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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
repeated dose toxicity: oral, other
Remarks:
Combined repeated dose repro-devp. Screen
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is from NTRL report

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2006
Report date:
2006

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
Combined repeated dose repro-developmental toxicity study was performed to determine the toxic nature of Methylamine hydrochloride upon repeated administration by oral route.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Methylammonium chloride
EC Number:
209-795-0
EC Name:
Methylammonium chloride
Cas Number:
593-51-1
Molecular formula:
CH5N.ClH
IUPAC Name:
methanamine
Constituent 2
Reference substance name:
Methylamine hydrochloride
IUPAC Name:
Methylamine hydrochloride
Details on test material:
- Name of test material (as cited in study report): Methylamine hydrochloride
- Molecular formula (if other than submission substance): CH5N.Cl H

- Molecular weight (if other than submission substance): 67.5184 g/mol
- Substance type: Organic
- Physical state:
Purity No data available.
Specific details on test material used for the study:
- Name of test material: Methylamine hydrochloride (MAH)
- IUPAC name: Methanaminium chloride
- Molecular formula: CH5NClH
- Molecular weight: 67.5184 g/mol
- Substance type: Organic
- Physical state: No data
- Purity: No data
- Impurities (identity and concentrations): No data

Test animals

Species:
rat
Strain:
not specified
Details on species / strain selection:
No data
Sex:
male/female
Details on test animals or test system and environmental conditions:
No data

Administration / exposure

Route of administration:
oral: gavage
Details on route of administration:
No data
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The chemical was dissolved in water to give a dose range of 0, 250, 500 or 1000 mg/Kg bw

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data

VEHICLE
- Justification for use and choice of vehicle (if other than water): Water
- Concentration in vehicle: 0, 250, 500, or 1000 mg/kg/day
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
Total: 110 days
Premating period -71 days
Mating period-14 days
Gestation period-21 days
Postpartum day -4
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
0, 250, 500, or 1000 mg/kg/day
No. of animals per sex per dose:
Total no of animals-96
0 mg/kg/day - 12 male and 12 female
250 mg/kg/day- 12 male and 12 female
500 mg/kg/day- 12 male and 12 female
1000 mg/kg/day- 12 male and 12 female
Control animals:
yes, concurrent vehicle
Details on study design:
No data
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Not specified
- Time schedule: Not specified
- Cage side observations checked in table [No.?] were included. Not specified

DETAILED CLINICAL OBSERVATIONS: Not specified
- Time schedule: Not specified

BODY WEIGHT: Yes
- Time schedule for examinations: Not specified

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not specified

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Not specified

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Not specified
- Time schedule for examinations: Not specified

OPHTHALMOSCOPIC EXAMINATION: Not specified
- Time schedule for examinations: Not specified
- Dose groups that were examined: Not specified

HAEMATOLOGY: Not specified
- Time schedule for collection of blood: Not specified
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: Not specified
- Parameters checked in table [No.?] were examined. Not specified

CLINICAL CHEMISTRY: Not specified
- Time schedule for collection of blood: Not specified
- Animals fasted: Not specified
- How many animals: Not specified
- Parameters checked in table [No.?] were examined. Not specified

URINALYSIS: Not specified
- Time schedule for collection of urine: Not specified
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Not specified
- Parameters checked in table [No.?] were examined. Not specified

NEUROBEHAVIOURAL EXAMINATION: Not specified
- Time schedule for examinations: Not specified
- Dose groups that were examined: Not specified
- Battery of functions tested: sensory activity / grip strength / motor activity / other: Not specified

IMMUNOLOGY: Not specified
- Time schedule for examinations: Not specified
- How many animals: Not specified
- Dose groups that were examined: Not specified
- Parameters checked in table [No.?] were examined. Not specified

OTHER: Not specified
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, Gross pathological examination was performed at terminal sacrifice.

HISTOPATHOLOGY: Yes, Uterine implantation sites and ovarian corpora lutea were counted in P1 females. A histological examination of all tissues saved was conducted for all animals in the control and 1000 mg/kg/day group. Tissue examination in the other groups was limited to relevant gross lesions and tissues demonstrating treatment-related histological effects at 1000 mg/kg/day.
Other examinations:
No data
Statistics:
Standard Deviation

Results and discussion

Results of examinations

Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
Clinical signs and mortality: No data available

Body weight and weight gain: Significant reductions in body weight in P1

Animals was observed at 1000 mg/kg/day. Weight gain of pregnant females was less for the high-dose group (1000 mg /k g/day) from gestational day 1 to day 7 (87.5% of control) but similar to the other groups at intervals after gestational day 7.

Food consumption and compound intake: Significant reductions in food consumption parameters in P1 animals at 1000 mg/Kg day.

Food efficiency: No data available

Water consumption and compound intake: No data available

Opthalmoscopic examination: No data available

Haematology: No data available

Clinical chemistry: No data available

Urinanalysis: No data available

Neurobehaviour: No data available

Organ weights: No data available

Gross pathology: Significantly reduced corpora lutea counts and subsequently lower implantation site counts and litter sizes at 1000 mg/kg/day was observed

Histopathology: No data available

Effect levels

Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant change was observed in body weight, food consumption, corpora lutea counts, implantation site counts and litter sizes.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The No Observed Adverse Effect Level (NOAEL) is considered to be 500 mg/kg/day for Methylamine hydrochloride in male and female rats by oral gavage.
Executive summary:

Combined repeated dose repro-developmental toxicity study was performed (NTRL, 2006) to determine the toxic nature of Methylamine hydrochloride ( IUPAC name: Methanaminium chloride) upon repeated administration by oral route. Groups of 12 rats of each sex per dose level were dosed with methylamine hydrochloride in water once daily by gavage at dose levels of 0, 250, 500, or 1000 mg/kg/day. Following a 71-day premating period, P1 males and females were co-housed for up to 2 weeks within their respective treatment groups to produce F1 litters. Dams were allowed to deliver and rear their offspring until postpartum day 4.  All P1 rats were given a gross pathological examination at terminal sacrifice. Uterine implantation sites and ovarian corpora lutea were counted in PI females. A histological examination of all tissues saved was conducted for all animals in the control and 1000 mg /kg /day group. Tissue examination in the other groups was limited to relevant gross lesions and tissues demonstrating treatment-related histological effects at 1000 mg/kg/day. Significant changes in body weight and food consumtion were observed at 1000 mg/kg/day. Significantly reduced corpora lutea counts and subsequently lower implantation site counts and litter sizes at 1000 mg/kg/day was observed. No significant changes were observed at 0, 250, or 500 mg/kg/day. The No Observed Adverse Effect Level (NOAEL) is considered to be 500 mg/kg/day for Methylamine hydrochloride in male and female rats by oral gavage.