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https://ntp.niehs.nih.gov/go/dart03abs

Abstract for DART-03

Prenatal Developmental Toxicity Studies of Vinpocetine in Sprague Dawley (Hsd:Sprague Dawley SD) Rats and New Zealand White (Hra:NZW SPF) Rabbits (Gavage Studies)

CASRN: 42971-09-5
Chemical Formula: C22H26N2O2
Molecular Weight: 350.46
Synonyms/Common Names: Apovincaminic acid ethyl ester; cis-apovincaminic acid ethyl ester; ethyl (+)-apovincaminate; ethyl apovincamin-22-oate; ethyl (+)-cis-apovincaminate; ethyl (3α,16α)-eburnamenine-14-carboxylate
Peer Review Date: July 31, 2019

DRAFT REPORT PDF

Abstract

NOTE: The following abstract is from the draft NTP report for external peer review. The final report will be available in PDF format.

Vinpocetine is mainly marketed as a dietary supplement for cognitive enhancement, Alzheimer’s, dementia, and ischemic stroke; however, several products are marketed towards students as brain supplements for increased cognitive performance. Additionally, vinpocetine is used by bodybuilders to enhance visual acuity, memory, and focus and to rapidly reduce body fat. Human exposure to vinpocetine typically occurs through oral consumption. Marketed as a dietary supplement in the United States, vinpocetine is regulated by the Food and Drug Administration (FDA) under the Dietary Supplement Health and Education Act of 1994. Analysis of vinpocetine supplements have shown that in a significant number of products, the actual vinpocetine content varied from what was stated on the label which could result in higher doses than what is recommended by the product labels. Due to limited literature indicating that vinpocetine may not be safe for use during pregnancy and the possibility for widespread exposure to women of childbearing age, the National Toxicology Program (NTP) conducted prenatal developmental toxicology studies. In these studies, time-mated Sprague Dawley (Hsd:Sprague Dawley SD) rats and New Zealand White (Hra:NZW SPF) rabbits received vinpocetine (99.3% pure) in 0.5% methylcellulose by gavage from implantation on gestation day (GD) 6 (rats) or 7 (rabbits) to the day before expected parturition (GD 20 for rats; GD 28 for rabbits). Evidence of vinpocetine-related maternal and fetal toxicity was examined in the dose range-finding study in rats followed by the standard prenatal developmental toxicity study in rats. A dose range-finding study in rabbits was conducted to see if effects occurred in a second species, but a standard prenatal developmental toxicity study was not performed in rabbits.

Dose Range-Finding Prenatal Developmental Toxicity Study in Rats

Groups of 10 time-mated female rats were administered 0, 20, 40, 80, 160, or 320 mg vinpocetine/kg body weight per day, based on the most recent body weight, in 0.5% aqueous methylcellulose by gavage from GD 6 to GD 20. Vehicle control (0 mg/kg) animals received aqueous methylcellulose.

All animals survived to the end of the study. Clinical observations were limited to red and/or brown vaginal discharge, discoloration of the nares, and piloerection. There were dose-related decreases in mean maternal body weight and mean body weight gains from GD 6 to GD 21 in groups administered 40 mg/kg or greater. When adjusted for gravid uterine weight, maternal body weights of the 160 and 320 mg/kg groups were significantly lower than those of the vehicle controls. Concomitant treatment-related, dose-dependent decreases in maternal feed consumption in groups receiving 40 mg/kg or greater was also noted. There was a significant, treatment-related effect on percent post-implantation loss in all dose groups. At doses of 80 mg/kg or greater, dams exhibited total resorption of their litters with the exception of one dam in the 160 mg/kg group with live fetuses.

No external malformation or variations attributed to vinpocetine administration in fetuses were observed.

Prenatal Developmental Toxicity Study in Rats

Due to the post-implantation loss observed at doses of 80 mg/kg and greater in the dose ranging-finding study, 60 mg/kg was chosen as the high dose for the prenatal developmental toxicity study. Groups of 25 time-mated female rats were administered 0, 5, 20, or 60 mg vinpocetine/kg body weight per day, based on the most recent body weight, in 0.5% aqueous methylcellulose by gavage from GD 6 to GD 20. Vehicle control (0 mg/kg) animals received aqueous methylcellulose. 

All animals survived to the end of the study. Treatment-related clinical findings were red and/or brown vaginal discharge in the 20 and 60 mg/kg groups. There were significantly decreased mean maternal body weights and mean body weight gains in the 60 mg/kg group which were associated with a significant increase in postimplantation loss, including total litter resorption in 12 dams. There was also a treatment-related decrease in feed consumption in the 60 mg/kg group. Due to the increased post-implantation loss in the 60 mg/kg group, there was a significant decrease in the number of live fetuses per litter and in gravid uterine weight.

There were a small number of viable litters and fetuses for evaluation at 60 mg/kg. In the viscera, there were treatment-related increased incidences of ventricular septum defect in all exposed groups. In the skeleton, treatment-related findings included significantly increased incidences of incomplete ossification of the thoracic centrum in the 20 and 60 mg/kg groups and full supernumerary thoracolumbar ribs in the 60 mg/kg group.

Dose Range-Finding Study in Rabbits

Groups of 8 time-mated female rabbits were administered 0, 25, 75, 150, or 300 mg vinpocetine/kg body weight per day, based on the most recent body weight, in 0.5% aqueous methylcellulose by gavage from GD 7 to GD 28. Vehicle control (0 mg/kg) animals received aqueous methylcellulose.

All rabbits survived until the end of the study except one 150 mg/kg female that was removed on GD 25 due to abortion. There were no clinical observations related to vinpocetine treatment. There were significant decreases in mean maternal body weights gains in the 150 and 300 mg/kg groups. The decreased maternal body weight gains were consistent with a treatment-related decrease in feed consumption in these groups.

There was an exposure-related effect on embryo-fetal survival in the 300 mg/kg group with a significant decrease in the number of live fetuses per litter and an increase in early resorptions per litter resulting in an increase in percent post-implantation loss. These findings in the 300 mg/kg group were also associated with a significant decrease in mean gravid uterine weight. There were no exposure-related effects on embryo-fetal survival in any group administered 150 mg/kg or less. There were no external malformations or variations attributed to vinpocetine exposure.

Data from this rabbit dose range-finding study supported findings observed in the rat dose range-finding study and rat prenatal developmental toxicity studies (increase in post-implantation loss) with exposure to vinpocetine.

Conclusions

Under the conditions of the rat prenatal study, there was clear evidence of developmental toxicity of vinpocetine in Hsd:Sprague Dawley SD rats based on increased post-implantation loss and increased incidences of ventricular septum defects, thoracolumbar ribs (full), and incomplete ossification of the thoracic centrum in the absence of overt maternal toxicity.

Studies

Summary of Exposure-Related Findings in Rats in the Prenatal Developmental Toxicity Gavage Study of Vinpocetine

0 mg/kg      5 mg/kg      20 mg/kg      60 mg/kg     
Maternal Parameters
Animals on study 25 25 25 25
Number pregnant 21 20 22 20
Number died or euthanized moribund 0 0 0 0
Clinical Observations None None Red or brown vaginal discharge Red or brown vaginal discharge
Body Weight and Feed Consumption[a]
Terminal body weight 385.7 ± 34.2** 368.5 ± 8.2 370.0 ± 5.5 296.1 ± 8.2**
Body weight change GD 6 to 21 142.8 ± 3.4** 128.7 ± 7.4 130.0 ± 5.1 55.3 ± 7.9**
Feed consumption GD 6 to 21 22.0 ± 0.3** 21.6 ± 0.4 22.2 ± 0.3 19.9 ± 0.4**
Necropsy Observations None None None None
Developmental/Fetal Parameters
Number of litters examined 21 19 21 8
Number of live fetuses evaluated 293 239 261 51
Number of live fetuses per litter[b] 13.95 ± 0.55** 11.95 ± 1.06 11.86 ± 0.88 2.5 ± 1.00**
Number of early resorptions 7 12 19 208
Number of late resorptions 1 0 2 0
Number of dead fetuses 1 0 0 0
Number of whole litter resorption 0** 1 1 12**
Percent post-implantation loss[b] 3.29 ± 1.33** 10.67 ± 5.29 11.13 ± 4.65 83.13 ± 6.47**
Fetal body weight per litter[a] 5.15 ± 0.07 5.29 ± 0.16 5.21 ± 0.12 5.11 ± 0.10
Male fetal weight per litter[a] 5.28 ± 0.06 5.49 ± 0.21 5.35 ± 0.12 5.18 ± 0.08
Female fetal weight per litter[a] 5.03 ± 0.07 5.10 ± 0.10 5.09 ± 0.12 4.63 ± 0.06
Gravid uterine weight[a] 97.79 ± 3.11** 83.89 ± 6.59 85.07 ± 5.28 19.52 ± 6.53**
External Findings None None None None
Visceral Findings[c]
Heart
Ventricle, ventricular septum defect — [M]
Fetuses 0   (0.00) 3   (1.26) 8   (3.07) 2   (3.92)
Litters 0   (0.00) 3   (15.79) 7   (33.33)** 2   (25.00)
Skeletal Findings
Thoracic centrum
Incomplete ossification, total — [V]
Fetuses 1   (0.34)## 1   (0.42) 6   (2.31)# 8   (17.02)##
Litters 1   (4.76)** 1   (5.26) 5   (23.81) 3 (42.86)*
Supernumerary rib
Thoracolumbar, full, total — [M]
Fetuses 1   (0.34)## 5   (2.09) 12   (4.62) 12   (25.53)##
Litters 1   (4.76)* 3   (15.79) 4   (19.05) 3   (42.86)*


Level of evidence of developmental toxicity:
Clear evidence


Summary of Exposure-Related Findings in Rabbits in the Dose Range-Finding Gavage Study of Vinpocetine

0 mg/kg 25 mg/kg 75 mg/kg 150 mg/kg 300 mg/kg
Maternal Parameters  
Animals on study 8 8 8 8 8
Number pregnant 8 7 8 8 8
Number died or euthanized moribund 0 0 0 0 0
Number euthanized –abortion 0 0 0 1 0
Clinical Observations None None None Red vaginal discharge Red vaginal discharge
Body Weight and Feed Consumption[a]
Necropsy body weight                           3,499.4 ± 64.6* 3,406.5 ± 58.0 3,467.7 ± 95.0 3,358.4 ± 105.6 3,271.4 ± 34.2
Body weight change GD 7 to 29            460.2   ± 33.8** 458.2 ± 46.2 399.3 ± 58.4 256.7 ± 40.9** 304.1 ± 33.2**
Feed consumption GD 7 to 29                137.6 ± 4.3 131.8 ± 5.7 125.2 ± 4.0 101.3 ± 11.4** 113.8 ± 8.9*
Necropsy Observations None None None None None
Developmental/Fetal Parameters
Number of litters examined                          8 7 8 7 8
Number of live fetuses evaluated                          73 54 72 53 52
Number of live fetuses/litter[b] 9.13 ± 0.44* 7.71 ± 0.42 9.00 ± 0.53 7.57 ± 0.81 6.50 ± 0.73*
Number of early resorptions                          1 0 0 1 13
Number of late resorptions                          0 1 2 0 2
Dead fetuses                          0 1 0 0 0
Number of whole litter resorption                0 0 0 0 0
Percent post-implantation loss[b] 1.39 ± 1.39 3.37 ± 2.18 2.53 ± 1.66 3.57 ± 3.57 20.42 ± 9.05
Fetal body weight per litter[a] 39.72 ± 1.33** 41.47 ± 0.95 37.53 ± 0.90 39.36 ± 1.74 35.78 ± 1.15
Male fetal weight per litter[a] 40.87 ± 1.59** 42.70 ± 0.97 38.50 ± 1.15 38.06 ± 1.62 36.49 ± 2.00
Female fetal weight per litter[a] 38.76 ± 1.57* 40.37 ± 1.12 36.35 ± 1.01 39.29 ± 1.75 34.65 ± 0.95
Gravid uterine weight[a] 515.25 ± 14.70** 470.05 ± 20.66 483.91 ± 32.24 421.86 ± 39.25* 340.94 ± 27.73**
External Findings                          None None None None None



*     Statistically significant (P≤0.05) trend (denoted in vehicle control column) or pairwise comparison (denoted in dosed group column);
**   P≤0.01.
#    Statistically significant (P≤0.05) trend (denoted in vehicle control column) or pairwise comparison (denoted in dosed group column) for
##  P≤0.01.
[a] 
Results given in grams. Data are displayed as mean ± standard error.
[b]  
Data are displayed as mean ± standard error.
[c]  
Upper row denotes the number of affected fetuses and (%) and lower row the number of affected litters and (%).< /p>
GD = Gestation Day
[M] = Malformation
[V] = Variation