Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
0.01 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):
75
Dose descriptor starting point:
LOAEC
3 mg/kg bw/day
Modified dose descriptor starting point:
BMCL05
0.85 mg/m³
Explanation for the modification of the dose descriptor starting point:

Based on the developmental effects observed in the developmental toxicity study, the LOAEL for developmental toxicity is used as the most sensitive endpoint for overall DNEL derivation. This value should be used for short term and repeated exposure as an effect at a vulnerable stage of pregnancy adter a single exposure cannot be excluded.To better reflect the dose response in the developmental toxicity study a bench mark dose calculation of the incidence the most sensitive visceral malformations was calculated, both on a single foetal and litter basis using the US EPA Bench mark dose model version 2.6.0 and the Gamma model for dichotomous data Normally the statisitical reference in developmental toxicity studies is the litter data to avoid bias for litter mates. However, as in this case at the mid and high dose level all litters were affected, the benchmark dose calculation based on single foetal incidences seems to be more reliable and discriminatory.The BMD5based on single foetal incidences of renal pelvic malformations was

1.02 mg/kg/d with a BMDL (95% confidence interval) of 0.69 mg/kg/day.

Correction for absorption

The basic toxicokinetic assessment indicates that the substance is well absorbed via the oral route. However,as it is likely that the substance is metabolized in the liver,a first pass effect cannot be excluded completely.Therefore the default assessment factor of 2 for the difference in availability between the oral and inhalation route is applied as a worst case assumption (ECHA guidance on information requirements R.8, 2012).

Route to rout extrapolation

Rat: Division by 0.38 m3/kg bw to account for an 8h inhalation exposure of rats allometric scaling and multiplication with 6.7m3/10m3 to account for the difference between rest and light activity.

For developmental toxicity this results in an modified starting point for inhaltion exposure of: 0.6 mg/m3

Correction for 7 day exposure of rats versus 5 day exposure of workers: x 7/5: results in 0.85 mg/m3 for developmental toxicity.

AF for dose response relationship:
1
Justification:
the dose response was modelled in the BMD approach.
AF for differences in duration of exposure:
1
Justification:
This was accounted for in the modification of the stating poitn above
AF for interspecies differences (allometric scaling):
1
Justification:
Included in the route to toute extrapolation from oral to inhalation rat to human.
AF for other interspecies differences:
2.5
Justification:
Remaining factor for possible differences in toxicodynamics according to ECHA guidance
AF for intraspecies differences:
5
Justification:
See ECHA guidance
AF for the quality of the whole database:
1
Justification:
Based on recent guideline studies and most sensitive endppoint.
AF for remaining uncertainties:
1
Justification:
No specifc remaining uncertainties identified.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
0.12 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
5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
6.2 mg/m³
Explanation for the modification of the dose descriptor starting point:

see CSR

AF for dose response relationship:
6
Justification:
Repeated dose toxicity: As the NOAEL derived from the study is close to an effect level and additional assessment factor of 2 is used to correct for the uncertainty around the NOAEL.
AF for interspecies differences (allometric scaling):
1
Justification:
see CSR
AF for other interspecies differences:
2.5
Justification:
see CSR
AF for intraspecies differences:
5
Justification:
see CSR
AF for the quality of the whole database:
1
Justification:
see CSR
AF for remaining uncertainties:
1
Justification:
see CSR

Local effects

Long term exposure
Hazard assessment conclusion:
No-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
No-threshold effect and/or no dose-response information available
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
No-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
No-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
No-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
No-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
0.003 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):
150
Dose descriptor starting point:
LOAEC
3 mg/kg bw/day
Modified dose descriptor starting point:
BMCL05
0.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

Although an inhalation exposure of the general population is unlikely and the substance is not expected to be present in consumer products due to its reactivity, the inhalaion DNEL is derived. However, due to the absence of consumer exposure no risk characterisation is performed.

The basic toxicokinetic assessment indicates that the substance is well absorbed via the oral route. However,as it is likely that the substance is metabolized in the liver,a first pass effect cannot be excluded completely.Therefore the default assessment factor of 2 for the difference in availability between the oral and inhalation route is applied as a worst case assumption (ECHA guidance on information requirements R.8, 2012). This results in a corrected BMDL for developmental toxicity of: 0.35 mg/kg bw/ day.

Route to route extrapolation rat: Divisionby1.15m3/kgbw: (See ECHA R 8., 2012)

This results in a starting value for inhalation exposure for developmental toxicity of 0.4 mg/m3.

AF for dose response relationship:
1
Justification:
Included in the benchmark dose calculation.
AF for differences in duration of exposure:
1
Justification:
included in the route to troute extrapolation
AF for interspecies differences (allometric scaling):
1
Justification:
Included in the route to route extrapolation.
AF for other interspecies differences:
2.5
Justification:
For remaining dynamic differences according to ECHA guidance
AF for intraspecies differences:
10
Justification:
According to ECHA guidane
AF for the quality of the whole database:
1
Justification:
The assessment is based on recent guideline studies.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties identified.
Acute/short term exposure
Hazard assessment conclusion:
Exposure based waiving
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
No-threshold effect and/or no dose-response information available
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:
DNEL (Derived No Effect Level)
0.001 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):
600
Dose descriptor starting point:
LOAEL
3 mg/kg bw/day
Modified dose descriptor starting point:
BMDL05
0.69 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Although a dermal exposure of the general population is unlikely and the substance is not expected to be present in consumer products due to its reactivity, the dermal DNEL is derived. However, due to the absence of consumer exposure no risk characterisation is performed.

Based on basic toxicokinetic considerations for the substance it can reasonably be assumed that the absorption is comparable after oral and dermal exposure and no correction is made.Normally dermal absorption will be lower than oral absorption.

 

 

AF for dose response relationship:
1
Justification:
covered by the BMD calculation
AF for differences in duration of exposure:
1
Justification:
no drmal exposure anticipated
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA guidance
AF for other interspecies differences:
2.5
Justification:
ECHA guidance
AF for intraspecies differences:
10
Justification:
ECHA guidance
AF for the quality of the whole database:
1
Justification:
Based on recent guideline studies
AF for remaining uncertainties:
1
Justification:
No further uncertainties identified.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information
Explanation for the modification of the dose descriptor starting point:

Acute dermal exposure of consumers to the substance is not

anticipated from the uses. The substance as such is not contained in consumer products.

Local effects

Long term exposure
Hazard assessment conclusion:
No-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
Exposure based waiving

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
0.001 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):
600
Dose descriptor starting point:
LOAEL
3 mg/kg bw/day
Modified dose descriptor starting point:
BMDL05
0.69 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Although an oral exposure of the general population is unlikely and the substance is not

expected to be present in consumer products due to its reactivity, the DNEL is derived. However, due to the absence of consumer exposure no risk characterisation is performed.

Based on the developmental effects observed in the developmental toxicity study, the LOAEL for developmental toxicity is used as the most sensitive endpoint for overall DNEL derivation. This value should be used for short term and repeated exposure as an effect at a vulnerable stage of pregnancy adter a single exposure cannot be excluded.To better reflect the dose response in the developmental toxicity study a bench mark dose calculation of the incidence the most sensitive visceral malformations was calculated, both on a single foetal and litter basis using the US EPA Bench mark dose model version 2.6.0 and the Gamma model for dichotomous data Normally the statisitical reference in developmental toxicity studies is the litter data to avoid bias for litter mates. However, as in this case at the mid and high dose level all litters were affected, the benchmark dose calculation based on single foetal incidences seems to be more reliable and discriminatory.The BMD5based on single foetal incidences of renal pelvic malformations was

1.02 mg/kg/d with a BMDL (95% confidence interval) of 0.69 mg/kg/day.

AF for dose response relationship:
1
Justification:
Covered by the BMD calculation
AF for differences in duration of exposure:
1
Justification:
covered by the data
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA guidance
AF for other interspecies differences:
2.5
Justification:
ECHA guidance
AF for intraspecies differences:
10
Justification:
ECHA guidance
AF for the quality of the whole database:
1
Justification:
Based on recent guideline studies.
AF for remaining uncertainties:
1
Justification:
none identified
Acute/short term exposure
Hazard assessment conclusion:
Exposure based waiving
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population