Registration Dossier

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 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

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 derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

ECHA REACH Guidance

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 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

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

no hazard identified

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.

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 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

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 derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

ECHA REACH Guidance

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 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

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

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 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

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Hazard assessment conclusion:

no hazard identified

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.

Registration Dossier

Registration Dossier

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Diss Factsheets

Dichloromethylbenzene

Toxicological Summary

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Workers - Hazard for the eyes

Local effects

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

DNEL related information

Acute/short term exposure

General Population - Hazard via oral route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

General Population - Hazard for the eyes

Local effects

Additional information - General Population