4,4'-isopropylidenedi-2,6-xylol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.29 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):

30

Modified dose descriptor starting point:

NOAEC

Value:

8.8 mg/m³

Explanation for the modification of the dose descriptor starting point:

The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 2 in case of oral-to-inhalation extrapolation.

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

Extrapolation to chronic exposure based on a sub-acute toxicity study.

AF for interspecies differences (allometric scaling):

1

Justification:

No assessment factor for allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.

AF for intraspecies differences:

5

Justification:

Default assessment factor for workers.

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:

0.83 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):

120

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Based on the water solubility of 3.17 mg/L, the Log Pow of 4.51 and the physical state of the substance (solid), the dermal absorption will be low and the rate of penetration will be limited. Furthermore, no effects were observed in an acute dermal toxicity study. Therefore, a factor 0.1 is proposed for oral-to-dermal extrapolation.

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

Extrapolation to chronic exposure based on a sub-acute toxicity study.

AF for interspecies differences (allometric scaling):

4

Justification:

Default assessment factor for allometric scaling in case of a study with rats.

AF for intraspecies differences:

5

Justification:

Default assessment factor for workers.

AF for the quality of the whole database:

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

According to the REACH “Guidance on information requirements and chemical safety assessment”, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

Kinetics (absorption figures for oral, dermal and inhalation route of exposure)

No information on absorption of Tetramethyl Bisphenol A is available. In accordance with Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) is proposed to be used in the case of oral-to-inhalation extrapolation. Based on the water solubility of 3.17 mg/L, the Log Pow of 4.51 and the physical state of the substance (solid), the dermal absorption will be low and the rate of penetration will be limited. Furthermore, no effects were observed in an acute dermal toxicity study. Therefore, a factor 0.1 is proposed for oral-to-dermal extrapolation.

 

Acute toxicity

The substance does not need to be classified for acute toxicity. Therefore, derivation of a short-term DNEL is not necessary.

 

Irritation

The substance is not irritating to skin and eyes, therefore a DNEL for these endpoints does not need to be derived.

 

Sensitisation

The substance is not sensitising to skin, therefore a DNEL for this endpoint does not need to be derived.

Repeated dose toxicity

In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test, the test substance was administered by gavage once daily at 0, 10, 100, or 1000 mg/kg bw/d to male and female rats, 12/sex/group. In addition, 5 additional males per group included in the 0 and 1000 mg/kg bw/d dose groups were designated as recovery animals and held without dosing for two weeks after the dosing period. Clinical findings, mean body weight losses or lower mean body weight gains, and lower mean food consumption were noted in the 100 and 1000 mg/kg/day group F0 males and females. In addition, minimal to mild vacuolation of the lamina propria in the duodenum and jejunum was noted in the 100 (duodenum only) and 1000 mg/kg/day group F0 males and females at the primary necropsy and the persistence of minimal vacuolation in the duodenum and jejunum at slightly higher incidence was noted in the 1000 mg/kg/day group F0 males at the recovery necropsy. Therefore, the NOAEL for F0 male and female systemic toxicity was considered to be 10 mg/kg/day.

Clinical findings were noted in the 1000 mg/kg/day group F1 males and females following test substance administration (PND 22-49); therefore, the NOAEL for F1 systemic toxicity was considered to be 100 mg/kg/day.

 

Mutagenicity

The substance was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537 and Escherichia coli strain WP2 uvrA and was negative for the induction of structural and numerical chromosome aberrations in CHO cells. In the mouse lymphoma assay with L5178Y cells, the substance tested positive after 24-hour exposure in the absence of metabolic activation, and negative after 4-hour exposure with and without metabolic activation.

 

Reproduction toxicity

In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test, the test substance was administered by gavage once daily at 0, 10, 100, or 1000 mg/kg bw/d to male and female rats, 12/sex/group. No test substance-related effects were observed on F0 reproductive performance, gestation length, parturition, or spermatogenesis at any dosage level. Therefore, a dosage level of 1000 mg/kg/day was considered to be the no-observed-adverse-effect level (NOAEL) for F0 male and female reproductive toxicity.

Based on the absence of an effect on postnatal survival and pup body weights, the NOAEL for F1 neonatal toxicity was considered to be 1000 mg/kg/day. Based on the shorter anogenital distances noted in the 100 and 1000 mg/kg/day group F1 male pups, and the presence of thoracic nipples in the 100 and 1000 mg/kg/day F1 males, the NOAEL for F1 developmental toxicity was considered to be 10 mg/kg/day.

 

 

Worker DNELs

 

Long-term –inhalation, systemic effects(based on a combined oral repeated dose toxicity study and reproduction/developmental toxicity screening test in rats)

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 10 mg/kg bw/day	Based on mean body weight losses or lower mean body weight gains, lower mean food consumption, and minimal to mild vacuolation of the lamina propria in the duodenum and jejunum.
Step 2) Modification of starting point	: 2           : 0.38 m^3/kg bw           x 6.7 m^3/10 m^3	The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 2 in case of oral to inhalation extrapolation.   Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance on information requirements and chemical safety assessment (R.8.4.2).   Correction for activity driven differences of respiratory volumes in workers compared to workers in rest.
Modified dose-descriptor	10 / 2 / 0.38 x (6.7/10) = 8.8 mg/m^3
Step 3) Assessment factors
Interspecies	1	No assessment factor for allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.
Intraspecies	5	Default assessment factor for workers.
Exposure duration	6	Extrapolation to chronic exposure based on a sub-acute toxicity study.
Dose response	1
Quality of database	1
DNEL	Value
	8.8 / (1 x 5 x 6 x 1 x 1) =0.29mg/m^3

 

 

Long-term - inhalation, local effects

No data are available based on which a DNEL for local effects can be derived. There are also no data to suggest that the substance may cause local effects by inhalation exposure.

 

 

Long-term –dermal, systemic effects(based on a combined oral repeated dose toxicity study and reproduction/developmental toxicity screening test in rats)

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 10 mg/kg bw/day	Based onmean body weight losses or lower mean body weight gains, lower mean food consumption, and minimal to mild vacuolation of the lamina propria in the duodenum and jejunum.
Step 2) Modification of starting point	: 0.1	Based on the water solubility of 3.17 mg/L, the Log Pow of 4.51 and the physical state of the substance (solid), the dermal absorption will be low and the rate of penetration will be limited. Furthermore, no effects were observed in an acute dermal toxicity study. Therefore, a factor 0.1 is proposed for oral-to-dermal extrapolation.
Modified dose-descriptor	10 / 0.1 = 100 mg/kg bw/day
Step 3) Assessment factors
Interspecies	4	Default assessment factor for allometric scaling in case of a study with rats.
Intraspecies	5	Default assessment factor for workers.
Exposure duration	6	Extrapolation to chronic exposure based on a sub-acute toxicity study.
Dose response	1
Quality of database	1
DNEL	Value
	100 / (4 x 5 x 6 x 1 x 1) =0.83mg/kg bw/day

 

 

Long-term - dermal, local effects

No data are available based on which a DNEL for local effects can be derived. There are also no data to suggest that the substance may cause local effects by dermal exposure.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

Assessment is not applicable as there are no consumer-related uses for the substance.