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Administrative data

Description of key information

 In the 90 days repeated dose oral toxicity test [Anon. (1993)], the NOAEL (dietary, rat, 90 days) was considered to be 19 mg/kg bw/day. In the OECD combined repeated dose and reproductive/developmental toxicity screening test [Anon. (1997)], the NOAEL (gavage, rat, male 49 days, female 39-53 days) was considered to be 20  mg/kg bw/day.  From the data of these two studies, the lower NOAEL for repeated dose toxicity is 19 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was performed according to OECD guideline study with GLP compliance.
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
The males weighed 185 to 238 g and the females weighed 145 to 192 g and were five to six week old.
environmental conditions were continuously monitored by a computerised system. Room temperature (20- 24 °C) and humidities (29 - 78 %) were included in the study report.
Route of administration:
oral: feed
Vehicle:
other: none
Details on oral exposure:
type of exposure: oral
post exposure period: none
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
Dietary concentration (ppm): 0.0, 25, 250,2000
Basis:

No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
Post-exposure period: none
Positive control:
none
Observations and examinations performed and frequency:
Clinic signs:
All animals were examined for overt signs of toxicity, ill-health or behavioural change once daily.

Bodyweight: Individual bodyweights were recorded on day 0 and at weekly intervals therafter.

Food consumption: Food consumption was recorded for each cage group at weekly intervals.

Water consumption: Water consumption was observed daily for each cage group.

Opthalmoscopic Examination: The eyes of all control and high dose animals were examined before admistration of hte test and control diets and before termination of treatment (during 12 weeks)

Haematolgy: Haematolgy were preformed at the end of the study.


Sacrifice and pathology:
Pathology: All animals were subjected to a full external and internal examination.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
high dose animals of either sex showed a substantially lower gain in body-weight than control during the treatment.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The food intake of high dose animals was lower than that of controls during the treatment period, although females appeard less adversely affected than males
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No treatment-related ocular were detected
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
no toxicologically significants changes were detected
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
High dose females showed a statistically significant increase in liver weight, relative to body weight, compared with controls. Absolute liver weights were also increased for these animals although statistical significants was not achieved.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
several high dose animals of either sex showed pale adrenals and/or a darkened liver at terminal kill
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Treatment related morphological changes were observed in the liver, spleen , kidneys, pancrease and adrenal glands.
Histopathological findings: neoplastic:
no effects observed
Details on results:
ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX
- number of deaths at each dose: no deaths during the study
TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:
- body weight gain: High dose animals of either sex showed a
substantially lower gain in bodyweight than control during the treatment
period.
- food / water consumption: High dose animales of either was lower than
that of controls during the treatment period, although females appeared
less adversely less advercely affected than males.
- ophthalmoscopic examination: No treatment-related ocular were detected.
- clinical chemistry: High dose animals of either sex showed a slight but
statistically significant increase in plasm alanine aminotransferase and
bilirubin levels compare with controles. Plasma sodium concentration was
also reduced in high dose males, although this was considered to be of
dubious toxicological significance in the absense of a concurrent effect on
plasma chloride. Intermediate and low dose animals showed no
treatment-ralated changes.
- haematology: No toxicologically significant change were detected.
- organ weights: High dose females showed a statistically significant
increase in liver weight, relative to body weight compared with controles.
Absolute liver weights were also increased for these animals although
statistical significance was not achieved. A possible treatment-related
increase in relative liver and adrenal weight was also identified for high
dose males. Intemediate and low dose animals showed not reatment-
related organ weight changes.
- gross pathology:
- histopathology: Treatment-related morphological changes were
observed in the liver,spleen, kidney, pancreas and adrenal glands. High
dose animals showed centrilobular hepatocyte enlargement, an increased
severity of splenic extramedullaly haemopiesis, hypertrophy and
vacuolation of adrenal zona glomerulosa cells together with associated
inflammatory cell infiltrates. An increased severity and/or incidence of
haemosiderin pigmnent accumulation was also observed in both the
kidneys and the spleen of high dose animals of either sex. At the
intermediate dose level, the sole treatment-related change was confined to
males and identified as an increase in the severity of hemosiderin pigment
accumulation in the spleen.
No treatment-related morphological changes were observed either for
intermediate dose females or for low dose animals of either sex.
- other: several high dose aimals of either sex showed pale adrenals and
/or a darkened liver at terminal kill whilst two of the females also had pale
kidneys. Intermediate and low dose animals showed no treatment- related
changes.
Key result
Dose descriptor:
NOAEL
Effect level:
19 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
food consumption and compound intake
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
Critical effects observed:
not specified

Histopathological findings

Summary incidence of spleen

 Animals  Findings           Dose group (mg/kg/day)
     control 1,9   19  173
 Male  Extramedullary haemopoiesis        
   (minimal) 6 8 5
   (slight)   4  2
   (moderate)   0  0
   Pigment deposition        
   (minimal)  1  0
   (slight)  9  0
   (moderate)  0 10 
   (marked)  0
           
 Female  Extramedullary haemopoiesis        
   (minimal)  9
   (slight)  1
   (moderate)  0
   Pigment deposition        
   (minimal)  0  2  0  0
   (slight)  5
   (moderate)  5
   (marked)  0 0

 
Conclusions:
Benzoguanamine has a NOAEL of 19 mg/kg bw for the 90 days repeated dose toxicity.
Executive summary:

In the 90-day feeding study of rats at 0,1.9,19.0 and 173.0 mg/kg/day [OECD], the body weight gain was decreased in the high dose group. Inthe histopathological examination, centrilobular hepatocyte enlargement, an increased severity of extramedullary hemopoiesis in the spleen and hemosiderin pigment accumulation in the kidney and the spleen, hypertrophy and vacuolation of adrenal zona glomerulosa cells, and degeneration of pancreatic exocrine cells together with associated inflammatory cell infiltrates were observed in the high dose group. At the mid dose, the severity of hemosiderin pigment accumulation in the spleen was also increased moderately in males. This change in the spleen was considered not to be adverse effects because no other changes were observed at this dose level. Therefore, the NOAEL in the study was considered to be 19 mg/kg/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
19 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The study is a GLP compliant and has Klimisch score 1.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

 Item  Result  Test method  Reference
 Rat 90 days  NOAEL = 19 mg/kg bw/day  OECD TG 408 Anon 1993
 Rat male 49 days, Female 39 -53 days   NOAEL = 20 mg/kg bw/day  OECD TG 422 (Gavage) Izumi 1997


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The study was preformed according to OECD guideline study with Klimisch Score 1.

Justification for classification or non-classification

The presented data for repeated dose toxicity are reliable and adequate guideline studies. The observations within the studies are conclusive but not sufficient for a classification.