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Diss Factsheets

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2018-2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019
Report date:
2019

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
Minor deviation: see below
Qualifier:
according to guideline
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
Minor deviation: see below
Principles of method if other than guideline:
The study was conducted in accordance with the Study Plan and one Study Plan Amendment agreed upon. There were no major deviations from the Study Plan. One minor deviation from the Study Plan and one Study Plan Amendment was noted:
- Blood was taken from non-fasted animals on the day of necropsy and not from fasted animals as stated in the study protocol. Fasting was not necessary and can affect the fetuses negatively. This deviation was due to a copy and paste error in the Study Plan.
This minor deviation did not invalid the results of the study.
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
N-[3-(dimethylamino)propyl]-N,N',N'-trimethylpropane-1,3-diamine
EC Number:
223-362-3
EC Name:
N-[3-(dimethylamino)propyl]-N,N',N'-trimethylpropane-1,3-diamine
Cas Number:
3855-32-1
Molecular formula:
C11H27N3
IUPAC Name:
(3-{[3-(dimethylamino)propyl](methyl)amino}propyl)dimethylamine
Test material form:
liquid: viscous
Specific details on test material used for the study:
Designation PU-2018-788 (Polycat 77)
Chemical name N-[3-(Dimethylamino)propyl]-N,N’,N’- trimethylpropan-1,3-diamin
CAS no. 3855-32-1
Batch no. 2302276
Receipt no. 66072
Date of receipt 25 June 2018
Characteristics Colourless liquid
Storage conditions At +10°C to +25°C, in a tightly closed
container and stored at a dry, cool and wellventilated place.
Stability / Expiry date 13 April 2020
Purity 96.3%

Test animals

Species:
rat
Strain:
CD-1
Remarks:
Rat / CD / Crl:CD(SD)
Details on test animals or test system and environmental conditions:
Age on day 0 of pregnancy: 62 - 65 days
Body weight on day 0 of pregnancy: 202.8 g - 280.7 g
Number of animals:
Groups 1 - 4: 25 females per group
Groups 1 - 4: 25 females per group

Evaluated litters
Groups 1 - 4: 20 litters per group

The animals were kept singly in MAKROLON cages (type III plus) with a basal surface of approx. 39 cm x 23 cm and a height of approx. 18 cm. The room temperature was 22°C ± 3°C (maximum range) and the relative humidity 55% ± 10%
(maximum range). Granulated textured wood released for animal bedding (Granulat A2, J. Brandenburg, 49424 Goldenstedt/Arkeburg, Germany) was used as bedding material in the cages. The cages were cleaned and changed once a week.
Periodic analysis of the bedding material for contaminants based on EPA/USA is conducted at least once a year by LUFA-ITL.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
Distilled water
Details on exposure:
Dose levels Group 1: Control (vehicle)
Group 2: 7.5 mg/kg b.w./day
Group 3: 25 mg/kg b.w./day
Group 4: 75 mg/kg b.w./day
Vehicle Distilled water
Route of administration:Oral, via gavage
Frequency of administration: Once daily
Duration of administration Day 6 to 20 of gestation

Administration volume: 10 mL/kg b.w./day
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Sexually mature ('proven') male rats of the same breed serve as partners. The
female breeding partners are randomly chosen. Mating is monogamous: one male
and one female animal are placed in one cage during the dark period. Each morning a
vaginal smear is taken to check for the presence of sperm. If findings are negative,
mating is repeated with the same partner. Day of conception (day 0 of gestation) is
considered to be the day on which sperm is found. This procedure is repeated until
enough pregnant dams are available for all groups. Rats that do not become
pregnant are excluded from the analysis of the results and replaced by other
animals. A post-mortem negative staining according to SALEWSKI is carried out in the
replaced animals in order to confirm the non-pregnancy status.
Duration of treatment / exposure:
Treatment period: Day 6 to 20 of gestation
Frequency of treatment:
Once daily, via oral gavage
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Control group
Dose / conc.:
7.5 mg/kg bw/day (nominal)
Dose / conc.:
25 mg/kg bw/day (nominal)
Dose / conc.:
75 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25 Females per dose group
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
Individual animals were observed daily for behavioural changes, reaction to treatment, or illness. Further checks were made early in the morning and again in the afternoon of each
working day to look for dead or moribund animals.

The weight of each rat was recorded on day 0 of gestation (the day of detection of a positive mating sign), followed by daily weighing - always at the same time of the day.
The quantity of food consumed by each rat was recorded daily. Food intake per rat (g/rat/day) was calculated using the total amount of food given to and left by each rat in each group on completion of a treatment day.
In order to obtain approximately 2 x 150 µL serum for each endocrine endpoint (T3, T4, TSH), a sufficient volume of blood was taken from the retrobulbar venous plexus under isoflurane anaesthesia from animals fasted overnight following a
randomisation scheme. Blood samples were taken always at the same time of day (approximately from 7:00 a.m. to 10:00 a.m.)
Ovaries and uterine content:
On gestation day 21, the rats were laparotomised under CO2 narcosis. The thyroids (including parathyroids) and the gravid uterus (in toto) of the dams were removed.
In order to check for possible test item effects, a dissection with macroscopic examination of the internal organs and placentae of the dams was carried out on
the day of sacrifice or on the day on which the animals were found dead. The thyroids and any organs with macroscopic findings of all dams (including deceased
or prematurely sacrificed animals) were fixed in 7% neutral buffered formalin
Fetal examinations:

The fetuses were removed and the following examinations performed:
(a) Macroscopic inspection (gross evaluation) of the placentae for example for focal
indurations or abnormal appearance (e.g. size, colour, shape).
(b) The number of fetuses (alive and dead) and placentae (location in the uterus and
the assignment of the fetuses) was determined.
(c) Sex and viability of fetuses were determined. Animals are said to be viable when
they are found alive (spontaneous breathing, spontaneous movement).
(d) Number and size of resorptions were determined.
(e) Corpora lutea in the ovaries, implantations and location of fetuses in the uterus
were determined.
(f) Weights of fetuses and weights of the placentae were determined (fetuses were
considered as runts if their weight was less than 70% of the mean litter weight).
(g) The ano-genital distance (AGD) of all live fetuses was determined using a scale.
(h) All fetuses (dead and alive) were inspected externally for damages, especially
for malformations9.
(i) The fetuses were sacrificed in an ether atmosphere.
Statistics:
Homogeneity of variances and normality of distribution were tested using the BARTLETT's and SHAPIRO-WILK's test. In case of heterogeneity and/or nonnormality of distribution, stepwise transformation of the values into logarithmic or
rank values was performed prior to ANOVA. If the ANOVA yielded a significant effect (p ≤ 0.05), intergroup comparisons with the control group were made by the DUNNETT’s test (p ≤ 0.01 and p ≤ 0.05).
Historical control data:
Yes

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
No influences on the behaviour, external appearance or on the faeces were noted for the dose groups (7.5, 25 or 75 mg PU 2018 788/kg b.w./day).
Mortality:
no mortality observed
Description (incidence):
No test item-related premature deaths were noted in any of the test groups.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
At 75 mg PU-2018-788/kg b.w./day, a slightly reduced body weight was noted from GD 20 until study termination on GD 21 (4.3% or 6.1% below the value of the control group, statistically not significant).
Furthermore, the high dose group revealed a decrease in body weight gain (20.1% below the value of the control group, p ≤ 0.05) for the period from GD 6 to GD 21.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
In the high dose group (75 mg PU 2018 788/kg b.w./day) a slightly reduced food consumption (around 10% below the control group) was noted between gestation days 15 and 20 (statistically significant at p ≤ 0.05 or not).
Between GD 20 and GD 21 the food consumption of the high dosed animals was moderately reduced by 29.3% in comparison to the control (p ≤ 0.01).
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Description (incidence and severity):
Macroscopic inspection of the dams at necropsy revealed no test item-related changes in any of the dose groups.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
Microscopic examination of the thyroids of the dams revealed no test item-related changes.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Description (incidence and severity):
The determination of the concentration of the thyroid hormones of the dams (T3,
T4 and TSH) revealed no differences between the control group and the low and
intermediate dose group (7.5 or 25 mg PU-2018-788/kg b.w./day).
At 75 mg PU-2018-788/kg b.w./day, statistically significant increased values were
noted for the concentration of T3 and TSH (66.6% or 96.0% above the control
group, both statistically significant at p ≤ 0.01). However, histopathologic
examination of the thyroids displayed no changes and also no differences were
noted for the thyroid weights.
It is known that histopathological examination of the thyroids is usually more
sensitive than hormone levels (Beekhuijzen et al., 2016). The validation report of
OECD 407 states that “thyroid histopathology was consistently the most reliable
and most sensitive endpoint for the detection of thyroid modulation. Thyroid weight
was reliable, but was somewhat less sensitive when compared to thyroid
histopathology. Circulating thyroid hormone levels (T3, T4, and TSH) were not
always reliable and sensitive, but standard operating procedures for blood sampling
and for thyroid hormone analyses were not standardized to reduce stress induced
variability, respectively. Circulating T4 levels were the most promising of the three
thyroid hormone values.”
Therefore, the increased serum concentrations of T3 and TSH were considered to
be spontaneous and not test item-related.

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
No abortion or premature delivery occurred in the study.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
No test item-related influence was noted on the reproductive parameters (number of resorptions and fetuses).
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
No test item-related influence was noted on the reproductive parameters (number of resorptions and fetuses).
Early or late resorptions:
no effects observed
Description (incidence and severity):
No test item-related influence was noted on the reproductive parameters (number of resorptions and fetuses).
Dead fetuses:
no effects observed
Description (incidence and severity):
No death of fetuses was noted.
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
25 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
A slightly reduced fetal weight was noted at the high dose level (75 mg PU 2018 788/kg b.w./day) (6.0% below the control value, statistically not significant).
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
effects observed, non-treatment-related
Description (incidence and severity):
A slightly reduced fetal weight was noted at the high dose level (75 mg PU 2018 788/kg b.w./day) (6.0% below the control value, statistically not significant).
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Description (incidence and severity):
No test item-related malformations were noted during the macroscopic examinations at laparotomy (external inspection and inspection of the organs and tissues for gross lesions), and no malformations were noted during the skeletal examination according to DAWSON and the soft tissue examination according to WILSON.
The macroscopic examinations at laparotomy, the skeletal examination according to DAWSON and the soft tissue examination according to WILSON revealed no test item-related variations.
Skeletal malformations:
no effects observed
Description (incidence and severity):
No test item-related malformations were noted during the macroscopic examinations at laparotomy (external inspection and inspection of the organs and tissues for gross lesions), and no malformations were noted during the skeletal examination according to DAWSON and the soft tissue examination according to WILSON.
The macroscopic examinations at laparotomy, the skeletal examination according to DAWSON and the soft tissue examination according to WILSON revealed no test item-related variations.
Visceral malformations:
no effects observed
Description (incidence and severity):
No test item-related malformations were noted during the macroscopic examinations at laparotomy (external inspection and inspection of the organs and tissues for gross lesions), and no malformations were noted during the skeletal examination according to DAWSON and the soft tissue examination according to WILSON.
The macroscopic examinations at laparotomy, the skeletal examination according to DAWSON and the soft tissue examination according to WILSON revealed no test item-related variations.
Other effects:
no effects observed

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
75 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
changes in postnatal survival
external malformations
skeletal malformations
visceral malformations
other: Thyroid hormone (T3, T4, TSH) determination

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no
Lowest effective dose / conc.:
75 mg/kg bw/day (nominal)
Treatment related:
no

Applicant's summary and conclusion

Conclusions:
Under the present test conditions, the no-observed-adverse-effect level (NOAEL) was 25 mg PU-2018-788/kg b.w./day for the dams.
A test item-related reduction was noted for the food consumption, the body weight, the body weight gain and the carcass weight of the high dose animals.
No premature death was noted.
No changes in behaviour, external appearance or faeces were noted for the treatment groups.
No endocrine disruptor activity (influence on T3, T4 or TSH serum concentration) was noted.
No test item-related pathologic changes were noted for any of the dose groups.
The no-observed-adverse-effect level (NOAEL) for the fetal organism was 75 mg PU-2018-788/kg b.w./day.
The reproductive parameters (number of resorptions and fetuses) were not influenced by the test item.
No test item-related influence was noted on the ano-genital distance and the testicles of the male fetuses.
No dead fetuses, malformations and test item-related variations or retardations were noted.
At the materno-toxic dose level (75 mg PU-2018-788/kg b.w./day) a slightly reduced fetal body weight was noted. This was considered as a secondary effect to the reduced body weight and food consumption of the dams and not as a sign of developmental toxicity.
Under the conditions of the study, the test item PU-2018-788 did not show any teratogenic potential in rats.
Executive summary:

In a Prenatal Developmental Toxicity (PNDT) Study conducted according to OECD TG 414, the test item PU-2018-788 was administered orally to female rats at dose levels of 7.5, 25 or 75 mg/kg b.w./day from the 6th to 20th day of pregnancy.

The no-observed-adverse-effect level (NOAEL) was 25 mg PU-2018-788/kg b.w./day for the dams.

A test item-related reduction was noted for the food consumption, the body weight, the body weight gain and the carcass weight of the high dose animals.

No premature death was noted. No changes in behaviour, external appearance or faeces were noted for the treatment groups.

No endocrine disruptor activity (influence on T3, T4 or TSH serum concentration) was noted.

No test item-related pathologic changes were noted for any of the dose groups.

The no-observed-adverse-effect level (NOAEL) for the fetal organism was 75 mg PU-2018-788/kg b.w./day.

The reproductive parameters (number of resorptions and fetuses) were not influenced by the test item.

No test item-related influence was noted on the ano-genital distance and the testicles of the male fetuses.

No dead fetuses, malformations and test item-related variations or retardations were noted.

At the materno-toxic dose level (75 mg PU-2018-788/kg b.w./day) a slightly reduced fetal body weight was noted. This was considered as a secondary effect to the reduced body weight and food consumption of the dams and not as a sign of developmental toxicity.

Under the conditions of the study, the test item PU-2018-788 did not show any teratogenic potential in rats.