Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.76 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
Modified dose descriptor starting point:
NOAEC
DNEL value:
132.2 mg/m³
Explanation for the modification of the dose descriptor starting point:
In the absence of specific data for both the starting route (oral) and the end route (inhalation), worst case assumptions have to be 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 on page 19 of Guidance Document, Chapter R.8. Finally 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 inhalation NOAEC for workers is: corrected inhalation NOAEC=oral NOAEL×1/sRV_rat ×ABS_(oral-rat)/ABS_(inh-human) ×sRV_human/wRV; corrected inhalation NOAEC=150×1/0.38×1/2×6.7/10=132.2 mg/m^3 Thus, the corrected dose descriptor for inhalation is 132.2 mg/m3 for workers.
AF for dose response relationship:
1
Justification:
NOAEL
AF for differences in duration of exposure:
6
Justification:
sub-acute to chronic extrapolation
AF for interspecies differences (allometric scaling):
1
Justification:
Not applicable
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
Justification:
Worker
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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:
500 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):
30
Modified dose descriptor starting point:
NOAEL
DNEL value:
15 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There were no systemic effects noted in an acute dermal toxicology study using the dermal dose route (Costello, 1985) but systemic toxicity, secondary to local irritant effects in the stomach, were observed via the oral dose route (OECD 421, WIL, 2012). The LogPow, at 4.5, does not preclude absorption via the dermal route and therefore systemic effects via the dermal route are possible and the DNEL has been calculated. AF for Differences in absorption depending on route of exposure (route-route extrapolation, human/animal) = 0.01 (1/100 oral to dermal, a study has shown that dermal absorption of similar substances is <1% over 8 hours)
AF for dose response relationship:
1
Justification:
NOAEL
AF for differences in duration of exposure:
6
Justification:
sub-acute to chronic extrapolation
AF for interspecies differences (allometric scaling):
1
Justification:
local effect of irritation not affected by interspecies differences
AF for other interspecies differences:
1
Justification:
toxicodynamic and toxicokinetic; interspecies differences when considering local irritant effects
AF for intraspecies differences:
5
Justification:
Worker
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
69.3 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
15
Dose descriptor:
other: EC 3
AF for dose response relationship:
3
AF for differences in duration of exposure:
1
Justification:
Skin sensitization is considered as local immunological effect. Mechanistically, the biological sequelae that take place for the immune system to mount a response are the same across mammalian species, so, toxicokinetic and toxicodynamic effects are minimal (Api, 2006; Basketter, 2000) : Api AM, Basketter DA, Cadby PA, Cano M-F, Graham E, Gerberick F, Griem P, McNamee p, Ryan CA, Safford B. (2006). Dermal Sensitization Quantitative Risk Assessment (QRA) for fragrance ingredients. Technicaldossier. June 22, 2006. Basketter, D.A., Blaikie, L., Dearman, R.J., Kimber, I., Ryan, C.A.. Gerberick, G.F., Harvey, P., Evans, P., White, I.R. and Rycroft, R.J.G. (2000). Use of the local lymph node assay for the estimation of relative contact allergenic potency. Contact Dermatitis, 42(6), 344-348.
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
1
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

Substance is identified as corrosive.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.44 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
Modified dose descriptor starting point:
NOAEC
DNEL value:
65.3 mg/m³
Explanation for the modification of the dose descriptor starting point:
For potential inhalation exposure, route-to-route extrapolation from the oral NOAEL value of 150 mg/kg bw/day was performed. 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 on page 19 of Guidance Document, Chapter R.8. Finally 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 inhalation NOAEC for general population is: corrected inhalation NOAEC=oral NOAEL×1/sRV_rat ×ABS_(oral-rat)/ABS_(inh-human) corrected inhalation NOAEC=150×1/1.15×1/2=65.3 mg/m3 Thus, the corrected dose descriptor for inhalation is 65.3 mg/m3 for the general population.
AF for dose response relationship:
1
Justification:
NOAEL
AF for differences in duration of exposure:
6
Justification:
sub-acute to chronic extrapolation
AF for interspecies differences (allometric scaling):
1
Justification:
Not applicable
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
Justification:
General population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.6 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
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEC
DNEL value:
65.3 mg/m³
Explanation for the modification of the dose descriptor starting point:
For potential inhalation exposure, route-to-route extrapolation from the oral NOAEL value of 150 mg/kg bw/day was performed. 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 on page 19 of Guidance Document, Chapter R.8. Finally 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 inhalation NOAEC for general population is: corrected inhalation NOAEC=oral NOAEL×1/sRV_rat ×ABS_(oral-rat)/ABS_(inh-human) corrected inhalation NOAEC=150×1/1.15×1/2=65.3 mg/m3 Thus, the corrected dose descriptor for inhalation is 65.3 mg/m3 for the general population.
AF for dose response relationship:
1
Justification:
NOAEL
AF for interspecies differences (allometric scaling):
1
Justification:
Not applicable
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
Justification:
General population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1

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:
62.5 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):
60
Modified dose descriptor starting point:
NOAEL
DNEL value:
15 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There were no systemic effects noted in an acute dermal toxicology study using the dermal dose route (Costello, 1985) but systemic toxicity, secondary to local irritation in the stomach, were observed via the oral dose route (OECD 407, Eapen, 2006). The LogPow, at 4.5, does not preclude absorption via the dermal route and therefore systemic effects via the dermal route are possible and the DNEL has been calculated. AF for Differences in absorption depending on route of exposure (route-route extrapolation, human/animal) = 0.01 (1/100 oral to dermal, a study has shown that dermal absorption of similar substances is <1% over 8 hours)
AF for dose response relationship:
1
Justification:
NOAEL
AF for differences in duration of exposure:
6
Justification:
sub-acute to chronic extrapolation
AF for interspecies differences (allometric scaling):
1
Justification:
local effect of irritation not affected by interspecies differences
AF for other interspecies differences:
1
Justification:
toxicodynamic and toxicokinetic; such parameters are not significant for interspecies differences when considering local irritant effects
AF for intraspecies differences:
10
Justification:
General population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
34.65 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
30
Dose descriptor:
other: EC 3
AF for dose response relationship:
3
AF for differences in duration of exposure:
1
Justification:
Sensitization occurs with acute or single exposures
AF for interspecies differences (allometric scaling):
1
Justification:
Skin sensitization is considered as local immunological effect. Mechanistically, the biological sequelae that take place for the immune system to mount a response are the same across mammalian species, so, toxicokinetic and toxicodynamic effects are minimal
AF for other interspecies differences:
1
AF for intraspecies differences:
10
Justification:
General population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 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):
60
AF for dose response relationship:
1
Justification:
NOAEL
AF for differences in duration of exposure:
6
Justification:
sub-acute to chronic extrapolation
AF for interspecies differences (allometric scaling):
1
Justification:
al effect of irritation not affected by interspecies differences
AF for other interspecies differences:
1
Justification:
toxicodynamic and toxicokinetic; such parameters are not significant for interspecies differences when considering local irritant effects
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
15 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):
10
DNEL extrapolated from long term DNEL
AF for dose response relationship:
1
Justification:
NOAEL
AF for interspecies differences (allometric scaling):
1
Justification:
local effect of irritation not affected by interspecies differences
AF for other interspecies differences:
1
Justification:
toxicodynamic and toxicokinetic; such parameters are not significant for interspecies differences when considering local irritant effects
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population