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Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read-across data (CAS 19767-45-4) found via OECD QSAR Toolbox. The publication is well documented and meets basic scientific principles.
Cross-reference
Reason / purpose:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
other: predcition by the OECD QSAR Toolbox
Title:
Unnamed
Year:
2012
Report Date:
2012
Reference Type:
publication
Title:
Delay of bladder cancer induction in rats treated with N-Nitroso-N-Butyl-N- (4-hydroxybutyl)amine by administration of sodium-2-mercaptoethanesulfonate (MESNA).
Author:
Tacchi, A.M., Schmaehl, D., Habs, M.
Year:
1984
Bibliographic source:
Cancer Letters, 22 (1984), pp.89-94.

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
not specified
Principles of method if other than guideline:
92 male Sprague-Dawley rats, 8 weeks old, were divided into two groups. Group A received 70 mg/kg N-nitroso-N-butyl-N-(4-hydroxybutyl)amine (BBNOH) twice a week by gavage, whereas to Group B, BBNOH was administered at the same dose level together with 350 mg/kg Mesna given 5 times a week in drinking water. Two control groups of 40 animals each were given Mesna alone or were totally untreated.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: solution in water
Details on test material:
Target substance:
SMILES: C(S)CCS(=O)(=O)O{-}.[Na]{+}

Read-across substance:
SMILES: C(S)CS(=O)(=O)O{-}.[Na]{+}

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Süddeutsche Versuchstierfarm, Tuttlingen, F.R.G
- Age at study initiation: 8 weeks
- Weight at study initiation: no data (the weight was checked regularly during the entire period of the treatment).
- Housing: 2 per cage
- Diet (e.g. ad libitum): Altrominm pellets diet; ad libitum
- Water (e.g. ad libitum): tap water; ad libitum

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: 20 mL Mesna solutions were given to rats 5 days a week.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
39 weeks
Frequency of treatment:
5 times a week
Doses / concentrations
Remarks:
Doses / Concentrations:
350 mg/kg bw
Basis:
nominal in water
No. of animals per sex per dose:
40
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: The high dose of Mesna was chosen in order to provide an excess amount that could interfere with the metabolites of BBNOH in the urinary bladder.
Positive control:
N-nitroso-N-butyl-N-(4-hydroxybutyl)amine (BBNOH) alone.

Examinations

Observations and examinations performed and frequency:
The body weight was checked regularly during the entire period of the treatment.
Sacrifice and pathology:
At the end of the treatment animals were observed for life, with the exception of a few that were killed when moribund. After dissection, urinary bladders and all other organs showing macroscopical alterations were collected for histological examination.
Statistics:
Kaplan-Meier method.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
No significant differences were observed in the animals of the 4 experimental groups from a general point of view. Control animals did not show any pathological alteration at the end of the experiment. There were no signs of toxicity in the animals that received Mesna alone. A statistically significant increase of the lifespan of the Mesna treated animals was observed (P< 0.05).

BODY WEIGHT AND WEIGHT GAIN
Administration of Mesna did not have a significant effect on the weight; an increase in body weight was observed at the beginning of the treatment, up to the eighteenth week, followed by a slight decrease and a steady phase at the end of the experiment. Values ranged between 300 g and 500 g for all experimental groups.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
Mesna solutions were completely consumed within 24 h from the time of administration. The total Mesna consumption was 63.35 g/kg.

GROSS PATHOLOGY
No findings.

HISTOPATHOLOGY: NON-NEOPLASTIC
No findings.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
No findings.

Effect levels

Dose descriptor:
NOAEL
Effect level:
350 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The nearest analogue mesna was not carcinogenic in a two-year carcinogenicity study in rats. 350 mg/kg bw, which rats received daily during the exposure period of 39 weeks, can be considered as NOAEL since no clinical signs of toxicity and no findings of necropsy were noted in treated animals.
Executive summary:

Mesna is known as a cytoprotective agent that helps to prevent haemorrhagic cystitis caused by a widely used class of antineoplastic drugs, comprising cyclophosphamide, ifosfamide, and trofosfamide (Tacchi et al., 1984). A direct chemical interaction between Mesna and the active metabolites of antineoplastic drugs is supposed to be involved in the protective effects on the urinary bladder. In this respect, the influence of mesna on urinary bladder cancer induced by N-nitroso-N-butyl-N-(4 hydroxybutyl)amine (BBNOH) was studied in male Sprague-Dawley rats.
The treatment consisted of the administration of BBNOH alone per gavage, BBNOH with Mesna, Mesna alone and untreated control. The health effects in treated animals receiving Mesna alone is relevant for this endpoint. The group of 40 male animals (8-week old) received 350 mg/kg bw (total Mesna consumption was 63 g/kg bw (mean for all animals)) in drinking water over a period of 39 weeks. The rats received daily the dose in 20 mL water solution 5 days a week. Health condition of the animals and their body weights were checked regularly during the entire period of the treatment. At the end of the treatment animals were killed and dissected and urinary bladders and all other organs showing macroscopical alterations were collected for histological examination.
No significant differences were observed in the animals of the 4 experimental groups from a general point of view. Mesna solutions were completely consumed within 24 h from the time of administration. Administration of mesna did not have a significant effect on the weight; an increase in body weight was observed at the beginning of the treatment, up to the eighteenth week, followed by a slight decrease and a steady phase at the end of the experiment. Values ranged between 300 g and 500 g for all experimental groups. Control animals (untreated and receiving mesna alone) did not show any pathological alteration at the end of the experiment and there were no signs of toxicity. A statistically significant increase of the lifespan of the mesna treated animals was observed (P< 0.05).
There were no findings at necropsy.
As no toxicological findings were observed in animals treated with mesna alone, 350 mg/kg bw can be considered as chronic NOAEL.