4-tert-butylbenzoic acid

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.067 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: MOS approache

Overall assessment factor (AF):

37.5

Modified dose descriptor starting point:

NOAEC

Value:

2.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

The experimental NOAEC of 5 mg/m3 is (1) adapted by a factor of 6/8 to account for differences between the experimental inhalation duration of 6 hours per day and the average working day of 8 hours per day, and (2) is multiplied by a factor of 6.7/10 for activity-driven differences of respiratory volumes in workers. This results in an adjusted inhalation starting point of 2.5 mg/m3 (5 • 6/8 • 6.7/10).

AF for dose response relationship:

1

Justification:

already NOAEC

AF for differences in duration of exposure:

3

Justification:

For PTBBA, N(L)OAELs from studies with variable duration show only little differences: The LOAEL of a 11-day inhalation study was 3.6 mg/kg/d (lowest tested concentration), in a 28-day inhalation study the LOAEL was 4.32 mg/kg/d (NOAEL 1.44 mg/kg/d), in both cases based on liver weight changes. A 28-day dermal rat study showed a LOAEL of 7.5 mg/kg/d (NOAEL 15 mg/g), in a 90-day dermal rat study the LOAEL was 17.5 mg/kg/d (lowest tested dose). Based on these data for extrapolation from a subacute to chronic exposure an adjusted duration factor of 3 is used.

AF for interspecies differences (allometric scaling):

1

Justification:

the factor for allometric scaling is already implicitly applied

AF for other interspecies differences:

2.5

Justification:

default factor

AF for intraspecies differences:

5

Justification:

default factor for workers

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.2 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: MOS approache

Overall assessment factor (AF):

12.5

Modified dose descriptor starting point:

NOAEC

Value:

15 mg/m³

Explanation for the modification of the dose descriptor starting point:

no route-toroute extrapolation since starting point is for the same route (inhalation)

AF for dose response relationship:

1

Justification:

Starting point already NOAEC

AF for interspecies differences (allometric scaling):

1

Justification:

the factor for allometric scaling is already implicitly applied

AF for other interspecies differences:

2.5

Justification:

default factor

AF for intraspecies differences:

5

Justification:

default factor for workers

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

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:

0.017 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

other: MOS approache

Overall assessment factor (AF):

450

Modified dose descriptor starting point:

LOAEL

Value:

7.5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Two dermal studies (one subacute and one subchronic study) are available. The 90-day rat study showed a LOAEL of 17.5 mg/kg/day at the lowest tested dose, the LOAEL of the 28- day study was 7.5 mg/kg/day. For assessing the dermal toxicity after dermal contact the subacute 28-day rat study is taken. In this study 8 male and 8 female rats received 0, 7.5, 15, 30 and 60 mg/kg/day PTBBA topically on the skin. Dose related significant increases in absolute and relative liver weights were seen in female rats of all dose groups and in male rats exposed to 15 mg/kg/day and above. Histopathology of the testes revealed a degeneration of germinal epithelium in males exposed to 60 mg/kg bw/d. The LOAEL was 7.5 mg/kg/daybased on the liver weight increases of female rats.

AF for dose response relationship:

3

Justification:

factor of 3 to extrapolate from the LOAEL to a possible NAEL

AF for differences in duration of exposure:

3

Justification:

For PTBBA, N(L)OAELs from studies with variable duration show only little differences: The LOAEL of a 11-day inhalation study was 3.6 mg/kg/d (lowest tested concentration), in a 28-day inhalation study the LOAEL was 4.32 mg/kg/d (NOAEL 1.44 mg/kg/d), in both cases based on liver weight changes. A 28-day dermal rat study showed a LOAEL of 7.5 mg/kg/d (NOAEL 15 mg/g), in a 90-day dermal rat study the LOAEL was 17.5 mg/kg/d (lowest tested dose). Based on these data for extrapolation from a subacute to chronic exposure an adjusted duration factor of 3 is used.

AF for interspecies differences (allometric scaling):

4

Justification:

species rat

AF for other interspecies differences:

2.5

Justification:

default factor

AF for intraspecies differences:

5

Justification:

default factor for workers

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.15 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

other: MOS approache

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

LOAEL

Value:

7.5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For assessing the acute dermal toxicity of PTBBA a subacute 28 day rat study is taken which resulted in a LOAEL of 7.5 mg/kg bw/d

AF for dose response relationship:

1

Justification:

No specific factor is taken to extrapolate from the LOAEL to a possible NOAEL, because this 28-day LOAEL might be a clear NOAEL for a shorter period of exposure.

AF for interspecies differences (allometric scaling):

4

Justification:

species rat

AF for other interspecies differences:

2.5

Justification:

default factor

AF for intraspecies differences:

5

Justification:

default factor for workers

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Discussion in EU risk assessment report, p. 92: Summary of risk characterisation for workers: The toxicological profile of 4-tert-butylbenzoic acid is characterised by the toxicological effects after acute and repeated exposure. The main target organs are liver, kidneys, the central nervous systemand male reproductive organs. There is concern for acute toxicity, repeated dose toxicity and male fertility. For mutagenicity conclusion i is expressed, for developmental toxicity the conclusion i is set on hold.

Conclusion (i) There is a need for further information and/or testing. Conclusion (i) applies to mutagenicity. For adequate assessment of the genotoxic potential of 4-tert-butylbenzoic acid preferably a combination of an in vivo COMET assay (directly exposed tissue and liver) and a bone marrow micronucleus test is recommended. (EU risk assessment report, p.VII)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard 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:

7.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

other: MOS approache

Overall assessment factor (AF):

1

Modified dose descriptor starting point:

LOAEL

Value:

7.5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

see justification and comments

AF for dose response relationship:

1

Justification:

see justification and comments

AF for differences in duration of exposure:

1

Justification:

see justification and comments

AF for interspecies differences (allometric scaling):

1

Justification:

see justification and comments

AF for other interspecies differences:

1

Justification:

see justification and comments

AF for intraspecies differences:

1

Justification:

see justification and comments

AF for the quality of the whole database:

1

Justification:

see justification and comments

AF for remaining uncertainties:

1

Justification:

see justification and comments

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:

1.6 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: MOS approache

Overall assessment factor (AF):

1

Modified dose descriptor starting point:

NOAEL

Value:

1.6 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

see justification and comments

AF for dose response relationship:

1

Justification:

see justification and comments

AF for differences in duration of exposure:

1

Justification:

see justification and comments

AF for interspecies differences (allometric scaling):

1

Justification:

see justification and comments

AF for other interspecies differences:

1

Justification:

see justification and comments

AF for intraspecies differences:

1

Justification:

see justification and comments

AF for the quality of the whole database:

1

Justification:

see justification and comments

AF for remaining uncertainties:

1

Justification:

see justification and comments

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

Discussion in the EU risk assessment report (2009), p.100:

Summary of risk characterisation for consumers: Due to the presence of PTBBA in consumer products and the decision of the C&L meeting in September 2007 for classifying PTBBA as repr. Cat2, R60 there is a need for restricting the substance. These measures will protect consumers also for possible effects on mutagenicity as well on developmental toxicity, therefore for both the conclusion (i) is on hold in the light of risk reduction strategy.

Conclusion (i) There is a need for further information and/or testing. Conclusion (i) applies to mutagenicity. For adequate assessment of the genotoxic potential of 4-tert-butylbenzoic acid preferably a combination of an in vivo COMET assay (directly exposed tissue and liver) and a bone marrow micronucleus test is recommended. (EU risk assessment report, p.VII)