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Toxicity to reproduction: other studies

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toxicity to reproduction: other studies
Type of information:
experimental study
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference Type:
The Effect of Prenatal Alcohol Exposure on Fetal Growth and Cardiovascular Parameters in a Baboon Model of Pregnancy.
Tobiasz AM, Duncan JR, Bursac Z, Sullivan RD, Tate DL, Dopico AM, Bukiya AN, Mari G.
Bibliographic source:
Reprod Sci. 25(7): p1116-23.

Materials and methods

Principles of method if other than guideline:
To address the weakness in the measurement of alcohol exposure when assessing the impact of alcohol exposure during primate pregnancy, pregnant baboons were exposed to alcohol by infusion. Blood alcohol levels were measured along with the use of Doppler ultrasonography for longitudinal assessment of fetal biometric parameters and fetal cardiovascular indices.
GLP compliance:
not specified
Type of method:
in vivo

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Test material form:
Specific details on test material used for the study:
- Source and lot/batch number of test material: American Bioanalytical (Natick, MA).
- Purity: Ultra pure, 200 proof ethanol

Test animals

other: baboon (papio)
Details on test animals or test system and environmental conditions:
Age: 7-20 years, previously used in other research but alcohol naive.

Administration / exposure

Route of administration:
oral: gavage
Details on exposure:
Dosing by gastric catheter applied over a period of 10 minutes. Animals were fasted for 12 hours prior to exposure. Dosing and blood collection was carried out under anasthesia which monitoring animals vital signs.
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Blood ethanol measurements during exposure procedure using catheter placed into the saphenous vein with blood collected for up to 3 hours post exposure at 10 minute intervals for analysis of blood ethanol levels. Measurements showed blood ethanol levels were shown to reach 80mg/dL within 30-60 minutes of exposure.
Frequency of treatment:
Animals were dosed on GD 90, 100 and 110, equivalent to human second trimester.
Duration of test:
Study terminated at 165 days when pups delivered by cesaerean section.
Doses / concentrations
Dose / conc.:
1 800 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
Control animals:
yes, concurrent vehicle
Details on study design:
The study effectively assessed the impact of heavy binge drinking. Doppler Ultrasonography was used to measure Fetal Growth and Cardiovascular Parameters. Measurements were carried out immediately before and at 120 minutes postinfusion at each gestational age, and also at 135, 155, and 165 days of gestation. The latter corresponds to near term in humans.
Comparison of means was: either by analysis of variance (ANOVA) or student t test, depending on the number of independent variable levels.
Following ANOVA, multiple comparison testing with Tukey adjustments for P values was performed. Linear regression used to assess clustering (repeated measures). Statistical significance considered at p=0.01.

Results and discussion

Effect levels

Remarks on result:
not determinable
The study was not designed to determine a no effect level

Observed effects

Abdominal and head circumference were significantly reduced at the end of gestation but not at earlier time periods. (The changes were stlll relatively modest with ~10% reduction in adominal and ~5% in head circumference. Results only presented graphically so exact figures not available.) There was no effect on femur length. Peak systolic velocity of anterior and middle cerebral arteries decreased during episodes of alcohol intoxication, but there was no difference in Doppler indices between groups near term. Acute alcohol intoxication affected fetal cerebral blood flow independent of changes in the fetal cardiac output. Unlike fetal growth parameters, changes in vascular indices did not persist over gestation.

Applicant's summary and conclusion

Executive summary:

A study was performed on baboons to assess he impact of binge drinking during pregnancy. The animals were exposed three times by gavage to doses of 1.8/kg ethanol to produce peak blood ethanol levels of 80mg/dL. Doppler ultrasonography was used for longitudinal assessment of fetal biometric parameters and fetal cardiovascular indices at different time points following exposure. Temporary cardiovascular effects were seen but these did not persist until the end of pregnancy. Resultant growth retardation was seen in the ethanol exposed animals (5 -10% compared to controls) manifest as a reduction in head and abdominal circumference but not in terms of femur length. The study provides support for the impact of binge drinking/heavy alcohol consumption on fetal growth but the single, large dose cannot be used to support effects at lower doses or exposure by routes other than deliberate oral consumption.