg bw/day
Basis:

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.
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
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
Dose descriptor:
NOAEL
Effect level:
75 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOEL
Effect level:
150 mg/kg bw/day
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOEL
Effect level:
150 mg/kg bw/day
Basis for effect level:
other: other:
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)
Abnormalities:
not specified
Developmental effects observed:
not specified
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.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
150 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
There is a developmental oral study in rats available according to OECD TG 414 and GLP which was evaluated with Klimisch score 1
Additional information

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 the NOEL (No Adverse Effect Level) for reproductive and developmental toxicity is considered 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.


Justification for selection of Effect on developmental toxicity: via oral route:
There is a developmental oral study in rats available according to OECD TG 414 and GLP which was evaluated with Klimisch score 1

Toxicity to reproduction: other studies

Additional information

There are subacute toxicity studies available using the oral exposure route in which also the reproductive organs were considered. Male and female rats were given N,N-dimethylbenzylamine daily up to doses of 400 mg/kg bw /day. No significant compound related effects on reproductive organs were reported (MHLW1997, BG Chemie 1990)

Justification for classification or non-classification

The substance is not classified in one of the categories for fertility assessment or developmental toxicity.

N,N-dimethylbenzylamine has not shown specific effects on reproductive organs in male and female rats in tests with repeated dose toxicity. Thus, there is no reason for classification.