Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
16.5 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
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1 234.21 mg/m³
Explanation for the modification of the dose descriptor starting point:

The systemic NOAEL from the oral study according to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test) has been modified accounting for the standard respiratory volume for rats (8 h) of 0.38 m³/kg bw, the standard respiratory volume for human under normal conditions (8 h) of 6.7 m³/person and under light activity of 10 m³/person (default weight of 70 kg).


In addition, the oral and inhalative absorption was accounted for. As default value, since no route specific information is available, oral absorption is considered to be half of the inhalatory absorption (factor 1/2).


Since the study is performed at 7 days/week, while the exposure of workers is 5 days/week, the NOAEL is also corrected by the factor of 1.4 (7/5). The resulting corrected NOAEC is the following:


 


NOAECcorr = 1000 mg/kg bw/day*(1/0.38 m³/kg bw/d)*(6.7 m³/10 m³)*(1/2)*1.4 = 1234.21 mg/m³

AF for dose response relationship:
1
Justification:
starting point is a NOAEL
AF for differences in duration of exposure:
6
Justification:
default (sub-acute to chronic)
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling should be applied in case of oral-to-inhalation extrapolation, as this was already considered during the correction of the starting point
AF for other interspecies differences:
2.5
Justification:
default, since no specific information is available
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
The study was performed according to guideline and GLP. Therefore, the quality of the database is high.
AF for remaining uncertainties:
1
Justification:
no remaining 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:
46.7 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
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
14 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The systemic NOAEL from the oral study according to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test) has been modified accounting for the difference in exposure for workers and test animals. Since the study is performed at 7 days/week, while the exposure of workers is 5 days/week, the NOAEL is corrected by the factor of 1.4 (7/5). Furthermore, this value is corrected for the differences in absorption rates between the dermal and the oral route. The dermal absorption is 10 % and the oral absorption is 100 %. The resulting corrected NOAEC is the following:


 


NOAECcorr = 1000 mg/kg bw/day*100%/10%*1.4 = 14000 mg/kg bw/day

AF for dose response relationship:
1
Justification:
starting point is a NOAEL
AF for differences in duration of exposure:
6
Justification:
default (sub-acute to chronic)
AF for interspecies differences (allometric scaling):
4
Justification:
default for rats
AF for other interspecies differences:
2.5
Justification:
default, since no specific information is available
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
good quality as GLP study according to Guideline is used as PoD
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

The calculation of the DNELs is in general performed in accordance with the principles given in ECHA (2012) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.”


Workers:


Acute inhalation and dermal exposure - systemic effects:


Chapter 8.7.3 of the REACH TGD (R.8) indicates that acute exposure DNEL values are not normally required. It is specified: "For some toxic substances, for which there may be peak exposures, a DNELacute needs to be set and assessed in relation to the human peak exposure levels". This would be the case for substances with classification & labelling for acute hazards.


However, for p-diisopropylbenzene no hazard is identified as it is not classified for acute systemic hazards via the inhalation route of exposure and has additionally a very low volatility with a vapor pressure of only 41.5 Pa at 20 °C (determined according to EU Method A4). Furthermore, for p-diisopropybenzene no hazard is identified as it is also not classified for acute systemic hazards via the dermal route of exposure (the acute dermal study on the test substance revealed an LD50 > 20 mL/kg bw (no mortalities occurred; Topping, 1984)).


So, based on results of animal studies and the low vapour pressure p-diisopropylbenzene does not pose an inhalation nor a dermal hazard . Therefore, no DNEL is required and a DNEL is not quantifiable, not relevant (no adequate route-specific information) and the hazard assessment conclusion "no hazard identified" is chosen according to ECHA's Guidance Part E (v3, May 2016) in both cases.


 


Acute short-term / Long-term inhalation or dermal exposure - local effects:


Chapter 8.7.3 of the REACH TGD (R.8) indicates that acute and long-term local DNEL values are required for substances causing irritation, corrosion and/or sensitisation, assuming that the data allow setting a DNEL.


p-diisopropylbenzene has been found to be only irritating to the skin and the Classification and labelling as Skin Irrit. Cat. 2 (H315 - Harmful in contact with skin) has been derived. However, no skin corrosion nor skin sensitisation was observed. 


Therefore, no DNEL is required and a DNEL is not quantifiable (no adequate route-specific information for setting a long-term or acute / short-term inhalation or dermal DNEL for local effects) and the hazard conclusion "no hazard identified" is chosen for inhalation exposure and the hazard conclusion "low hazard (no threshold derived)" was chosen for dermal exposure according to ECHA's Guidance Part E (v3, May 2016).


 


Long-term inhalation exposure - systemic effects:


 


An oral Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test gave a NOAEL of 1000 mg/kg. Extrapolating from subacute oral toxicity to chronic inhalation, the NOAEL first must be converted to mg/mby dividing by a factor of 0.38, and then corrected for oral bioavailability (50 %) by multiplying by a factor of 0.5. Further corrections are then necessary for 7-day experimental exposure to 5-day work week (1.4) and to adjusted for respiration for light work (0.67). The following Assessment factors were applied, which consisted of subacute to chronic studies (6), for intraspecies (5), for remaining interspecies differences (2.5), for a total of 75.


 


- Converting mg/kg to mg/m= 1000/0.38 = 2631.6 mg/m3


- Correcting for oral bioavailability = 263.16*0.5 = 1315.89 mg/m3


- Correcting for 7-day experimental exposure to 5-day work week, and light work = 1315.89 mg/m3* (1.4) *(0.67) = 1234.21 mg/m3


- Application of adjustment factors: 1234.21 mg/m3/75 = 16.5 mg/m3


 


Long-term dermal exposure - systemic effects:


 


An oral Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test gave a NOAEL of 1000 mg/kg. Extrapolating from subacute oral toxicity to chronic dermal, the NOAEL first must be corrected for 7-day experimental exposure to 5-day work week (1.4).


The following Assessment factors were applied, which consisted of subacute to chronic studies (6), for intraspecies (5), for interspecies (4) and for remaining interspecies differences (2.5), for a total of 300.


 


- Correcting for absorption rates = 1000*(10 %/100 %) = 10,000 mg/kg bw/day 


- Correcting for 7-day experimental exposure to 5-day work week, and light work = 10,000 mg/kg*(1.4) = 14,000 mg/kg


- Application of adjustment factors: 14,000 mg/kg/300 = 46.7 mg/kg


 


Modification of the starting point:


From all available data for the different human health endpoints it is clear that p-diisopropylbenzene (CAS 100-18-5) exerts its effects by a threshold mode of action. Thus, DNELs can be calculated for the different threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived based on the available toxicity data for the target substance reflecting the routes, the duration and the frequency of exposure.


 


Bioavailability (absorption)


There is no substance-specific information on absorption by the oral, dermal and inhalation routes available for p-diisopropylbenzene (CAS 100-18-5). The absorption rates are assessed based on the physico-chemical properties of the substance.


No data needed to be derived for dermal exposure, because the physicochemical and toxicological properties do not suggest a potential for a significant rate of absorption through the skin. Due to the high water solubility of the substance (40.5 µg/L at T = 25 °C), its log Kow of 5.2 and molecular weight of 162 g/mol, dermal absorption is expected to a minor extent. As such, taking into account the negligible ability of p-diisopropylbenzene to penetrate the stratum corneum, an absorption rate of 10 % after dermal exposure needs to be considered for DNEL derivation.


Also, no data is needed for the application of p-diisopropylbenzene via inhalation, because it has a very low vapor pressure of 41.5 Pa at 20 °C and a high boiling point of 210.1 °C, so the potential for the generation of inhalable forms is low and no dust with inhalable particles will be formed. Howevera worst-case absorption rate of 100 % after inhalation exposure is to be considered for DNEL derivation.


In addition, an absorption rate of 100 % after oral exposure is considered appropriate.


 


Route-to-route extrapolation:


Oral-to-inhalation extrapolation is performed to obtain a long-term inhalation NOAEC for systemic effects from the systemic NOAEL from the Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in rats. That value has been modified accounting for the difference in exposure for workers and test animals as described below. According to "Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8, in case of oral-to-inhalation extrapolation a default factor of 2 for absorption should be introduced.


The following formular was used: corrected inhalative NOAEC = oral NOAEL x (1/sRVrat) x (ABSoral-rat/ABSinh-human) x (ABSinhalation-rat/ABS inhalation-human) x (6.7 m³/10 m³) x (7/5);


where sRV is standard respiratory volume of rats during 8 hours (= 0.38 m³/kg/day); ABS-absorption and 6.7 m³ and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity, and 7d/5d is the different exposure duration in rats and human workers - workers (5 working days) vs. rats (7 days continuous exposure)


 


Oral-to-dermal extrapolation is performed to obtain long-term dermal NOAEL for systemic effects. The following formula was used:


corrected dermal NOAEL = oral NOAEL * (ABS oral-rat/ABS dermal-rat) * (ABS dermal-rat/ ABSs dermal-human), * 7d/5d;


where ABS is absorption, and 7d/5d is the different exposure duration in rats and human workers - workers (5 working days) vs. rats (7 days continuous exposure)


 


Exposure conditions and respiratory volumes:


Differences in the respiratory volumes between experimental animals and humans were used when an oral rat NOAEL from the Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in rats was used to assess inhalation exposure in humans. 0.38 m³/kg/day is the standard respiratory volumes in rats during 8h exposure. 6.7 and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity, respectively. Furthermore, the different exposure condition in human workers and rats was taken into account (workers - 5 working days - versus - rats - 7 days continuous exposure).


 


Applying of assessment factors and calculation of DNELs:


The assessment factors have been applied to the corrected starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data.


 


Interspecies differences:


The species-specific default assessment factor of 4 for allometric scaling for rats was applied in case of the oral NOAEC from the Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in rats which was used to derive the dermal long-term DNEL.


No allometric scaling factor was applied in case of derivation of the inhalation DNEL from the above mentioned oral NOAEC.


An assessment factor of 2.5 was applied for remaining interspecies differences in toxicodynamics between rat and human in case of derivation of systemic inhalation DNEL.


 


Intraspecies differences:


An assessment factor of 5 was applied for workers in cases of DNEL derivation for systemic effects by long-term exposure.


 


Extrapolation of duration:


An assessment factor of 6 was applied for duration of exposure (subacute study).


 


Quality of whole data base:


A default assessment factor of 1 was used.


 


Issues related to dose response:


A default assessment factor of 1 is applied when the NOAEL form the subacute  Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in rats was used (three doses were tested, using a spacing range of 2-4 fold).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.9 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):
150
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
434.78 mg/m³
Explanation for the modification of the dose descriptor starting point:

The systemic NOAEL from the oral study according to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test) has been modified accounting for the standard respiratory volume for rats (24 h) of 1.15 m³/kg bw.


In addition, the oral and inhalative absorption was accounted for. As default value, since no route specific information is available, oral absorption is considered to be half of the inhalatory absorption (factor 1/2).


As the study is performed at 7 days/week, and the exposure of the general population is 7 days/week, as well, the NOAEL does not need to be further corrected.


The resulting corrected NOAEC is the following:


 


NOAECcorr = 1000 mg/kg bw/day*(1/1.15 m³/kg bw/d)(1/2) = 434.78 mg/m³


 

AF for dose response relationship:
1
Justification:
starting point is a NOAEL
AF for differences in duration of exposure:
6
Justification:
default (sub-acute to chronic)
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling should be applied in case of oral-to-inhalation extrapolation, as this was already considered during the correction of the starting point
AF for other interspecies differences:
2.5
Justification:
default, since no specific information is available
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
The study was performed according to guideline and GLP. Therefore, the quality of the database is high.
AF for remaining uncertainties:
1
Justification:
no remaining 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

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
16.7 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):
600
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
10 000
Explanation for the modification of the dose descriptor starting point:

The systemic NOAEL from the oral study according to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test) has been modified accounting for the differences in absorption rates between the dermal and the oral route. The dermal absorption is 10 % and the oral absorption is 100 %. The resulting corrected NOAEC is the following:


NOAECcorr = 1000 mg/kg bw/day*100 %/10 % = 10,000 mg/kg bw/day

AF for dose response relationship:
1
Justification:
starting point is a NOAEL
AF for differences in duration of exposure:
6
Justification:
default (sub-acute to chronic)
AF for interspecies differences (allometric scaling):
4
Justification:
default for rats
AF for other interspecies differences:
2.5
Justification:
default, since no specific information is available
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
The study was performed according to guideline and GLP. Therefore, the quality of the database is high.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.67 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):
600
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The systemic NOAEL from the oral study according to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test). No modification of this starting point is needed as the oral absorption is considered to be identical between rats and humans. 

AF for dose response relationship:
1
Justification:
starting point is a NOAEL
AF for differences in duration of exposure:
6
Justification:
default (sub-acute to chronic)
AF for interspecies differences (allometric scaling):
4
Justification:
default for rats
AF for other interspecies differences:
2.5
Justification:
default, since no specific information is available
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
The study was performed according to guideline and GLP. Therefore, the quality of the database is high.
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
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

General Population


 


Acute inhalation, dermal and oral exposure - systemic effects:


Chapter 8.7.3 of the REACH TGD (R.8) indicates that acute exposure DNEL values are not normally required. It is specified: "For some toxic substances, for which there may be peak exposures, a DNELacute needs to be set and assessed in relation to the human peak exposure levels". This would be the case for substances with classification & labelling for acute hazards.


However, for p-diisopropylbenzene no hazard is identified as it is not classified for acute systemic hazards via the inhalation, dermal or oral route of exposure.


For the inhalation route of exposure the following is relevant:  p-diisopropylbenzene has a very low volatility with a vapor pressure of only 41.5 Pa at 20 °C (determined according to EU Method A4). For the dermal route of exposure the acute dermal study on the test substance revealed an LD50 > 20 mL/kg bw in rats (no mortalities occurred; Topping, 1984). For the oral route of exposure the acute oral study on the test substance revealed an LD50 > 3200 mg/kg bw in rats (no mortalities occurred; Topping, 1984)).


So based on results of animal studies p-diisopropylbenzene does not pose an inhalation, dermal or oral hazard. Therefore, no DNEL is required and a DNEL is not quantifiable, not relevant (no adequate route-specific information) and the hazard assessment conclusion "no hazard identified" is chosen according to ECHA's Guidance Part E (v3, May 2016) in all three cases.


 


Acute short-term / Long-term inhalation or dermal exposure - local effects:


Chapter 8.7.3 of the REACH TGD (R.8) indicates that acute and long-term local DNEL values are required for substances causing irritation, corrosion and/or sensitisation, assuming that the data allow setting a DNEL.


p-diisopropylbenzene has been found to be only irritating to the skin and the Classification and labelling as Skin Irrit. Cat. 2 (H315 - Harmful in contact with skin) has been derived. However, no skin corrosion nor skin sensitisation was observed. 


Therefore, no DNEL is required and a DNEL is not quantifiable (no adequate route-specific information for setting an long-term or acute / short-term inhalation or dermal DNEL for local effects) and the hazard conclusion "no hazard identified" is chosen for inhalation exposure and the hazard conclusion "low hazard (no threshold derived)" was chosen for dermal exposure according to ECHA's Guidance Part E (v3, May 2016).


 


Long-term inhalation exposure - systemic effects:


An oral Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test gave a NOAEL of 1000 mg/kg. Extrapolating from subacute oral toxicity to chronic inhalation, the NOAEL first must be converted to mg/mby dividing by a factor of 1.15, and then corrected for oral bioavailability (50%) by multiplying by a factor of 0.5.


As the study is performed at 7 days/week, and the exposure of the general population is 7 days/week, as well, the NOAEL does not need to be further corrected.


 


The following Assessment factors were applied, which consisted of subacute to chronic studies (6), for intraspecies (10), for remaining interspecies differences (2.5) for a total of 150.


   


 - Converting mg/kg to mg/m= 1000/1.15 = 869.6 mg/m3


- Correcting for oral bioavailability = 869.6*0.5 = 434.78 mg/m3


- Application of adjustment factors – 434.78 mg/m3/ 150 = 2.9 mg/m3


 


Long-term dermal exposure - systemic effects:


An oral Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test gave a NOAEL of 1000 mg/kg. Extrapolating from subchronic oral toxicity to chronic dermal, the NOAEL first must be corrected for differences in absorption rates. The dermal absorption is 10 % and the oral absorption is 100 %. 


The following Assessment factors were applied, which consisted of subacute to chronic studies (6), for intraspecies (10), for interspecies (4), for remaining interspecies differences (2.5) for a total of 600.


 


- Correcting for absorption rates =1000*(10 %/100 %) = 10,000 mg/kg bw/day 


- Application of adjustment factors: 10,000 mg/kg/600 = 16.67 mg/kg


 


Long-term oral exposure - systemic effects:


An oral Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test gave a NOAEL of 1000 mg/kg. No extrapolation or corrections were necessary.


The following Assessment factors were applied, which consisted of subacute to chronic studies (4), for intraspecies (10), for interspecies (4) and for remaining interspecies differences (2.5), for a total of 600.


 


- Application of adjustment factors: 1000 mg/kg/600 = 1.67 mg/kg


 


Modification of the starting point:


Please refer to the specification made already for workers.


In addition, please take into account that for the modification of the starting point in case of Oral-to-inhalation extrapolation /Exposure conditions and respiratory volumes here the standard respiratory volume of rats during 24 hours (=1.15 m³/kg/day) and no correction for activity level) needs to be considered. Furthermore, here no adjustment for exposure duration is necessary as for workers 7 day per week have to be considered. 


 


Last but not least, the intraspecies differences assessment factor for the general population is 10 versus 5 for workers.