Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.11 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
DNEL value:
350 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
308.55 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 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. This is in accordance with 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] x (1/SRVrat x ABS(oral-rat)/ABS(inh-human) x sRVhuman/wRV

= [350 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 308.55 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:
6
Justification:
Default factor for a sub-acute 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:
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
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.17 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
DNEL value:
350 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
350 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

For potential dermal exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate since a maximal absorption already occurred via the oral route, no additional factor was introduced.

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:
6
Justification:
Default factor for a sub-acute 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:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

NOAEL (Systemic toxicity) = 750 mg/kg /day; (reproductive toxicity) = 350 mg/kg bw/day in an OECD 422; S. Flucher. (2019)

The study was designed to investigate the systemic toxicity and potential adverse effects of the test item on reproduction (including offspring development), to evaluate some endocrine disruptor relevant endpoints and is designed to be compatible with the requirements of the OECD Guidelines for Testing of Chemicals No. 422 “Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test” (adopted 29 July 2016). Additionally, the Comet assay was added for the detection of DNA strand breaks in cells or nuclei isolated from tissues taken from male rats.  Three groups, each of twelve male and twelve female Wistar HanTM:RccHanTM:WIST strain rats, were dosed for approximately six weeks for males and for approximately eight weeks for females (including a two week pre-pairing phase, pairing, gestation and early lactation for females), at dose levels of 100, 350 and 750 mg/kg bw/day. A control group of twelve males and twelve females were dosed with vehicle alone (Polyethylene Glycol ) over the same period. A further three males were dosed with N- Nitroso-N-methylurea (vehicle: distilled water) for two consecutive days to act as a positive control group for the comet assay investigation.

No advert clinical signs, no behavioural or functional as well as sensory reactivity effects were observed. Food and water consumption were unaffected and the body weights were also unaffected. There was no effect of treatment on mating, estrous cycles of females, pregnancy and gestation lengths.

At 750 mg/kg bw/day, the mean number of implantations was lower than control leading to lower litter size from birth, however, there was no effect of maternal treatment on post-implantation loss or post-natal survival.  Offspring body weight gain was slightly lower than control, despite the lower litter size at this dosage, leading to lower mean offspring body weight at Day 13 of age. Litter weight at 750 mg/kg bw/day, was lower than control throughout, initially reflecting the lower litter size and additionally the lower weight gain as lactation progressed. There was a higher incidence of small offspring consistent with the lower offspring growth at this dosage, but otherwise, offspring clinical signs appeared unaffected by maternal treatment at 100, 350 or 750 mg/kg bw/day. There was a higher incidence of small offspring at necropsy, consistent with the lower offspring growth at this dosage, but otherwise, offspring necropsy findings appeared unaffected by maternal treatment at 100, 350 or 750 mg/kg bw/day. No effects on offsping viability or sex ratio were seen at any dose. It was noted that absolute and body weight-relative thyroid weights were statistically significantly higher than control for females at 350 and 750 mg/kg bw/day. This increase in thyroid weights appeared to reflect follicular hypertrophy in the thyroid of some females at these dosages, however, neither the incidence of this microscopic finding nor the differences in mean thyroid weights showed any dosage relationship and this finding was considered not to represent an adverse effect of treatment.

No effects on haematology, blood chemistry, necropsy and histopathological examinations indicated any adverse effect of treatment at 100, 350 and 750 mg/kg bw/day.

Comet assay investigations during the study did not show any treatment induced DNA damage in the jejunum, glandular stomach or liver under the conditions of the test at 100, 350 and 750 mg/kg bw/day.

Reproductive performance was unaffected; the test article did not affect estrous cycles, mating, fertility, pregnancy or parturition.

The No Observed Adverse Effect Level (NOAEL) for systemic toxicity for the adult animal was considered to be 750 mg/kg bw/day.

Lower numbers of implantations were apparent for females at 750 mg/kg bw/day, therefore, the NOAEL for reproduction was considered to be 350 mg/kg bw/day.

At 750 mg/kg bw/day, offspring growth was lower than control, therefore, the NOAEL for the offspring was considered to be 350 mg/kg bw/day

NOAEL (Reproductive toxicity) = 350 mg/kg /day was therefore used to derive the workers DNELs in accordance with ECHA Guideline

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.014 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
DNEL value:
350 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
152.17 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. This is in accordance with 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

= [NOAEL] x [350 mg/kg bw/day] x [1/1.15 m3/kg bw/ day] x [1/2].

Thus, the corrected dose descriptor for inhalation is 152.17 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:
6
Justification:
Default factor for a sub-acute. 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
Explanation for the modification of the dose descriptor starting point:

The substance is not volatile with a low vapour pressuere of < 3.2 x 10-3 Pa at 25 °C , uptake via inhalation route is limited. Furthermore, the substance was not acutely toxic via both oral and dermal routes of exposure.

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:
0.583 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
DNEL value:
350 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
350 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

For potential dermal exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. Since a maximal absorption already occurred via the oral route, no additional factor was introduced.

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:
6
Justification:
Default factor for a sub-acute 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
Explanation for the modification of the dose descriptor starting point:

The substance is not considered to be acutely toxic with reported dermal LD50 = > 2,000 mg/kg bw in rats. Therefore not meeting the criteria for classification under GHS or Regulation (EC) No 1272/2008 (CLP).

Local effects

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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.583 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
DNEL value:
350 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
350 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The calculation of the DNELs is performed in accordance with the principles given in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012). An NOAEL in mg/kg bw/day for systemic effects was established in a repeated (sub-chronic) dose toxicity study (OECD 422) in rats. 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:
6
Justification:
Default factor for a sub-acute 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 good/standard quality of the database taken into account completeness, consistency and the standard information requirements for the tonnage band.
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:

The substance is not considered to be acutely toxic with reported oral LD50 = > 2,000 mg/kg bw in rats. Therefore not meeting the criteria for classification under GHS or Regulation (EC) No 1272/2008 (CLP).

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

NOAEL (Systemic toxicity) = 750 mg/kg /day; (reproductive toxicity) = 350 mg/kg bw/day in an OECD 422; S. Flucher. (2019)

The study was designed to investigate the systemic toxicity and potential adverse effects of the test item on reproduction (including offspring development), to evaluate some endocrine disruptor relevant endpoints, and is designed to be compatible with the requirements of the OECD Guidelines for Testing of Chemicals No. 422 “Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test” (adopted 29 July 2016). Additionally, the Comet assay was added for the detection of DNA strand breaks in cells or nuclei isolated from tissues taken from male rats.  Three groups, each of twelve male and twelve female Wistar HanTM:RccHanTM:WIST strain rats, for approximately six weeks for males and for approximately eight weeks for females (including a two week pre-pairing phase, pairing, gestation and early lactation for females), at dose levels of 100, 350 and 750 mg/kg bw/day. A control group of twelve males and twelve females was dosed with vehicle alone (Polyethylene Glycol ) over the same period. A further three males were dosed with N- Nitroso-N-methylurea (vehicle: distilled water) for two consecutive days to act as a positive control group for the comet assay investigation.

No advert clinical signs, no behavioural or functional as well as sensory reactivity effects were observed. Food and water consumption were unaffected and the body weights were also unaffected. There was no effect of treatment on mating, estrous cycles of females, pregnancy and gestation lengths.

At 750 mg/kg bw/day, the mean number of implantations was lower than control leading to lower litter size from birth, however, there was no effect of maternal treatment on post- implantation loss or post-natal survival.  Offspring body weight gain was slightly lower than control, despite the lower litter size at this dosage, leading to lower mean offspring body weight at Day 13 of age. Litter weight at 750 mg/kg bw/day, was lower than control throughout, initially reflecting the lower litter size and additionally the lower weight gain as lactation progressed. There was a higher incidence of small offspring consistent with the lower offspring growth at this dosage, but otherwise, offspring clinical signs appeared unaffected by maternal treatment at 100, 350 or 750 mg/kg bw/day. There was a higher incidence of small offspring at necropsy, consistent with the lower offspring growth at this dosage, but otherwise, offspring necropsy findings appeared unaffected by maternal treatment at 100, 350 or 750 mg/kg bw/day. It was noted that absolute and body weight-relative thyroid weights were statistically significantly higher than control for females at 350 and 750 mg/kg bw/day. This increase in thyroid weights appeared to reflect follicular hypertrophy in the thyroid of some females at these dosages, however, neither the incidence of this microscopic finding nor the differences in mean thyroid weights showed any dosage relationship and this finding was considered not to represent an adverse effect of treatment.

No effects on haematology, blood chemistry, necropsy and histopathological examinations did not indicate any adverse effect of treatment at 100, 350 and 750 mg/kg bw/day.

Comet assay investigations during the study did not show any treatment induced DNA damage in the jejunum, glandular stomach or liver under the conditions of the test at 100, 350 and 750 mg/kg bw/day.

Reproductive performance was unaffected; the test article did not affect estrous cycles, mating, fertility, pregnancy or parturition.

The No Observed Adverse Effect Level (NOAEL) for systemic toxicity for the adult animal was considered to be 750 mg/kg bw/day.

Lower numbers of implantations were apparent for females at 750 mg/kg bw/day, therefore, the NOAEL for reproduction was considered to be 350 mg/kg bw/day.

At 750 mg/kg bw/day, offspring growth was lower than control, therefore, the NOAEL for the offspring was considered to be 350 mg/kg bw/day

NOAEL (Reproductive toxicity) = 350 mg/kg /day was therefore used to derive the workers DNELs in accordance with ECHA Guideline.