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https://ntp.niehs.nih.gov/go/dart04abs

Abstract for DART-04

Prenatal Development Studies of Dimethylaminoethanol Bitartrate in Sprague Dawley (Hsd:Sprague Dawley SD) Rats (Gavage Studies)

CASRN: 5988-51-2
Chemical Formula: C4H11NO • C4H6O6
Molecular Weight: 239.23
Synonyms/Common Names: 2-Dimethylaminoethanol bitartrate; 2-dimethylaminoethanol tartrate; dimethylethanolamine bitartrate; N,N-dimethylethanolamine-tartaric acid salt; ethanol, 2-(dimethylamino)-, [R(R*,R*)]-2,3-dihydroxybutanedioate; ethanol, 2-(dimethylamino)-, tartrate
Report Date: June 2020

FULL REPORT PDF

Abstract

Dimethylaminoethanol is a close structural analog of choline, an essential nutrient. Dietary supplements containing dimethylaminoethanol bitartrate, a salt of dimethylaminoethanol, are marketed to improve memory and general cognitive function due to the ability of dimethylaminoethanol to increase levels of acetylcholine in the brain. Human exposure to dimethylaminoethanol may also occur through occupational and industrial routes (e.g., spray painting, beverage can lacquering). Dimethylaminoethanol was nominated by the National Institute of Environmental Health Sciences (NIEHS) for toxicological characterization due to concerns for widespread human exposure through its use in industrial and consumer products. Because of the limited literature indicating that dimethylaminoethanol could be a teratogen and reproductive toxicant and because of the possibility for widespread exposure to the salt form of dimethylaminoethanol (dimethylaminoethanol bitartrate) as a dietary supplement in women of childbearing age, the National Toxicology Program (NTP) conducted prenatal developmental toxicology studies in Sprague Dawley (Hsd:Sprague Dawley SD) rats. In these studies, time-mated female rats received dimethylaminoethanol bitartrate in sterile water by gavage from implantation on gestation day (GD) 6 to the day before expected parturition (GD 20). To identify dose levels that would appropriately challenge the model system, dimethylaminoethanol bitartrate-related maternal and fetal toxicity were examined in the dose range-finding study followed by the prenatal developmental toxicity study.

Dose range-finding prenatal developmental toxicity study

Groups of 10 time-mated female rats were administered 0, 250, 500, or 1,000 mg dimethylaminoethanol bitartrate/kg body weight per day (mg/kg/day) in sterile water by gavage from GD 6 to GD 20. Vehicle control (0 mg/kg) animals received sterile water.

There were no indications of maternal or fetal toxicity in the dose range-finding study. All animals survived to study termination. There were no dose-related effects on maternal body weights, body weight gains, body weights corrected for live litter size, or feed consumption. The number of pregnant females, mean number of corpora lutea, dead fetuses, early and late resorptions, and fetal sex ratio were similar across all treatment groups. There was a significant positive trend in the mean number of live female fetuses per litter relative to dose. There were no exposure-related fetal findings.

Prenatal developmental toxicity study

As no maternal toxicity was observed in the dose range-finding study, groups of 25 time-mated female rats were administered 0, 250, 500, or 1,000 mg/kg/day in sterile water by gavage from GD 6 to GD 20. Vehicle control (0 mg/kg) animals received sterile water. In this study, dimethylaminoethanol bitartrate was well tolerated and there were no significant effects on mortality, maternal body weights, body weight gains, body weights corrected for litter size, or feed consumption during gestation. In the 1,000 mg/kg/day group, one dam was euthanized moribund (GD 21) and one was found dead (GD 10); however, those deaths were not considered dose-related. Clinical observations were limited to single or sporadic incidences with the exception of brown or red vaginal discharge, which was observed between GD 14 and GD 21 in 10/20, 3/20, 4/20, and 10/24 dams in the 0, 250, 500, and 1,000 mg/kg/day groups, respectively. There were no notable placental or other maternal gross observations at necropsy except for a significant, but not biologically relevant, positive trend in mean absolute liver weight.

The number of pregnant animals, mean number of corpora lutea, implantations, litter size, live fetuses per litter, and fetal sex ratio were similar across all treatment groups.

External and visceral malformations were limited to common background findings and singular or sporadic incidences. There were no observed incidences of fetal head, specifically brain, abnormalities. Skeletal malformations and variations occurred predominantly in the ribs. A significant increase in the incidence of absent innominate artery (a variation) and total, short thoracolumbar ribs (a variation) was observed in the 1,000 mg/kg group, along with a significant positive trend. Additionally, there was a significant increase in the number of supernumerary sites, or ossification sites, in the skull in 1,000 mg/kg fetuses as well as a significant positive trend across all exposed groups. These effects might be reversible (supernumerary ribs) or of uncertain biological significance (supernumerary sites in the skull); however, in the absence of maternal toxicity or effects on fetal body weight, the increased incidences of extra ossification sites in two separate locations, each occurring through two different skeletal developmental pathways, suggest that these effects could be related to dimethylaminoethanol bitartrate exposure.

Conclusions

Under the conditions of the prenatal study, there was equivocal evidence of developmental toxicity of dimethylaminoethanol bitartrate in Sprague Dawley (Hsd:Sprague Dawley SD) rats attributable to increased incidences of absent innominate artery, short thoracolumbar ribs, and supernumerary sites in the skull in the absence of overt maternal toxicity.

National Toxicology Program (NTP). 2020. NTP developmental and reproductive toxicity technical report on the prenatal development studies of dimethylaminoethanol bitartrate (CASRN 5988-51-2) in Sprague Dawley (Hsd:Sprague Dawley SD) rats (gavage studies). Research Triangle Park, NC: National Toxicology Program. DART Report 04. https://doi.org/10.22427/NTP-DART-04

Studies

Summary of Exposure-related Findings in Rats in the Prenatal Developmental Toxicity Gavage Study of Dimethylaminoethanol Bitartrate

 

   0 mg/kg

    250 mg/kg

   500 mg/kg

1,000 mg/kg

Maternal parameters

Animals on study

25

25

25

25

Number pregnant

20

20

20

24

Number found dead

0

0

0

1

Number euthanized moribund

0

0

0

1

Number euthanized - early delivery

1

0

0

1

Clinical observations

None

None

None

None

Body weight and feed consumption[a]

Terminal body weight

359.6 ± 8.8

375.2 ± 5.3

380.3 ± 5.1

367.1 ± 6.5

Body weight change GD 6 to 21

120.5 ± 7.5

135.2 ± 4.7

140.0 ± 4.2*

127.7 ± 5.8

Feed consumption GD 6 to 21

21.2 ± 0.4

21.6 ± 0.4

22.0 ± 0.3

21.5 ± 0.4

Necropsy observations

None

None

None

None

Developmental/Fetal parameters

Number of litters examined

19

20

20

22

Number of live fetuses evaluated

209

265

260

249

Number of live fetuses per litter[b]

11.00 ± 1.12

13.25 ± 0.60

13.00 ± 0.56

11.32 ± 1.07

Number of early resorptions[c]

9

10

10

14

Number of late resorptions[c]

0

0

0

0

Number of dead fetuses[c]

0

0

0

11

Number with whole litter resorptions

0

0

0

0

Percent postimplantation loss[b]

5.05 ± 1.57

3.80 ± 1.53

3.45 ± 1.10

11.17 ± 5.56

Fetal body weight per litter[a]

5.38 ± 0.15

5.26 ± 0.05

5.33 ± 0.06

5.22 ± 0.09

Male fetal weight per litter[a]

5.44 ± 0.16 (18)

5.37 ± 0.05 (19)

5.50 ± 0.06 (20)

5.51 ± 0.09 (20)

Female fetal weight per litter[a]

5.15 ± 0.12 (18)

5.14 ± 0.06 (20)

5.18 ± 0.07 (20)

5.21 ± 0.08 (20)

Gravid uterine weight[a]

80.18 ± 7.36

95.85 ± 3.93

96.17 ± 3.82

85.25 ± 6.38

External findings

None

None

None

None

Visceral findings [d]

Arteries
Innominate artery, absent – [V]

Fetuses

3 (1.44)**## 4 (1.51) 6 (2.31) 12 (4.62)*#

Litters

3 (15.79)* 4 (20.00) 4 (20.00) 10 (45.45)*

Skeletal findings[d]

Supernumerary rib

Thoracolumbar short, total – [V]

Fetuses

56 (26.79)**##

56 (21.21)

59 (22.69)

100 (38.46)**#

Litters

17 (89.47)

18 (90.00)

18 (90.00)

19 (86.36)

Skull

General, supernumerary site – [V]

Fetuses

1 (1.0)**##

3 (2.34)

2 (1.59)

13 (10.16)**#

Litters

1 (5.56)**

3 (15.00)

2 (10.00)

10 (50.00)**


Level of evidence of developmental toxicity: Equivocal evidence


*    Statistically significant (p≤0.05) trend (denoted in vehicle control column) or pairwise comparison (denoted in dose group column);
**  p≤0.01.
#   Statistically significant (p≤0.05) trend (denoted in vehicle control column) or pairwise comparison (denoted in dose group column) in litter-based analysis of fetuses;
## p≤0.01.
GD = gestational day; [V] = variation.
[a] Results given in grams. Data are displayed as mean ± standard error.
[b] Data are displayed as mean ± standard error.
[c] No statistical analyses were performed on number of early resorptions, number of late resorptions, or number of dead fetuses.

[d] Upper row denotes number of affected fetuses (%) and lower row the number of affected litters (%).