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Toxicological information

Repeated dose toxicity: oral

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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:
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)

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1978

Materials and methods

Test guideline
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

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): (4-)isopropylbiphenyl
- no further information

Test animals

Species:
other: no definite data, probably rats
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
no data

Administration / exposure

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
Doses / concentrationsopen allclose all
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

Examinations

Observations and examinations performed and frequency:
no data
Sacrifice and pathology:
no data

Results and discussion

Results of examinations

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

Effect levels

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

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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 authors´ conclusion about that nephrotoxicity would be unlikely to develop in humans is taken for granted (see Toxicokinetics).