2,6-xylenol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Modified dose descriptor starting point:

NOAEC

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

default value - subacute to chronic

AF for other interspecies differences:

2.5

Justification:

default value - remaining differences

AF for intraspecies differences:

5

Justification:

default value - 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:

6 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Dose descriptor:

NOAEC

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

default value - subacute to chronic

AF for other interspecies differences:

2.5

Justification:

default value - remaining differences

AF for intraspecies differences:

5

Justification:

default value - 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:

16 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Overall assessment factor (AF):

12.5

Dose descriptor starting point:

NOAEC

AF for dose response relationship:

1

AF for other interspecies differences:

2.5

Justification:

default value - remaining differences

AF for intraspecies differences:

5

Justification:

default value - workers

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.2 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):

300

Modified dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

default value - subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

default value - rat

AF for other interspecies differences:

2.5

Justification:

default value - remaining differences

AF for intraspecies differences:

5

Justification:

default value - 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:

0.6 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - workers

Based on the physico-chemical parameters, it could be concluded that absorption will be 100% for all routes of exposure (more details can be found in the part on toxicokinetics).

DNEL for long-term exposure - systemic effects – inhalation :

Batelle Columbus Division (BCD) (1991) performed a repeated dose toxicity study in male and female rats that were exposed to 2,6-xylenol (67, 200, 670 mg/m³) by whole body inhalation for 6 hours/day, 5 days/week, for a total of ten exposures, conducted within 14 days. The NOAEC for local and systemic effects was determined to be 200 mg/m³.

To compensate for the difference in exposure duration, the inhalation NOAEC is multiplied by a factor 6h/day/8h/day and is 150 mg/m³.

Following assessment factors were used:

-interspecies differences: 2.5 (no allometric scaling is required for inhalation)

-intraspecies differences: 5

-differences in duration: 6

-dose-response relationship: 1

With an overall assessment factor of 75, a DNEL of 150 mg/m³/75 = 2 mg/m³ is derived for the inhalation route – long-term systemic effects.

DNEL for acute exposure - systemic effects – inhalation :

The substance is classified for acute oral toxicity therefore, to protect from any possible adverse acute systemic effect, a DNEL for acute exposure inhalation has been set at 3x the long-term systemic DNEL.

DNEL for long-term exposure - local effects – inhalation:

Batelle Columbus Division (BCD) (1991) performed a repeated dose toxicity study in male and female rats that were treated with 2,6-xylenol (67, 200, 670 mg/m³) by whole body inhalation for 6 hours/day, 5 days/week, for a total of ten exposures, conducted within 14 days. The NOAEC for local effects was determined to be 200 mg/m³.

To compensate for the difference in exposure duration, the inhalation NOAEC is multiplied by a factor 6h/day/8h/day and is 150 mg/m³.

Following assessment factors were used:

-interspecies differences: 2.5

-intraspecies differences: 5

-differences in duration: 6

-dose-response relationship: 1

With an overall assessment factor of 75, a DNEL of 150 mg/m³/75 = 2 mg/m³ is derived for the inhalation route – local effects.

DNEL for acute exposure - local effects – inhalation :

Batelle Columbus Division (BCD) (1991) performed a repeated dose toxicity study in male and female rats that were treated with 2,6-xylenol (67, 200, 670 mg/m³) by whole body inhalation for 6 hours/day, 5 days/week, for a total of ten exposures, conducted within 14 days. Local effects appeared after 1 day of exposure: the NOAEC for local effects was determined to be 200 mg/m³.

Although the study is a repeated dose study, effects were observed after the first day of exposure. Therefore, 200 mg/m³ can be used as the starting dose for the acute DNEL derivation.

Following assessment factors were used:

-interspecies differences: 2.5

-intraspecies differences: 5

-differences in duration: 1

-dose-response relationship: 1

With an overall assessment factor of 12.5, an acute DNEL of 200 mg/m³/12.5 = 16 mg/m³ is derived for the inhalation route – local effects.

DNEL for long-term exposure - systemic effects – dermal :

No long-term data were available for the dermal route of exposure. Therefore, reliable data for the oral route were used.

RTI International Center for Life Sciences (2005) performed a combined repeated dose toxicity study with reproduction/developmental toxicity screening test using a structurally related analogous. F0 Sprague-Dawley Rats were dosed (via gavage) premating through the day prior to necropsy. Recovery males, females and 28 days females were dosed for 28 days. F1 animals were dosed post-weaning until the day before scheduled necropsy, at least 7 weeks duration. Animals received 0, 10, 100, or 200 mg/kg bw/day. A parental and F0 offspring NOEL of >= 200 mg/kg bw/day was observed. In addition to this study, a pre-natal developmental toxicity study was conducted with the registered substance where female rats received 0, 60, 180 or 540 mg/kg bw/day from gestation day 6 to 15. A lowest NOAEL for maternal toxicity (systemic toxicity) was obtained in this study because treatment at 180 mg/kg bw/day caused reductions in body weight gain and food consumption, and a statistically significant lower terminal weight when corrected for the uterus weight. Therefore, the starting dose for DNEL derivation is the NOAEL of 60 mg/kg bw/day for maternal toxicity, the lowest NOAEL obtained among the available studies.

Following assessment factors were used:

- interspecies differences: 2.5 x 4 = 10

- intraspecies differences: 5

- differences in duration: 6

- dose-response relationship: 1

With an overall assessment factor of 300, a DNEL for long-term exposure - systemic effects of 60 mg/kg bw/300 = 0.2 mg/kg bw/day is derived.

DNEL for acute exposure - systemic effects – dermal :

The substance is classified for acute dermal toxicity therefore, to protect from any possible adverse acute systemic effect, a DNEL for acute exposure dermal has been set at 3x the long-term systemic DNEL.

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:

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

General Population - Hazard via oral 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

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

For the general population, no DNEL was derived since 2,6-xylenol is only used in closed systems: no indirect exposure via the environment will occur. Moreover, no consumer use is considered.