Potassium N,N-dimethylglycinate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP and guideline compliant study report

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reporduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Potassium N,N-dimethylglycinate

EC Number:

241-629-2

EC Name:

Potassium N,N-dimethylglycinate

Cas Number:

17647-86-8

Molecular formula:

C4H8NO2.K

IUPAC Name:

potassium 2-(dimethylamino)acetate

Details on test material:

- Name of test material (as cited in study report): Potassium N,N-dimethylglycinate
- Physical state: solid, white
- Analytical purity: 99.76 area-% (HPLC) minus water content and potassium hydroxide = 94.2 g/100 g (1H-NMR)
- Lot/batch No.: 212922-3
- Expiration date of the batch: 04 Sep 2016
- Storage condition of test material: at room temperature, highly hygroscopic

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Age at study initiation: about 11-12 weeks (males and females)
- Housing: individually in polycarbonate cages type III
- Diet (e.g. ad libitum): ad libitum, ground Kliba maintenance diet mouse-rat “GLP”, meal, supplied by Provimi Kliba SA, Kaiseraugst, Switzerland
- Water (e.g. ad libitum): ad libitum, deionized water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): 30 - 70%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Details on mating procedure:

In general, each of the male and female animals was mated overnight in a 1:1 ratio for a maximum of 2 weeks. Throughout the mating period, each female animal was paired with a predetermined male animal from the same test group. The animals were paired by placing the female in the cage of the male mating partner from about 16.00 h until 06.30 - 09.00 h of the following morning. Deviations from the specified times were possible on weekends and public holidays and were reported in the raw data. A vaginal smear was prepared after each mating and examined for the presence of sperm. If sperm was detected, pairing of the animals was discontinued. The day on which sperm was detected was denoted gestation day (GD) 0 and the following day "GD 1".

Duration of treatment / exposure:

males: 29 days
females: 53 days

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
1500, 4000, 12000 ppm
Basis:
nominal in water

Doses / concentrations 2

Remarks:

Doses / Concentrations:
1592, 4246, 12739 ppm
Basis:
other: content of the test substance (94.2 g/100 g)

No. of animals per sex per dose:

10

Control animals:

yes, concurrent no treatment

Examinations

Maternal examinations:

WATER CONSUMPTION
During pre-mating water consumption was significantly decreased between study day 0 and 3 in male animals of test group 3 (12000 ppm, -47.2%) and in female animals of the same test group 3 between study day 0 and 3 (-29.9%) as well as between study day 10 and 13 (-29.3%). Whereas no effect can be seen in both sexes after the first two weeks of administration, it can be concluded, that the reason for this finding was assessed to be caused by the taste of the test item in the highest concentration, which the animals get accustomed to. So these findings were considered as treatment related, but not adverse. During gestation and lactation no significant findings were observed.
FOOD CONSUMPTION
Food consumption was significantly decreased (-23.7%) in male animals of test group 3 (12000 ppm) during pre-mating between study day 0 and 7. No further effects were seen in food consumption. This finding was considered as treatment-related, but based on the degree of change as well as on its transient character it was assessed as not adverse.
BODY WEIGHT DATA
Male animals of test group 3 (12000 ppm) showed a slight significant lower body weight on pre-mating days 7 (-6.0%) and 13 (-5.0%). The body weight change in male animals of test group 3 (12000 ppm) was decreased (-90.4%) during pre-mating between day 0 and 7. The overall value for pre-mating body weight change was decreased significantly (-42.3%). No further alterations of the body weight were observed after the first two weeks of administration in males. These findings were considered as treatment-related, but based on the degree of change as well as on its transient character they were assessed as not adverse. Body weights and body weight changes were not significantly affected in female animals during pre-mating, mating, post-mating and gestation.

Fetal examinations:

Pup number and status at delivery
The mean number of delivered F1 pups per dam was evenly distributed about test groups 0 - 3. The respective values reflect the normal range of biological variation inherent in the strain used in this study. Each one stillborn pup was found in the litter of dams Nos. 133 and 138 of test group 3 (12000 ppm). This incidence were within the normal range of the historical control data.
Pup viability/ mortality
The viability index indicating pup mortality during lactation (PND 0 - 4) was 100.0% (test groups 1 and 3) and 99.0% (test groups 0 and 2) based on 1 pup of the control group (0 ppm) was found dead and one pup of test group 2 (4000 ppm) was missing (cannibalized). These findings reflected the normal range of biological variation inherent in the strain of rats used for this study as all respective values were within the range of the historical control data.
Sex ratio
The sex distribution and sex ratios of live F1 pups on the day of birth and PND 4 did not show substantial differences between the control and the test substance-treated groups; slight differences were regarded to be spontaneous in nature.
Pup clinical observations
The surviving F1 pups of any test group did not show adverse clinical signs up to scheduled sacrifice on PND 4. However, in test group 2 (4000 ppm) one female pups could be assessed only until PND 1 because it was missed (cannibalized) on PND 2 and in test group 3 (12000 ppm) one male and one female pup from different litters could not be assessed because they were stillborn on PND 0.
Pup body weight data
Mean pup body weights/pup body weight changes of all pups in all test groups were comparable to the control group. One female runt was seen in test group 0 (0 ppm) and two female runts were seen in test group 2 (4000 ppm). These values were within the range of the biological variation inherent in the strain of rats used for this study.
Pup necropsy observations
One male pup of test group 3 (12000 ppm) and one female pup of control group (0 ppm) showed post mortem autolysis. Furthermore, in test group 2 (4000 ppm) one female pup could not be assessed because it was missing (cannibalized). These findings were assessed as being spontaneous in nature and thereby not related to treatment. No other findings were seen in any pup of any test group.

Statistics:

Kruskal-Wallis Test; Wilcoxon-Test

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

3

Dose descriptor:

NOAEL

Effect level:

12 000 ppm

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Under the conditions of this Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, the oral administration via drinking water of Potassium N,N-dimethylglycinate to Wistar rats revealed no signs of general systemic toxicity in male and female parental animals up to a concentration of 12000 ppm (731 mg/kg bw/d in males and 960 mg/kg bw/d in females).
Thus, the no observed adverse effect level (NOAEL) for general systemic toxicity was 12000 ppm in male and in female parental animals (731 mg/kg bw/d in males and 960 mg/kg bw/d in females).
The no observed adverse effect level (NOAEL) for reproductive performance and fertility was 12000 ppm (731 mg/kg bw/d) in male and 12000 ppm (960 mg/kg bw/d) in female Wistar rats. The NOAEL for developmental toxicity in the F1 progeny was 12000 ppm.