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EC number: 249-854-8 | CAS number: 29797-40-8
- 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
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- 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:
- 14.8 mg/m³
- Most sensitive endpoint:
- effect on fertility
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 25
- Dose descriptor starting point:
- NOAEL
- Value:
- 300 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 370.2 mg/m³
- AF for dose response relationship:
- 1
- Justification:
- Default factor according to ECHA REACH guidance documentation. Starting point NOAEL.
- AF for differences in duration of exposure:
- 2
- Justification:
- Default value (ECHA) (subchronic study to chronic exposure).
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- Rat versus human: According to table R.8-4 in chapter R.8 of the ECHA guidance document (version 2.1, November 2012) the AF of 4 is already included in the route to route extrapolation.
- AF for other interspecies differences:
- 2.5
- Justification:
- Default value (ECHA)
- AF for intraspecies differences:
- 5
- Justification:
- Default value (ECHA) for worker.
- AF for the quality of the whole database:
- 1
- Justification:
- Guideline study
- AF for remaining uncertainties:
- 1
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 29.6 mg/m³
- Most sensitive endpoint:
- effect on fertility
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- DNEL extrapolated from long term DNEL
Local effects
Long term exposure
- Hazard assessment conclusion:
- low hazard (no threshold derived)
- Most sensitive endpoint:
- skin irritation/corrosion
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
Acute/short term exposure
- Hazard assessment conclusion:
- low hazard (no threshold derived)
- Most sensitive endpoint:
- skin irritation/corrosion
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
Workers - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 4.2 mg/kg bw/day
- Most sensitive endpoint:
- effect on fertility
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 100
- Dose descriptor starting point:
- NOAEL
- Value:
- 300 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 420 mg/kg bw/day
- AF for dose response relationship:
- 1
- AF for differences in duration of exposure:
- 2
- Justification:
- Default value (ECHA) (subchronic study to chronic exposure).
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Default value (ECHA) for rat versus human.
- AF for other interspecies differences:
- 2.5
- Justification:
- Default value (ECHA).
- AF for intraspecies differences:
- 5
- Justification:
- Default value (ECHA) for worker.
- AF for the quality of the whole database:
- 1
- Justification:
- Guideline study
- AF for remaining uncertainties:
- 1
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
- Most sensitive endpoint:
- acute toxicity
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
Local effects
Long term exposure
- Hazard assessment conclusion:
- low hazard (no threshold derived)
- Most sensitive endpoint:
- skin irritation/corrosion
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
Acute/short term exposure
- Hazard assessment conclusion:
- low hazard (no threshold derived)
- Most sensitive endpoint:
- skin irritation/corrosion
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
Workers - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- no hazard identified
Additional information - workers
Dichloromethylbenzene (CAS no 29797-40-8) =
Mixture of the isomers 2,4-dichlorotoluene, 2,5- dichlorotoluene, 3,4- dichlorotoluene, 2,3-dichlorotoluene and 2,6-dichlorotoluene
(CAS No. 29797-40-8)
DNELs (worker/general population)
I. Introduction:
Classification
Harmonized classification – Annex VI of Regulation (EC) (No 1272/2008) (CLP Regulation):
Not classified
Self-classification: Skin Irrit.2 (H315, Causes skin irritation).
Known health based occupational exposure limit(s):
SCOEL: no data
TRGS 900: 8 mg/m³ (inhalation long-term)
MAK: no data
Remarks/Limitations
No remarks/limitations
DNELs (worker)
II: Conclusion - worker (systemic and local effects):
Route of exposure |
Local effect |
Systemic effect |
Dermal (long term) |
Low hazard band |
DNEL = 4.2 mg/kg bw/day |
Dermal (short term) |
Low hazard band |
No hazard identified |
Inhalation (long term) |
Low hazard band |
DNEL = 14.8 mg/m³ |
Inhalation (short term) |
Low hazard band |
DNEL = 29.6 mg/m³ |
Hazard for eyes |
No hazard identified |
III. DNEL systemic (worker)
Study Reference
Title:
Dichlorotoluene Mixture: Extended One Generation Reproductive Toxicity Study in the Han Wistar Rat by Oral Gavage Administration
Administration period:
Males: ca. 17 weeks
Females: ca. 17 days
F1: ca. 9 weeks
Doses:
Males: 0, 50, 150, 300 mg/kg bw/d
Females: 0, 50, 150, 300 mg/kg bw/d
NOAEL = 300 mg/kg bw/day
NOAEL, Effects:
NOAEL = 300 mg/kg bw/day
Based on the following effects:
No Observed Adverse Effect Level (NOAEL) for systemic toxicity in F0 and F1 male rats, when treated with Dichlorotoluene Mixture was 50 mg/kg/day, due to hyaline droplets with associated degenerative changes (basophilic tubules and granular casts) alpha 2u globulin nephropathy was considered adverse at 150 or 300 mg/kg/day. However, it is acknowledged that this finding is specific to the male rat and is generally considered to be of no relevance to man. Excluding this finding the NOAEL for male rats is 300 mg/kg/day. Leggett A. (2020)
Reference:
Leggett A. (2020)
OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)
Covance CRS Limited
Eye
Suffolk
IP23 7PX
UK
Covance study number: MM97GJ
Basis for delineation of the DNELs systemic:
Three groups of 25 male and 25 female Han Wistar rats received Dichlorotoluene Mixture at doses of 50, 150 or 500/300 mg/kg bw/day (treatment to Group 4 (500 mg/kg bw/day) was lowered to 300 mg/kg bw/day from Week 11 (commencement of pairing)) at a volume dose of 5 mL/kg/day. Males were treated for ten weeks before pairing, up to necropsy after litters were weaned. Females were treated for ten weeks before pairing, throughout pairing up to necropsy on Day 28 of lactation. In the F1 generation, 20 males and 20 females were treated at 50, 150 or 300 mg/kg bw/day from weaning to their scheduled termination, at the same volume-dose as the F0 generation. A similarly constituted Control group received the vehicle, polyethylene glycol 400 (specific gravity 1.125), at the same volume dose throughout the same period.
Based on the results of this study a No Observed Adverse Effect Level (NOAEL) for systemic toxicity in F0 and F1 male rats, when treated with Dichlorotoluene Mixture was 50 mg/kg/day, due to hyaline droplets with associated degenerative changes (basophilic tubules and granular casts) alpha 2u globulin nephropathy was considered adverse at 150 or 300 mg/kg/day. However, it is acknowledged that this finding is specific to the male rat and is generally considered to be of no relevance to man. Excluding this finding the NOAEL for male rats is 300 mg/kg/day.
The NOAEL for systemic and reproductive toxicology in adult female rats was concluded to be 300 mg/kg/day. The dose of 300 mg/kg/day is also concluded to be the NOAEL for the offspring based on the low observed body weight gain following weaning.
Long-term toxicity – systemic effects (worker)
Long-term inhalation route – systemic effects (worker) using extrapolation factors:
Correction of the starting point according ECHA Guidance Chapter R.8:
Corrected inhalatory NOAEC = Oral NOAEL (300 mg/kg) x 1/0.38 m³/kg x 7/5x 6.7 m³/10m³ x 0.5
=> NOAEC worker = 370.2 mg/m³
Factors to be applied
Justification
AF for dose response relationship: 1
AF for differences in duration of exposure: 2 Default value (ECHA) (subchronic study to chronic exposure)
AF for interspecies differences: 1 rat versus human: According to table R.8-4 in chapter R.8 of the ECHA guidance document (version 2.1, November 2012) the AF of 4 is already included in the route to route extrapolation.
AF for intraspecies differences: 5 Default value (ECHA) for worker
AF for other interspecies differences: 2.5 Default value (ECHA)
AF for quality of the whole database : 1 Guideline study
AF for remaining differences: 1
Overall factor: 25
Worker DNEL long-term for inhalation route - systemic: 14.8 mg/m³
Short-term toxicity (inhalation) – systemic effects (worker)
No valid acute inhalation toxicity study is available. According to ECHA guidance on information requirements and chemical safety assessment chapter R.8: Characterisation of dose [concentration]-response for human health, no. R 8.7.1 in the absence of experimental data, the acute DNEL can by default set as 1-5 times the long-term DNEL. An exceeding factor of 2 seems appropriate.
Therefore:
Worker DNEL short-term for inhalation exposure: 29.6 mg/m³
Long-term dermal route systemic effects (worker)
NOAEL(oral) = NOAEL(dermal) = 300 mg/kg bw/day x 7/5 = 420 mg/kg bw/day (exposure in animal study 7 days per week/exposure in workers 5 days per week).
On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e. factor 1) is used for oral-to-dermal extrapolation.
Factors to be applied
Justification
AF for dose response relationship: 1
AF for differences in duration of exposure: 2 Default value (ECHA) (subchronic study to chronic exposure)
AF for interspecies differences: 4 Default value (ECHA) for rat versus human
AF for intraspecies differences: 5 Default value (ECHA) for worker
AF for other interspecies differences: 2.5 Default value (ECHA)
AF for quality of the whole database: 1 Guideline study
AF for remaining differences: 1
Overall factor 100
Worker DNEL long term for oral and dermal route - systemic: 4.2 mg/kg bw/day
Short-term toxicity (oral and dermal) – systemic effects (worker)
In the key study for oral toxicity a LD50 > 2000 mg/kg bw was found. The key study for acute dermal toxicity revealed a discriminating dose of > 2000 mg/kg bw (no mortality occurred and no clinical signs of toxicity were observed).
Therefore:
Worker DNEL short-term for oral and dermal exposure: no hazard identified
Reproductive Toxicity – systemic effects (worker)
Basis for delineation of the DNELs systemic is the Extended One Generation Reproductive Toxicity Study in the Han Wistar Rat by Oral Gavage Administration according to OECD TG 443.
Based on the results of this study a No Observed Adverse Effect Level (NOAEL) for systemic toxicity in F0 and F1 male rats, when treated with Dichlorotoluene Mixture was 50 mg/kg/day, due to hyaline droplets with associated degenerative changes (basophilic tubules and granular casts) alpha 2u globulin nephropathy was considered adverse at 150 or 300 mg/kg/day. However, it is acknowledged that this finding is specific to the male rat and is generally considered to be of no relevance to man. Excluding this finding the NOAEL for male rats is 300 mg/kg/day.
The NOAEL for systemic and reproductive toxicology in adult female rats was concluded to be 300 mg/kg/day. The dose of 300 mg/kg/day is also concluded to be the NOAEL for the offspring based on the low observed body weight gain following weaning.
No separate DNEL for fertility are therefore necessary.
In a developmental toxicity study according to OECD TG 414, twenty-five respectively thirty (250 mg/kg group, only) inseminated female Wistar rats each were treated daily orally by gavage with Dichlortoluol (purity 99.1 %) in polyethylene glycol 400 from day 6 to day 20 p.c. in the following doses: 0, 250, 500, and 750 mg/kg body weight (bw)/day, respectively. The fetuses were delivered by cesarean section on day 21 of gestation. Investigation was performed on general tolerance of the test substance by the females as well as on its effect on intrauterine development.
A treatment related effect on malformations (incidence or type) and external and visceral deviations was not evident at dose levels up to the highest dose tested: 750 mg/kg/day. A treatment related effect on skeletal deviations (retardations, variations, including cartilaginous tissue findings) is assumed for retarded ossification of several localizations at the 750 mg/kg
level, and it cannot totally be excluded for retarded ossification of several localizations at the 500 mg/kg level and for borderline effects at the 250 mg/kg level in relation to dose-dependently though only marginally to slightly decreased fetal weights at all dose levels.
Summarizing and evaluating all data investigated the following no-observed-adverse-effect levels (NOAELs) were determined:
Maternal toxicity: 250 mg/kg bw/day
Developmental toxicity except fetuses: 750 mg/kg bw/day (Fetal weight and degree of ossification was affected borderline at the lower doses).
In a developmental toxicity study according to OECD TG 414, New Zealand White rabbits were dosed with the test item in 1% carboxymethyl cellulose + 0.1% Tween-80 by daily oral gavage from days 6 to 28 post-coitum at doses of 40, 100 and 250 mg/kg/day. All animals surviving to Day 29 post-coitum were subjected to an examination post-mortem and external, thoracic and abdominal macroscopic findings were recorded.
There were no toxicologically relevant effects on the developmental parameters investigated in this study (i.e. litter size, sex ratio, fetal body weights, external, visceral and skeletal developmental malformations or variations) with treatment up to 250 mg/kg.
In summary, the available developmental toxicity studies in rats and rabbits no treatment related effect on malformations (incidence or type) and external and visceral deviations was evident at any dose tested. In the rat study fetal toxicity (weight and degree of ossification) was seen with borderline to slight effects starting at the low dose, 250 mg/kg/day. No fetal toxicity was observed in the rabbit study up to the highest dose tested (250 mg/kg/day). Dichlorotoluene is considered not to be a developmental toxicant.
In conclusion, no separate DNELs for toxicity to fertility and developmental toxicity are required for dichlorotoluene.
VII. DNEL local (worker)
Basis for delineation of the DNELs local (long and short term toxicity):
Irritation/corrosion
Skin irritation:
In a skin irritation study according OECD Guideline 404, 3 female New Zealand White rabbits were treated with 500 µl of test substance to the abraded skin of one flank. The other flank served as control and was treated only with water. The test area was covered with a semiocclusive plaster. After 4 h the plasters were removed and the test areas were washed with water. Erythema and edema formation were evaluated after 24h, 48h, 72h, 7d and 14d. In all animals from day 7 up to day 14 formation of scales was observed. The test substance was found to be irritating.
According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification as Skin Irrit. 2 (H315: Causes skin irritation) is justified.
Eye Irritation:
In an eye irritation study according to OECD guideline 405 the test substance (100 µl) was applied to one eye of 3 New Zealand White rabbits. The other eye was left untreated and served as control. After 24h the treated eyes were rinsed with physiological saline solution. Examinations took place after 1h, 24h, 48h, 72h and 7d and were evaluated according to DRAIZE.
Slight effects were observed, but according to classification and labelling the substance is not irritating to the eye.
According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification is not justified.
Sensitization:
In an OECD guideline 406 skin sensitsation study according to Magnusson and Klingman the test substance was found to be non-sensitising to the skin.
According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification is not justified.
Conclusion on local DNEL:
For local effects:
Low hazard band for local effects (inhalation and dermal toxicity).
No hazard identified for eye and skin sensitization.
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 2.6 mg/m³
- Most sensitive endpoint:
- effect on fertility
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 50
- Dose descriptor starting point:
- NOAEL
- Value:
- 300 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 130.4 mg/m³
- AF for dose response relationship:
- 1
- AF for differences in duration of exposure:
- 2
- Justification:
- Default value (ECHA) (subchronic study to chronic exposure).
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- Rat versus human: According to table R.8-4 in chapter R.8 of the ECHA guidance document (version 2.1, November 2012) the AF of 4 is already included in the route to route extrapolation.
- AF for other interspecies differences:
- 2.5
- Justification:
- Default value (ECHA).
- AF for intraspecies differences:
- 10
- Justification:
- Default value (ECHA) for general population.
- AF for the quality of the whole database:
- 1
- Justification:
- Guideline study.
- AF for remaining uncertainties:
- 1
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 5.2 mg/m³
- Most sensitive endpoint:
- effect on fertility
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- DNEL extrapolated from long term DNEL
Local effects
Long term exposure
- Hazard assessment conclusion:
- low hazard (no threshold derived)
- Most sensitive endpoint:
- skin irritation/corrosion
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
Acute/short term exposure
- Hazard assessment conclusion:
- low hazard (no threshold derived)
- Most sensitive endpoint:
- skin irritation/corrosion
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 1.5 mg/kg bw/day
- Most sensitive endpoint:
- effect on fertility
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 200
- Dose descriptor starting point:
- NOAEL
- Value:
- 300 mg/kg bw/day
- AF for dose response relationship:
- 1
- AF for differences in duration of exposure:
- 2
- Justification:
- Default value (ECHA) (subchronic to chronic study).
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Default value (ECHA) for rat versus human.
- AF for other interspecies differences:
- 2.5
- Justification:
- Default value (ECHA).
- AF for intraspecies differences:
- 10
- Justification:
- Default value (ECHA) for general population.
- AF for the quality of the whole database:
- 1
- Justification:
- Guideline study.
- AF for remaining uncertainties:
- 1
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
- Most sensitive endpoint:
- acute toxicity
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
Local effects
Long term exposure
- Hazard assessment conclusion:
- low hazard (no threshold derived)
- Most sensitive endpoint:
- skin irritation/corrosion
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
Acute/short term exposure
- Hazard assessment conclusion:
- low 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:
- 1.5 mg/kg bw/day
- Most sensitive endpoint:
- effect on fertility
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 200
- Dose descriptor starting point:
- NOAEL
- Value:
- 300 mg/kg bw/day
- AF for dose response relationship:
- 1
- Justification:
- Default factor according to ECHA REACH guidance documentation. Starting point NOAEL.
- AF for differences in duration of exposure:
- 2
- Justification:
- Default value (ECHA) (subchronic study to chronic exposure).
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Default value (ECHA) for rat versus human.
- AF for other interspecies differences:
- 2.5
- Justification:
- Default value (ECHA).
- AF for intraspecies differences:
- 10
- Justification:
- Default value (ECHA) for general population
- AF for the quality of the whole database:
- 1
- Justification:
- Guideline study.
- AF for remaining uncertainties:
- 1
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
- Most sensitive endpoint:
- acute toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
General Population - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- no hazard identified
Additional information - General Population
DNELs (general population)
V: Conclusion - general population (systemic and local effects):
Route of exposure |
Local effect |
Systemic effect |
Oral (long term) |
- |
DNEL = 1.5 mg/kg bw/day |
Oral (short term) |
- |
No hazard identified |
Dermal (long term) |
Low hazard band |
DNEL = 1.5 mg/Kg bw/day |
Dermal (short term) |
Low hazard band |
No hazard identified |
Inhalation (long term) |
Low hazard band |
DNEL = 2.6 mg/m³ |
Inhalation (short term) |
Low hazard band |
DNEL = 5.2 mg/m³ |
Hazard for eyes |
No hazard identified |
VI. DNEL systemic (general population)
Basis for delineation of the DNELs systemic:
Three groups of 25 male and 25 female Han Wistar rats received Dichlorotoluene Mixture at doses of 50, 150 or 500/300 mg/kg bw/day (treatment to Group 4 (500 mg/kg bw/day) was lowered to 300 mg/kg bw/day from Week 11 (commencement of pairing)) at a volume dose of 5 mL/kg/day. Males were treated for ten weeks before pairing, up to necropsy after litters were weaned. Females were treated for ten weeks before pairing, throughout pairing up to necropsy on Day 28 of lactation. In the F1 generation, 20 males and 20 females were treated at 50, 150 or 300 mg/kg bw/day from weaning to their scheduled termination, at the same volume-dose as the F0 generation. A similarly constituted Control group received the vehicle, polyethylene glycol 400 (specific gravity 1.125), at the same volume dose throughout the same period.
Based on the results of this study a No Observed Adverse Effect Level (NOAEL) for systemic toxicity in F0 and F1 male rats, when treated with Dichlorotoluene Mixture was 50 mg/kg/day, due to hyaline droplets with associated degenerative changes (basophilic tubules and granular casts) alpha 2u globulin nephropathy was considered adverse at 150 or 300 mg/kg/day. However, it is acknowledged that this finding is specific to the male rat and is generally considered to be of no relevance to man. Excluding this finding the NOAEL for male rats is 300 mg/kg/day.
The NOAEL for systemic and reproductive toxicology in adult female rats was concluded to be 300 mg/kg/day. The dose of 300 mg/kg/day is also concluded to be the NOAEL for the offspring based on the low observed body weight gain following weaning.
Long-term toxicity – systemic effects (general population)
Long-term inhalation route – systemic effects (general population) using extrapolation factors:
NOAEL(oral) = 300 mg/kg bw/day (7 days a week)
Correction of the starting point according ECHA Guidance Chapter R.8:
Corrected inhalation NOAEC = Oral NOAEL (300 mg/kg) x 1/1.15 m³/kg x 0.5
=> NOAEC general population = 130.4 mg/m³
Factors to be applied
Justification
AF for dose response relationship
AF for differences in duration of exposure : 2 Default value (ECHA) (subchronic study to chronic exposure)
AF for interspecies differences: 1 rat versus human: According to table R.8-4 in chapter R.8 of the ECHA guidance document (version 2.1, November 2012) the AF of 4 is already included in the route to route extrapolation.
AF for intraspecies differences: 10 Default value (ECHA) for general population
AF for other interspecies differences: 2.5 Default value (ECHA)
AF for quality of the whole database: 1 There is information available to cover all relevant toxicological endpoints. The available studies are performed according to guideline and GLP.
AF for remaining differences: 1
Overall factor 50
General population DNEL long-term for inhalation route - systemic: 2.6 mg/m³
Short-term toxicity (inhalation) – systemic effects (general population)
No valid acute inhalation toxicity study is available. According to ECHA guidance on information requirements and chemical safety assessment chapter R.8: Characterisation of dose [concentration]-response for human health, no. R 8.7.1 in the absence of experimental data, the acute DNEL can by default set as 1-5 times the long-term DNEL. An exceeding factor of 2 seems appropriate.
Therefore:
General population DNEL short-term for inhalation exposure: 5.2 mg/m³.
Long-term oral and dermal route systemic effects (general population)
NOAEL(oral) = NOAEL(dermal) = 300 mg/kg bw/day
Factors to be applied
Justification
AF for dose response relationship: 1
AF for differences in duration of exposure: 2 Default value (ECHA) (subchronic study to chronic exposure)
AF for interspecies differences: 4 Default value (ECHA) for rat versus human
AF for intraspecies differences: 10 Default value (ECHA) for general population
AF for other interspecies differences: 2.5 Default value (ECHA)
AF for quality of the whole database 1 There is information available to cover all relevant toxicological endpoints. The available studies are performed according to guideline and GLP.
AF for remaining differences: 1
Overall factor 200
General population DNEL long term
for oral and dermal route - systemic: 1.5 mg/kg bw/day
Short-term toxicity (oral and dermal) – systemic effects (general population)
In the key study for oral toxicity a LD50 > 2000 mg/kg bw was found. The key study for acute dermal toxicity revealed a discriminating dose of > 2000 mg/kg bw (no mortality occurred and no clinical signs of toxicity were observed).
According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification is therefore not justified.
Therefore:
General population DNEL short-term for oral and dermal exposure: no hazard identified
Reproductive Toxicity – systemic effects (general population)
Basis for delineation of the DNELs systemic is the Extended One Generation Reproductive Toxicity Study in the Han Wistar Rat by Oral Gavage Administration according to OECD TG 443.
Based on the results of this study a No Observed Adverse Effect Level (NOAEL) for systemic toxicity in F0 and F1 male rats, when treated with Dichlorotoluene Mixture was 50 mg/kg/day, due to hyaline droplets with associated degenerative changes (basophilic tubules and granular casts) alpha 2u globulin nephropathy was considered adverse at 150 or 300 mg/kg/day. However, it is acknowledged that this finding is specific to the male rat and is generally considered to be of no relevance to man. Excluding this finding the NOAEL for male rats is 300 mg/kg/day.
The NOAEL for systemic and reproductive toxicology in adult female rats was concluded to be 300 mg/kg/day. The dose of 300 mg/kg/day is also concluded to be the NOAEL for the offspring based on the low observed body weight gain following weaning.
No separate DNEL for fertility are therefore necessary.
In a developmental toxicity study according to OECD TG 414, twenty-five respectively thirty (250 mg/kg group, only) inseminated female Wistar rats each were treated daily orally by gavage with Dichlortoluol (purity 99.1 %) in polyethylene glycol 400 from day 6 to day 20 p.c. in the following doses: 0, 250, 500, and 750 mg/kg body weight (bw)/day, respectively. The fetuses were delivered by cesarean section on day 21 of gestation. Investigation was performed on general tolerance of the test substance by the females as well as on its effect on intrauterine development.
A treatment related effect on malformations (incidence or type) and external and visceral deviations was not evident at dose levels up to the highest dose tested: 750 mg/kg/day. A treatment related effect on skeletal deviations (retardations, variations, including cartilaginous tissue findings) is assumed for retarded ossification of several localizations at the 750 mg/kg level, and it cannot totally be excluded for retarded ossification of several localizations at the 500 mg/kg level and for borderline effects at the 250 mg/kg level in relation to dose-dependently though only marginally to slightly decreased fetal weights at all dose levels..
Summarizing and evaluating all data investigated the following no-observed-adverse-effect levels (NOAELs) were determined:
Maternal toxicity: 250 mg/kg bw/day
Developmental toxicity except fetuses: 750 mg/kg bw/day
Fetal weight and degree of ossification affected borderline: < 250 mg/kg bw/day
In a developmental toxicity study according to OECD TG 414, New Zealand White rabbits were dosed with the test item in 1% carboxymethyl cellulose + 0.1% Tween-80 by daily oral gavage from days 6 to 28 post-coitum at doses of 40, 100 and 250 mg/kg/day. All animals surviving to Day 29 post-coitum were subjected to an examination post-mortem and external, thoracic and abdominal macroscopic findings were recorded.
There were no toxicologically relevant effects on the developmental parameters investigated in this study (i.e. litter size, sex ratio, fetal body weights, external, visceral and skeletal developmental malformations or variations) with treatment up to 250 mg/kg.
In summary, the available developmental toxicity studies in rats and rabbits no treatment related effect on malformations (incidence or type) and external and visceral deviations was evident at any dose tested. In the rat study fetal toxicity (weight and degree of ossification) was seen with borderline to slight effects starting at the low dose, 250 mg/kg/day. No fetal toxicity was observed in the rabbit study up to the highest dose tested (250 mg/kg/day). Dichlorotoluene is considered not to be a developmental toxicant.
In conclusion, no separate DNELs for toxicity to reproduction and developmental toxicity are required for dichlorotoluene.
VII. DNEL local (general population)
Basis for delineation of the DNELs local (long and short term toxicity):
Skin irritation:
In a skin irritation study according OECD Guideline 404, 3 female New Zealand White rabbits were treated with 500 µl of test substance to the abraded skin of one flank. The other flank served as control and was treated only with water. The test area was covered with a semiocclusive plaster. After 4 h the plasters were removed and the test areas were washed with water. Erythema and edema formation were evaluated after 24h, 48h, 72h, 7d and 14d. In all animals from day 7 up to day 14 formation of scales was observed. The test substance was found to be irritating.
According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification as Skin Irrit. 2 (H315: Causes skin irritation) is justified.
Eye Irritation:
In an eye irritation study according to OECD guideline 405 the test substance (100 µl) was applied to one eye of 3 New Zealand White rabbits. The other eye was left untreated and served as control. After 24h the treated eyes were rinsed with physiological saline solution. Examinations took place after 1h, 24h, 48h, 72h and 7d and were evaluated according to DRAIZE.
Slight effects were observed, but according to classification and labelling the substance is not irritating to the eye.
According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification is not justified.
Sensitization
In an OECD guideline 406 skin sensitsation study according to Magnusson and Klingman the test substance was found to be non-sensitising to the skin.
According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification is not justified.
Conclusion on local DNEL:
For local effects:
Low hazard band for local effects (inhalation and dermal toxicity)
No hazard identified for eye and skin sensitization.
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