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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: allantoin content in forming placenta and serum of pregnant women
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
no data
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Scientifically robust study, however, minimal information was provided on methodology and thus reliability could not be confirmed.

Data source

Reference
Reference Type:
publication
Title:
Biological Functions of Allantoin
Author:
Shestopalov, A.V., T. P. Shkurat, Z. I. Mikashinovich, I. O. Kryzhanovskaya, M. A. Bogacheva, S. V. Lomteva, V. N. Prokof’ev and E. P. Gus’kov
Year:
2006
Bibliographic source:
Biology Bulletin, Vol. 33, No. 5, pp. 437-440

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The allantoin content in the forming human placenta and serum of pregnant women was quantified by spectrophotometry.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
other: human
Sex:
female

Administration / exposure

No. of animals per sex per dose:
The material from 72 women was analyzed: blood serum and abortion material (4–12 weeks of pregnancy, 32 patients), placenta in trimester II of pregnancy (15 patients with social abortion), and full-term placenta (25 patients).

Results and discussion

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Allantoin level was shown to remain nearly unaltered in placental homogenates during the whole physiological pregnancy except for an small but significant increase in weeks 7–8 (Table 1). The significant increase in allantoin level in the placenta in weeks 7–8 of pregnancy was felt to confirm the study authors' proposal on the induction of allantoin synthesis in embryonic tissues. It was stated by the authors that since weeks 6–8 represent the period of the first wave of cytotrophoblast invasion into endometrium accompanied by active proliferative processes, allantoin can be somehow involved in these events.

Table 1. Allantoin content in placental homogenates in the course of physiological pregnancy

Pregnancy term Allantoin, μmol/g protein
Weeks 4 - 6 (n = 11) 5.43 +/- 0.16
Weeks 7 - 8 (n = 14) 6.02 +/- 0.20*
Weeks 9 - 12 (n = 5) 5.37 +/- 0.19
Trimester II (n = 15) 5.01 +/- 0.34
Trimester III (n = 10) 5.23 +/- 0.30

* As compared to weeks 4 -6, p<0.05

Allantoin quantification in the serum of pregnant women demonstrated a different time-related pattern during pregnancy (Table 2). Serum allantoin level in pregnant women was three times that in nonpregnant ones and demonstrated no changes in trimester I. In trimester II, serum allantoin level significantly increased to peak in week 15 of pregnancy. In trimester III, allantoin concentrations considerably decreased and approached those observed in men and nonpregnant women. No definite conclusion on the origin of allantoin detected in the serum during pregnancy can be drawn currently; however, the study authors believe that the considerable accumulation of allantoin in the serum of pregnant women can be attributed to its fetal origin. It is believed that uricase is most active during this period and uricase-produced allantoin, which has anabolic, antioxidant, and antimutagen effects provides for active fetal growth observed in trimester II as well as for fetus protection from pathogens.

Table 2. Allantoin content and luminescence indices in the serum of pregnant women

Pregnancy term, weeks Allantoin, μmol/l H, mm Sm
Nonpregnant 4.75 +/- 0.40 23.30 +/- 2.8 83.8 +/- 8.0
6 13.30 +/- 0.75* 66.00 +/- 7.90* 150 +/- 27*
8 12.00 +/- 0.30* 52.80 +/- 7.10* 86.9 +/- 14.8
10 11.50 +/- 0.63* 56.90 +/- 5.18* 128 +/- 19*
13 18.5 +/- 7.15 33.20 +/- 4.40 47.4 +/- 8.9*
15 38.01 +/- 0.95*
17 22.20 +/- 0.95*
28 3.41 +/- 2.10
37-40 6.14 +/- 1.70

Note: H, fast burst height; Sm, light sum within 100 s luminescence.

* As compared to nonpregnant women, p < 0.01

Allantoin level decreased in the placental homogenates and serum of mothers with chronic placental insufficiency (Table 3). A trend to decreased allantoin level in the tissue was observed, which agrees with the data on allantoin as a marker of oxidative stress, since the pathological processes underlying placental insufficiency are accompanied by oxidative stress development in the placental tissues. In addition, increased uric acid levels were detected in the placental tissues in developing placental insufficiency. Thus, excessive uric acid is accumulated in the placental tissues in placental insufficiency, which makes possible its nonenzyme oxidation (oxidative stress), while the allantoin level decreases.

Conversely, allantoin level in the serum increases in abnormal pregnancy, which agrees with the common notion of oxidative stress in placental insufficiency and confirms a compensatory response of the mother’s body towards fetus preservation.

Table 3. Allantoin levels in placenta during abnormal pregnancy

Group Allantoin
Physiological pregnancy (placenta) 5.23 +/- 0.30 μmol/g protein
Placental insufficiency (placenta) 4.42 +/- 0.65 μmol/g protein
Physiological pregnancy (serum) 6.14 +/- 1.70 μmol/l
Placental insufficiency (serum) 13.9 +/- 2.1 μmol/l*

* Difference from physiological pregnancy significant at p < 0.05

Applicant's summary and conclusion