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Administrative data

Description of key information

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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Study according to accepted scientific standard, limited number of endpoints considered; documentation insufficient for assessment, but toxicokinetic data given in detail (see Basic toxicokinetics)
Reference:
Composition 1
Qualifier:
no guideline followed
Principles of method if other than guideline:
90 d repeated dose toxicity study with daily doses at three levels. This study was part of a comprehensive testing programme on pharmacodynamics and toxicology of a MIPB isomer.
GLP compliance:
no
Limit test:
no
Test material information:
Composition 1
Species:
other: no definite data, probably rats
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
no data
Route of administration:
oral: unspecified
Vehicle:
not specified
Details on oral exposure:
no data
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
90 d
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
200 mg/kg bw/day
Basis:
no data
Remarks:
Doses / Concentrations:
400 mg/kg bw/day
Basis:
no data
Remarks:
Doses / Concentrations:
200 mg/kg bw/day (may be an reporting error: supposed to be >400 mg/kg bw/d)
Basis:

No. of animals per sex per dose:
no data
Control animals:
not specified
Positive control:
no
Observations and examinations performed and frequency:
no data
Sacrifice and pathology:
no data
Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Details on results:
no data
Dose descriptor:
NOAEL
Remarks:
(assumed: see explanation below)
Effect level:
200 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
not specified
Basis for effect level:
other: nephrotoxicity
Critical effects observed:
not specified

High dose (not explicitely specified but probably above 200 mg/kg bw/day) gave rise to nephrotoxicity, the formation of renal lesions, and the presence of small calculi in the renal pelvis and bladder. Histologically, interstitial nephritis and papillary atrophy, oedema, degeneration and necroses were detected.

The renal pelvis, ureters and bladder contained concretions that ranged from amorphous chalky material in the pelvis of some animals to bladder stones in others. From collected calculi which were resistant to enzymatic hydrolysis but not to 6 M HCl, the biphenyl derivative of methylglycolic acid could be isolated, a metabolite of isopropylbiphenyl. Its calcium salt is insufficiently soluble to be readily excreted into the urine. It tends to become sequestered in a crystalline state in the renal tubules over time thereby producing renal toxicity. Renal toxicity of isopropylbiphenyl may especially be evident in species which predominantly form 2-biphenyl methylglycolic acid (2 -biphenyl lactic acid) as major metabolite.

Conclusions:
Only one key aspect, potential nephrotoxicity, was addressed: The limited information available does not enable one to draw robust conclusions about the toxicity profile of 4-IPB or the target compound, MIPN isomer mixture. However, in synopsis with the results from species-specific metabolic studies, the authorsĀ“ conclusion about that nephrotoxicity would be unlikely to develop in humans is taken for granted (see Toxicokinetics).
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
limited, but reviewing the link between metabolism and toxic effect (see more details Basic toxikokinetics 7.1.1).
System:
urinary
Organ:
kidney

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

Mode of Action Analysis / Human Relevance Framework

Additional information

Comprehensive results from long-term toxicity testing are not accessible. In a pharmacological test programme, one key endpoint for a relevant constituent in MIPB isomer mixture had been identified, potential nephrotoxicity. The limited information available does not enable one to draw robust conclusions about the toxicity profile of 4-IPB or the target compound, MIPB isomer mixture. However, in synopsis with the results from species-specific metabolic studies, the authorsĀ“ conclusion about that nephrotoxicity would be unlikely to develop in humans is taken for granted (see Toxicokinetics).


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Only relevant publication on an MIPB component, NOAEL defined in study is provisional

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: kidneys

Justification for classification or non-classification

Based on the current data, no classification for specific organ toxicity (STOT) is required.