4,4'-cyclohexylidenedi-o-cresol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

11.75 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

880 mg/m³

Explanation for the modification of the dose descriptor starting point:

detailed explanation provided under Discussion

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:

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:

3.33 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:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

detailed explanation provided under Discussion

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:

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Based on the available acute toxicity data for the oral and dermal routes of exposure, both reporting LD50s >2000 mg/kg bw, DMBPC is not expected to be an acute toxicant by these routes, and therefore, derivation of long-term DNELs will be sufficient to control potential risks associated with short-term exposures. Sufficient information is available from studies performed according to OECD Guidelines to conclude that DMBPC does not produce local toxicity effects (e.g., skin and eye irritation, skin sensitisation). Skin irritation/corrosion and eye irritation tests on rabbits performed according to GLP/OECD Guidelines 404 and 405, respectively, are available which conclude that DMBPC is considered not irritating to skin and eyes. In addition, a skin sensitisation test on guinea pigs performed according to GLP/OECD Guideline 406 reported that DMBPC is not sensitising. Therefore, derivation of DNELs for local effects is not necessary.

A Derived-Minimal-Effect-Level (DMEL) is derived for substances classified as a carcinogen and/or mutagen. Genotoxicity data for DMPBC are available: a negative in vitro reverse bacterial mutation assay (Ames), a positive chromosomal aberration assay with Chinese Hamster Ovary (CHO) cells and a negative mouse lymphoma forward mutation assay. In addition, an in vivo mouse bone marrow micronucleus assay is available which reported that DMBPC was negative for inducing micronuclei. All of these assays were performed according to GLP/OECD Guidelines and the overall weight of evidence demonstrates a lack of genotoxicity. No carcinogenicity data are available for DMBPC; however, given the negative in vitro and in vivo genotoxicity results for DMBPC and a lack of neoplasia/hyperplasia in a 28-day repeated dose study performed according to GLP/OECD 422, it is unlikely that DMBPC is carcinogenic. Therefore, derivation of a DMEL is not appropriate and only a DNEL will be generated to assess effects resulting from long-term exposure to DMBPC.

The key study for derivation of the DNELs is a combined repeated dose toxicity / reproductive toxicity screening assay performed according to GLP/OECD 422 in which 10 rats/sex/dose were administered DMBPC via gavage for 28 d (males) and approximately 56 d (females) at doses of 0, 50, 200 and 1000 mg/kg bw/d (nominal). In addition, five additional males per group from the control and 1000 mg/kg bw/d dose groups were designated as recovery animals and held without dosing for two weeks after the dosing period.

The NOAEL reported in the combined repeated dose toxicity was 200 mg/kg bw/d based on statistically significant reductions in body weight and body weight gain in the 1000 mg/kg bw/d dose group. However, consistent with CLP classification guidelines these changes are not considered toxicologically relevant as there were no additional signs of overt toxicity. Therefore, for purposes of derivation of DNELs, the NOAEL is considered to be 1000 mg/kg bw/day.

A DNEL for systemic effects for the worker population is normally derived for the dermal and inhalation routes of exposure. Therefore, route-to-route extrapolation from the oral toxicity study was utilized for derivation of the DNEL. For route-to-route extrapolation from an oral dose to an inhalation dose the starting point needs to be modified to correct for the breathing volume of the rat and respiratory volume under standard conditions (6.7 m3/person) versus under conditions of light activity for workers (10 m3/person). Based on ECHA’s recommendations, it is assumed that respiratory absorption is equivalent between the animals and humans. Therefore, the inhalation starting dose = oral NOAEL x 1/(0.38 m3/kg bw/d) x 6.7 m3/10 m3. In addition, potential toxicokinetic properties inferred from existing toxicology studies and the physical chemical properties determined moderate (50%) oral absorption and complete (100%) inhalation absorption. Therefore, the inhalation starting dose for the worker population = 1000 mg/kg bw/d x 1/(0.38 m3/kg bw/d) x 6.7 m3/10 m3 x (50/100) = 880 mg/m3.

For route-to-route extrapolation for the dermal route, the absorption differences between the animal and human need to be considered for both the dermal and oral routes. The potential toxicokinetic properties inferred from existing toxicology studies and physical chemical properties set a dermal absorption value of 25% for humans, in accordance with principle adopted by the EFSA guidance on estimating dermal absorption of pesticide active substances. Therefore, the starting dose for calculation of the systemic dermal DNEL is 1000 mg/kg bw/d x (50/25) = 2000 mg/kg bw/day.

The AF for interspecies variability includes an allometric scaling (AS) factor plus an additional factor of 2.5. In the case of the rat, the ECHA recommended AS factor is 4. So the interspecies AF is equal to 4 x 2.5 = 10. However, for the inhalation route an AS factor is not used. Therefore, for inhalation, only an interspecies factor of 2.5 is used. ECHA R.8 Guidance Document (ECHA, 2010) recommends an AF of 5 to account for intraspecies variability among workers.

The AF for extrapolation from a subacute (e. g., 28-d) toxicity study to a chronic is 6.

The total AF used to derive the systemic DNELlong-term for the inhalation route for the worker is 75 (2.5 x 5 x 6).

The total AF used to derive the systemic DNELlong-term for the dermal route for the worker is 300 (4 x 2.5 x 5 x 6)

Worker DNEL long-term systemic for the inhalation route = 880/75 = 11.7 mg DMBPC/m3.

Worker DNEL long-term systemic for the dermal route = 2000/300 = 6.7 mg DMBPC/kg bw/d

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