Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.53 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):
25
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
88.16 mg/m³
Explanation for the modification of the dose descriptor starting point:

Regarding absorption, in the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst case assumptions were made. It was assumed that a limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100 %) leading to a low external NOAEL. Thus, in the case of oral-to- inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012).

To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 0.38 m3/kg bw/8 h). For workers a correction was added for the difference between respiratory rates under standard conditions (sRVhuman: 6.7 m3 for an 8 h exposure period) and under conditions of light activity (wRV: 10 m3 for an 8 h exposure period).

The corrected dose descriptor for inhalation is determined using the following equation:

Corrected Inhalatory NOAEC =NOAEL (oral) x 1/SRVrat x ABS(oral-rat)/ABS(inh-human) x sRVhuman/wRV

= [100 mg/kg bw/day] x  [1/0.38 m3/kg bw/day] x [1/2] X [6.7 m3/10m3].

Thus, the corrected dose descriptor for inhalation is 88.16 mg/m3 for workers.

AF for dose response relationship:
1
Justification:
The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance
AF for differences in duration of exposure:
2
Justification:
Default factor for a semi/sub-chronic study. Table R.8-5 ECHA REACH Guidance.
AF for interspecies differences (allometric scaling):
1
Justification:
Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in the metabolic rate/bw has already been taken into account in the corrected dose descriptor.
AF for other interspecies differences:
2.5
Justification:
Table R.8-4 ECHA REACH Guidance.
AF for intraspecies differences:
5
Justification:
Default factor for worker. Table R.8-6 ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

In accordance with Annex VIII, Section 8.5.2, Column 2 of REACH, testing by the inhalation route was waived due to low vapour pressure of 2.0E-04 Pa and a use pattern resulting in exposure to humans was considered negligible.  No acute toxicity hazard (leading to classification & labelling) has been identified for the substance following dermal and oral exposure.  No acute inhalation hazard is therefore identified for this substance.

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:
1 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):
100
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

For systemic hazard assessment via the dermal route of exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. As no data on dermal penetration are available, dermal absorption is considered to be the same as oral absorption (i.e. 100 %). Therefore the dermal NOAEL is considered the same as the oral NOAEL (ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012)).

AF for dose response relationship:
1
Justification:
The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.
AF for differences in duration of exposure:
2
Justification:
Default factor for a semi/sub-chronic study. Table R.8-5 ECHA REACH Guidance.
AF for interspecies differences (allometric scaling):
4
Justification:
Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.
AF for other interspecies differences:
2.5
Justification:
Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.
AF for intraspecies differences:
5
Justification:
Default factor for worker. Table R.8-6 ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

NOAEL (systemic toxicity – STOT-RE) = 100 mg/kg bw/day; OECD 408 (2012)

There are several sub-acute and sub-chronic studies conducted on the test item and the long-term systemic hazard assessment is based on a sub-chronic toxicity study conducted on rats in accordance with OECD 408 under GLP (2012).  In this study, the test item was administered to rats by oral gavage at dose levels of 100, 300 and 1000 mg/kg bw/day without the inclusion of satellite group but control groups. The test item was well-tolerated by the animals in the in-life phase of the study with no animals dying prematurely, no clinical signs related to treatment or of toxicological importance and no effects seen on sensory reactivity, grip strength or motor activity. Bodyweight and food consumption were also unaffected and there were no treatment-related ophthalmic lesions reported. However, specific target organ toxicity in the liver and kidney was observed at mid to high dose groups which was considered to be treatment related. These effected included Periportal hepatocyte vacuolation (fatty change) which was characterised by cytoplasmic fat accumulation and centrilobular hepatocyte hypertrophy in the liver and hyaline droplet accumulation in the cortical tubules, accompanied by the accumulation of granular casts in the corticomedullary junction in the kidney. The centrilobular hepatocyte hypertrophy was considered an adaptive response as it was associated with hepatic enzyme induction and decrease in thyroid hormones. The test item contribution the observed periportal hepatocyte vacuolation could not be ruled out as it was also gender specific with observed dose respond effects. The hyaline droplet nephropathy was also does related, however, this is a common problem observed in rat following exposure to xenobiotic. Therefore, it is considered that under the conditions of this study, the no-observed-adverse-effect-level (NOAEL) on this study is 100 mg/kg/day based on the terminal investigations indicated the liver, thyroids and kidneys as target organs which were considered to be adverse in nature at dose levels of 300 and 1000 mg/kg/day. The substance meet the criteria for classification for specific target organ toxicity - repeated exposure (STOT-RE) in accordance with Regulation (EC) No 1272/2008 (CLP). 

Other sub-acute/chronic studies were conducted to address the potential reproductive and developmental toxicity effect of the test item in rat, the studies follow OECD 421, OECD 416 and OECD 414 guidelines. In the screening study OECD 421, the animals were exposed at up to 1000 mg/kg bw/day test item without including recovery group.  Non-treatment related mortalities were observed at mid and high dose groups without any overt toxicity observed. There were no effects on reproductive performance, mating, estrous cycle, fertility with all gestation lengths, however, changes of an uncertain relationship to treatment were seen in the ovary of females at all dose groups. Offspring bodyweight and birth weights were slightly lower than control groups at 300 and 1000 mg/kg/day, respectively. It is concluded that that the No-Observed-Adverse-Effect-Level (NOAEL) was 1000 mg/kg/day for reproductive performance and 100 mg/kg/day was considered to be the overall NOAEL because of the effects seen on birth weight at 300 and 1000 mg/kg/day.  In the two-generation study (OECD 416), rats received oral garage dose of 30, 100 or 300 mg/kg/day including control groups receiving vehicle only. There was no evidence of any adverse effect on clinical condition, bodyweight, bodyweight change, food consumption or food conversion efficiency in the F0 or F1 generations at all dose groups. Reproductive performance of F0 and F1 adults such as oestrous cycles, mating performance, pre-coital interval, gestation length, litter size and subsequent offspring clinical condition and sex ratio were unaffected. The survival of F1 offspring was unaffected but the viability index (%) of F2 was statistically significantly lower in the high dose groups and a relationship to parental treatment with the test item could not be ruled out. Abnormalities in the form of hyaline droplet nephropathy were observed in the kidneys of F0 or F1 males in the 100 or 300 mg/kg/day groups. Based on the results of this study it was concluded that the no-observed-adverse-effect-level (NOAEL) for general toxicity and reproductive performance of the F0 and F1 adult animals is 300 mg/kg/day. The NOAEL for offspring survival and growth is 100 mg/kg/day, based on reduced survival of the F2 offspring between Day 1 and 4 of age, and the low Day 1 body weights of the offspring on both generations at 300 mg/kg/day. In the Embryo-Fetal Developmental toxicity study (OECD 414), the test item was administered to rats via oral gavage at dose of 100, 300 and 1000 mg/kg/day. There were no deaths and no clinical signs seen, no effects on organ weight or any macroscopic findings at necropsy or effects on maternal bodyweight and bodyweight gain and food consumption was not affected. Embyro-fetal survival, growth and development were also unaffected, however, incidence of major and minor abnormalities and skeletal variants without any relationship to treatment. This included a slightly higher incidence of incompletely ossified/ unossified cranial centres, hyoid, and pelvic bones compared with concurrent controls at 1000 mg/kg/day. Based on the results of this study, it is concluded that the no-observed-adverse-effect-level (NOAEL) for both maternal toxicity and embryo-fetal development was 1000 mg/kg/day.

NOAEL(general toxicity and reproductive performance of the F0 and F1) = 300 mg/kg bw/day

NOAEL (development & teratogenicity) = 1000 mg/kg bw/day, with no hazard identified.

NOAEL for offspring survival and growth = 100 mg/kg bw/day based om reduction in survival of F2 offspring.

NOAEL (Systemic toxicity) = 100 mg/kg bw/day, with classification for specific target organ toxicity - repeated exposure (STOT-RE) in accordance with Regulation (EC) No 1272/2008 (CLP). 

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:
repeated dose toxicity
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:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
43.48 mg/m³
Explanation for the modification of the dose descriptor starting point:

Concerning absorption, in the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst case assumptions were made. It was assumed that a limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100 %) leading to a low external NOAEL. Thus, in the case of oral-to- inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012).

To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 1.15 m3/kg bw/24 h).

The corrected dose descriptor for inhalation is determined using the following equation:

Corrected Inhalator NOAEC = 1/sRVrat x ABSoral-rat/ABSinh-rat x ABSinh-rat/ABSinh-human

= [100 mg/kg bw/day] x [1/1.15 m3/kg bw/ day] x [1/2] x [1/1]

Thus, the corrected dose descriptor for inhalation is 43.48 mg/m3 for the general population.

AF for dose response relationship:
1
Justification:
The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.
AF for differences in duration of exposure:
2
Justification:
Default factor for a sub-chronic. Table R.8-5 ECHA REACH Guidance.
AF for interspecies differences (allometric scaling):
1
Justification:
Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in metabolic rate/bw has already been taken into account for the corrected dose descriptor
AF for other interspecies differences:
2.5
Justification:
Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.
AF for intraspecies differences:
10
Justification:
Default factor for general population. Table R.8-6 ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.
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:
0.5 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:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

For systemic hazard assesment via the dermal route of exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. As no data on dermal penetration are available, dermal absorption is considered to be the same as oral absorption (i.e. 100 %). Therefore the oral NOAEL is considered the same as the dermal NOAEL (ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012))

AF for dose response relationship:
1
Justification:
The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.
AF for differences in duration of exposure:
2
Justification:
Default factor for a semi/sub-chronic study. Table R.8-5 ECHA REACH Guidance.
AF for interspecies differences (allometric scaling):
4
Justification:
Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.
AF for other interspecies differences:
2.5
Justification:
Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.
AF for intraspecies differences:
10
Justification:
Default factor for general population. Table R.8-6 ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.
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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 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:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No modification of the dose descriptor starting point is required. The endpoint used to derive the DNEL uses the oral route for exposure.

AF for dose response relationship:
1
Justification:
The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.
AF for differences in duration of exposure:
2
Justification:
Default factor for a semi/sub-chronic study. Table R.8-5 ECHA REACH Guidance.
AF for interspecies differences (allometric scaling):
4
Justification:
Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.
AF for other interspecies differences:
2.5
Justification:
Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.
AF for intraspecies differences:
10
Justification:
Default factor for general population. Table R.8-6 ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.
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

NOAEL (systemic toxicity – STOT-RE) = 100 mg/kg bw/day; OECD 408 (2012)

There are several sub-acute and sub-chronic studies conducted on the test item and the long-term systemic hazard assessment is based on a sub-chronic toxicity study conducted on rats in accordance with OECD 408 under GLP (2012).  In this study, the test item was administered to rats by oral gavage at dose levels of 100, 300 and 1000 mg/kg bw/day without the inclusion of satellite group but control groups. The test item was well-tolerated by the animals in the in-life phase of the study with no animals dying prematurely, no clinical signs related to treatment or of toxicological importance and no effects seen on sensory reactivity, grip strength or motor activity. Bodyweight and food consumption were also unaffected and there were no treatment-related ophthalmic lesions reported. However, specific target organ toxicity in the liver and kidney was observed at mid to high dose groups which was considered to be treatment related. These effected included Periportal hepatocyte vacuolation (fatty change) which was characterised by cytoplasmic fat accumulation and centrilobular hepatocyte hypertrophy in the liver and hyaline droplet accumulation in the cortical tubules, accompanied by the accumulation of granular casts in the corticomedullary junction in the kidney. The centrilobular hepatocyte hypertrophy was considered an adaptive response as it was associated with hepatic enzyme induction and decrease in thyroid hormones. The test item contribution the observed periportal hepatocyte vacuolation could not be ruled out as it was also gender specific with observed dose respond effects. The hyaline droplet nephropathy was also does related, however, this is a common problem observed in rat following exposure to xenobiotic. Therefore, it is considered that under the conditions of this study, the no-observed-adverse-effect-level (NOAEL) on this study is 100 mg/kg/day based on the terminal investigations indicated the liver, thyroids and kidneys as target organs which were considered to be adverse in nature at dose levels of 300 and 1000 mg/kg/day. The substance meet the criteria for classification for specific target organ toxicity - repeated exposure (STOT-RE) in accordance with Regulation (EC) No 1272/2008 (CLP). 

Other sub-acute/chronic studies were conducted to address the potential reproductive and developmental toxicity effect of the test item in rat, the studies follow OECD 421, OECD 416 and OECD 414 guidelines. In the screening study OECD 421, the animals were exposed at up to 1000 mg/kg bw/day test item without including recovery group.  Non-treatment related mortalities were observed at mid and high dose groups without any overt toxicity observed. There were no effects on reproductive performance, mating, estrous cycle, fertility with all gestation lengths, however, changes of an uncertain relationship to treatment were seen in the ovary of females at all dose groups. Offspring bodyweight and birth weights were slightly lower than control groups at 300 and 1000 mg/kg/day, respectively. It is concluded that that the No-Observed-Adverse-Effect-Level (NOAEL) was 1000 mg/kg/day for reproductive performance and 100 mg/kg/day was considered to be the overall NOAEL because of the effects seen on birth weight at 300 and 1000 mg/kg/day.  In the two-generation study (OECD 416), rats received oral garage dose of 30, 100 or 300 mg/kg/day including control groups receiving vehicle only. There was no evidence of any adverse effect on clinical condition, bodyweight, bodyweight change, food consumption or food conversion efficiency in the F0 or F1 generations at all dose groups. Reproductive performance of F0 and F1 adults such as oestrous cycles, mating performance, pre-coital interval, gestation length, litter size and subsequent offspring clinical condition and sex ratio were unaffected. The survival of F1 offspring was unaffected but the viability index (%) of F2 was statistically significantly lower in the high dose groups and a relationship to parental treatment with the test item could not be ruled out. Abnormalities in the form of hyaline droplet nephropathy were observed in the kidneys of F0 or F1 males in the 100 or 300 mg/kg/day groups. Based on the results of this study it was concluded that the no-observed-adverse-effect-level (NOAEL) for general toxicity and reproductive performance of the F0 and F1 adult animals is 300 mg/kg/day. The NOAEL for offspring survival and growth is 100 mg/kg/day, based on reduced survival of the F2 offspring between Day 1 and 4 of age, and the low Day 1 body weights of the offspring on both generations at 300 mg/kg/day. In the Embryo-Fetal Developmental toxicity study (OECD 414), the test item was administered to rats via oral gavage at dose of 100, 300 and 1000 mg/kg/day. There were no deaths and no clinical signs seen, no effects on organ weight or any macroscopic findings at necropsy or effects on maternal bodyweight and bodyweight gain and food consumption was not affected. Embyro-fetal survival, growth and development were also unaffected, however, incidence of major and minor abnormalities and skeletal variants without any relationship to treatment. This included a slightly higher incidence of incompletely ossified/ unossified cranial centres, hyoid, and pelvic bones compared with concurrent controls at 1000 mg/kg/day. Based on the results of this study, it is concluded that the no-observed-adverse-effect-level (NOAEL) for both maternal toxicity and embryo-fetal development was 1000 mg/kg/day.

NOAEL(general toxicity and reproductive performance of the F0 and F1) = 300 mg/kg bw/day

NOAEL (development & teratogenicity) = 1000 mg/kg bw/day, with no hazard identified.

NOAEL for offspring survival and growth = 100 mg/kg bw/day based om reduction in survival of F2 offspring.

NOAEL (Systemic toxicity) = 100 mg/kg bw/day, with classification for specific target organ toxicity - repeated exposure (STOT-RE) in accordance with Regulation (EC) No 1272/2008 (CLP).