Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.05 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:
NOAEC
Modified dose descriptor starting point:
NOAEC
Value:
176.3 mg/m³
Explanation for the modification of the dose descriptor starting point:
Modification of the dose descriptors is necessary, because the routes of exposure are different between animals (oral) and humans (inhalation). For this purpose the default respiratory volume for the rat corresponding to the daily duration of human exposure is considered in the first step, followed by a correction for the difference between respiratory rates of workers under standard conditions and under light activity in the second step. NAECcorr_inh = oral NOAEL (from OECD 408 study (100) x 1/0.38 m3/kg bw x 6.7 m3/10 m3 = 176.3 mg/m3. Oral absorption in rats is assumed to be 20%, based on the toxicokinetic study. Evaluation of rat intestinal absorption data and correlation with human intestinal absorption, ref Eur J Med Chem. 2003 Mar;38(3):233-43 by Zhao et all indicates that the extent of absorption in these two species is similar. For the purposes of risk assessment, absorption in humans is also taken as 20%. Therefore, NAECcorr_inh = 176.3 x 20/20 = 176.3 mg/m3.
AF for dose response relationship:
1
Justification:
Default assessment factor when the starting point for the DNEL calculation is a NOAEC (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for differences in duration of exposure:
2
Justification:
Default assessment factor for extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling required for inhalation route.
AF for other interspecies differences:
2.5
Justification:
Default assessment factor
AF for intraspecies differences:
5
Justification:
Default assessment factor of 5 for workers
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for remaining uncertainties:
1
Justification:
It is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

Not required under Guidance R8 Appendix 8.8 as no distinct acute systemic effects have been established.

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
280 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Dose descriptor starting point:
NOAEC
AF for dose response relationship:
1
Justification:
Default assessment factor when the starting point for the DNEL calculation is a NOAEC (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for interspecies differences (allometric scaling):
1
Justification:
Not required for inhalation; see below
AF for other interspecies differences:
2.5
Justification:
Default assessment factor
AF for intraspecies differences:
5
Justification:
Default assessment factor of 5 for workers
AF for the quality of the whole database:
1
Justification:
Default assessment factor
AF for remaining uncertainties:
1
Justification:
It is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.

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
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No data on skin absorption is available. The substance is a skin sensitiser. As a worst case, assume that oral absorption in rats is 100% and dermal absorption in humans is 100%. Therefore dose descriptor after route to route extrapolation is 100 x 100/100 = 100 mg/kg bw/day.
AF for dose response relationship:
1
Justification:
Default assessment factor when the starting point for the DNEL calculation is a NOAEL (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for differences in duration of exposure:
2
Justification:
Default assessment factor for extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling factor for rat = 4
AF for other interspecies differences:
2.5
Justification:
Default assessment factor
AF for intraspecies differences:
5
Justification:
Default assessment factor of 5 for workers
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for remaining uncertainties:
1
Justification:
It is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
0.82 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
15
Dose descriptor:
other: LOAEL
AF for dose response relationship:
3
Justification:
Default assessment factor when starting point is a LOAEL
AF for differences in duration of exposure:
1
Justification:
Not applicable to sensitisation
AF for interspecies differences (allometric scaling):
1
Justification:
Not applicable for local effects
AF for other interspecies differences:
1
Justification:
Not applicable for local effects
AF for intraspecies differences:
5
Justification:
Workers. Table R8-6
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for remaining uncertainties:
1
Justification:
It is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.
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

DNEL was derived on the basis of the 90-day study (OECD 408), with a NOAEL of 100 mg/kg/day as the starting dose descriptor.  There is a 28-day repeated dose oral toxicity study (OECD 407) available for the substance itself (K1) study . A NOAEL of 40 mg/kg bw/day was established in this study. In addition, a developmental / reproduction toxicity study (OECD 421) is also available, with a NOAEL of 50 mg/kg/day (the highest dose tested with no effects.).

Review of the effects noted in the subacute study are read in conjunction with the toxicokinetics report on the substance.  The result of this is as follows:

• The kidney effects noted in the females only are not dose dependant.

• The report indicates that these are degenerative effects, not necrotic effects. As such the report states that these are “probably reversible”.

• The satellite group females appear to be recovering in that the incidence is significantly lower at 14 days and adding further evidence of reversibility.

• The toxicokinetics study indicates that the substance is not absorbed by the kidneys.

As a result of this, it is proposed that the effects noted are due to adaptive changes, rather than actual toxicity, particularly as the effects noted do not seem to be dose dependant. The effects may also be specific to the rat strain (Wistar) used in the study. It is well-known from the literature (Barthold, 1979; Gray et al., 1982) that chronic progressive nephropathy (CPN) is a common disease occurring spontaneously in various strains of laboratory rats. The lesion affects female rats earlier and more severely than male animals which may explain the sex-specificity of the findings in this study. The syndrome is not inflammatory and its basic etiology and early pathogenesis are not completely understood (Barthold, 1979). Gray (1986) mentions that in long-term toxicity studies with certain compounds, a dose-related acceleration of CPN may occur. The gross appearance of the kidneys of rats with CPN was described by Gray (1986) to be swollen and pale with irregular, indented surfaces.

This opinion is reinforced by the text of the CLP Regulation (EC No 1272/2008), specifically section 3.9.2.9.9 which states that:

“Thus it is feasible that a specific profile of toxicity occurs in repeat-dose animal studies at a dose/concentration below the guidance value, such as < 100 mg/kg bw/day by the oral route, however the nature of the effect, such as nephrotoxicity seen only in male rats of a particular strain known to be susceptible to this effect may result in the decision not to classify. “

The effects noted appear to be specific to females, but could be considered to be applicable to the Wistar strain, as this this is documented, albeit in males rather than females.

References: Barthold, S. W. Chronic Progressive Nephropathy in Aging Rats. Toxicol. Pathol. 7, 1-6, 1979 Gray, J. E. et al. Early Light Microscopic Changes of Chronic Progressive Nephrosis in Several Strains of Aging Laboratory Rats, J. Gerontol, 37, 142-150, 1982 Gray, J. E. Chronic Progressive Nephrosis, Rat, in: Jones, T. C. et al. (eds.): Urinary System, Monographs on Pathology of Laboratory Animals, Springer, Berlin, 1986, pp. 174-179

The above is born out by the results noted in the 90-day study which was conducted to further assess the results of the 90-day study. Given these results, the decision was made to disregard the 28-day results, and utilise the 90-day NOAEL of 100 mg/kg/day, the highest dose level tested to derive the DNEL. This is justifiable as:

 

1)   The OECD 421 study results for the reproduction / developmental toxicity is a shorter term study, and showed no results at highest dose level tested, 50 mg/kg/day

2)   The subchronic test as a higher tier test showed no results at a higher concentration over a longer term. Therefore these results are considered to be a better indicator than both the OECD 421 and OECD 407 studies.

And hence these results were selected as starting point for deriving the long-term systemic inhalation DNEL and the long-term systemic dermal DNEL on the basis of being the most appropriate dose showing no effects. Long-term local DNELs (inhalation) were not derived as the substance is not classified for local effects and it is considered that the derivation from long term systemic effects provides a suitable margin of safety for use. An acute systemic DNEL for inhalation was derived on the basis of the guidance, utilising the acute oral value. Acute and systemic DNELs for dermal were not derived because the substance is not classified for acute effects. A long term local effects DNEL was derived on the basis of the sensitisation data for the substance.

In practice, occupational protection for workers does not allow a direct exposure of workers to the test item at a concentration causing irritation, due to PPE as standard in the workplace. The RMMs installed to protect workers are sufficient to prevent any hazard from local dermal exposure. It is considered that the derivation from long term systemic effects provides a suitable margin of safety for use.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.74 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
Modified dose descriptor starting point:
NOAEC
Value:
86.96 mg/m³
Explanation for the modification of the dose descriptor starting point:
Modification of the dose descriptors is necessary, because the routes of exposure are different between animals (oral) and humans (inhalation). For this purpose, the oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/kg for 24 hrs exposure of general public). NAECcorr_inh = oral NOAEL (100) x 1/1.15 m3/kg bw = 86.96 mg/m3. Oral absorption in rats is assumed to be 20%, based on the toxicokinetic study. Evaluation of rat intestinal absorption data and correlation with human intestinal absorption, ref Eur J Med Chem. 2003 Mar;38(3):233-43 by Zhao et all indicates that the extent of absorption in these two species is similar. For the purposes of risk assessment, absorption in humans is also taken as 20%. Therefore, NAECcorr_inh = 86.96 x 1 = 86.96 mg/m3.
AF for dose response relationship:
1
Justification:
Default assessment factor when the starting point for the DNEL calculation is a NOAEC (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for differences in duration of exposure:
2
Justification:
Default assessment factor for extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling required for inhalation route.
AF for other interspecies differences:
2.5
Justification:
Default assessment factor
AF for intraspecies differences:
10
Justification:
Default assessment factor of 10 for general population
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for remaining uncertainties:
1
Justification:
It is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.
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:
DNEL (Derived No Effect Level)
Value:
69.56 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEC
Value:
1 739.1 mg/m³
AF for dose response relationship:
1
Justification:
Default assessment factor when the starting point for the DNEL calculation is a NOAEC (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for interspecies differences (allometric scaling):
1
Justification:
Not required for inhalation; see below
AF for other interspecies differences:
2.5
Justification:
Default assessment factor
AF for intraspecies differences:
10
Justification:
Default assessment factor of 10 for the general public
AF for the quality of the whole database:
1
Justification:
Default assessment factor
AF for remaining uncertainties:
1
Justification:
is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.

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
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
As worst case, assume that oral absorption in rats is 100% and dermal absorption in humans is 100%. Therefore dose descriptor after route to route extrapolation is 100 x 100/100 = 100 mg/kg bw/day.
AF for dose response relationship:
1
Justification:
Default assessment factor when the starting point for the DNEL calculation is a NOAEL (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for differences in duration of exposure:
2
Justification:
Default assessment factor for extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling factor for rat = 4
AF for other interspecies differences:
2.5
Justification:
Default assessment factor
AF for intraspecies differences:
10
Justification:
Default assessment factor for general population
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for remaining uncertainties:
1
Justification:
It is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
0.41 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
30
Dose descriptor:
other: LOAEL
AF for dose response relationship:
3
Justification:
Default assessment factor when starting point is a LOAEL
AF for differences in duration of exposure:
1
Justification:
Not applicable for sensitisation
AF for interspecies differences (allometric scaling):
1
Justification:
Not applicable for local effects
AF for other interspecies differences:
1
Justification:
Not applicable ofr local effects
AF for intraspecies differences:
10
Justification:
Default assessment factor for general population
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for remaining uncertainties:
1
Justification:
It is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor
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
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Most sensitive endpoint: 100 mg/kg bw/day NOAEL for 90-day sub-chronic oral toxicity study.
AF for dose response relationship:
1
Justification:
Default assessment factor when the starting point for the DNEL calculation is a NOAEC
AF for differences in duration of exposure:
2
Justification:
Default assessment factor for extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Factor for allometric scaling for rat
AF for other interspecies differences:
2.5
Justification:
Default assessment factor
AF for intraspecies differences:
10
Justification:
Default assessment factor for general population
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)
AF for remaining uncertainties:
1
Justification:
It is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor
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

DNEL was derived on the basis of the 90-day study (OECD 408), with a NOAEL of 100 mg/kg/day as the starting dose descriptor.  There is a 28-day repeated dose oral toxicity study (OECD 407) available for the substance itself (K1) study . A NOAEL of 40 mg/kg bw/day was established in this study. In addition, a developmental / reproduction toxicity study (OECD 421) is also available, with a NOAEL of 50 mg/kg/day (the highest dose tested with no effects.).

Review of the effects noted in the subacute study are read in conjunction with the toxicokinetics report on the substance.  The result of this is as follows:

• The kidney effects noted in the females only are not dose dependant.

• The report indicates that these are degenerative effects, not necrotic effects. As such the report states that these are “probably reversible”.

• The satellite group females appear to be recovering in that the incidence is significantly lower at 14 days and adding further evidence of reversibility.

• The toxicokinetics study indicates that the substance is not absorbed by the kidneys.

As a result of this, it is proposed that the effects noted are due to adaptive changes, rather than actual toxicity, particularly as the effects noted do not seem to be dose dependant. The effects may also be specific to the rat strain (Wistar) used in the study. It is well-known from the literature (Barthold, 1979; Gray et al., 1982) that chronic progressive nephropathy (CPN) is a common disease occurring spontaneously in various strains of laboratory rats. The lesion affects female rats earlier and more severely than male animals which may explain the sex-specificity of the findings in this study. The syndrome is not inflammatory and its basic etiology and early pathogenesis are not completely understood (Barthold, 1979). Gray (1986) mentions that in long-term toxicity studies with certain compounds, a dose-related acceleration of CPN may occur. The gross appearance of the kidneys of rats with CPN was described by Gray (1986) to be swollen and pale with irregular, indented surfaces.

This opinion is reinforced by the text of the CLP Regulation (EC No 1272/2008), specifically section 3.9.2.9.9 which states that:

“Thus it is feasible that a specific profile of toxicity occurs in repeat-dose animal studies at a dose/concentration below the guidance value, such as < 100 mg/kg bw/day by the oral route, however the nature of the effect, such as nephrotoxicity seen only in male rats of a particular strain known to be susceptible to this effect may result in the decision not to classify. “

The effects noted appear to be specific to females, but could be considered to be applicable to the Wistar strain, as this this is documented, albeit in males rather than females.

References: Barthold, S. W. Chronic Progressive Nephropathy in Aging Rats. Toxicol. Pathol. 7, 1-6, 1979 Gray, J. E. et al. Early Light Microscopic Changes of Chronic Progressive Nephrosis in Several Strains of Aging Laboratory Rats, J. Gerontol, 37, 142-150, 1982 Gray, J. E. Chronic Progressive Nephrosis, Rat, in: Jones, T. C. et al. (eds.): Urinary System, Monographs on Pathology of Laboratory Animals, Springer, Berlin, 1986, pp. 174-179

The above is born out by the results noted in the 90-day study which was conducted to further assess the results of the 90-day study. Given these results, the decision was made to disregard the 28-day results, and utilise the 90-day NOAEL of 100 mg/kg/day, the highest dose level tested to derive the DNEL. This is justifiable as:

 

1)   The OECD 421 study results for the reproduction / developmental toxicity is a shorter term study, and showed no results at highest dose level tested, 50 mg/kg/day

2)   The subchronic test as a higher tier test showed no results at a higher concentration over a longer term. Therefore these results are considered to be a better indicator than both the OECD 421 and OECD 407 studies.

And hence these results were selected as starting point for deriving the long-term systemic inhalation DNEL and the long-term systemic dermal DNEL on the basis of being the most appropriate dose showing no effects. Long-term local DNELs (inhalation) were not derived as the substance is not classified for local effects and it is considered that the derivation from long term systemic effects provides a suitable margin of safety for use. An acute systemic DNEL for inhalation was derived on the basis of the guidance, utilising the acute oral value. Acute and systemic DNELs for dermal were not derived because the substance is not classified for acute effects. A long term local effects DNEL was derived on the basis of the sensitisation data for the substance.

In practice, occupational protection for workers does not allow a direct exposure of workers to the test item at a concentration causing irritation, due to PPE as standard in the workplace. The RMMs installed to protect workers are sufficient to prevent any hazard from local dermal exposure. It is considered that the derivation from long term systemic effects provides a suitable margin of safety for use.