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Description of key information

Oral (dietary) exposure route:
Five Klimisch 2 studies are available. The NOAEL was based on the 2-year study in male/female rats of Umeda et al. (2002) as this study shows the lowest NOAEL, which is 38 mg/kg bw/d (recalculated from the dietary concentration of 500 ppm). The study was performed according to OECD Guideline 453.
Dermal exposure route:
Only two Klimisch 4 studies were available. Based on these studies, no key NOAEL could be defined.
Inhalation exposure route:
Only one Klimisch 4 study was available. Based on this study, no key NOAEC could be defined.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
38 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
acceptable

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available (further information necessary)
Quality of whole database:
not assignable

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available (further information necessary)

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
subacute
Species:
rabbit
Quality of whole database:
not assignable

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
subacute
Species:
rabbit
Quality of whole database:
not assignable

Additional information

Oral (dietary) exposure route:

In the 2-year study conducted by Umeda et al. (2002), adverse effects were mainly observed in the kidney, both in male and female rats, and in the male urinary bladder where neoplastic lesions (tumours) were observed. The NOAEC was 500 ppm in female rats and 1500 ppm in male rats (concentrations of biphenyl in the diet). It was suggested that bladder tumours in male rats are induced by calculi formation triggered by a different metabolic pathway compared to female rats. In a 2-year study with mice (Umeda et al., 2005), liver tumours were observed in female mice, rather than in male mice. Non-neoplastic kidney lesions were observed in both males and females. The NOAEC was 667 ppm biphenyl in the diet in female mice and 2000 ppm in male mice. Recent Zhang, Clark et al., (2013) absorption, metabolism and elimination (AME) study indicated clear gender differences in the elimination rates of the biphenyl-derived radioactivity in the BDF1 mice and not in the proportion of biphenyl metabolites formed in males and females.  Liver injury would thus be attributed to gender-specific elimination differences in the BDF1 mouse strain, but not in other strains or species. MOA involving sustained regenerative and proliferative changes in the livers of high-dose treated BDF1 females in response to cytotoxicity from prolonged exposure to reactive metabolites of biphenyl is consistent with the results of both Zhang et al., 2013 and Umeda et al., 2005. As a result of cytotoxicity in the liver of biphenyl-treated females, significant regenerative cellular proliferation has to occur to compensate for the damaged tissue. Finally, no adverse effects have been observed in a 90-day female rat study by Newell et al. (1953) up to concentrations of 1000 ppm in the diet, nor in a 1-year monkey study conducted by the same authors up to concentrations of 1% (i.e. 10000 ppm) in the diet. The lowest NOAEL was based on the lowest NOAEC of 500 ppm obtained for female rats by Umeda et al. (2002). The NOAEL was recalculated using the NOAEC, the maximal final weight of female control rats, which was 300 g, and a default food consumption of 22.5 g for rats of 300 g, calculated using the formula mentioned in the TGD: Food consumption (kg/d) = 0.040 x body weight (kg)^0.479. This way, the NOAEL was calculated to be 38 mg/kg bw/day.

Dermal exposure route:

Only two Klimisch 4 studies were available (Deichmann et al., 1947; Newell, 1953). Although based on these studies, no key NOAEL could be defined, these studies indicate that no toxicologically adverse effects occur up to concentrations of 2000 mg/kg bw/d in rabbits.

Inhalation exposure route:

Only one Klimisch 4 study was available (Deichmann et al., 1947). This study indicates that lung effects and minor effects to kidney and liver occur, however, details are lacking. Animals (rats, mice and rabbits) had been exposed to 0.005, 0.04 and 0.3 mg/L air. The animals were exposed to air contaminated with dust composed of 50% biphenyl on celite (i.e. diatomaceous earth or kieselgur). It cannot be ruled out that the celite (partly) induced the observed effects. No key NOAEC could be defined based on the available information.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
a weight of evidence approach was used to address this endpoint - no single key study is assigned

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
a weight of evidence approach was used to address this endpoint - no single key study is assigned.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; urogenital: kidneys; urogenital: urinary bladder

Justification for classification or non-classification

The substance does not need to be classified for long-term effects, as adverse effects did not occur at a concentration of 50 mg/kg bw/d or below after repeated oral exposure.