Registration Dossier
Registration Dossier
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EC number: - | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicological Summary
- Administrative data
- Workers - Hazard via inhalation route
- Workers - Hazard via dermal route
- Workers - Hazard for the eyes
- Additional information - workers
- General Population - Hazard via inhalation route
- General Population - Hazard via dermal route
- General Population - Hazard via oral route
- General Population - Hazard for the eyes
- Additional information - General Population
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.28 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):
- 5
- Dose descriptor starting point:
- NOAEL
- Value:
- 2 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 1.4 mg/m³
- Explanation for the modification of the dose descriptor starting point:
The calculation of the DNEL is based on an oral NOAEL observed in a chronic oral toxicity study in mice (OECD 453; 2012).
To correct the interspecies difference between mouse and human the no observed effect level has to be corrected as follows:
Corrected starting point for the inhalative route for workers:
= NOAEL(oral) * (1/0.67 m³/kg bw/day) * (ABSoral-mouse/ABSinh-human) * 6.7 m³ (8h) /10 m³ (8h)* (7 days exposure mouse/5 days exposure worker)
= 2 mg/kg bw/day * (1/0.67 m³/kg bw/day) * (1/2) * 0.67 m³ * 1.4= 1.4 mg/m³
As worst case as recommended in the ECHA Guidance R.8 (2012), it is assumed that oral absorption rate is 50% of that of of inhalation absorption.
(ABSoral-mouse = oral absorption in mice, ABSinh-human = inhalation absorption rate in humans)
Thus, the corrected starting point for workers was 1.4 mg/m³ for inhalation.
- AF for dose response relationship:
- 1
- Justification:
- Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
- AF for differences in duration of exposure:
- 1
- Justification:
- Chronic study – no time extrapolation required
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- Default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation
- AF for other interspecies differences:
- 1
- Justification:
- No additional AF for remaining interspecies differences is required: repeated dose toxicity data from several species (mouse, rat, dog) as well as developmental toxicity studies in two species (rat, rabbit) are available showing no remarkable differences in susceptibility.
- AF for intraspecies differences:
- 5
- Justification:
- Default AF for intraspecies differences (worker)
- AF for the quality of the whole database:
- 1
- Justification:
- The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
- AF for remaining uncertainties:
- 1
- Justification:
- No uncertainties remaining
Acute/short term exposure
- Hazard assessment conclusion:
- hazard unknown (no further information necessary)
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)
DNEL related information
Workers - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 4 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):
- 35
- Dose descriptor starting point:
- NOAEL
- Value:
- 2 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 140 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
Long term dermal studies are not available. The long term systemic DNEL for the dermal route has been derived from the oral repeated dose toxicity study. Based on the available toxicokinetic data, an oral absorption rate of 50%, and a dermal absorption rate of 1% is applied for extrapolation from the oral route.
Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal) * (7 days exposure rat/5 days exposure worker) = 2 mg/kg bw/day *(50%/1%) * 1.4 = 140 mg/kg bw/day.
- AF for dose response relationship:
- 1
- Justification:
- Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
- AF for differences in duration of exposure:
- 1
- Justification:
- Chronic study – no time extrapolation required
- AF for interspecies differences (allometric scaling):
- 7
- Justification:
- Allometric scaling mouse to humans AF 7 (ECHA 2008).
- AF for other interspecies differences:
- 1
- Justification:
- No additional AF for remaining interspecies differences is required: repeated dose toxicity data from several species (mouse, rat, dog) as well as developmental toxicity studies in two species (rat, rabbit) are available showing no remarkable differences in susceptibility.
- AF for intraspecies differences:
- 5
- Justification:
- Default AF for intraspecies differences (worker)
- AF for the quality of the whole database:
- 1
- Justification:
- The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
- AF for remaining uncertainties:
- 1
- Justification:
- No uncertainties remaining
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)
- Most sensitive endpoint:
- skin irritation/corrosion
Acute/short term exposure
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
- Most sensitive endpoint:
- skin irritation/corrosion
Workers - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
Additional information - workers
NOAELs used for derivation of DNEL(s):
Correction of starting point and justification of assessment factors
Dose descriptors identified for the endpoints of concern:
Endpoint |
Quantitative dose descriptor or other information on potency |
Associated relevant effect |
Remarks on the study |
|
|
Local effect |
Systemic effect |
|
|
Acute Toxicity |
||||
Oral |
- |
LD50 > 300 mg/kg bw; LD50 cut-off 500 mg/kg bw |
- |
Rat acute study |
Dermal |
Irritating effects noted |
LD50 > 400 mg a.i./ kg bw (Although the substance has only been tested at 400 mg a.i./kg bw, the consideration of all available data on acute dermal toxicity, acute oral toxicity, toxicokinetics and dermal penetration leads to the conclusion, that the dermal LD50 will be > 2000 mg a.i./kg bw and thus no classification for acute dermal toxicity will be required (see EPS on acute dermal toxicity). |
No effects, but no higher dose levels tested |
Rat acute study |
Irritation/corrosivity |
||||
Eye |
Irreversible effects to the eye (Cat. 1, H318) |
No systemic effect |
20% a.i.: conjunctival redness grade 3, iridial reaction grade 2
|
Rabbit study, OECD TG 405 |
Skin |
Category 1C, H314 (corrosive) |
No systemic effect |
Full thickness destruction of the skin tissue in 1/3 animals; study with 20% a.i.: irritating, Category 2 |
Rabbit studies, OECD TG 404 |
Skin sensitisation |
||||
Skin |
Not sensitising |
- |
Not sensitising |
OECD TG 406 |
Repeated dose toxicity (sub-acute/sub-chronic/chronic) |
||||
Oral |
- |
NOAEL = 2 mg a.i./kg bw/day (males) / LOAEL = 4 mg a.i./kg bw/day (females) |
Degeneration with cellular reaction in skeletal muscle, bone and heart |
Combined Chronic Toxicity / Carcinogenicity Study, mouse, OECD TG 453 |
Oral |
- |
NOAEL = 2.5 mg a.i./kg bw/day |
Increase of leucocytes and neutrophile granulocytes and decrease of lymphocytes |
90 day rat study, EPA OPP 82-1 |
Oral |
- |
NOAEL = 5 mg a.i./kg bw/day |
Increase of leucocytes, decreased body weight and food consumption |
90 day study, dog, OECD TG 409 |
Oral |
- |
NOAEL = 12 mg a.i./kg bw/day |
Increase of leucocytes, platelets, neutrophilic granulocytes, lymphocytes and basophilic granulocytes, urea, aspartate aminotransferase and decrease in creatinine, decreased body weight and food consumption |
90 day study, mouse, similar to OECD TG 408 (dose-range finder for OECD TG 453 Combined Chronic Toxicity / Carcinogenicity Study) |
Developmental toxicity |
||||
Oral
|
- |
NOAEL = 30 mg a.i./kg bw/day (rabbit)
|
No developmental effects
No developmental effects |
OECD TG 414,
OECD TG 414, rat |
Fertility |
||||
Oral |
- |
NOAEL (parental) = 6 mg a.i./kg bw/day
NOAEL (reproductive, development) = 20 mg a.i./kg bw/day |
Decreases in body weight, body weight gain and relative food consumption
No effects |
Rat 2 generation study, OECD TG 416 |
Carcinogenicity |
||||
Oral |
- |
NOAEL(carcinogenicity) = 7 mg a.i./kg bw/day (males) / NOAEL(carcinogenicity) = 13 mg a.i./kg bw/day (females) |
No carcinogenic effects |
Combined Chronic Toxicity / Carcinogenicity Study, mouse, OECD TG 453 |
Oral absorption
The systemic bioavailability of 14C labelled registration substance was 34% following oral administration (rat).
The Guidance on Information requirements and Chemical Safety Assessment, R.7c (Nov. 2012) states:
“In practice, an adjustment in oral toxicity factor (to account for absorbed dose in the dermal exposure pathway) is recommended when the following conditions are met: (1) the toxicity value derived from the critical study is based on an administered dose (e.g., delivery in diet or by gavage) in its study design; (2) a scientifically defensible database demonstrates that the GI absorption of the chemical in question, from a medium (e.g., water, feed) similar to the one employed in the critical study, is significantly less than 100% (e.g., <50%). A cut-off of 50% GI absorption is recommended to reflect the intrinsic variability in the analysis of absorption studies. Thus, this cut-off level obviates the need to make comparatively small adjustments in the toxicity value that would otherwise impart on the process a level of accuracy that is not supported by the scientific literature.”
Thus, an oral absorption of 50% is used for safety assessment.
Oral to inhalatory
No data for absorption after inhalatory exposure are available. By default an assessment factor of 2 is introduced for extrapolation from the oral route in accordance with REACH TGD.
Oral to dermal
In an in vitro dermal absorption assay with human skin, the systemically available dose as defined in the Guidance on Information requirements and chemical safety assessment, R.7c* of the registration substance was 0.6 ± 0.6% for the high exposure scenario (20% a.i.), and 5.0 ± 2.5% for the low exposure scenario (0.2% a.i.), respectively.
For the worker exposure scenarios only the value obtained with the high exposure scenario is relevant within the context of REACH.
Based on the available data, a dermal absorption rate of 1% is applied for extrapolation from the oral route.
* According to the Guidance on Information requirements and chemical safety assessment, R.7c:"Dermal absorption represents the amount of topically applied test substance that is found in the epidermis (stratum corneum excluded) and in the dermis, and this quantity is therefore taken as systemically available. Dermal absorption is influenced by many factors, e.g. physico-chemical properties of the substance, its vehicle and concentration, and the exposure pattern (e.g. occlusion of the application site) as well as the skin site of the body […]. The term percutaneous penetration refers to in vitro experiments and represents the amount of topically applied test substance that is found in the receptor fluid – this quantity is taken as systemically available."
Modification of the relevant dose descriptors to the correct starting point (derived from oral combined chronic toxicity / carcinogenicity test, OECD TG 453 in mouse)
CD1-mice were treated with the registration substance in diet for 78 weeks at dose levels of 0, 2, 6 and 20 (7) mg a.i./kg bw/day (males) and 0, 4, 12 and 40 (13) mg a.i./kg bw/day (females).
Histopathological examinations revealed the following treatment-related findings: degeneration with cellular reaction in skeletal muscle, bone and heart.
The chronic NOAEL derived from the combined chronic toxicity and carcinogenicity study in mice is established at 2 mg a.i./kg bw/day in males and was not identified in females (histological change to muscle at 4 mg a.i./kg bw/day).
From the other available repeated dose toxicity studies there was no evidence that females could be more susceptible to toxic effects of the registration substance than males. Thus, an assessment factor of 2 was applied for the extrapolation from LOAEL to NOAEL resulting in an extrapolated NOAEL of 2 mg/kg bw/day for females.
Uncertainties |
AF REACH |
Justification |
Allometric scaling (inhalation) |
1 |
Default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation |
Allometric scaling (dermal) |
7 |
Allometric scaling mouse to humans AF 7 (ECHA 2008). |
Remaining interspecies differences |
1 |
No additional AF for remaining interspecies differences is required: repeated dose toxicity data from several species (mouse, rat, dog) as well as developmental toxicity studies in two species (rat, rabbit) are available showing no remarkable differences in susceptibility. |
Intraspecies differences |
5 |
Default AF for intraspecies differences (worker) |
Differences in duration of exposure |
1 |
Chronic study – no time extrapolation required |
Dose response and endpoint specific/severity |
1 |
Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required. |
Quality of whole database |
1 |
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor. |
Remaining uncertainties |
1 |
No uncertainties remaining |
Justification for not applying an additional assessment factor of 2.5 for remaining interspecies differences:
In general, lower primary aliphatic amines are metabolised to the corresponding carboxylic acid and urea. The secondary/tertiary site would be expected to undergo oxidation mediated by cytochrome P-450 or mixed function amine oxidases. Based on this, no differences in toxicodynamics are expected. This is further supported by the availability of repeated dose toxicity studies in several species (mouse, rat, dog) which showed no remarkable differences in susceptibility. Thus, the use of the additional factor of 2.5 is not justified.
Worker-DNEL long-term for dermal route (systemic): 4 mg/kg bw/day
Start value: 2.0 mg/kg bw/day
Route of original study: oral
Dose descriptor starting point after route-to-route extrapolation: 140 mg/kg bw/day
Overall AF: 7*1*5*1*1*1*1 = 35
Worker-DNEL long-term for inhalation route (systemic): 0.28 mg/m³
Start value: 2.0 mg/kg bw/day
Route of original study: oral
Dose descriptor starting point after route-to-route extrapolation: 1.4 mg/m³
For workers the corrected inhalatory NOEC is calculated according to the following equation:
corrected inhalatory NOAEC = oral NOAEL x 1/sRVmousex ABSoral-mouse/ABSinh-humanx sRVhuman/wRV x (exposure duration mouse/exposure duration worker)
= 2.0 x 1/0.67 x 50/100 x 6.7/10 x 7day/week / 5day/week
The corrected inhalatory NOAECworker(8 h) is therefore:
= 1.4 mg/m³ (8 h-TWA)
Overall AF: 1*1*5*1*1*1*1 = 5
These DNELs do not address the potential for local irritation. The risk characterisation will consider whether specific risk management measures are necessary to protect against local effects.
The NOAELs derived from the oral two generation study (OECD TG 416) as well as from the developmental toxicity studies (OECD TG 414) were higher than the NOAEL derived from this repeated dose toxicity study. As no higher Assessment factors need to be applied for reproductive and developmental effects, the DNELs for those endpoints would also be higher. Thus, the repeated dose toxicity-DNELs are also protective for fertility as well as for development.
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.05 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):
- 10
- Dose descriptor starting point:
- NOAEL
- Value:
- 2 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 0.5 mg/m³
- Explanation for the modification of the dose descriptor starting point:
The calculation of the DNEL is based on an oral NOAEL observed in a chronic oral toxicity study in mice (OECD 453; 2012).
To correct the interspecies difference between mouse and human the no observed effect level has to be corrected as follows:
Corrected starting point for the inhalative route for general population:
= NOAEL(oral) * (1/2.01 m³/kg bw/day) * (ABSoral-mouse/ABSinh-human)
= 2 mg/kg bw/day * (1/2.01 m³/kg bw/day) * (1/2) = 0.5 mg/m³
As worst case as recommended in the ECHA Guidance R.8 (2012), it is assumed that oral absorption rate is 50% of that of inhalation absorption.
(ABSoral-mouse = oral absorption in mice, ABSinh-human = inhalation absorption rate in humans)
Thus, the corrected starting point for workers was 0.5 mg/m³ for inhalation.
- AF for dose response relationship:
- 1
- Justification:
- Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
- AF for differences in duration of exposure:
- 1
- Justification:
- Chronic study – no time extrapolation required
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- Default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation
- AF for other interspecies differences:
- 1
- Justification:
- No additional AF for remaining interspecies differences is required: repeated dose toxicity data from several species (mouse, rat, dog) as well as developmental toxicity studies in two species (rat, rabbit) are available showing no remarkable differences in susceptibility.
- AF for intraspecies differences:
- 10
- Justification:
- Default AF for intraspecies differences (general population)
- AF for the quality of the whole database:
- 1
- Justification:
- The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
- AF for remaining uncertainties:
- 1
- Justification:
- No uncertainties remaining
Acute/short term exposure
- Hazard assessment conclusion:
- hazard unknown (no further information necessary)
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)
DNEL related information
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.286 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):
- 70
- Dose descriptor starting point:
- NOAEL
- Value:
- 2 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 20 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
Long term dermal studies are not available. The long term systemic DNEL for the dermal route has been derived from the oral repeated dose toxicity study. Based on the available toxicokinetic data, an oral absorption rate of 50%, and a dermal absorption rate of 5% is applied for extrapolation from the oral route.
Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal) = 2 mg/kg bw/day *(50%/5%) = 20 mg/kg bw/day.
- AF for dose response relationship:
- 1
- Justification:
- Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
- AF for differences in duration of exposure:
- 1
- Justification:
- Chronic study – no time extrapolation required
- AF for interspecies differences (allometric scaling):
- 7
- Justification:
- Allometric scaling mouse to humans AF 7 (ECHA 2008).
- AF for other interspecies differences:
- 1
- Justification:
- No additional AF for remaining interspecies differences is required: repeated dose toxicity data from several species (mouse, rat, dog) as well as developmental toxicity studies in two species (rat, rabbit) are available showing no remarkable differences in susceptibility.
- AF for intraspecies differences:
- 10
- Justification:
- Default AF for intraspecies differences (general population)
- AF for the quality of the whole database:
- 1
- Justification:
- The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
- AF for remaining uncertainties:
- 1
- Justification:
- No uncertainties remaining
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)
- Most sensitive endpoint:
- skin irritation/corrosion
Acute/short term exposure
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
- Most sensitive endpoint:
- skin irritation/corrosion
General Population - Hazard via oral route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.029 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):
- 70
- Dose descriptor starting point:
- NOAEL
- Value:
- 2 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
No modification of the dose descriptor starting point required as the NOAEL is based on a chronic oral toxicity study.
- AF for dose response relationship:
- 1
- Justification:
- Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
- AF for differences in duration of exposure:
- 1
- Justification:
- Chronic study – no time extrapolation required
- AF for interspecies differences (allometric scaling):
- 7
- Justification:
- Allometric scaling mouse to humans AF 7 (ECHA 2008).
- AF for other interspecies differences:
- 1
- Justification:
- No additional AF for remaining interspecies differences is required: repeated dose toxicity data from several species (mouse, rat, dog) as well as developmental toxicity studies in two species (rat, rabbit) are available showing no remarkable differences in susceptibility.
- AF for intraspecies differences:
- 10
- Justification:
- Default AF for intraspecies differences (general population)
- AF for the quality of the whole database:
- 1
- Justification:
- The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor
- AF for remaining uncertainties:
- 1
- Justification:
- No uncertainties remaining
Acute/short term exposure
- Hazard assessment conclusion:
- hazard unknown but no further hazard information necessary as no exposure expected
- Most sensitive endpoint:
- acute toxicity
- Route of original study:
- Oral
DNEL related information
General Population - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
Additional information - General Population
NOAELs used for derivation of DNEL(s):
Correction of starting point and justification of assessment factors
Dose descriptors identified for the endpoints of concern:
Endpoint |
Quantitative dose descriptor or other information on potency |
Associated relevant effect |
Remarks on the study |
|
|
Local effect |
Systemic effect |
|
|
Acute Toxicity |
||||
Oral |
- |
LD50 > 300 mg/kg bw; LD50 cut-off 500 mg/kg bw |
- |
Rat acute study |
Dermal |
Irritating effects noted |
LD50 > 400 mg a.i./ kg bw (Although the substance has only been tested at 400 mg a.i./kg bw, the consideration of all available data on acute dermal toxicity, acute oral toxicity, toxicokinetics and dermal penetration leads to the conclusion, that the dermal LD50 will be > 2000 mg a.i./kg bw and thus no classification for acute dermal toxicity will be required.(see EPS on acute dermal toxicity) |
No effects, but no higher dose levels tested |
Rat acute study |
Irritation/corrosivity |
||||
Eye |
Irreversible effects to the eye (Cat. 1, H318) |
No systemic effect |
20% a.i.: conjunctival redness grade 3, iridial reaction grade 2
|
Rabbit study, OECD TG 405 |
Skin |
Category 1C, H314 (corrosive) |
No systemic effect |
Full thickness destruction of the skin tissue in 1/3 animals; study with 20% a.i.: irritating, Category 2 |
Rabbit studies, OECD TG 404 |
Skin sensitisation |
||||
Skin |
Not sensitising |
- |
Not sensitising |
OECD TG 406 |
Repeated dose toxicity (sub-acute/sub-chronic/chronic) |
||||
Oral |
- |
NOAEL = 2 mg a.i./kg bw/day (males) / LOAEL = 4 mg a.i./kg bw/day (females) |
Degeneration with cellular reaction in skeletal muscle, bone and heart |
Combined Chronic Toxicity / Carcinogenicity Study, mouse, OECD TG 453 |
Oral |
- |
NOAEL = 2.5 mg a.i./kg bw/day |
Increase of leucocytes and neutrophile granulocytes and decrease of lymphocytes |
90 day rat study, EPA OPP 82-1 |
Oral |
- |
NOAEL = 5 mg a.i./kg bw/day |
Increase of leucocytes, decreased body weight and food consumption |
90 day study, dog, OECD TG 409 |
Oral |
- |
NOAEL = 12 mg a.i./kg bw/day |
Increase of leucocytes, platelets, neutrophilic granulocytes, lymphocytes and basophilic granulocytes, urea, aspartate aminotransferase and decrease in creatinine, decreased body weight and food consumption |
90 day study, mouse, similar to OECD TG 408 (dose-range finder for OECD TG 453 Combined Chronic Toxicity / Carcinogenicity Study) |
Developmental toxicity |
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Oral
|
- |
NOAEL = 30 mg a.i./kg bw/day (rabbit)
NOAEL = 50 mg a.i./kg bw/day (rat) |
No developmental effects No developmental effects |
OECD TG 414, rabbit
OECD TG 414, rat |
Fertility |
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Oral |
- |
NOAEL (parental) = 6 mg a.i./kg bw/day
NOAEL (reproductive, development) = 20 mg a.i./kg bw/day |
Decreases in body weight, body weight gain and relative food consumption
No effects |
Rat 2 generation study, OECD TG 416 |
Carcinogenicity |
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Oral |
- |
NOAEL(carcinogenicity) = 7 mg a.i./kg bw/day (males) / NOAEL(carcinogenicity) = 13 mg a.i./kg bw/day (females) |
No carcinogenic effects |
Combined Chronic Toxicity / Carcinogenicity Study mouse, OECD TG 453 |
Oral absorption
The systemic bioavailability of 14C labelled registration substance was 34% following oral administration (rat).
The Guidance on Information requirements and Chemical Safety Assessment, R.7c (Nov. 2012) states:
“In practice, an adjustment in oral toxicity factor (to account for absorbed dose in the dermal exposure pathway) is recommended when the following conditions are met: (1) the toxicity value derived from the critical study is based on an administered dose (e.g., delivery in diet or by gavage) in its study design; (2) a scientifically defensible database demonstrates that the GI absorption of the chemical in question, from a medium (e.g., water, feed) similar to the one employed in the critical study, is significantly less than 100% (e.g., <50%). A cut-off of 50% GI absorption is recommended to reflect the intrinsic variability in the analysis of absorption studies. Thus, this cut-off level obviates the need to make comparatively small adjustments in the toxicity value that would otherwise impart on the process a level of accuracy that is not supported by the scientific literature.”
Thus, an oral absorption of 50% is used for safety assessment.
Oral to inhalatory
No data for absorption after inhalatory exposure are available. By default an assessment factor of 2 is introduced for extrapolation from the oral route in accordance with REACH TGD.
Oral to dermal
In an in vitro dermal absorption assay with human skin, the systemically available dose as defined in the Guidance on Information requirements and chemical safety assessment, R.7c* of the registration substance was 0.6 ± 0.6% for the high exposure scenario (20% a.i.), and 5.0 ± 2.5% for the low exposure scenario (0.2% a.i.), respectively.
For the worker exposure scenarios only the value obtained with the high exposure scenario is relevant within the context of REACH.
Based on the available data, a dermal absorption rate of 1% is applied for extrapolation from the oral route.
* According to the Guidance on Information requirements and chemical safety assessment, R.7c:"Dermal absorption represents the amount of topically applied test substance that is found in the epidermis (stratum corneum excluded) and in the dermis, and this quantity is therefore taken as systemically available. Dermal absorption is influenced by many factors, e.g. physico-chemical properties of the substance, its vehicle and concentration, and the exposure pattern (e.g. occlusion of the application site) as well as the skin site of the body […]. The term percutaneous penetration refers to in vitro experiments and represents the amount of topically applied test substance that is found in the receptor fluid – this quantity is taken as systemically available."
Modification of the relevant dose descriptors to the correct starting point (derived from oral combined chronic toxicity / carcinogenicity test, OECD TG 453 in mouse)
CD1-mice were treated with the registration substance in diet for 78 weeks at dose levels of 0, 2, 6 and 20 (7) mg a.i./kg bw/day (males) and 0, 4, 12 and 40 (13) mg a.i./kg bw/day (females).
Histopathological examinations revealed the following treatment-related findings: degeneration with cellular reaction in skeletal muscle, bone and heart.
The chronic NOAEL derived from the combined chronic toxicity and carcinogenicity study in mice is established at 2 mg a.i./kg bw/day in males and was not identified in females (histological change to muscle at 4 mg a.i./kg bw/day).
From the other available repeated dose toxicity studies there was no evidence that females could be more susceptible to toxic effects of the registration substance than males. Thus, an assessment factor of 2 was applied for the extrapolation from LOAEL to NOAEL resulting in an extrapolated NOAEL of 2 mg/kg bw/day for females.
Uncertainties |
AF REACH |
Justification |
Allometric scaling (inhalation) |
1 |
Default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation |
Allometric scaling (dermal) |
7 |
Allometric scaling mouse to humans AF 7 (ECHA 2008). |
Remaining interspecies differences |
1 |
No additional AF for remaining interspecies differences is required: repeated dose toxicity data from several species (mouse, rat, dog) as well as developmental toxicity studies in two species (rat, rabbit) are available showing no remarkable differences in susceptibility. |
Intraspecies differences |
10 |
Default AF for intraspecies differences (general population) |
Differences in duration of exposure |
1 |
Chronic study – no time extrapolation required |
Dose response and endpoint specific/severity |
1 |
Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required. |
Quality of whole database |
1 |
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor. |
Remaining uncertainties |
1 |
No uncertainties remaining |
Justification for not applying an additional assessment factor of 2.5 for remaining interspecies differences:
In general, lower primary aliphatic amines are metabolised to the corresponding carboxylic acid and urea. The secondary/tertiary site would be expected to undergo oxidation mediated by cytochrome P-450 or mixed function amine oxidases. Based on this, no differences in toxicodynamics are expected. This is further supported by the availability of repeated dose toxicity studies in several species (mouse, rat, dog) which showed no remarkable differences in susceptibility. Thus, the use of the additional factor of 2.5 is not justified.
General population-DNEL long-term for dermal route (systemic): 0.286 mg/kg bw/day
Start value: 2.0 mg/kg bw/day
Route of original study: oral
Dose descriptor starting point after route-to-route extrapolation: 20 mg/kg bw/day
Overall AF: 7*1*10*1*1*1*1 = 70
General population-DNEL long-term for oral route (systemic): 0.029 mg/kg bw/day
Start value: 2.0 mg/kg bw/day
Route of original study: oral
Overall AF: 7*1*10*1*1*1*1 = 70
General population-DNEL long-term for inhalation route (systemic): 0.050 mg/m³
Start value: 2.0 mg/kg bw/day
Route of original study: oral
Dose descriptor starting point after route-to-route extrapolation: 0.50 mg/m³
For general population the corrected inhalatory NOEC is calculated according to the following equation:
corrected inhalatory NOAEC = oral NOAEL x 1/sRVmousex ABSoral-mouse/ABSinh-human
= 2.0 x1/2.01 x 50/100
The corrected inhalatory NOAECgeneral population(24 h) is therefore:
= 0.50 mg/m³ (24 h)
Overall AF: 1*1*10*1*1*1*1 = 10
These DNELs do not address the potential for local irritation. The risk characterisation will consider whether specific risk management measures are necessary to protect against local effects.
The NOAELs derived from the oral two generation study (OECD TG 416) as well as from the developmental toxicity studies (OECD TG 414) were higher than the NOAEL derived from this repeated dose toxicity study. As no higher Assessment factors need to be applied for reproductive and developmental effects, the DNELs for those endpoints would also be higher. Thus, the repeated dose toxicity-DNELs are also protective for fertility as well as for development.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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