Morpholinium sulphamate

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

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: Study with a structur analogous substance. For read-across justification please refer to IUCLID section 13.

Data source

Reference

Reference Type:

publication

Title:

Toxicological studies of ammonium sulfamate in rat after repeated oral administration

Author:

Gupta, B.N., Khanna, R.N., Datta, K.K.

Year:

1979

Bibliographic source:

Toxicology, 13, 45-49

Materials and methods

Principles of method if other than guideline:

90-day oral administration of the test item

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ammonium sulphamidate

EC Number:

231-871-7

EC Name:

Ammonium sulphamidate

Cas Number:

7773-06-0

Molecular formula:

H3NO3S.H3N

IUPAC Name:

ammonium sulfamate

Constituent 2

Reference substance name:

Ammonium sulphamate

EC Number:

237-372-0

EC Name:

Ammonium sulphamate

Cas Number:

13765-36-1

Molecular formula:

H3NO3S.xH3N

IUPAC Name:

ammonium sulfamate

Test material form:

solid: crystalline

Details on test material:

- Name of test material (as cited in study report): Ammonium sulfamate
- Molecular formula: H6N2O3S
- Molecular weight: 114.125 g/mol
- Smiles notation: [O-]S(=O)(=O)N.[NH4+]
- InChl: 1S/H3NO3S.H3N/c1-5(2,3)4;/h(H3,1,2,3,4);1H3
- Substance type: salt formed from ammonia and sulfamic acid
- Physical state: chrystalline
- Analytical purity: 99 %
- Impurities: moisture: 0.5 %, iron: 100 ppm
- Solubility: extremely soluble in water and moderatly soluble in glycerol, glycol and formamide

Test animals

Species:

rat

Strain:

not specified

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: ITRC animal house colony
- Weight at study initiation: 170-200 g
- Housing: 2 animals per cage
- Diet: Standard diet ad libitum
- Water: Tap water ad libitum

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Details on oral exposure:

VEHICLE
- Justification for use and choice of vehicle: water
- Concentration in vehicle: 100 mg/mL in distilled water

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

90 days

Frequency of treatment:

Once a day

Doses / concentrations

Remarks:

Doses / Concentrations:
100, 250, 500 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

20

Control animals:

yes, concurrent vehicle

Details on study design:

- Post-exposure recovery period in satellite groups: 30, 60 and 90 day post feeding
- Section schedule: 6 rats of each dose group on day 30, 60 and 90 post feeding

Positive control:

none

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: twice weekly during the first two month and once a week in the third month

FOOD CONSUMPTION: Yes
- Time schedule for examinations: prior to weighing: twice weekly during the first two month and once a week in the third month

WATER CONSUMPTION: Yes
- Time schedule for examinations: prior to weighing: twice weekly during the first two month and once a week in the third month

HAEMATOLOGY: Yes
- Time schedule for collection of blood: on day of sacrifice
- Anaesthetic used for blood collection: Yes, anaesthetic ether
- Animals fasted: No data
- How many animals: all animals
- Parameters checked: hemoglobine concentration, packe dcell volume, total red cell count, total and differential white cell counts.

CLINICAL CHEMISTRY: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, of heart, liver, stomach, spleen, kidneys, thyroid, adrenal glands, gonads, intestine, lung, lymph nodes
HISTOPATHOLOGY: Yes, of heart, liver, stomach, spleen, kidneys, thyroid, adrenal glands, gonads, intestine, lung, lymph nodes

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

lesser weight gain in group 4 (500 mg/kg bw/day)

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Description (incidence and severity):

water consumption increased generally in all groups. weanlings in group 4 (500 mg/kg bw/day), both male and female, consumed significantly more than controls

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

non-significant increase in the neutrophils in the adults and male weanling rats in group 4 (500 mg/kg bw/day)

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

liver of 1 rat in group 4 (500 mg/kg bw/day) showed slight fatty degerative changes in the hepatic cytoplasm after 90 days

Histopathological findings: neoplastic:

not examined

Details on results:

Throughout the test period, the general condition and health of all rats appeared good. However, one rat each from the adult (group 3) and one male weanling (group 4) died on day 64 and day 76 of the experiment, repsectively, due to bronchopneumonia.
No significant difference in mean body weight. Food intake relative to body weight gradually decreased in all groups of rats during the study, with no significant difference in case of adults. Food intake was significantly less (P<0.05) by the weanlings in group 4 (500 mg/kg bw/day). Adult rats of group 4 began to lag behind in weight gain after 45-day period. By end of the study period, the body weight of group 4 was significantly (P<0.05) less than the weight of controls. The weanlings of group 4, both males and females) consumed significantly (P<0.01) more water than the controls. Although there was no difference in food or water intage by group 4, this group showed lesser weight gain compared with all other groups.

Effect levels

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No adverse effects observed.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

The authors note that increase in water intake along with decrease in food intake relative to body weight without any change in the growth rate of the weanlings in group 4 (500 mg/kg bw/day), may be as a result of changes in the acid-base balance in the organisms resulting from the exposure to ammonium sulfamate. The authors anticpate that ammonium sulfamate readily dissociates in the body to form the ammonium and sulfamic acid ions.

Applicant's summary and conclusion

Conclusions:

A NOAEL of 500 mg/kg bw/day appears appropriate given the differences observed between groups.

Executive summary:

A 90-day study on adult female rats and male/female weanlings was conduced with dosing (via water) at 0 (group 1), 100 (group 2), 250 (group 3) and 500 mg/kg (group 4) of ammonium sulfamate 6 days a week. No adverse effect was observed regarding appearance, behaviour or survival of animals. In the case of adult rats (group 4), the body weight was significantly less than the controls after the end of 60 days. No significant change in relative organ weights were observed. Haematological examination conducted revealed non-significant increase in the neutrophils in the adults and male weanling rats (group 4) after 90 days. Histological examination found the liver of 1 rat in adults (group 4) to have slight fatty degenerative changes after 90 days.