Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
18
Modified dose descriptor starting point:
NOAEC
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:
23.59 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
43
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
198 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
63
Dose descriptor:
other: LOAEL
AF for dose response relationship:
3
Justification:
According to Guidance on information requirements and chemical safety assessment Chapter R.8. Characterisation of dose [concentration]-response for human health, Section r.8.4.3.1. page 35 and Appendix R. 8-10 page 128.
AF for differences in duration of exposure:
1
Justification:
According to Guidance on information requirements and chemical safety assessment Chapter R.8. Characterisation of dose [concentration]-response for human health Section R.8.4.3.1. page 35. .
AF for interspecies differences (allometric scaling):
7
Justification:
According to Guidance on information requirements and chemical safety assessment Chapter R.8. Characterisation of dose [concentration]-response for human health Section R.8.4.3. Table R. 8-3, page 30 and Table R. 8-4, page 32.
AF for other interspecies differences:
1
Justification:
Allometric scaling was used.
AF for intraspecies differences:
3
Justification:
According to Guidance on information requirements and chemical safety assessment Chapter R.8. Characterisation of dose [concentration]-response for human health Appendix R. 8-3, Table R. 8-19, page 76.
AF for the quality of the whole database:
1
Justification:
Generally, all studies are of high quality Klimisch 1 with GLP compliance.
Justification:
NA
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

Data from this study, among others, was used to support the use of read across from vinyl neodecanoate to vinyl 2-ethylhexanoate. The NOAEL in the 14 range finder in rats study was 200 mg/kg/day while a NOAEL from an OECD 422 for vinyl neodecanoatewas equivalent,250 mg/kg/day.(The different NOAEL’s were because slightlyu different doses were pre-selected, not because of any difference in toxicity.)This was supporting evidence that, due to structural similarity, the data from vinyl neodecanoate can be read across to vinyl 2-ethylhexanoate.

The REACH Technical Guidance Document R.8 contains default assessment factors which should be applied to a modified dose descriptor in order to obtain a DNEL. These factors are multiplicative and can lead to a human chronic NAEL that is 100 or 200 fold lower than the equivalent rat subchronic NOAEL. However other guidance is available from ECETOC (2003), which supports smaller assessment factors to account for inter- and intra- species differences; leading to a human chronic NAEL that is only 24 to 40 -fold lower than an equivalent rat sub\chronic NOAEL. The ECETOC technical report includes scientific justification for the magnitude of these assessment factors, including:

· Although “residual” interspecies variability may remain following allometric scaling, this is largely accounted for in the default assessment factor proposed for intraspecies variability.

· Following analysis of the inherent variability in human toxicokinetic and toxicodynamic parameters, a difference of 3 (close to the 90th percentile) was considered appropriate to account for variability present in worker groups while a value of 5 (equivalent to the 95th percentile) was appropriate for the general population.

Section R.8.4.3.3 of the REACH Technical Guidance Document recognizes that the overall assessment factor applied to an experimental NOAEL when developing a DNEL is multiplicative in nature, and that “Care should be taken to avoid double counting several aspects when multiplying the individual factors.” Based on the information presented in ECETOC (2003) and summarized above, use of the standard defaults for inter- and intra- species variability contained in REACH Technical Guidance Document appears to result in “double counting”, and if used inappropriately, would lead to a large, conservative overall assessment factor. In order to retain the scientific credibility in its DNEL setting process, we will adopt the assessment factors proposed by ECETOC (2003) when developing DNELs.

 

Critical NOAEL used = rabbit oral NOAEL 100 mg/kg/day (developmental toxicity study (maternal toxicity) – systemic)

Absorption rates: 10% dermal, 100% oral, and 100% inhalation regardless of species

Dermal - Systemic

Dose descriptor = NOAEL of 100 mg/kg/day; from a well described oral developmental toxicity study.

 

Modification of dose descriptor

= oral NOAEL * (rat oral absorption rate / human dermal absorption rate)

= 100 * (100% / 10%)

dermal NOAEL = 1000 mg/kg/day

 

Adjustment factors (ECETOC Technical Report #86): 

 

Criteria

Adjustment Factor

Allometric scaling - rabbit

2.4

Intraspecies - workers 

3

Subacute study to Chronic       

6

Overall Adjustment Factor

43.2

 

           

                                   

 

DNEL calculation

DNEL dermal = dermal NOAEL / (adjustment factors)

DNEL dermal = 1000 mg/kg/day / (2.4 * 3 * 6)

DNEL dermal = 23.15 mg/kg/day

 

Inhalation

Dose descriptor = NOAEL of 100 mg/kg/day; from a well described oral developmental toxicity study

 

Route-to-route extrapolation (calculation B.3 in ECHA Guidance R.8)

inhalatory NOAEC = oral LOAEL * (1/ sRV rat 8h) * (ABS oral / ABS inh) * (sRV human / wRV)

inhalatory NOAEC= 100 * (1/0.38) * (100/100) * (6.7/10)

inhalatory NOAEC = 176.32 mg/m3

 

Adjustment factors (ECETOC Technical Report #86):

Criteria

Adjustment Factor

Allometric scaling - rabbit

not applied

Intraspecies - workers 

3

Subacute study to Chronic    

6

Overall Adjustment Factor

18

           

DNEL calculation

DNEL inhalation = inhalation NOAEC / (adjustment factors)

DNEL inhalation = 176.32 mg/m3 / (18)

DNEL inhalation = 9.80 mg/m3

There were no local effects observed in repeated-dose rat studies upon which long-term exposure-local effects DNELs could be established.

A dermal local effects DNEL is based up on the outcome of an O.E.C.D. test guideline Mouse LLNA with an EC3 value of approximately 50 % v/v. Appropriate E.C.H.A. guidance recommended Assessment Factors were employeed to derive the DNEL value.

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
DNEL related information
Overall assessment factor (AF):
30
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:
13.89 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
72
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
119 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
105
Dose descriptor:
other: LOAEL
AF for dose response relationship:
3
Justification:
According to Guidance on information requirements and chemical safety assessment Chapter R.8. Characterisation of dose [concentration]-response for human health Section R.8.4.3.1, page 36 and Appendix R. 8-10, page 128.
AF for differences in duration of exposure:
1
Justification:
According to Guidance on information requirements and chemical safety assessment Chapter R.8. Characterisation of dose [concentration]-response for human health Section R.8.4.3.1. page 35.
AF for interspecies differences (allometric scaling):
7
Justification:
According to Guidance on information requirements and chemical safety assessment Chapter R.8. Characterisation of dose [concentration]-response for human health, Section R. 8.4.3. Table R 8-3, page 30 and Table R. 8-4, page 32.
AF for other interspecies differences:
1
Justification:
Allometric Scaling was used.
AF for intraspecies differences:
5
Justification:
According to Guidance on information requirements and chemical safety assessment Chapter R.8. Characterisation of dose [concentration]-response for human health. Appendix 8.3. Table R. 8-19, page 76.
AF for the quality of the whole database:
1
Justification:
Generally, all studies are of high quality, Klimisch1 with GLP compliance.
Justification:
NA
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:
1.39 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
72
Modified dose descriptor starting point:
NOAEL
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

Data from this study, among others, was used to support the use of read across from vinyl neodecanoate to vinyl 2-ethylhexanoate. The NOAEL in the 14 range finder in rats study was 200 mg/kg/day while a NOAEL from an OECD 422 for vinyl neodecanoate was 250 mg/kg/day. This was supporting evidence that, due to structural similarity, the data from vinyl neodecanoate can be read across to vinyl 2-ethylhexanoate.

The REACH Technical Guidance Document R.8 contains default assessment factors which should be applied to a modified dose descriptor in order to obtain a DNEL. These factors are multiplicative and can lead to a human chronic NAEL that is 100 or 200 fold lower than the equivalent rat subchronic NOAEL. However other guidance is available from ECETOC (2003), which supports smaller assessment factors to account for inter- and intra- species differences; leading to a human chronic NAEL that is only 24 to 40 -fold lower than an equivalent rat sub\chronic NOAEL. The ECETOC technical report includes scientific justification for the magnitude of these assessment factors, including:

· Although “residual” interspecies variability may remain following allometric scaling, this is largely accounted for in the default assessment factor proposed for intraspecies variability.

· Following analysis of the inherent variability in human toxicokinetic and toxicodynamic parameters, a difference of 3 (close to the 90th percentile) was considered appropriate to account for variability present in worker groups while a value of 5 (equivalent to the 95th percentile) was appropriate for the general population.

Section R.8.4.3.3 of the REACH Technical Guidance Document recognizes that the overall assessment factor applied to an experimental NOAEL when developing a DNEL is multiplicative in nature, and that “Care should be taken to avoid double counting several aspects when multiplying the individual factors.” Based on the information presented in ECETOC (2003) and summarized above, use of the standard defaults for inter- and intra- species variability contained in REACH Technical Guidance Document appears to result in “double counting”, and if used inappropriately, would lead to a large, conservative overall assessment factor. In order to retain the scientific credibility in its DNEL setting process, we will adopt the assessment factors proposed by ECETOC (2003) when developing DNELs.

Critical NOAEL used = rabbit oral NOAEL 100 mg/kg/day (developmental toxicity study (maternal toxicity) – systemic)

Absorption rates: 10% dermal, 100% oral, and 100% inhalation regardless of species

Dermal - Systemic

Dose descriptor = NOAEL of 100 mg/kg/day; from a well described oral developmental toxicity study.

 

Modification of dose descriptor

= dermal NOAEL * (rat oral absorption rate / human dermal absorption rate)

= 100 * (100% / 10%)

dermal NOAEL = 1000 mg/kg/day

 

Adjustment factors (ECETOC Technical Report #86):

Criteria

Adjustment Factor

Allometric scaling - rabbit

2.4

Intraspecies – general population

5

Subacute study to Chronic       

6

Overall Adjustment Factor

72

 

DNEL calculation

DNEL dermal = dermal NOAEL / (adjustment factors)

DNEL dermal = 1000 mg/kg/day / (2.4 * 5 * 6)

DNEL dermal = 13.89 mg/kg/day

 

 

Inhalation

Dose descriptor = NOAEL of 100 mg/kg/day; from a well described development toxicity study

 

Route-to-route extrapolation (calculation B.3 in ECHA Guidance R.8)

inhalatory NOAEC = oral NOAEL * (1/ sRV rat 24h) * (ABS oral / ABS inh)

inhalatory NOAEC= 100 * (1/1.15) * (100/100)

inhalatory NOAEC = 86.96 mg/m3

 

Adjustment factors (ECETOC Technical Report #86):

Criteria

Adjustment Factor

Allometric scaling - rabbit

not applied

Intraspecies – General Population

5

Subacute study to Chronic    

6

Overall Adjustment Factor

30

 

DNEL calculation

DNEL inhalation = inhalation NOAEC / (adjustment factors)

DNEL inhalation = 86.96 mg/m3 / (30)

DNEL inhalation = 2.90 mg/m3

 

Oral

Dose descriptor = NOAEL of 100 mg/kg/day; from a well described oral development toxicity study

 

Modification of dose descriptor: Not required

 

Adjustment factors (ECETOC Technical Report #86):

Criteria

Adjustment Factor

Allometric scaling - rabbit

2.4

Intraspecies – General Population

5

Subacute study to Chronic    

6

Overall Adjustment Factor

72

 

DNEL calculation

DNEL oral = oral NOAEL / (adjustment factors)

DNEL oral = 100 mg/kg/day / (72)

DNEL oral = 1.39 mg/kg/day

 There were no local effects observed in repeated-dose rat studies upon which long-term exposure-local effects DNELs could be established.

A dermal local effects DNEL for the General Population is based up on the outcome of an O.E.C.D. test guideline Mouse LLNA with an EC3 value of approximately 50 % v/v. The dermal DNEL was derived following the E.C.H.A. guidance document, "  

According toGuidance on information requirements and chemical safety assessment Chapter R.8. Characterisation of dose [concentration]-response for human health."