Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable well documented publication which meets basic scientific principles

Data source

Reference
Reference Type:
publication
Title:
Sodium 2-Mercaptoethane Sulfonate Protection against Cyclophosphamide-Induced Teratogenicity in Rats
Author:
Slott, V.L., Hales, B.F.
Year:
1986
Bibliographic source:
Toxicology and applied pharmacology: 82,80-86 (1986)

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Pregnant Sprague-Dawley rats were divided into nine treatment groups. Individual groups were administered 0.9% NaCl or cyclophosphamide (10 or 15 mg/kg) alone or in combination with MESNA at one of two doses (5 or 30 mg/kg), or MESNA alone on Day 13 of gestation.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: as solution in 0.9 % NaCl
Details on test material:
- Name of test material (as cited in study report): MESNA (in the form of sodium salt)
- Molecular formula (if other than submission substance): C2H5NaO3S2
- Molecular weight (if other than submission substance): 164.18
- Smiles notation (if other than submission substance): C(S)CCS(=O)(=O)O{-}.[Na]{+}
- InChl (if other than submission substance): 1S/C2H6O3S2.Na/c3-7(4,5)2-1-6;/h6H,1-2H2,(H,3,4,5);/q;+1/p-1
- Structural formula attached as image file (if other than submission substance): see Fig.1
- Substance type: organosulphur compound
- Physical state: pulver (Sigma Aldrich)
- Analytical purity: 98%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Canada Inc. (St. Constant, Quebec).
- Weight at study initiation: 225-250 g
- Housing: McIntyra Animal Center (McGill University, Montreal, Quebec)
- Diet (e.g. ad libitum): ad libitum (Purina Rat chow)
- Water (e.g. ad libitum): ad libitum

Administration / exposure

Route of administration:
intravenous
Vehicle:
physiological saline
Details on exposure:
MESNA or 0.9% NaCl was injected intravenously via jugular vein immediately followed by an ip dose of cyclophosphamide or 0.9% NaCl.


Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: purchased timed pregnant
Duration of treatment / exposure:
single injection
Frequency of treatment:
single treatment on day 13 of gestation
Duration of test:
20 Days
Doses / concentrations
Remarks:
Doses / Concentrations:
5 and 30 mg/kg bw
Basis:
nominal conc.
No. of animals per sex per dose:
7 (65 animals were divided into nine treatment groups)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: the MESNA doses of 5 and 30 mg/ kg were chosen to achieve ratios of MESNA to cyclophosphamide on a milligram per kilogram basis of I:3 (5 m/kg MESNA, 15 mg/kg cyclophosphamide; optimal for protection against urotoxicity) and 3: 1 (30 mg/kg MESNA, 10 mg/kg cyclophosphamide).

Examinations

Maternal examinations:
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: not reported
Ovaries and uterine content:
No data
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [all per litter]
- Head examinations: Yes: [all per litter]
Statistics:
Teratogenicity data were analysed with the fetus as the experimental unit by x² test with Yate's correction for discontinuity. The fetal weight data were analysed by one-way analysis of variance. The level of significance for all tests was taken as p<=0.05 unless stated otherwise. These procedures are described by Snedecor and Cochran (1967).
Indices:
No data
Historical control data:
No data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:not examined

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Mesna did not induce teratogenic effects in pups of rats until 30 mg/kg bw.
Executive summary:

The teratogenicity potential of MESNA could be evaluated from the results of a teratogenicity study conducted with cyclophosphamide known anti-cancer drug (Slott and Hales, 1986). The study was designed to determine whether the teratogenic effects of cyclophosphamide and its metabolites could be prevented by MESNA. On day 13 of gestation, pregnant Spague Dawley rats were administered MESNA intravenously at one of two dose levels (5 and 30 mg/kg bw) in combination with cyclophosphamide or alone. Vehicle control group included animals treated with 0.9% NaCl. Rats were killed on day 20 of gestation and fetuses were examined for gross external malformations, fetal body weight, and skeletal defects. The administration of MESNA alone had no significant effects on the incidence of malformations compared to vehicle control (2/62 malformed fetuses in 5 mg/kg bw group and 0/62 malformed fetuses in 30 mg/kg bw dose group). The administartion of MESNA had no sigificant effects on the incidence of dead or resorbed fetuses (similar to vehicle control). No effects of MESNA treatments were observed on fetal body weights. No skeletal malformations were recorded for MESNA treatment groups. MESNA significantly decreased a certain number of fetal malformations induced by cyclophosphamide administration confirming its protective effects against the teratogenic effects of cyclophosphamide.