(1-methylethyl)-1,1'-biphenyl

Endpoint summary

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)

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

Species:

other: no definite data, probably rats

Strain:

not specified

Sex:

not specified

Details on test animals or test system 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 authors´ 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

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 authors´ 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.