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Administrative data

Description of key information

Short-term repeat oral toxicity studies were conducted on four substances in the MDI category: A mixture of: 3,3'-dicyclohexyl-1,1'-methylenebis(4,1-phenylene)diurea; 3-cyclohexyl-1-(4-(4-(3-octadecylureido)benzyl)phenyl)urea; 3,3'-dioctadecyl-1,1'-methylenebis (4,1-phenylene)diurea (EC 406-530-2), 3,3'-dioctadecyl-1,1'- methylenebis(4,1-phenylene)diurea (EC 406-690-3), N,N''-(methylenedi-4,1-phenylene)bis[N'-octyl]urea (EC 445-760-8), 3,3'-dicyclohexyl-1,1'-methylenebis(4,1-phenylene)diurea (EC 406-370-3), N,N''-(methylenedi- 4,1-phenylene)bis[N'-octyl]urea (EC 451-060-3). All studies were conducted over 28 days with 7 days/week dosing at three concentrations up to 1000 mg/kg bw/day. In the studies conducted on 3,3'-dioctadecyl-1,1'- methylenebis(4,1- phenylene)diurea (EC 406-690-3), A mixture of: 3,3'-dicyclohexyl-1,1'-methylenebis(4,1-phenylene)diurea; 3-cyclohexyl-1- (4-(4-(3-octadecylureido)benzyl) phenyl)urea; 3,3'-dioctadecyl-1,1'-methylenebis(4,1-phenylene)diurea (EC 406-530-2) and 3,3'-dicyclohexyl-1,1'-methylenebis(4,1-phenylene)diurea (EC 406-370-3), no treatment related findings were observed at any of the nominal concentrations tested and, therefore, the NOAEL and NOEL were determined to be 1000 mg/kg/b.w. day. In the study conducted on N,N''-(methylenedi-4,1-phenylene)bis[N'-octyl]urea (EC 445-760-8),, no treatment related findings were observed at any of the nominal concentrations tested, except for a slight slowing of body weight gain in males treated at a dose of 1000 mg/kg bw/day. Non-treatment related findings of increase in serum sodium and chloride levels in males treated with 450 and 1000 mg/kg/day and increased potassium in females at 1000 mg/kg/d were observed. Therefore, the substance was clinically well-tolerated at all doses tested and no significant variation / observation was noted in organ weights and macroscopic examination. The NOAEL and NOEL were determined to be 450 and 150 mg/kg b.w./day, respectively. All tests concluded that no classification is required.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
This study is included in a NONS registration and therefore has been evaluated by a relevant competent authority and is considered to be reliable.
Qualifier:
according to guideline
Guideline:
OECD Guideline 424 (Neurotoxicity Study in Rodents)
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
methylcellulose
Remarks:
Aqueous solution of methylcellulose 0.5%.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Test duration: 28 days
Frequency of treatment:
Dosing regime: 7 days/week
Dose / conc.:
150 mg/kg bw/day (nominal)
Dose / conc.:
450 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5 male and 5 females per doses
Control animals:
yes
Details on study design:
The doses were chosen on the basis of the results of a preliminary oral study carried out for 7 days in rats, in which the animals were treated with doses of 150, 450 and 1000 mg / kg / day.
Positive control:
None reported
Observations and examinations performed and frequency:
Not reported
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
A slight slowing of body weight gain is noted in males treated at a dose of 1000 mg / kg / day.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
No toxicologically significant changes were noted for any of the parameters.
Blood biochemistry : Non-dose dependent increase in sodium and chlorine in males treated with 450 and 1000 mg/kg/day. Increased potassium in females at 1000 mg/kg/d
The toxicological significance of these minor abnormalities is questionable.
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No significant difference was noted between control and treated animals.
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Dose descriptor:
NOAEL
Effect level:
450 mg/kg bw/day (nominal)
Based on:
other: nominal
Sex:
male/female
Remarks on result:
other: original NCD unit is mg/kg/day
Dose descriptor:
NOEL
Effect level:
150 mg/kg bw/day (nominal)
Based on:
other: nominal
Sex:
male/female
Remarks on result:
other: original NCD unit is mg/kg/day
Critical effects observed:
no

The substance was clinically well-tolerated at all doses tested and no significant variation / observation was noted in organ weights and macroscopic examination.

Conclusions:
No treatment related findings were observed at any of the nominal concentrations tested, except for a slight slowing of body weight gain noted in males treated at a dose of 1000 mg/kg/day. A non-treatment related finding of an increase in sodium and chlorine in males treated with 450 and 1000 mg/kg/day and increased potassium in females at 1000 mg/kg/d was also noted. Therefore, the substance was clinically well-tolerated at all doses tested and no significant variations or observations were noted in organ weights or macroscopic examinations. The NOAEL and NOEL were determined to be 450 and 150 mg/kg b.w./day, respectively.
Executive summary:

The test item was investigated for repeated dose oral toxicity to male and female Sprague Dawley rats at nominal concentrations of 150, 450 and 1000 mg/kg/b.w. day over 28 days with dosing 7 days / week. The study followed the standard guidelines OECD 424 and EU method B7. No treatment related findings were observed at any of the nominal concentrations tested, except for a slight slowing of body weight gain noted in males treated at a dose of 1000 mg/kg/day. A non-treatment related finding of an increase in sodium and chlorine in males treated with 450 and 1000 mg/kg/day and increased potassium in females at 1000 mg/kg/d was also noted. Therefore, the substance was clinically well-tolerated at all doses tested and no significant variations or observations were noted in organ weights or macroscopic examinations. The NOAEL and NOEL were determined to be 450 and 150 mg/kg b.w./day, respectively.

The study is a GLP compliant, guideline study and is suitable for assessment of this endpoint with restrictions.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
450 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Guideline studies conducted according to GLP

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

Justification for classification or non-classification

Four studies were conducted on MDI category members and all studies concluded that the test items should not be classified.