Guanidine, N-phenyl-, compd. with carbonic acid, hydrate (2:1:2)

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Jun - Dec 2001

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2001

Report date:

2002

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Version / remarks:

1998

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

(N-phenylcarbamimidoyl)ammonium carbonate

EC Number:

613-106-2

Cas Number:

6291-89-0

IUPAC Name:

(N-phenylcarbamimidoyl)ammonium carbonate

Test animals

Species:

rat

Strain:

other: HanBrl:WIST (SPF)

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

90 days

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

50 ppm

Doses / concentrations 2

Dose / conc.:

300 ppm

Doses / concentrations 3

Dose / conc.:

2 000 ppm

Doses / concentrations 4

Dose / conc.:

8 000 ppm

No. of animals per sex per dose:

10

Control animals:

yes, plain diet

Examinations

Observations and examinations performed and frequency:

- diet analyses and test item intake
- mortality
- functional observational battery
- motor activity
- ophthalmology
- in life observations
- body weight and body weight change
- food consumption
- food utilization efficiency
- water consumption
- hematology
- blood chemistry
- urine analysis
- organ weights

Sacrifice and pathology:

- macroscopic examination
- microscopic examination

Statistics:

Statistical analyses of in-life and organ weight data were carried out using the statistical routines contained in the NOVATOX System.
All statistical tests were two-sided: testing for an overall difference rather than a difference in only one direction.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, non-treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

effects observed, treatment-related

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

effects observed, non-treatment-related

Ophthalmological findings:

effects observed, non-treatment-related

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, non-treatment-related

Behaviour (functional findings):

effects observed, non-treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, non-treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

300 ppm

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

2

Dose descriptor:

NOAEL

Effect level:

17.8 mg/kg bw/day (nominal)

Sex:

male

Basis for effect level:

body weight and weight gain

food consumption and compound intake

3

Dose descriptor:

NOAEL

Effect level:

22.1 mg/kg bw/day (nominal)

Sex:

female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

Applicant's summary and conclusion

Conclusions:

Oral administration of the test substance admixed to the diet for at least 90 days was tolerated in rats and most findings were restricted to the high dose group. At this dose level clinical signs were noted and ≥ 2000 ppm resulted in depression in body weight development and food consumption. Laboratory investigations and histopathological examinations point to the hematopoietic and lymphoreticular system, reproductive system, liver and pancreas as potential target organs. In addition, changes on laboratory parameters indicate disturbance in kidney function. However, some of these alterations may be related to nutritional deficiency. Based on food consumption and body weight, the No-Observable-Adverse-Effect Level (NOAEL) of 300 ppm was defined for both males and females, corresponding to a daily test item intake of 17.8 mg/kg bw/day for males and 22.1 mg/kg bw/day for females.