Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Referenceopen allclose all

Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP; guideline study
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 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 (if applicable):
nose/head only
Vehicle:
air
Details on 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.
Details on mating procedure:
Each of the male and female animals was mated overnight in a 1:1 ratio for a maximum of 2 weeks. Throughout the mating period, each female animal was paired with a predetermined male animal from the same test group. Mating was accomplished by placing the female in the cage of the male mating partner from about 16.00 h until 07.00-09.00 h of the following morning. Deviations from these specified times were possible on weekends and public holidays and were reported in the raw data. A vaginal smear was prepared after each mating and examined for sperm. If sperm was detected, pairing of the animals was discontinued. The day on which sperm was detected was denoted "gestation day (GD) 0" and the following day "GD 1".
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
6 hours
Frequency of treatment:
daily
Details on study schedule:
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 animals 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 urinalyses 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 females per test group. All surviving F0 parental animals were sacrificed assessed by gross pathology. Organ weights were recorded and a histopathological examination was performed.
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 vehicle
For all F0 parental males, which were placed with females to generate F1 pups, copulation was confirmed. Thus, the male mating index was 100% in all test groups (0, 4, 16 and 40 mg/m³). Fertility was proven for most of the F0 parental males within the scheduled mating interval for F1 litter. One male of the 4 mg/m³ test group did not generate F1 pups. The apparently infertile male rat did not show histopathological findings that could explain infertility. Thus, the male fertility index was 90% in the 4 mg/m³ test group and 100% in all remaining groups including the control. This reflected the normal range of biological variation inherent in the strain of rats used for this study. All respective values were within the range of the historical control data of the test facility.
The female mating index calculated after the mating period for F1 litter was 100% in all test groups (0, 4, 16 and 40 mg/m³).
The mean duration until sperm was detected (GD 0) amounted to 3.1, 3.1, 2.7 and 3.3 days (0, 4, 16 and 40 mg/m³). All sperm positive rats delivered pups or had implants in utero with the exception of one low-dose female, that did not become pregnant. The female fertility index varied between 90% (4 mg/m³) and 100% (all other test groups). These values reflect the normal range of biological variation inherent in the strain of rats used for this study. All respective values were within the range of the historical control data of the test facility and did not show any relation to dosing. There were no corroborative histopathological findings in the sexual organs of the nonpregnant female rat. The mean duration of gestation values varied between 22.0 (test groups 4 and 16 mg/m³) and 22.2 days (test groups 0 and 40 mg/m³) without any relation to dosing. The gestation index was 100% in all test groups including the control. Implantation was not affected by the treatment since the mean number of implantation sites was comparable between all test substance-treated groups and the controls, taking normal biological variation into account (10.6, 11.1, 12.3 and 11.4 implants per dam at 0, 4, 16 and 40 mg/m³, respectively). Furthermore, there were no indications for test substance-induced intrauterine embryo-/fetolethality since the postimplantation loss did not show any significant differences between the test groups, and the mean number of F1 pups delivered per dam remained unaffected (9.3, 10.1, 11.6 and 10.7 pups per dam at 0, 4, 16 and 40 mg/m³, respectively). The rate of liveborn pups was not affected by the test substance, as indicated by live birth indices of 97% (test group 16 mg/m³) and 100% (all other test groups). Moreover, the number of stillborn pups was comparable between the test groups.
Dose descriptor:
NOAEC
Effect level:
40 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: reproductive performance, fertility
Dose descriptor:
NOAEC
Effect level:
40 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: systemic toxicity
Dose descriptor:
NOAEC
Effect level:
4 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: local effects
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
40 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: developmental toxicity
Reproductive effects observed:
not specified
Conclusions:
The NOAEC for reproductive performance and fertility in male and female Wistar rats was 40 mg/m³ (highest dose tested).
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. For all F0 parental males, which were placed with females to generate F1 pups, copulation was confirmed. Thus, the male mating index was 100% in all test groups (0, 4, 16 and 40 mg/m³). Fertility was proven for most of the F0 parental males within the scheduled mating interval for F1 litter. One male of the 4 mg/m³ test group did not generate F1 pups. The apparently infertile male rat did not show histopathological findings that could explain infertility. Thus, the male fertility index was 90% in the 4 mg/m³ test group and 100% in all remaining groups including the control. This reflected the normal range of biological variation inherent in the strain of rats used for this study. All respective values were within the range of the historical control data of the test facility. The female mating index calculated after the mating period for F1 litter was 100% in all test groups (0, 4, 16 and 40 mg/m³). The mean duration until sperm was detected (GD 0) amounted to 3.1, 3.1, 2.7 and 3.3 days (0, 4, 16 and 40 mg/m³). All sperm positive rats delivered pups or had implants in utero with the exception of one low-dose female, that did not become pregnant. The female fertility index varied between 90% (4 mg/m³) and 100% (all other test groups). These values reflect the normal range of biological variation inherent in the strain of rats used for this study. All respective values were within the range of the historical control data of the test facility and did not show any relation to dosing. There were no corroborative histopathological findings in the sexual organs of the nonpregnant female rat. The mean duration of gestation values varied between 22.0 (test groups 4 and 16 mg/m³) and 22.2 days (test groups 0 and 40 mg/m³) without any relation to dosing. The gestation index was 100% in all test groups including the control. Implantation was not affected by the treatment since the mean number of implantation sites was comparable between all test substance-treated groups and the controls, taking normal biological variation into account (10.6, 11.1, 12.3 and 11.4 implants per dam at 0, 4, 16 and 40 mg/m³, respectively). Furthermore, there were no indications for test substance-induced intrauterine embryo-/fetolethality since the postimplantation loss did not show any significant differences between the test groups, and the mean number of F1 pups delivered per dam remained unaffected (9.3, 10.1, 11.6 and 10.7 pups per dam at 0, 4, 16 and 40 mg/m³, respectively). The rate of liveborn pups was not affected by the test substance, as indicated by live birth indices of 97% (test group 16 mg/m³) and 100% (all other test groups). Moreover, the number of stillborn pups was comparable between the test groups.

Thus, the NOAEC for reproductive performance and fertility in male and female Wistar rats was 40 mg/m³.

Endpoint:
toxicity to reproduction
Remarks:
other: OECD 411
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
see section 13, read across justification
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: no deviation from OECD guideline (OECD 411). Not GLP.
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
other: OECD 411
Deviations:
no
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
- Name of test material (as cited in study report): DGA
- Substance type: clear, colorless
- Physical state: liquid
- Lot/batch No.: 9F10
- Expiration date of the lot/batch: 15 July 2001
- Stability under test conditions: stability information was not provided
- Storage condition of test material: room temp
Route of administration:
dermal
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
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, 87, 175 mg/kg bw
Basis:
nominal in water
No. of animals per sex per dose:
10 male and 10 female rats per dose

Control animals:
yes, concurrent vehicle
Parental animals: Observations and examinations:
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 using 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.
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
Effect level:
>= 17 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: dermal effects
Dose descriptor:
NOAEL
Effect level:
>= 175 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: systemic effects
Reproductive 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. No effects on the reproductive organs (weight, gross pathology or histopathology) were reported.
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.
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
50.8 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
No studies were identified for DMEE. A reliable (Klimisch 2) combined repeated dose toxicity study with the reproduction/developmental toxicity screening test conducted under GLP and according to OECD 422 is available on a structurally similar substance, 2-(2-aminoethoxy)ethanol, see section 13, read across justfication
Effect on fertility: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
222.25 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
see section 13, read across justfication
Additional information

In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test according to OECD 422 (BASF SE, 2010) 2-(2-Aminoethoxy) ethanol was administered via inhalation (aerosol) to groups of 10 male and 10 female Wistar rats (F0 animals) at concentrations of 4, 16, and 40 mg/m³.

For all F0 parental males, which were placed with females to generate F1 pups, copulation was confirmed. Thus, the male mating index was 100% in all test groups (0, 4, 16 and 40 mg/m³). Fertility was proven for most of the F0 parental males within the scheduled mating interval for F1 litter. One male of the 4 mg/m³ test group did not generate F1 pups. The apparently infertile male rat did not show histopathological findings that could explain infertility. Thus, the male fertility index was 90% in the 4 mg/m³ test group and 100% in all remaining groups including the control. The female mating index calculated after the mating period for F1 litter was 100% in all test groups (0, 4, 16 and 40 mg/m³). The mean duration until sperm was detected (GD 0) amounted to 3.1, 3.1, 2.7 and 3.3 days (0, 4, 16 and 40 mg/m³). All sperm positive rats delivered pups or had implantsin utero with the exception of one low-dose female that did not become pregnant. The female fertility index varied between 90% (4 mg/m³) and 100% (all other test groups). There were no corroborative histopathological findings in the sexual organs of the nonpregnant female rat. The mean duration of gestation values varied between 22.0 (test groups 4 and 16 mg/m³) and 22.2 days (test groups 0 and 40 mg/m³) without any relation to dosing. The gestation index was 100% in all test groups including the control. Implantation was not affected by the treatment since the mean number of implantation sites was comparable between all test substance-treated groups and the controls, taking normal biological variation into account (10.6, 11.1, 12.3 and 11.4 implants per dam at 0, 4, 16 and 40 mg/m³, respectively). Furthermore, there were no indications for test substance-induced intrauterine embryo-/fetolethality since the postimplantation loss did not show any significant differences between the test groups, and the mean number of F1 pups delivered per dam remained unaffected (9.3, 10.1, 11.6 and 10.7 pups per dam at 0, 4, 16 and 40 mg/m³, respectively). The rate of liveborn pups was not affected by the test substance, as indicated by live birth indices of 97% (test group 16 mg/m³) and 100% (all other test groups). Moreover, the number of stillborn pups was comparable between the test groups.

Thus, the NOAEC for reproductive performance and fertility in male and female Wistar rats was 40 mg/m³.

In a subchronic dermal study on a structurally similar substance, 2-(2-aminoethoxy)ethanol (CAS# 929-06-6) following OECD test guideline 411 (Huntsman, 2002), no effects on the male and female reproductive organs were observed up to the highest dose tested (175 mg/kg/day). Application of the test substance to an intact cutaneous site for approximately 6 hours, once daily for 90 consecutive days resulted in ulceration, epidermal hyperplasia, fibrosis and inflammation at doses of 87 and 175 mg/kg bw/d. These changes represent local irritation following topical administration. No effects on the reproductive organs (weight, gross pathology, histopathology) were reported. Based on the results of the study, the systemic NOAEL was at least 175 mg/kg bw/d.

Short description of key information:
In a 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), the no observed adverse effect concentration (NOAEC) for reproductive performance and fertility in male and female Wistar rats was 40 mg/m³ (aerosol). The NOAEC for local signs of toxicity in male and female Wistar rats was 4 mg/m³. 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 reproductive 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 on a structurally similar substance, 2-(2-aminoethoxy) ethanol (CAS# 929-06-6) following OECD test guideline 411, no effects on the male and female reproductive organs were observed up to the highest dose tested (175 mg/kg/day). 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 reproductive effects is 175 mg/kg bw/day * 1.27 = 222.25 mg/kg bw/day.

Justification for selection of Effect on fertility via inhalation route:
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). 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. 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 effects were observed up to a dose level of 40 mg/m3. 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 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 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 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 reproductive 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.

Justification for selection of Effect on fertility via dermal route:
In a subchronic dermal toxicity study on a structurally similar substance, 2-(2-aminoethoxy) ethanol (CAS# 929-06-6) following OECD test guideline 411, no effects on the male and female reproductive organs were observed up to the highest dose tested (175 mg/kg/day). 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. Application of the test substance to an intact cutaneous site for approximately 6 hours, once daily for 90 consecutive days resulted in ulceration, epidermal hyperplasia, fibrosis and inflammation at doses of 87 and 175 mg/kg bw/d. These changes represent local irritation following topical administration. No effects on the reproductive organs (weight, gross pathology, histopathology) were reported. Based on the results of the study, the NOAEL for local effects was at least 17 mg/kg bw/d while 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 reproductive effects is 175 mg/kg bw/day * 1.27 = 222.25 mg/kg bw/day.

Effects on developmental toxicity

Description of key information
In an inhalatory (aerosol) combined repeated dose toxicity study with the reproduction/developmental toxicity screening test on a structurally similar substance, 2-(2-aminoethoxy)ethanol that differs from DMEE only by the absence of two methyl groups on the terminal nitrogen, the no observed adverse effect concentration (NOAEC) for developmental toxicity in male and female Wistar rats was the highest dose tested, 40 mg/m³. The NOAEC for local signs of toxicity in male and female Wistar rats was 4 mg/m³.  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 developmental 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. 
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP; guideline study
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:
other: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (OECD 422)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Wistar
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 (if applicable):
nose/head only
Vehicle:
air
Details on 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 mating procedure:
Each of the male and female animals was mated overnight in a 1:1 ratio for a maximum of 2 weeks. Throughout the mating period, each female animal was paired with a predetermined male animal from the same test group. Mating was accomplished by placing the female in the cage of the male mating partner from about 16.00 h until 07.00-09.00 h of the following morning. Deviations from these specified times were possible on weekends and public holidays and were reported in the raw data. A vaginal smear was prepared after each mating and examined for sperm. If sperm was detected, pairing of the animals was discontinued. The day on which sperm was detected was denoted "gestation day (GD) 0" and the following day "GD 1".
Duration of treatment / exposure:
6 hours
Frequency of treatment:
daily
Duration of test:
females: 46-48 days
males: 29 days
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
local toxic effects on the nasal cavity due to corrosive properties of the test substance
Dose descriptor:
NOAEC
Effect level:
40 mg/m³ air
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEC
Effect level:
40 mg/m³ air
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEC
Effect level:
4 mg/m³ air
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Dose descriptor:
NOAEC
Effect level:
40 mg/m³ air
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Dose descriptor:
NOAEC
Effect level:
40 mg/m³ air
Based on:
test mat.
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOAEC
Effect level:
40 mg/m³ air
Based on:
test mat.
Basis for effect level:
other: fetotoxicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
The NOAEC for developmental toxicity in male and female Wistar rats was 40 mg/m³ (highest dose tested).
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. The mean number of delivered pups per dam and the rate of liveborn and stillborn pups were evenly distributed among the test groups (control, 4, 16 and 40 mg/m³). The respective values reflect the normal range of biological variation inherent in the strain used in this study. The viability index as indicator for pup mortality between PND 0-4 varied between 99% and 100% in all test groups. The sex distribution and sex ratios of live F1 pups on the day of birth and on PND 4 did not show biologically relevant differences between the test groups. The F1 pups did not show any test substance-induced or spontaneous clinical signs up to scheduled sacrifice on PND 4. Mean pup body weights and pup body weight changes of all test substance-treated groups were generally comparable to the concurrent control group throughout the lactation period. Some F1 pups showed spontaneous findings at necropsy, such as post mortem autolysis, aneurysm of ductus arteriosus, short innominate, empty stomach and hemorrhagic testis. These pup necropsy findings occurred without relation to dosing and/or can be found in the historical control data at comparable or even higher incidences. Therefore, these findings were not considered to be associated to the test substance. Thus, the NOAEC for developmental toxicity was 40 mg/m3.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
50.8 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
No studies were identified for DMEE. A reliable (Klimisch 2) combined repeated dose toxicity study with the reproduction/developmental toxicity screening test conducted under GLP and according to OECD 422 is available on a structurally similar substance, 2-(2-aminoethoxy)ethanol. 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.
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test according to OECD 422 (BASF SE, 2010) 2-(2-Aminoethoxy)ethanol was administered via inhalation (aerosol) to groups of 10 male and 10 female Wistar rats (F0 animals) at concentrations of 4, 16, and 40 mg/m³.

The mean number of delivered pups per dam and the rate of liveborn and stillborn pups were evenly distributed among the test groups (control, 4, 16 and 40 mg/m³). The respective values reflect the normal range of biological variation inherent in the strain used in this study. The viability index as indicator for pup mortality between PND 0-4 varied between 99% and 100% in all test groups. The sex distribution and sex ratios of live F1 pups on the day of birth and on PND 4 did not show biologically relevant differences between the test groups. The F1 pups did not show any test substance-induced or spontaneous clinical signs up to scheduled sacrifice on PND 4. Mean pup body weights and pup body weight changes of all test substance-treated groups were generally comparable to the concurrent control group throughout the lactation period. Some F1 pups showed spontaneous findings at necropsy, such as post mortem autolysis, aneurysm of ductus arteriosus, short innominate, empty stomach and hemorrhagic testis. These pup necropsy findings occurred without relation to dosing and/or can be found in the historical control data at comparable or even higher incidences. Therefore, these findings were not considered to be associated to the test substance. Thus, the NOAEC for developmental toxicity was 40 mg/m3.


Justification for selection of Effect on developmental toxicity: via inhalation route:
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. 2-(2-Aminoethoxy)ethanol was administered via inhalation (aerosol) to groups of 10 male and 10 female Wistar rats (F0 animals) at concentrations of 4, 16, and 40 mg/m³. No test substance-related effects were seen in any test groups (control, 4, 16, and 40 mg/m3) with regard to the mean number of delivered pups per dam; rate of liveborn and stillborn pups; viability index; sex distribution and sex ratios; substance-induced or spontaneous clinical signs; and mean pup body weights and pup body weight changes throughout the lactation period. Spontaneous findings at necropsy were found to have occurred without relation to dosing and/or to be within the historical control data at comparable or even higher incidences. The NOAEC for developmental toxicity was therefore the highest dose tested, 40 mg/m³. 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 developmental effects is 40 mg/m3 * 1.27 = 50.8 mg/m3.

Justification for classification or non-classification

Classification for toxicity to reproduction 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.