Registration Dossier

Administrative data

Description of key information

Reliable subchronic dermal and subacute inhalative data are available and provided below on a structurally similar substance, 2-(2-aminoethoxy)ethanol (CAS# 929-06-6), which differs from DMEE only by the lack of two methyl groups on the terminal nitrogen. As a result, these studies are felt to be representative of DMEE for the repeated dose toxicity endpoint.[ES1] 

In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test, the no observed adverse effect concentration (NOAEC) for general systemic toxicity as well as reproductive performance, fertility and developmental toxicity in male and female Wistar rats was 40 mg/m³, the highest dose tested. The NOAEC for local signs of toxicity in male and female Wistar rats was 4 mg/m³due to local effects in the larynx (level 1). A molar conversion was applied to the NOAECs to account for the differences in molecular weight of DMEE and the read across substance of 133.19/105.14 = 1.27. Thus, the adjusted NOAEC for systemic effects is 40 mg/m3 * 1.27 = 50.8 mg/m3 and the adjusted NOAEC for local effects is 4 mg/m3 * 1.27 = 5.08 mg/m3.

In a subchronic dermal study following OECD test guideline 411, the NOAEL for systemic toxicity was determined to be 175 mg/kg/day (highest dose tested). A molar conversion was applied to the NOAEL to account for the differences in molecular weight of DMEE and the read across substance of 133.19/105.14 = 1.27. Thus, the adjusted NOAEL for systemic effects is 175 mg/kg bw/day * 1.27 = 222.25 mg/kg bw/day. Insufficient dose information was available to derive a definitive local effects NOAEL for read-across purposes. Given the corrosive nature of DMEE (Skin Corrosion Category 1C),a medium hazard was assignedfor qualitative risk assessment purposes per the ECHA Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation (Version 2.0, Nov

Reliable subchronic dermal and subacute inhalative data are available and provided below on a structurally similar substance, 2-(2-aminoethoxy)ethanol (CAS# 929-06-6), see section 13 read across justification.
In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test, the no observed adverse effect concentration (NOAEC) for general systemic toxicity as well as reproductive performance, fertility and developmental toxicity in male and female Wistar rats was 40 mg/m³, the highest dose tested. The NOAEC for local signs of toxicity in male and female Wistar rats was 4 mg/m³ due to local effects in the larynx (level 1). A molar conversion was applied to the NOAECs to account for the differences in molecular weight of DMEE and the read across substance of 133.19/105.14 = 1.27. Thus, the adjusted NOAEC for systemic effects is 40 mg/m3 * 1.27 = 50.8 mg/m3 and the adjusted NOAEC for local effects is 4 mg/m3 * 1.27 = 5.08 mg/m3.
In a subchronic dermal study following OECD test guideline 411, the NOAEL for systemic toxicity was determined to be 175 mg/kg/day (highest dose tested). A molar conversion was applied to the NOAEL to account for the differences in molecular weight of DMEE and the read across substance of 133.19/105.14 = 1.27. Thus, the adjusted NOAEL for systemic effects is 175 mg/kg bw/day * 1.27 = 222.25 mg/kg bw/day. Insufficient dose information was available to derive a definitive local effects NOAEL for read-across purposes. Given the corrosive nature of DMEE (Skin Corrosion Category 1C), a high hazard was assigned for qualitative risk assessment purposes per the ECHA Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation (Version 2.0, November 2012).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP; guideline study according to OECD 422
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Male and female Wistar rats, strain Crl:WI(Han), supplied by Charles River Laboratories, Research Models and Services, UK
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose/head only
Vehicle:
clean air
Remarks on MMAD:
MMAD / GSD: 4 mg/m³ (n=2)
MMAD: 0.8-not detectable
SD: 2.5-not detectable

16 mg/m³ (n=2)
MMAD: 3.0-2.6
SD: 1.8-1.7

40 mg/m³ (n=2)
MMAD: 1.9-2.6
SD: 1.9-1.6
Details on inhalation exposure:
For each concentration the test substance was supplied to a two-component atomizer at a constant rate by means of an infusion pump. The aerosol was generated with compressed air mixed with conditioned dilution air and passed into the inhalation system.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentrations of the inhalation atmospheres were analyzed by gas chromatography in all test groups including control. Daily means were calculated based on 2 measured samples per concentration and exposure. From the daily mean values of each concentration, mean concentrations and standard deviations for the entire study were derived.
In the control group, one sample per exposure period was analyzed.
The analyses were carried out at the Analytical Chemistry Laboratory of the Experimental Toxicology and Ecology of BASF SE, Ludwigshafen, Germany.
Duration of treatment / exposure:
females: 46-48 days
males: 29 days
Frequency of treatment:
6 hours daily
Remarks:
Doses / Concentrations:
0; 3.88±0.63; 16.6±3.1; 41.2±6.5 mg/m3
Basis:
analytical conc.
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Observations and examinations performed and frequency:
After 2 weeks of premating treatment the F0 animals were mated to produce F1 generation pups. Mating pairs were from the same test group. Mating was discontinued as soon as sperm was detected in the vaginal smear. F0 animals were examined for their reproductive performance including determination of the number of implantation sites and the calculation of postimplantation loss for all F0 females. A detailed clinical observation (DCO) was performed in all F0 animals before test substance administration and thereafter at weekly intervals. Food consumption of the F0 parents was determined regularly during premating and after the mating period and during the gestation and lactation periods in dams. In general, body weights of F0 an mals were determined once a week. During gestation and lactation period, F0 females were weighed on gestation days (GD) 0, 7, 14 and 20, on the parturition day (postnatal day [PND] 0) and on PND 4. Pups were sexed on PND 0 and weighed one day after birth and on PND 4. Their viability was recorded twice daily on each working day or only in the morning on Saturday and Sunday. Clinicochemical and hematological examinations as well as urinal ses were performed in 5 randomly selected F0 parental animals of either sex towards the end of the administration period. At the end of the administration period a functional observational battery was performed and motor activity was measured in 5 randomly selected F0 parental males and female per test group. All surviving F0 parental animals were sacrificed assessed by gross pathology. Organ weights were recorded and a histopathological examination was performed.
Sacrifice and pathology:
All F0 parental animals were sacrificed under pentobarbitone anesthesia by exsanguination from the abdominal aorta and vena cava. The exsanguinated animals were necropsied and assessed by gross pathology, special attention being given to the reproductive organs. All pups with scheduled sacrifice on PND 4 were sacrificed under isoflurane anesthesia with CO2. All pups were examined externally, eviscerated and their organs were assessed
macroscopically, paying particular attention to potential changes of pericardial blood vessels. All pups that die before schedule or were sacrificed in a moribund state were examined externally, eviscerated and their organs were assessed macroscopically, paying particular attention to potential changes of pericardial blood vessels.
Dose descriptor:
NOAEC
Effect level:
40 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: general systemic toxicity; reproductive performance and fertility
Dose descriptor:
NOAEC
Effect level:
4 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: local effects
Critical effects observed:
not specified
Conclusions:
Under the conditions of this Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test the no observed adverse effect concentration (NOAEC) for general systemic toxicity as well as reproductive performance, fertility and developmental toxicity in male and female Wistar rats was 40 mg/m³. The NOAEC for local signs of toxicity in male and female Wistar rats was 4 mg/m³.
Executive summary:

2-(2-Aminoethoxy)ethanol was administered via inhalation to groups of 10 male and 10 female Wistar rats (F0 animals) at concentrations of 4, 16, and 40 mg/m³. Regarding clinical examinations, no signs of general systemic toxicity were observed in male and female parental animals at any dose level during the entire study period. During the exposure period, the target concentrations were maintained as constant and stable as could be provided with liquid aerosol generation techniques in the concentration range tested. Fertility indices for male and female animals were not impaired by test-substance administration even at a dose level of 40 mg/m³. In addition, live birth and viability indices of pups in all test groups were not influenced. Concerning clinical pathology no treatment-related, adverse effects were observed up to a dose level of 40 mg/m3. With regard to pathology, treatment-related microscopic changes were observed in larynx (level 1) and consisted of increased squamous metaplasia of the respiratory epithelium and chronic (active) inflammation at level 1 of the larynx only to a marginal or slight degree. This was observed in both sexes. Histopathological examination of the mid- and low-dose groups of the larynx at this level 1 revealed that these treatment-related findings (squamous metaplasia and chronic [active] inflammation) were also observed in the mid-dose group (16 mg/m³), however, to a lesser severity degree compared to the high-dose groups (40 mg/m³). Other macroscopic and/or microscopic changes observed were either non-dose related and/or considered to be normal background changes. No treatment-related changes were observed in both sexes at a concentration of 4 mg/m³.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
50.8 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
A reliable, GLP study conducted according to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) on a structurally similar substance, 2-(2-aminoethoxy)ethanol (CAS# 929-06-6) is available as a read-across study. DMEE, 2-(2-(dimethylamino)ethoxy)ethanol, and 2-(2-aminoethoxy)ethanol are close structural analogues which differ only by the presence of two methyl groups on the terminal nitrogen.

A supporting study on DMEE conducted in 1993 under GLP guidelines according to a laboratory specific protocol and methods similar to OECD guidelines study method is also available. In this study, rats were exposed to DMEE vapour (3.1, 18.9 and 42.7 ppm) for 9 exposures over an 11-day period. Clinical and necropsy observations indicated nasal irritation (42.7 ppm dose group only), effects on body weight (males only), increased blood CO2 levels, and ophthalmologic findings (corneal crystals) at concentrations of 18.9 and 42.7 ppm. Histologic lesions in the nasal cavity were noted in animals in the 18.9 and 42.7 ppm groups and also in 2 of the 10 female rats in the 3.1 ppm dose group. A NOEL of 3.1 ppm was reported for local effects. No significant systemic toxicity was reported.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP; guideline study according to OECD 422
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Male and female Wistar rats, strain Crl:WI(Han), supplied by Charles River Laboratories, Research Models and Services, UK
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose/head only
Vehicle:
clean air
Remarks on MMAD:
MMAD / GSD: 4 mg/m³ (n=2)
MMAD: 0.8-not detectable
SD: 2.5-not detectable

16 mg/m³ (n=2)
MMAD: 3.0-2.6
SD: 1.8-1.7

40 mg/m³ (n=2)
MMAD: 1.9-2.6
SD: 1.9-1.6
Details on inhalation exposure:
For each concentration the test substance was supplied to a two-component atomizer at a constant rate by means of an infusion pump. The aerosol was generated with compressed air mixed with conditioned dilution air and passed into the inhalation system.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentrations of the inhalation atmospheres were analyzed by gas chromatography in all test groups including control. Daily means were calculated based on 2 measured samples per concentration and exposure. From the daily mean values of each concentration, mean concentrations and standard deviations for the entire study were derived.
In the control group, one sample per exposure period was analyzed.
The analyses were carried out at the Analytical Chemistry Laboratory of the Experimental Toxicology and Ecology of BASF SE, Ludwigshafen, Germany.
Duration of treatment / exposure:
females: 46-48 days
males: 29 days
Frequency of treatment:
6 hours daily
Remarks:
Doses / Concentrations:
0; 3.88±0.63; 16.6±3.1; 41.2±6.5 mg/m3
Basis:
analytical conc.
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Observations and examinations performed and frequency:
After 2 weeks of premating treatment the F0 animals were mated to produce F1 generation pups. Mating pairs were from the same test group. Mating was discontinued as soon as sperm was detected in the vaginal smear. F0 animals were examined for their reproductive performance including determination of the number of implantation sites and the calculation of postimplantation loss for all F0 females. A detailed clinical observation (DCO) was performed in all F0 animals before test substance administration and thereafter at weekly intervals. Food consumption of the F0 parents was determined regularly during premating and after the mating period and during the gestation and lactation periods in dams. In general, body weights of F0 an mals were determined once a week. During gestation and lactation period, F0 females were weighed on gestation days (GD) 0, 7, 14 and 20, on the parturition day (postnatal day [PND] 0) and on PND 4. Pups were sexed on PND 0 and weighed one day after birth and on PND 4. Their viability was recorded twice daily on each working day or only in the morning on Saturday and Sunday. Clinicochemical and hematological examinations as well as urinal ses were performed in 5 randomly selected F0 parental animals of either sex towards the end of the administration period. At the end of the administration period a functional observational battery was performed and motor activity was measured in 5 randomly selected F0 parental males and female per test group. All surviving F0 parental animals were sacrificed assessed by gross pathology. Organ weights were recorded and a histopathological examination was performed.
Sacrifice and pathology:
All F0 parental animals were sacrificed under pentobarbitone anesthesia by exsanguination from the abdominal aorta and vena cava. The exsanguinated animals were necropsied and assessed by gross pathology, special attention being given to the reproductive organs. All pups with scheduled sacrifice on PND 4 were sacrificed under isoflurane anesthesia with CO2. All pups were examined externally, eviscerated and their organs were assessed
macroscopically, paying particular attention to potential changes of pericardial blood vessels. All pups that die before schedule or were sacrificed in a moribund state were examined externally, eviscerated and their organs were assessed macroscopically, paying particular attention to potential changes of pericardial blood vessels.
Dose descriptor:
NOAEC
Effect level:
40 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: general systemic toxicity; reproductive performance and fertility
Dose descriptor:
NOAEC
Effect level:
4 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: local effects
Critical effects observed:
not specified
Conclusions:
Under the conditions of this Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test the no observed adverse effect concentration (NOAEC) for general systemic toxicity as well as reproductive performance, fertility and developmental toxicity in male and female Wistar rats was 40 mg/m³. The NOAEC for local signs of toxicity in male and female Wistar rats was 4 mg/m³.
Executive summary:

2-(2-Aminoethoxy)ethanol was administered via inhalation to groups of 10 male and 10 female Wistar rats (F0 animals) at concentrations of 4, 16, and 40 mg/m³. Regarding clinical examinations, no signs of general systemic toxicity were observed in male and female parental animals at any dose level during the entire study period. During the exposure period, the target concentrations were maintained as constant and stable as could be provided with liquid aerosol generation techniques in the concentration range tested. Fertility indices for male and female animals were not impaired by test-substance administration even at a dose level of 40 mg/m³. In addition, live birth and viability indices of pups in all test groups were not influenced. Concerning clinical pathology no treatment-related, adverse effects were observed up to a dose level of 40 mg/m3. With regard to pathology, treatment-related microscopic changes were observed in larynx (level 1) and consisted of increased squamous metaplasia of the respiratory epithelium and chronic (active) inflammation at level 1 of the larynx only to a marginal or slight degree. This was observed in both sexes. Histopathological examination of the mid- and low-dose groups of the larynx at this level 1 revealed that these treatment-related findings (squamous metaplasia and chronic [active] inflammation) were also observed in the mid-dose group (16 mg/m³), however, to a lesser severity degree compared to the high-dose groups (40 mg/m³). Other macroscopic and/or microscopic changes observed were either non-dose related and/or considered to be normal background changes. No treatment-related changes were observed in both sexes at a concentration of 4 mg/m³.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
5.08 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
See "Quality of whole database" for Repeated dose toxicity: inhalation - systemic effects.

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal, other
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No deviation from OECD guideline (OECD 411).
Justification for type of information:
See "Read across Justification" as cross-referenced under section 13.
Reason / purpose:
read-across: supporting information
Qualifier:
according to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Sprague Dawley, strain Hsd:SD
- Age at study initiation: 6 weeks
- Weight at study initiation: 143-247 grams
- Fasting period before study:
- Housing:
* before the study: rats were groups-housed by sex
* during the study: animals were housed individually in stainless steel cages
- Diet (e.g. ad libitum): Teklad Certified LM-485 rodent diet, ad libitum, except overnight prior to scheduled blood collectiong
- Water (e.g. ad libitum): ad libitum
- Acclimation period: min 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25°C
- Humidity (%): 30-70% (during 2 days of the study, relative humidity was outside this range. However, this is not considered to have had any adverse
effect on the outcome of this study)
- Photoperiod (hrs dark / hrs light): 12h light, 12h dark


Type of coverage:
occlusive
Vehicle:
water
Details on exposure:
TEST SITE
- Area of exposure: between 10 and 20% of the body surface
- Type of wrap if used: gauze pad, rubber dam and an elastic bandage
- Time intervals for shavings or clipplings: minimum of twice weekly


REMOVAL OF TEST SUBSTANCE
- Washing (if done): gently cleansed with gauze soaked in warm water and gently dried
- Time after start of exposure: 6h


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml/kg bw /d
- Concentration (if solution): 0 - 17- 87- 175 mg/kg bw/d
- Constant volume or concentration used: yes


VEHICLE = deionized water
- Amount(s) applied (volume or weight with unit): 0.5 ml/kg bw/d
- Lot/batch no. (if required): 071099, 201099, 011199, 091199, 171199, 221199, 031299, 081299, 151299, 171299, 281299


USE OF RESTRAINERS FOR PREVENTING INGESTION: no data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
nominal concentration (mg/kg bw/d): 0 - 50 - 250 - 500 respectively
actual concentration (mg/kg bw/d): 0 - 17 - 87 - 175 respectively
Duration of treatment / exposure:
approximately 6h
Frequency of treatment:
once daily, 90 consecutive days
Remarks:
Doses / Concentrations:
17
Basis:
analytical per unit body weight
Remarks:
Doses / Concentrations:
87
Basis:
analytical per unit body weight
Remarks:
Doses / Concentrations:
175
Basis:
analytical per unit body weight
No. of animals per sex per dose:
10 male and 10 female rats per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: dose level selected by the sponsor
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: no satellite group
Positive control:
no data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily


DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: once daily


BODY WEIGHT: Yes
- Time schedule for examinations:
at the time of randomisation
prior to dose administration on day 1
weekly (after that)
on day 91 (fasted)


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes (weekly)


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data


WATER CONSUMPTION: No data


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: before treatment + prior to terminal sacrifice
- Dose groups that were examined: all animals


HAEMATOLOGY: Yes
- Time schedule for collection of blood: on day 91, prior to terminale sacrifice
- Anaesthetic used for blood collection: Yes, CO2
- Animals fasted: Yes , overnight
- How many animals: all surviving animals (= all animals, 80)
- Following parameters were examined.
* Hematology: differential white blood cell count, hematocrit, hemoglobin, mean corpuscular hemoglobin,
mean corpuscular hemoglobin concntration, mean corpuscular volume, platelet count, red blood cell count and morphology,
white blood cell count
* Coagulation: prothrombin time, acctivated partial thromboplastin time


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:on day 91, prior to terminale sacrifice
- Animals fasted: Yes , overnight
- How many animals: all animals (80)
- Following parameters were examined:
* serum clinical chemistry: alanine aminotransferase, albumin, albumin/globulin ratio (calculated), aspartate aminotransferase, calcium,
chloride, cholesterol, creatinine, creatine phosphokinase, globulin (calculated), glucose, phosphorus, potassium, sodium, total bilirubin,
total protein, triglycerides, urea nitrogen


URINALYSIS: Yes
- Time schedule for collection of urine: on day 90, urine was collected overnight
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Following parameters were examined:
* volume, specific gravity, appearance/color, semi-quantitative estimation: pH, protein, glucose, ketone, urobilinoen, bilirubin,
blood, leukocytes, nitrites, microscopic examination of spun deposit

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: on day 28 and day 90 during treatment
- Dose groups that were examined: all
- Battery of functions tested: observation of animals / sensory activity / grip strength / motor activity / other: loss of righting reflex,
spontaneous locomotor activity, right pupil examination, various reflex responses


OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
external surface of the body, all orifices, cranial, thoracic and abdominal cavities together with their content

HISTOPATHOLOGY: Yes
gross abnormalities, adrenals, aorta, whole brain, cecum, colon, duodenum, epididymides, esophagus, exorbital lachrymal gland,
eyes w/optic nerve, femur, fat (mesentery), heart, ileum, jejunum, kidneys, liver, lungs with mainstem bronchus, mammary gland(s), mesenteric
lymph nodes, ovaries, pancreas, pituitary, prostate, rectum, salivary glands (mandibular lymph nodes), sciatic nerve, seminal vesicle(s),
skin (with subcutis from a site other than the treated site), spinal cord at three levels - cervical, midthoracic, lumbar - spleen, sternum with bone
marrow, stomach, testes, thigh musculature (skeletal muscle), thymus, thyroids/parathyroids, tongue, trachea, treated site (dorsal thoracic region
with subcutis), urinary bladder, uterus, vagina

Statistics:
evaluation of equality of means: one-way analysis of variance usiing the F distribution to assess statistical significance
is differences between the means are statistically significant, Dunnett's test was used to determine the degree of significance.
Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
* no animals died during the study
* no clinical signs of toxicity observed during the study
* clinical signs of dermal irritation were noted.
-Erythema and edema of varying degrees was observed in both male and female 87 and 175 mg/kg bw/d groups.
-Very slight erythema first appeared on day 6, 7 or 8 of 87 - 175 mg/kg bw/d groups.
-Very slight edema first appeared on day 7 in females receiving 175 mg/kg bw/d and progressed to severe edema by the end of the study.
-Very slight edema was seen on days 28, 38 or 33 respectively in females (87mg/kg bw/d) and males (87 or 175 mg/kg bw/d). This progresses to moderate to severe during the following 90 days of treatment. There was slightly more eythema and edema in females (87 mg/kg bw/d) compared to males recieving the same dose.
- additional signs noted in the male/female 87 and 175 mg/kg bw/d dose groups were all related to irritation at the application site and included scab formation, sloughing, and black areas on the dosing site.


BODY WEIGHT AND WEIGHT GAIN
* no test article-related differences in group mean bw or body weight gains throughout the study


FOOD CONSUMPTION
* no test article-related differences in group mean food consumption throughout the study


FOOD EFFICIENCY
* no data


WATER CONSUMPTION
* no data


OPHTHALMOSCOPIC EXAMINATION
* no test article-related differences in ophthalmology examination, conducted during the final week of treatment


HAEMATOLOGY
* Females, 87 mg/kg bw/d: statistically significant increase in absolute and relative neutrophil counts
* no test article-related differences in erythrocyte morphology for males or females
* no test article-related differences in hematology for males


CLINICAL CHEMISTRY
* males, 175 mg/kg bw/d + females, 87 and 175 mg/kg bw/d: statistically significant increases in globulin + decreases in albumin/globulin ratios
* all other stat. significant differences were withing normal historical ranges : were not considered to be test article-related


URINALYSIS
* no test article-related changes in any of the urinalyses parameters observed in M or F rates at the end of the treatment period


NEUROBEHAVIOUR
* no test article-related neurotoxicity observed on day 28 or day 90.


ORGAN WEIGHTS
* no test article-related differences in absolute organ weights, relative organ to body weight ratios, or relative organ to brain weight-ratios
following 90 d of treatment.


GROSS PATHOLOGY
* scab formation of varying degrees was observed at the treatment site of males and females receiving 87 or 175 mg/kg bw/d (see table 9, p. 148)
* varous gross lesions on the skin at the treatment site were test article-related in male and females receiving 87 or 175 mg/kg bw/d
(namely respecitvely in 8/10 males and 10/10 females in 87 mg/kg bw/d dosing group; and 9/10 males and 9/10 females in 175 mg/kg bw/d).

HISTOPATHOLOGY: NON-NEOPLASTIC
test article-related microscopic changes were limited to the site of exposure and included ulceration, epidermal hyperplasia, fibrosis and
inflammation. there was some variation in the severity of these changes, however: most of the males and females in 87 - 175 mg/kg bw/d groups were affected with one or more of these changes. No evidence of a similar effect was seen in the control group and the lowest dose group.



Dose descriptor:
NOAEL
Remarks:
dermal effects
Effect level:
>= 17 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
dermal irritation
Dose descriptor:
NOAEL
Remarks:
systemic effects
Effect level:
>= 175 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
dermal irritation
clinical biochemistry
gross pathology
histopathology: non-neoplastic
Critical effects observed:
not specified
Conclusions:
Application of DGA to an intact cutaneous site for approximately six hours, once daily for 90 consecutive days to male and female Sprague-Dawley rats, results in ulceration, epidermal hyperplasia, fibrosis and/or inflamation at doses of 87 and 175 mg/kg bw/d. These changes represent local irritation following topical administration.
Based on the results of the study, the dermal NOAEL was at least 17 mg/kg bw/d while the systemic NOAEL was at least 175 mg/kg bw/d.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
222.25 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
A reliable GLP 90-day repeated dose dermal toxicity study conducted according to OECD Guideline 411 on a structurally similar substance, 2-(2-aminoethoxy)ethanol (CAS# 929-06-6), is available as a read-across study, see section 13, read across justification. In addition, two supporting studies are available and are described below.

A supporting GLP study on DMEE conducted in 1987 using methods similar to OECD guideline 410 is available. New Zealand White rabbits (5/sex/group) were exposed to the test substance by occluded cutaneous exposure at doses of 0, 50, 250, or 500 mg/kg body weight for a total of nine applications (6 hr/day) over an 11-day period , during which severe skin lesions were observed at all doses. The LOEL was reported to be
A 14-day range finder study in Sprague Dawley rats (5 male/5 female per dose) conducted equivalent to OECD Guideline 410 at dose levels of 0, 500, 1000, 2000, 3000 mg/mL is also available for the read-across substance, 2-(2-aminoethoxy)ethanol (CAS# 929-06-6). A NOAEL for dermal effects of 250 mg/kg/day was reported based on erythema of various degrees occurring in males and females in all dose groups at or above 500 mg/kg-bw/day.

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal, other
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No deviation from OECD guideline (OECD 411).
Justification for type of information:
See "Read across Justification" as cross-referenced under section 13.
Reason / purpose:
read-across: supporting information
Qualifier:
according to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Sprague Dawley, strain Hsd:SD
- Age at study initiation: 6 weeks
- Weight at study initiation: 143-247 grams
- Fasting period before study:
- Housing:
* before the study: rats were groups-housed by sex
* during the study: animals were housed individually in stainless steel cages
- Diet (e.g. ad libitum): Teklad Certified LM-485 rodent diet, ad libitum, except overnight prior to scheduled blood collectiong
- Water (e.g. ad libitum): ad libitum
- Acclimation period: min 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25°C
- Humidity (%): 30-70% (during 2 days of the study, relative humidity was outside this range. However, this is not considered to have had any adverse
effect on the outcome of this study)
- Photoperiod (hrs dark / hrs light): 12h light, 12h dark


Type of coverage:
occlusive
Vehicle:
water
Details on exposure:
TEST SITE
- Area of exposure: between 10 and 20% of the body surface
- Type of wrap if used: gauze pad, rubber dam and an elastic bandage
- Time intervals for shavings or clipplings: minimum of twice weekly


REMOVAL OF TEST SUBSTANCE
- Washing (if done): gently cleansed with gauze soaked in warm water and gently dried
- Time after start of exposure: 6h


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml/kg bw /d
- Concentration (if solution): 0 - 17- 87- 175 mg/kg bw/d
- Constant volume or concentration used: yes


VEHICLE = deionized water
- Amount(s) applied (volume or weight with unit): 0.5 ml/kg bw/d
- Lot/batch no. (if required): 071099, 201099, 011199, 091199, 171199, 221199, 031299, 081299, 151299, 171299, 281299


USE OF RESTRAINERS FOR PREVENTING INGESTION: no data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
nominal concentration (mg/kg bw/d): 0 - 50 - 250 - 500 respectively
actual concentration (mg/kg bw/d): 0 - 17 - 87 - 175 respectively
Duration of treatment / exposure:
approximately 6h
Frequency of treatment:
once daily, 90 consecutive days
Remarks:
Doses / Concentrations:
17
Basis:
analytical per unit body weight
Remarks:
Doses / Concentrations:
87
Basis:
analytical per unit body weight
Remarks:
Doses / Concentrations:
175
Basis:
analytical per unit body weight
No. of animals per sex per dose:
10 male and 10 female rats per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: dose level selected by the sponsor
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: no satellite group
Positive control:
no data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily


DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: once daily


BODY WEIGHT: Yes
- Time schedule for examinations:
at the time of randomisation
prior to dose administration on day 1
weekly (after that)
on day 91 (fasted)


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes (weekly)


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data


WATER CONSUMPTION: No data


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: before treatment + prior to terminal sacrifice
- Dose groups that were examined: all animals


HAEMATOLOGY: Yes
- Time schedule for collection of blood: on day 91, prior to terminale sacrifice
- Anaesthetic used for blood collection: Yes, CO2
- Animals fasted: Yes , overnight
- How many animals: all surviving animals (= all animals, 80)
- Following parameters were examined.
* Hematology: differential white blood cell count, hematocrit, hemoglobin, mean corpuscular hemoglobin,
mean corpuscular hemoglobin concntration, mean corpuscular volume, platelet count, red blood cell count and morphology,
white blood cell count
* Coagulation: prothrombin time, acctivated partial thromboplastin time


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:on day 91, prior to terminale sacrifice
- Animals fasted: Yes , overnight
- How many animals: all animals (80)
- Following parameters were examined:
* serum clinical chemistry: alanine aminotransferase, albumin, albumin/globulin ratio (calculated), aspartate aminotransferase, calcium,
chloride, cholesterol, creatinine, creatine phosphokinase, globulin (calculated), glucose, phosphorus, potassium, sodium, total bilirubin,
total protein, triglycerides, urea nitrogen


URINALYSIS: Yes
- Time schedule for collection of urine: on day 90, urine was collected overnight
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Following parameters were examined:
* volume, specific gravity, appearance/color, semi-quantitative estimation: pH, protein, glucose, ketone, urobilinoen, bilirubin,
blood, leukocytes, nitrites, microscopic examination of spun deposit

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: on day 28 and day 90 during treatment
- Dose groups that were examined: all
- Battery of functions tested: observation of animals / sensory activity / grip strength / motor activity / other: loss of righting reflex,
spontaneous locomotor activity, right pupil examination, various reflex responses


OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
external surface of the body, all orifices, cranial, thoracic and abdominal cavities together with their content

HISTOPATHOLOGY: Yes
gross abnormalities, adrenals, aorta, whole brain, cecum, colon, duodenum, epididymides, esophagus, exorbital lachrymal gland,
eyes w/optic nerve, femur, fat (mesentery), heart, ileum, jejunum, kidneys, liver, lungs with mainstem bronchus, mammary gland(s), mesenteric
lymph nodes, ovaries, pancreas, pituitary, prostate, rectum, salivary glands (mandibular lymph nodes), sciatic nerve, seminal vesicle(s),
skin (with subcutis from a site other than the treated site), spinal cord at three levels - cervical, midthoracic, lumbar - spleen, sternum with bone
marrow, stomach, testes, thigh musculature (skeletal muscle), thymus, thyroids/parathyroids, tongue, trachea, treated site (dorsal thoracic region
with subcutis), urinary bladder, uterus, vagina

Statistics:
evaluation of equality of means: one-way analysis of variance usiing the F distribution to assess statistical significance
is differences between the means are statistically significant, Dunnett's test was used to determine the degree of significance.
Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
* no animals died during the study
* no clinical signs of toxicity observed during the study
* clinical signs of dermal irritation were noted.
-Erythema and edema of varying degrees was observed in both male and female 87 and 175 mg/kg bw/d groups.
-Very slight erythema first appeared on day 6, 7 or 8 of 87 - 175 mg/kg bw/d groups.
-Very slight edema first appeared on day 7 in females receiving 175 mg/kg bw/d and progressed to severe edema by the end of the study.
-Very slight edema was seen on days 28, 38 or 33 respectively in females (87mg/kg bw/d) and males (87 or 175 mg/kg bw/d). This progresses to moderate to severe during the following 90 days of treatment. There was slightly more eythema and edema in females (87 mg/kg bw/d) compared to males recieving the same dose.
- additional signs noted in the male/female 87 and 175 mg/kg bw/d dose groups were all related to irritation at the application site and included scab formation, sloughing, and black areas on the dosing site.


BODY WEIGHT AND WEIGHT GAIN
* no test article-related differences in group mean bw or body weight gains throughout the study


FOOD CONSUMPTION
* no test article-related differences in group mean food consumption throughout the study


FOOD EFFICIENCY
* no data


WATER CONSUMPTION
* no data


OPHTHALMOSCOPIC EXAMINATION
* no test article-related differences in ophthalmology examination, conducted during the final week of treatment


HAEMATOLOGY
* Females, 87 mg/kg bw/d: statistically significant increase in absolute and relative neutrophil counts
* no test article-related differences in erythrocyte morphology for males or females
* no test article-related differences in hematology for males


CLINICAL CHEMISTRY
* males, 175 mg/kg bw/d + females, 87 and 175 mg/kg bw/d: statistically significant increases in globulin + decreases in albumin/globulin ratios
* all other stat. significant differences were withing normal historical ranges : were not considered to be test article-related


URINALYSIS
* no test article-related changes in any of the urinalyses parameters observed in M or F rates at the end of the treatment period


NEUROBEHAVIOUR
* no test article-related neurotoxicity observed on day 28 or day 90.


ORGAN WEIGHTS
* no test article-related differences in absolute organ weights, relative organ to body weight ratios, or relative organ to brain weight-ratios
following 90 d of treatment.


GROSS PATHOLOGY
* scab formation of varying degrees was observed at the treatment site of males and females receiving 87 or 175 mg/kg bw/d (see table 9, p. 148)
* varous gross lesions on the skin at the treatment site were test article-related in male and females receiving 87 or 175 mg/kg bw/d
(namely respecitvely in 8/10 males and 10/10 females in 87 mg/kg bw/d dosing group; and 9/10 males and 9/10 females in 175 mg/kg bw/d).

HISTOPATHOLOGY: NON-NEOPLASTIC
test article-related microscopic changes were limited to the site of exposure and included ulceration, epidermal hyperplasia, fibrosis and
inflammation. there was some variation in the severity of these changes, however: most of the males and females in 87 - 175 mg/kg bw/d groups were affected with one or more of these changes. No evidence of a similar effect was seen in the control group and the lowest dose group.



Dose descriptor:
NOAEL
Remarks:
dermal effects
Effect level:
>= 17 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
dermal irritation
Dose descriptor:
NOAEL
Remarks:
systemic effects
Effect level:
>= 175 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
dermal irritation
clinical biochemistry
gross pathology
histopathology: non-neoplastic
Critical effects observed:
not specified
Conclusions:
Application of DGA to an intact cutaneous site for approximately six hours, once daily for 90 consecutive days to male and female Sprague-Dawley rats, results in ulceration, epidermal hyperplasia, fibrosis and/or inflamation at doses of 87 and 175 mg/kg bw/d. These changes represent local irritation following topical administration.
Based on the results of the study, the dermal NOAEL was at least 17 mg/kg bw/d while the systemic NOAEL was at least 175 mg/kg bw/d.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Study duration:
subchronic
Species:
rat
Quality of whole database:
See "Quality of whole database" for Repeated dose toxicity: dermal - systemic effects.

Additional information

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
No studies of sufficient quality are available for this endpoint.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
A reliable, GLP study was conducted in Wistar rats according to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) on a structurally similar substance, 2-(2-aminoethoxy)ethanol (CAS# 929-06-6). Animals (10 per sex per dose) were exposed nose/head only to 0, 4, 16, or 40 mg/m3 aerosol concentrations of the test substance. No treatment-related, adverse systemic effects were observed up to a dose level of 40 mg/m3. A NOAEC for systemic effects of 40 mg/m3 air was reported on the basis of lack of general systemic toxicity and lack of reproductive performance and fertility effects. A molar conversion was applied to the NOAEC to account for the differences in molecular weight of DMEE and the read across substance of 133.19/105.14 = 1.27. Thus, the adjusted NOAEC for systemic effects is 40 mg/m3 * 1.27 = 50.8 mg/m3.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
A reliable, GLP study was conducted in Wistar rats according to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) on a structurally similar substance, 2-(2-aminoethoxy)ethanol (CAS# 929-06-6). Animals (10 per sex per dose) were exposed nose/head only to 0, 4, 16, or 40 mg/m3 aerosol concentrations of the test substance. Treatment-related microscopic changes were observed in the larynx and consisted of increased squamous metaplasia of the respiratory epithelium and chronic (active) inflammation at level 1 of the larynx only to a marginal or slight degree. A NOAEC for local effects of 4 mg/m3 air was reported due to the local effects observed in the larynx (level 1). A molar conversion was applied to the NOAEC to account for the differences in molecular weight of DMEE and the read across substance of 133.19/105.14 = 1.27. Thus, the adjusted NOAEC for local effects is 4 mg/m3 * 1.27 = 5.08 mg/m3.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:

A reliable GLP 90-day repeated dose dermal toxicity study with Sprague-Dawley rats conducted according to OECD Guideline 411 on a structurally similar substance, 2-(2-aminoethoxy)ethanol (CAS# 929-06-6), is available as a read-across study (see Annex 13, Read across Justification). DMEE, 2-(2-(dimethylamino)ethoxy)ethanol and 2-(2-aminoethoxy)ethanol are close structural analogues, which differ only by the presence of two methyl groups on the terminal nitrogen. In this study, the test substance was applied to intact cutaneous sites of the rats for approximately 6 hours, once daily for 90 consecutive days at doses of 0, 17, 87, and 175 mg/kg bw/d. No clinical signs of systemic toxicity were noted during the study. Based on the results of the study, the systemic NOAEL was at least 175 mg/kg bw/d. A molar conversion was applied to the NOAEL to account for the differences in molecular weight of DMEE and the read across substance of 133.19/105.14 = 1.27. Thus, the adjusted NOAEL for systemic effects is 175 mg/kg bw/day * 1.27 = 222.25 mg/kg bw/day.

 

Justification for selection of repeated dose toxicity dermal - local effects endpoint:

A reliable GLP 90-day repeated dose dermal toxicity study with Sprague-Dawley rats conducted according to OECD Guideline 411 on a structurally similar substance, 2-(2-aminoethoxy)ethanol (CAS# 929-06-6), is available as a read-across study (see Annex 13, Read across Justification). In this study, the test substance was applied to an intact cutaneous site of the rats for approximately 6 hours, once daily for 90 consecutive days at doses of 0, 17, 87, and 175 mg/kg bw/d. Reported local effects included ulceration, epidermal hyperplasia, fibrosis and inflammation at doses of 87 and 175 mg/kg bw/d. These changes represent local irritation following topical administration. Based on the results of the study, the NOAEL for local effects was at least 17 mg/kg bw/d. A molar conversion was applied to the NOAEL to account for the differences in molecular weight of DMEE and the read across substance of 133.19/105.14 = 1.27. Thus, the adjusted NOAEL for local effects is 17 mg/kg bw/day * 1.27 = 21.59 mg/kg bw/day. Given the corrosive nature of DMEE, a high hazard was assigned for qualitative risk assessment purposes per the ECHA Guidance on information requirements and chemical safety assessment Part E: Risk Characterization (Version 2.0, November 2012).

These result are supported by a 11-day repeated dose dermal toxicity study with New Zealand White rabbits equivalent with OECD 410 and in compliance with GLP with DMEE, 2-(2-(dimethylamino)ethoxy)ethanol. In this study, the test substance was applied to intact cutaneous sites of the rabbits for approximately 6 hours, once daily for 11 consecutive days at doses of 0, 50, 250 and 500 mg/kg bw/d. Crusting or scaling dermatitis and epidermitis described as excoriation and encrustation were noted at the application at necropsy. There were no clinical signs of systemic toxicity. Hematology changes (increased segmented heterophils at 500 mg/kg bw/day; increased total leukocyte count in females only at 500 mg/kg bw; increased platelets in males at all doses; decreased hemoglobin and hematocrit levels in males at 500 mg/kg bw) and organ weight effects (reduction in absolute/relative adrenal weight in males at 500 mg/kg bw; increased relative liver weight in males at 250 and 500 mg/kg bw) were observed. These changes were probably secondary changes in consequence of the skin barrier destruction and a subsequent infection. Similar findings have been reported to occur in rabbits for other irritating /corrosive compounds as well as in an interlaboratory evaluation. The study duration was insufficient for the determination of an NOAEL for DMEE, however, the test substance was considered to be a severe skin irritant at doses of 50 mg/kg bw/day and above in male and female rabbits.

Justification for classification or non-classification

Based on the available data, classification for repeated dose toxicity is not warranted according to the criteria of EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.