Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.5 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
88.2 mg/m³
Explanation for the modification of the dose descriptor starting point:
The long-term inhalation DNEL for systemic effects has been extrapolated from the oral NOAEL of 50 mg/kg bw/day obtained in a 2-generation reproductive toxicity study (Nemec, 1995). Using a correction factor: ((1/sRVrat(0.38))x(ABSoral-rat(50)/ABSinh-human(50))x(sRVhuman(6.7)/wRV(10))) gives a corrected inhalation NOAEC value of 88.2 mg/m3. An assessment factor of 25 is based on the following: 2.5 for interspecies difference (remaining difference), intraspecies difference (5 for workers), duration extrapolation (2 for sub-chronic to chronic exposure), and quality of the data (1 for a reliable study).
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic from a 2-generation reproduction toxicity study
AF for other interspecies differences:
2.5
Justification:
REACH default
AF for intraspecies differences:
5
Justification:
REACH default
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:
133.6 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
NOAEC
Value:
1 670 mg/m³
Explanation for the modification of the dose descriptor starting point:
N/A
AF for dose response relationship:
1
AF for other interspecies differences:
2.5
Justification:
REACH default
AF for intraspecies differences:
5
Justification:
REACH default
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:
8.33 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
833 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The oral 2-generation study (Nemec, 1995) was used as the starting value for derivation of the long term, systemic dermal DNEL. The dose descriptor was modified to include the low dermal absorption potential of 3% (50% oral/3% dermal). Applying the dermal absorption data from the TPP impurity is justified for the following reasons:

1. The risk assessment is conducted on TPP, not the registered phenate substance because it has been demonstrated that the phenate itself is non-hazardous for repeat dose, reproductive, and developmental toxicity.

2. Further to point 1, the NOAEL of 50 mg/kg bw/day is based on the presence of TPP as the source of toxicity, so it is appropriate to apply the TPP dermal absorption data

3. A comparison of the physiochemical properties demonstrates that the phenate will have less dermal absoprtion than TPP (see TK section for further information).

4. A 28 day dermal toxicity study with the registered substance exhibted no toxicity at the highest dose of 250 mg/kg bw/day

AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic from a 2-generation reproduction toxicity study
AF for interspecies differences (allometric scaling):
4
Justification:
REACH default
AF for other interspecies differences:
2.5
Justification:
REACH default
AF for intraspecies differences:
5
Justification:
REACH default
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:
80 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEL
Value:
4 000 mg/kg bw/day
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
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

Long-term systemic DNELs are derived for both the registered alkyl phenate sulfide substances and tetrapropenyl phenol (“TPP”, EC 310-154-3; AKA phenol, dodecyl-, branched (PDB, PDDP)). TPP is a reproductive hazard (CLP category 1B) and is present as residual starting material in alkyl phenate sulfides. Alkyl phenate sulfides themselves are not classified as hazardous and have low toxicity; the reproductive toxicity is due to the presence of TPP, which is justified in the reproductive hazard assessment in this dossier. Therefore, the risk assessment (section 9 and 10) is conducted on exposure to TPP from the use and handling of alkyl phenate sulfides. This approach is consistent with the substance evaluation decision for EC 701-251-5 (November, 2015). This same approach is applied to the alkyl phenate category members such as EC 701 -208 -0, including the exposure monitoring of TPP, which is justifiable because there is a similar or less amount of residual TPP. In addition, multiple alkyl phenate sulfides may be manufactured and formulated with simultaneously and this was the case during the exposure sampling. 

Alkyl phenate sulfides are not acutely toxic following oral and dermal routes of exposure. Inhalation exposure is unlikely to occur because the substance only exists in liquid form and it will not be aerosolized in its normal use pattern.

The substance is not irritating to the skin or eyes. On this basis, derivation of Acute DNELs for either systemic or local effects is not considered appropriate.

Long-term dermal DNEL for dermal and inhalation have been derived from the most robust study available, an OECD 416 two-generation reproductive toxicity study administered via oral gavage on EC 701-251-5. The NOAEL of 50 mg/kg bw/day for neonatal toxicity has been used as the starting dose descriptor.

Regarding the calculation of the long-term systemic inhalation DNEL, ECHA guidance recommends applying a correction factor of 2 to incorporate for higher absorption via inhalation compared to oral. However, based on the properties of this substance, this correction factor is not warranted. ECHA guidance (R.7.c, version 2.0 November, 2014 – section on “Respiratory absorption – Inhalation) states that only water soluble substances that are also lipophilic will be soluble in blood from the vapor phase. Based on the low water solubility and very high Kow for EC 701-251-5, it is unlikely to be absorbed after inhalation. In addition, based on the physical & chemical properties of this substance, inhalation exposure is expected to be very low or non-existent.

Setting a dermal DNEL for long-term local effects was not considered appropriate, because application of the substance 5 days a week for 4 consecutive weeks only cause a slight increase in the incidence and severity of dermal irritation (Korenaga, 1986).

All assessment factors used for the derivation of the DNEL values were taken from the ECHA guidance document “Guidance on information requirements and chemical safety assessment; Chapter R.8: Characterization of dose [concentration]-response for human health.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.87 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
43.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

The long-term inhalation DNEL for systemic effects has been extrapolated from the oral NOAEL of 50 mg/kg bw/day obtained in a 2 -generation reproductive toxcity study (Nemec, 1995).

The following correction factor was applied for oral to inhalation: ((1/sRVrat(1.15)) X (ABSoral-rat (50)/ABSinh-human (50)) gives a corrected inhalation NOAEC value of 43.5 mg/m3.

AF for dose response relationship:
1
Justification:
Adequate dose-response
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic from a 2-generation reproduction toxicity study
AF for interspecies differences (allometric scaling):
1
Justification:
REACH default
AF for other interspecies differences:
2.5
Justification:
REACH default
AF for intraspecies differences:
10
Justification:
REACH default
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:
0.067 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Value:
1.67 mg/m³
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10

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:
4.2 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
833 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The long-term dermal DNEL for systemic effects has been extrapolated from the oral NOAEL of 50 mg/kg bw/day obtained in a 2-generation reproductive toxicity study (Nemec, 1995). Similarly as for workers, the dermal absorption data obtained for TPP is applied to modify the dose descriptor by 50%/3%.

AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic from a 2-generation reproduction toxicity study
AF for interspecies differences (allometric scaling):
4
Justification:
REACH default
AF for other interspecies differences:
2.5
Justification:
REACH default
AF for intraspecies differences:
10
Justification:
REACH default
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:
40 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
4 000 mg/kg bw/day
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 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):
200
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic from a 2-generation reproduction toxicity study
AF for interspecies differences (allometric scaling):
4
Justification:
REACH default
AF for other interspecies differences:
2.5
Justification:
REACH default
AF for intraspecies differences:
10
Justification:
REACH default
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:
50 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
5 000 mg/kg bw/day
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The same end points have been used to derive DNELs for the general population as for workers. The increased AF of 10 for intraspecies sensitivity is considered to be sufficiently protective. The justification for applying a dermal absorption correction factor is found in the discussion for workers.

All assessment factors use for the derivation of the DNEL values were taken from the ECHA guidance document “Guidance on information requirements and chemical safety assessment; Chapter R.8: Characterisation of dose concentration-response for human health.

Categories Display