Biphenyl

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

11.17 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH and ECETOC guidance

Overall assessment factor (AF):

3

Modified dose descriptor starting point:

NOAEC

Value:

33.51 mg/m³

Explanation for the modification of the dose descriptor starting point:

Conservative factor of 2 has been included in NOAEC to address potential differences in inhalation and oral bioavailability (set at 100%)

AF for dose response relationship:

1

Justification:

Clear dose response with minimal toxicological findings up to the highest dose

AF for differences in duration of exposure:

1

Justification:

based on chronic exposure of 105 weeks

AF for interspecies differences (allometric scaling):

1

Justification:

ECHA guidance, route-to-route extrapolation addresses allometic scaling

AF for other interspecies differences:

1

Justification:

substance tested in number of different species

AF for intraspecies differences:

3

Justification:

based on ECETOC guidance for worker population

AF for the quality of the whole database:

1

Justification:

ECHA default

AF for remaining uncertainties:

1

Justification:

no extra uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

63 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH and ECETOC guidance

Overall assessment factor (AF):

12

Modified dose descriptor starting point:

NOAEL

Value:

760 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal absorption was reported to be less than 5%.

AF for dose response relationship:

1

Justification:

Clear dose response with minimal toxicological findings up to the highest dose

AF for differences in duration of exposure:

1

Justification:

based on chronic exposure of 105 weeks

AF for interspecies differences (allometric scaling):

4

Justification:

based on allometric scaling from rat to human (ECHA guidance)

AF for other interspecies differences:

1

Justification:

substance tested in number of different species

AF for intraspecies differences:

3

Justification:

based on ECETOC guidance for worker population

AF for the quality of the whole database:

1

Justification:

ECHA default

AF for remaining uncertainties:

1

Justification:

no other uncertainties identifed

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

Acute / short- term exposure - systemic and local effects

- An LD50 > 3980 mg/kg bw/day was observed for acute dermal toxicity in rabbits. As there is no acute toxicity hazard (leading to C&L), a DNEL for acute toxicity does not need to be derived.

- No reliable acute data were available for the inhalation route of exposure.

Long-term exposure - systemic effects

DERMAL

- No long-term dermal toxicity studies are available for biphenyl. Therefore, reliable data from the repeated dose toxicity study of Umeda et al. (2002) (oral exposure) are used to derive a dermal DNEL for long-term exposure, systemic effects. The lowest NOAEL observed in rats is 38 mg/kg bw/day. For route-to-route extrapolation from oral to dermal, it is assumed that oral bioavailability is approximately 100% and that dermal bioavailability is not more than 5% (refer to the toxicokinetics section). Therefore the NOEAL from the oral study will be adjusted by a factor of 20 to correct for bioavailability. The starting point for DNEL derivation is therefore 760 mg/kg bw/day. For interspecies extrapolation, the assessment factor was determined to be 4, based on allometric scaling from rat to human (based on ECHA guidance). The factor of 2.5 for 'additional uncertainty' in allometric scaling is not applied (set to 1) because recent research indicated that the factor is not justified in the majority of cases (based on ECETOC guidance) and because there is little evidence in this particular case that the observed effects were influenced by non-allometric factors. Based on ECETOC guidance, an intraspecies extrapolation factor of 3 was used for the worker population. No assessment factor should be applied for exposure duration as the NOAEL is observed in a repeated dose toxicity study of 105 weeks. Applying the overall assessment factor of 4 x 3 = 12 to the adjusted NOAEL mentioned above yields a DNEL of 63 mg/kg bw/day.

INHALATION

- No long-term inhalation toxicity studies are available for biphenyl. Therefore, reliable data from the repeated dose toxicity study of Umeda et al. (2002) (oral exposure) are used to derive an inhalation DNEL for long-term exposure, systemic effects. The lowest NOAEL observed in rats is 38 mg/kg bw/day. For route-to-route extrapolation from oral to inhalation, the dose descriptor starting point was calculated to be 38 mg/kg bw/day x 1/(0.38 m3/kg bw) x 6.7 m3/10 m3 x 0.5 = 33.5 mg/m3. The oral dose for rats was converted to the corresponding air concentration using a standard breathing volume for the rat (0.38 m3/kg bw during a period of 8 h, which is relevant for workers). When extrapolating this concentration to workers the resulting air concentration needs to be additionally corrected for the differences between basal caloric demand and caloric demand under light activity. This correction factor is represented by the ratio of the 8-h inhalative volumes for base level activity (6.7 m3) to that for light activity (10 m3). Even though the oral bioavailability of biphenyl is approximately 100%, a conservative factor of 2 has been included to address potential differences in inhalation and oral bioavailability. No factor of 2.5 for 'additional uncertainty' in allometric scaling was applied as explained above. Based on ECETOC guidance, an intraspecies extrapolation factor of 3 was used for the worker population. No assessment factor should be applied for exposure duration as the NOAEL is observed in a repeated dose toxicity study of 105 weeks. Applying the overall assessment factor of 3 to the starting point calculated above yields a DNEL of 11.17 mg/m3.

Long-term exposure - local effects

No reliable data from long-term toxicity studies are available for the dermal or inhalation route of exposure for biphenyl. Therefore, a DNEL for long-term exposure, local effects is not quantifiable for the dermal and inhalation routes.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.3 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH and ECETOC guidance

Overall assessment factor (AF):

5

Modified dose descriptor starting point:

NOAEC

Value:

16.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAEL was divided by 2 and converted to the corresponding air concentration using a standard breathing volume for rat

AF for dose response relationship:

1

Justification:

Clear dose response with minimal toxicological findings up to the highest dose

AF for differences in duration of exposure:

1

Justification:

based on chronic exposure of 105 weeks

AF for interspecies differences (allometric scaling):

1

Justification:

ECHA guidance, route-to-route extrapolation addresses allometic scaling

AF for other interspecies differences:

1

Justification:

substance tested in number of different species

AF for intraspecies differences:

5

Justification:

for general population differences (based on ECETOC guidance)

AF for the quality of the whole database:

1

Justification:

ECHA default

AF for remaining uncertainties:

1

Justification:

no extra uncertainties identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

38 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

20

Modified dose descriptor starting point:

NOAEL

Value:

760 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal absorption will not be higher than oral absorption (100%). Dermal absorption was reported to be less than 5%.

AF for dose response relationship:

1

Justification:

Clear dose response with minimal toxicological findings up to the highest dose

AF for differences in duration of exposure:

1

Justification:

based on chronic exposure of 105 weeks

AF for interspecies differences (allometric scaling):

4

Justification:

allometric scaling from rat to human (based on ECHA guidance)

AF for other interspecies differences:

1

Justification:

substance tested in number of different species

AF for intraspecies differences:

5

Justification:

for general population differences (based on ECETOC guidance)

AF for the quality of the whole database:

1

Justification:

ECHA default

AF for remaining uncertainties:

1

Justification:

no extra uncertainties identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.9 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

20

Modified dose descriptor starting point:

NOAEL

Value:

38 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

no extrapolation needed

AF for dose response relationship:

1

Justification:

Clear dose response with minimal toxicological findings up to the highest dose

AF for differences in duration of exposure:

1

Justification:

based on chronic exposure of 105 weeks

AF for interspecies differences (allometric scaling):

4

Justification:

allometric scaling from rat to human (based on ECHA guidance)

AF for other interspecies differences:

1

Justification:

substance tested in number of different species

AF for intraspecies differences:

5

Justification:

for general population differences (based on ECETOC guidance)

AF for the quality of the whole database:

1

Justification:

acceptable dataset, ECHA default

AF for remaining uncertainties:

1

Justification:

no extra uncertainties identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

The DNELS for General Population are provided for information only. There are no known consumer uses for Biphenyl that would lead to direct exposure of the general population. In addition, Biphenyl is not persistent or bioaccumulative, therefore there is no requirement to include the oral DNEL in an assessment of indirect exposure via the environment.

Acute / short-term exposure - systemic and local effects

- An LD50 > 3980 mg/kg bw/day was observed for acute dermal toxicity in rabbits. As there is no acute toxicity hazard (leading to C&L), a DNEL for acute toxicity does not need to be derived.

- No reliable acute data were available for the inhalation route of exposure.

- Based on the available information the LD50 for acute oral toxicity is expected to be higher than 2000 mg/kg bw. As there is no acute toxicity hazard (leading to C&L), a DNEL for acute toxicity does not need to be derived.

Long-term exposure - systemic effects

ORAL

- The lowest NOAEL observed in rats in an oral repeated dose toxicity study is 38 mg/kg bw/day (Umeda et al., 2002). For interspecies extrapolation, the assessment factor was determined to be 4, based on allometric scaling from rat to human (based on ECHA guidance). The factor of 2.5 for 'additional uncertainty' in allometric scaling is not applied (set to 1) because recent research indicated that the factor is not justified in the majority of cases (based on ECETOC guidance) and because there is little evidence in this particular case that the observed effects were influenced by non-allometric factors. Based on ECETOC guidance, an intraspecies extrapolation factor of 5 was used for the general population. No assessment factor should be applied for exposure duration as the NOAEL is observed in a repeated dose toxicity study of 105 weeks. Applying the overall assessment factor of 4 x 5 = 20 to the NOAEL mentioned above yields a DNEL of 1.9 mg/kg bw/day.

DERMAL

- For route-to-route extrapolation from oral to dermal, based on the toxicokinetics section, the dermal bioavailability is taken as 5%, and oral bioavailability as 100%. Therefore the NOAEL from the repeated dose oral study will be adjusted by a factor of 20. The starting point for Dermal DNEL derivation is therefore 76 0 mg/kg bw. Applying the assessment factor of 20 (refer to oral DNEL explanation) gives a DNEL of 38 mg/kg bw/day.

INHALATION

- For the route-to-route extrapolation from oral to inhalation, the dose descriptor starting point was calculated to be 38 mg/kg bw/day x 1/1.15 m3/kg bw x 0.5 = 16.5 mg/m3. The oral dose for rats was converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/kg bw during a 24-h period, which is relevant for the general public). In addition, the NOAEL needed to be divided by 2 as the bioavailability via the inhalation route is considered to be 100%, whereas that for the oral route is considered to be only 50%. No factor of 2.5 for 'additional uncertainty' in allometric scaling was applied as explained above. Based on ECETOC guidance, an intraspecies extrapolation factor of 5 was used for the general population. No assessment factor should be applied for exposure duration as the NOAEL is observed in a repeated dose toxicity study of 105 weeks. Applying the overall assessment factor of 5 to the starting point calculated above yields a DNEL of 3.3 mg/m3.

Long-term exposure - local effects

No reliable data from long-term toxicity studies are available for the dermal or inhalation route of exposure for biphenyl. Therefore, a DNEL for long-term exposure, local effects is not quantifiable for the dermal and inhalation routes.