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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Under the conditions of an OECD 422 combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in Wistar rats the following NOAEC was determined for 2-(2-ethoxyethoxy)-2-methylpropane after inhalation exposure:
The NOAEC for reproductive performance and fertility was 750 mg/m³ for the F0 parental rats. [BASF, 2015]

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
other: conditioned air: about 50% ± 20% relative humidity, 22°C ± 2°C
Details on mating procedure:
In general, 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.

The animals were paired by placing the female in the cage of the male mating partner from about 15:00-16.00 h until 06.00-07.00 h of the following morning. A vaginal smear was prepared after each mating and examined for the presence of 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:
6h/day, males: 32 days and females: 57 days
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
75, 250, and 750 mg/m3
Basis:

Remarks:
Doses / Concentrations:
81.1, 243.3, and 726.0 mg/m3
Basis:

No. of animals per sex per dose:
10
Control animals:
yes
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
male animals
For nearly all F0 parental males, which were placed with females to generate F1 pups, copulation was confirmed. Copulation was not confirmed for control male No. 6 paired with control female No. 106. Thus, the male mating index was 90% in the control and 100% in the low-, mid- and high-concentration groups. Fertility was proven for most of the F0 parental maleswithin the scheduled mating interval for F1 litter. One control male (No. 6), one low-concentration male (No. 11, test group 1, 75 mg/m³) and one mid-concentration male (No. 30, test group 2, 250 mg/m³) did not generate F1 pups. Thus, the male fertility index ranged between 90% and 100% without showing any relation to dosing. This reflects the normal range of biological variation inherent in the strain of rats used for this study. The apparently infertile male rats of the control (No. 6) and mid concentration group (No. 30, test group 2, 250 mg/m³) did not show relevant gross lesions or microscopic findings. The male animal No. 11 revealed a moderate reduction in the size of the left testis and epididymis, with a moderate tubular atrophy in the testis and a moderate oligospermia of the ipsilateral epididymis with additional cellular debris.

female animals
The female mating index calculated after the mating period for F1 litter was 90% in test group 0 and 100% in test groups 1-3. The mean duration until sperm was detected (GD 0) varied between 2.3 and 2.9 days without any relation to dosing. All female rats delivered pups or had implants in utero with the following exceptions:
Control female No. 106 (mated with male No. 6) did not become pregnant
Low-concentration female No. 111 (mated with male No. 11) did not become pregnant
Mid-concentration female No. 130 (mated with male No. 30) did not become pregnant
The fertility index varied between 90% (test groups 1 and 2) and 100% (test groups 0 and 3). These values reflect the normal range of biological variation inherent in the strain of rats used for this study. The non-pregnant female animal No. 130 showed a severe dilation of the uterus with cloudy fluid content. The apparently infertile female No. 106 (control group) and female No. 111 (test group 1, 75 mg/m³) did not show gross lesions or microscopic findings.
The mean duration of gestation was similar in all test groups (i.e. between 22.0 and 22.7 days). The gestation index was 100% in test groups 0, 1, and 3 and 88.9% in test group 2. These values reflect the normal range of biological variation inherent in the strain of rats used for this study. Implantation was not affected by the treatment since the mean number of implantation sites was comparable between all test substance-treated groups and the control, taking normal biological variation into account (11.4 / 11.2 / 9.4 and 11.4 implants/dam in test groups 0-3, respectively). Furthermore, there were no indications for any test substance-induced intrauterine embryo-/fetolethality since the post-implantation loss did not show any significant differences between the groups, and the mean number of F1 pups delivered per dam remained unaffected (11.1 / 10.4 / 10.4 and 11.2 pups/dam in test groups 0-3, respectively). The rate of liveborn pups was also not affected by the test substance, as indicated by live birth indices of 98.0% / 95.7% / 98.8% and 100% in test groups 0-3, respectively. Moreover, the number of stillborn pups was not significantly different between the test groups. All values are well covered by the historical control range.
Dose descriptor:
NOAEC
Effect level:
750 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Other effects:
not examined
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
750 mg/m³ air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
gross pathology
Reproductive effects observed:
no
Conclusions:
2-(2-ethoxyethoxy)-2-methylpropane did not adversely impact the reproduction of these rats, nor did treatment impact delivery and pup viability. Furthermore, none of the F1 generation pups showed any evidence of developmental toxicity in response to 2-(2-ethoxyethoxy)-2-methylpropane.
Executive summary:

During the exposure period, the target concentrations were met well and weremaintained as constant and stable as could be provided with the presented generation techniques in the concentration range tested.

Three pairs did not produce litter: one pair in the control group (No. 6 and 106), one pair in the test group 1 (No. 11 and 111) and one pair in the test group 2 (No. 30 and 130). Whereas no pathological findings were observed in sexual organs in the control group animals No. 6 and 106, histological findings were noted in one female (No. 130, test group 2, 250 mg/m³) and one male rat (No. 11, test group 1, 75 mg/m³). There was no concentration-response relationship, and the fertility was within the historical control range. Thus, no toxicologically relevant reproductive including fertility or developmental differences were observed between animals exposed to 75, 250 and 750 mg/m³ 2-(2-ethoxyethoxy)-2-methylpropane and controls. These concentrations of 2-(2-ethoxyethoxy)-2-methylpropane did not adversely impact the reproduction of these rats, nor did treatment impact delivery and pup viability. Furthermore, none of the F1 generation pups showed any evidence of developmental toxicity in response to 2-(2-ethoxyethoxy)-2-methylpropane.

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
750 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
modern guideline study
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

effects on fertility - inhalation

To evaluate the toxicity profile of 2-(2-ethoxyethoxy)-2-methylpropane after inhalation exposure, groups of ten male and ten female Wistar rats (F0 animals) per test group were exposed nose-only to dynamic atmosphere of 2-(2-ethoxyethoxy)-2-methylpropane for 6 hours per day on each day. The duration of treatment covered a 2-week pre-mating and 2-week mating period in both sexes, 3 days post-mating in males, and the entire gestation period of the females. After the lactation period and after necropsy of the pups total all parental females were exposed to the test substance on 8 days. The target concentrations were 75, 250 and 750 mg/m³. A concurrent control group was exposed to conditioned air. For adaptation to the experimental conditions all animals were transferred into chambers identical to those used in the study and exposed to fresh air on two days (6 hours per day) before start of the exposure period. 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 post-implantation loss for all F0 females. A detailed clinical observation (DCO) was performed in all animals before initial test substance exposure and, as a rule, thereafter at weekly intervals. Clinical observation was performed at least three times on exposure days and once a day during the other days. Food consumption of the F0 parents was determined once weekly during premating. In dams food consumption was determined for gestation days 0 - 7, 7 - 14, 14 - 20 and lactation days 1 - 4. During the 4 exposure days after necropsy of the pups the food consumption was determined also. Body weights of F0 parents were determined once a week, in males throughout the study and in females during premating. During gestation and lactation period, F0 females were weighed on gestation days (GD) 0, 7, 14 and 20,on the day after parturitionpostnatal day [PND] 1) and on PND 4. After the pups were sacrificed, the females that were exposed for further 8 days were weighed once weekly and once on the last exposure day. A functional observational battery (FOB) was performed and motor activity was measured in 5 parental males and females per group. The FOB of the female animals was on study day 54. The male animals were performed at the end of the exposure period on study day 26. The pups were sexed and examined for macroscopically evident changes on PND 0. They were weighed on PND 1 and on PND 4. Their viability was recorded. At necropsy on PND 4, all pups were sacrificed with CO2, under isoflurane anesthesia, and examined macroscopically for external and visceral findings. Clico-chemical and hematological examinations were performed in 5 animals per sex and grouptowards the end of the exposure period. A complete necropsy including gross pathological evaluation and weighing of selected organs was performed. Organs and tissues were examined histopathologically as required by the corresponding test guidelines. All F0 parental animals were sacrificed under pentobarbitone anesthesia by exsanguination from the abdominal aorta and vena cava and were assessed by gross pathology. Weights of selected organs were recorded and a histopathological examination was performed.

The following test substance-related adverse effects were noted:

All Test groups (up to 750 mg/m3)

No treatment-related, adverse effects were measured regarding effects on reproductive performance.

Effects on developmental toxicity

Description of key information

key information:

Under the conditions of this OECD 414 prenatal developmental toxicity study, the oral administration of 2-(2-ethoxyethoxy)-2-methylpropane to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) caused adverse findings at the highest dose level of 120 mg/kg bw/d. The effects in dams consisted of a temporary reduction in food consumption and decrease in body weight during GD 6-8, a macrocytic-hypochromic, regenerative anemia in clinical pathology and an increase in spleen weights in pathology. At this dose level, in presence of maternal toxicity, fetal findings affecting skeletal structures were observed in test group 3 fetuses (120 mg/kg bw/d):

The NOAEL for maternal toxicity is 40 mg/kg bw/d. [BASF, 2018]

The NOAEL and prenatal developmental toxicity is 40 mg/kg bw/d. [BASF, 2018]

supporting information:

Under the conditions of this OECD 422 combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in Wistar rats the following NOAEC (no observed adverse effect concentration) was determined for 2-(2-ethoxyethoxy)-2-methylpropane after inhalation exposure:

The NOAEC for developmental toxicity in the F1 offspring was 750 mg/m³. [BASF, 2015]

The NOAEC for developmental toxicity in the F1 offspring was 750 mg/m³. [BASF, 2015]

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany Gmb
- Age at study initiation: about 10-12 weeks
- Weight at study initiation: 148.2 - 191.1 g
- Housing: individually (Polycarbonate cages type III)
- Diet (e.g. ad libitum): ad libitum (ground Kliba maintenance diet mouse/rat “GLP”, meal, supplied by Provimi Kliba SA, Kaiseraugst, Switzerland)
- Water (e.g. ad libitum): drinking water (ad libitum)
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The oily test substance solutions were prepared at the beginning of the administration period and thereafter at intervals, which took into account the period of established stability. The preparations were kept at room temperature.
For the test substance preparations, the specific amount of test substance was weighed, topped up with corn oil in a graduated flask and intensely mixed with a magnetic stirrer until it was completely dissolved.


Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analytical investigations of the test substance preparations were carried out at the Analytical Chemistry Laboratory of Experimental Toxicology and Ecology of BASF SE, 67056 Ludwigshafen, Germany.The stability of the test substance in corn oil at room temperature over a period of 7 days had been verified prior to the start of the study.
Details on mating procedure:
The animals were paired by the breeder (“time-mated”); the day of evidence of mating (= detection of vaginal plug/sperm) was referred to as GD 0. The animals arrived on the same day (GD 0) at the experimental laboratory. The following day was designated as “GD 1”.
Duration of treatment / exposure:
From implantation to one day prior to the expected day of parturition (GD 6 to GD 19), always at approximately the same time in the morning
Frequency of treatment:
once daily
Duration of test:
On GD 20 all surviving dams were sacrificed and examined
Dose / conc.:
10 mg/kg bw/day (nominal)
Dose / conc.:
40 mg/kg bw/day (nominal)
Dose / conc.:
120 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Mortality: A check was made twice a day on working days or once a day on Saturdays, Sundays or on public holidays (GD 0-20).

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: A cage-side examination was conducted at least once daily for any signs of morbidity, pertinent behavioral changes and signs of overt toxicity. During the administration period (GD 6-19) all animals were checked daily for any abnormal clinically signs before administration as well as within 2 hours and within 5 hours after administration.

BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed on GD 0, 1, 3, 6, 8, 10, 13, 15, 17, 19 and 20. The body weight change of the animals was calculated based on the obtained results.

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- The consumption of food was recorded for the intervals GD 0-1, 1-3, 3-6, 6-8, 8-10, 10-13, 13- 15, 15-17, 17-19 and 19-20. Before start of the treatment period, some spilling of food in single dams on individual gestation days (GD 0-3) was observed in test groups 2 and 3 without relevance for the study.

POST-MORTEM EXAMINATIONS: Yes
Cesarean section:
On GD 20, the dams were sacrificed under isoflurane anesthesia by decapitation, in randomized order. After the dams had been sacrificed, they were necropsied and assessed for gross pathology. The uteri and the ovaries were removed and the
following data were recorded: weight of the unopened uterus, number of corpora lutea. Number and distribution of implantation sites classified as: live fetuses and dead implantations ( a) Early resorptions (only decidual or placental tissues visible or according to SALEWSKI from uteri from apparently non-pregnant animals and the empty uterus horn in the case of single horn pregnancy); b) Late resorptions (embryonic or fetal tissue in addition to placental tissue visible; c) Dead fetuses (hypoxemic fetuses which did not breathe spontaneously after the uterus had been opened).
After the weight of the uterus had been determined, all subsequent evaluations of the dams (except of gross pathology including organ weights) and the gestational parameters were conducted by technicians unaware of treatment group in order to minimize bias. For this purpose animal numbers were encoded.
Pathology:
Organ weights
The following weights were determined in all animals sacrificed on schedule: adrenal glands, kidneys, liver, spleen. The carcass weights (GROSSE-System) were transferred to the ACOPAT-System to calculate the relative organ weights.
Organ / Tissue fixation
The following organs or tissues were fixed in 4% neutral-buffered formaldehyde solution: all gross lesions, adrenal glands, kidneys, liver, spleen. No further examinations or procedures were performed in the study.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
Statistics:
DUNNETT-test (twosided), FISHER'S EXACT test (onesided), WILCOXON-test (onesided)
Indices:
The conception rate (in %) was calculated according to the following formula:
(number of pregnant animals/number of fertilized animals) x100

The preimplantation loss (in %) for each individual pregnant animal which underwent scheduled sacrifice was calculated according to the following formula:
((number of corpora lutea – number of implantations)/number of corpora lutea) x100

The postimplantation loss (in %) for each individual pregnant animal which underwent scheduled sacrifice was calculated according to the following formula:
((number of implantations – number of live fetuses)/number of implantations) x100
Historical control data:
Historical contraol data were available
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Eight out of 25 high-dose females (120 mg/kg bw/d) showed transient salivation during the treatment period. Salivation occurred in the respective animals shortly after treatment (i.e. within 2 hours post-dosing) and was observed from GD 12 to GD 19. After 2 hours and up to 5 hours post-dosing no clinical signs or changes of general behavior were detected in any female of all test groups (0, 10, 40 or 120 mg/kg bw/d), nor were any clinical signs observed before dosing in the morning. This transient salivation for a few minutes immediately after treatment was likely to be induced by the unpleasant taste of the test substance or by local irritation of the upper digestive tract. It is not considered to be a sign of systemic toxicity.
Mortality:
no mortality observed
Description (incidence):
There were no test substance-related or spontaneous mortalities in any females of all test groups (0, 10, 40 or 120 mg/kg bw/d).
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Corresponding to reduced food consumption, the mean body weight change of the high-dose dams (120 mg/kg bw/d) was statistically significantly reduced on GD 6-8 (approx. 41% below control), but recovered afterwards and was comparable to the concurrent control. This temporary decrease of body weight change in the high-dose group is considered as treatment-related and adverse. The mean body weights and average body weight change of the low- and mid-dose dams (10
or 40 mg/kg bw/d) were generally comparable to the concurrent control group throughout the entire study period.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The mean food consumption of the dams in test group 3 (120 mg/kg bw/d) was statistically significantly decreased during GD 6-8 (about 18% below control), but recovered afterwards and was comparable to the concurrent control group throughout the remaining study period (GD 8-20). If calculated for the entire treatment period (GD 6-19) or study period (GD 0-20), the mean food consumption of the high-dose dams was generally comparable to the concurrent control. This temporary reduction of food consumption during GD 6-8 was considered as treatment-related and adverse. The mean food consumption of the dams in test groups 1 and 2 (10 and 40 mg/kg bw/d) was comparable to the concurrent control throughout the entire study period.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
At the end of gestation in dams of test group 3 (120 mg/kg bw/d), red blood cell (RBC) counts and mean corpuscular hemoglobin concentration (MCHC) were significantly decreased and absolute reticulocyte counts, mean corpuscular hemoglobin content (MCH) and mean corpuscular hemoglobin volume (MCV) were significantly increased. RBC counts were significantly decreased in dams of test groups 1 and 2 (10 and 40 mg/kg bw/d). MCV in test group 2 (40 mg/kg bw/d) was higher compared to controls. However, MCV in test group 2 was within, and RBC counts in test groups 1 and 2 were only marginally below the historical control range (dams, MCV 50.4-54.3 fL, RBC 5.58-7.86 tera/L). RBC count means in test groups 1 and 2 were not dose-dependently changed, and RBC was the only measured red blood cell parameter which was altered in the mentioned test groups. Therefore, the RBC decrease in dams of test groups 1 and 2 as well as the MCV increase in dams of test group 2 were regarded as incidental and not treatment-related (ECETOC Technical Report No. 85, 2002).
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related changes among clinical chemistry parameters were observed. In dams of test group 3 (120 mg/kg bw/d) total bilirubin and creatinine levels were significantly decreased. Creatinine was already significantly lower in rats of test group 2 (40 mg/kg bw/d). However, all values were within historical control ranges (dams, creatinine 22.8-33.6 μmol/L; total bilirubin 0.74-1.37 μmol/L). Therefore, the creatinine and total bilirubin alterations were regarded as incidental and not treatment-related.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
When compared to control group 0 (set to 100%), the mean absolute weights of following organs were significantly increased or decreased in one or more test groups: spleen. All other mean absolute weight parameters did not show significant differences when compared to the control group 0.
When compared to control group 0 (set to 100%), the mean relative weights of following organs were significantly increased or decreased in one or more test groups: adrenal glandy, kidneys, liver and spleen.
The significantly decreased absolute and relative spleen weight as well as the significantly increased relative weight of adrenal glands in test group 2 animals was regarded as incidental, since there was no dose-response relationship. The significantly increased absolute and relative spleen weights in animals of test group 3 were regarded as treatment related.
The slightly, but significantly increased relative liver weights of animals in test groups 2 and 3 lay above the range of historical control values. Therefore, a relation to treatment cannot be excluded.
The significantly increased relative weight of kidneys in test groups 1 to 3 was regarded as incidental, since there was no clear dose-response relationship and the weight parameters lay within the range of historical control values.
All other mean relative weight parameters did not show significant differences when compared to the control group 0.
Gross pathological findings:
no effects observed
Description (incidence and severity):
Macroscopic findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment.
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
The postimplantation loss was statistically significantly lower in test groups 1 and 2 (mean: 11.9%/1.6%**/3.2%*/8.6% in test groups 0-3). Statistical significance was caused by the rather low values in the low- and mid-dose groups which showed no relation to dose and were assessed as incidental.
The mean gravid uterus weights of the animals of test groups 1-3 (10, 40 and 120 mg/kg bw/d) were not influenced by the test substance. The differences between these groups and the control group revealed no dose-dependency and were assessed to be without biological relevance.
Total litter losses by resorption:
effects observed, non-treatment-related
Description (incidence and severity):
The total number of resorptions was statistically significantly lower in the low- and mid-dose groups (1.5/0.2**[p<=0.01]/0.4**[p<=0.01]/0.8 in test groups 0-3). Consequently, the mean number of live fetuses was also higher in those dams (mean: 88.1%/98.4**%/96.8*%/91.4% in test groups 0-3). As specified above, these statistically significantly greater litters came from a comparatively low resorption rate at the low- and mid-dose levels and are neither treatmentrelated nor adverse.
Other effects:
no effects observed
Description (incidence and severity):
The mean placental weights of test groups 1-3 were comparable to the concurrent control group.
Details on maternal toxic effects:
The conception rate reached 96% in the control and the low-dose group (0 and 10 mg/kg bw/d) and 100% in the mid- and high-dose groups (40 and 120 mg/kg bw/d). With these rates, a sufficient number of pregnant females were available for the purpose of the study (according to the test guidelines). There were no test substance-related and/or biologically relevant differences between test groups 0, 1, 2 and 3 (0, 10, 40 and 120 mg/kg bw/d) in conception rate, in the mean number
of corpora lutea and implantation sites or in the values calculated for the preimplantation loss.
Dose descriptor:
NOAEL
Remarks:
maternal toxicity
Effect level:
40 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
food consumption and compound intake
haematology
organ weights and organ / body weight ratios
Abnormalities:
effects observed, treatment-related
Localisation:
other: spleen
Abnormalities:
effects observed, treatment-related
Localisation:
other: food consumption and compound intake
Abnormalities:
effects observed, treatment-related
Localisation:
other: haematology
Fetal body weight changes:
no effects observed
Description (incidence and severity):
The mean fetal weights of test groups 1, 2 and 3 were not influenced by the test substance and did not show any biologically relevant differences in comparison to the concurrent control group.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): The mean fetal weights of test groups 1, 2 and 3 were not influenced by the test substance and did not show any biologically relevant differences in comparison to the concurrent control group.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The sex distribution of the fetuses in test groups 1-3 (10, 40 and 120 mg/kg bw/d) was comparable to the control fetuses.
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Fetal external malformations:
External malformations were seen in one control litter (0 mg/kg bw/d) and one high-dose litter (120 mg/kg bw/d). For the one affected fetus of test group 3 with skeletal examination, these external findings were associated with skeletal malformations. The finding anasarca was observed in one litter of control and one litter of test group 3 (two affected fetuses). In the control, it was associated with gastroschisis. In test group 3, it was associated with microstomia. On a litter basis, litter incidence of the test group 3 was within the historical control data (HCD of anasarca, litters, range: 0.0 – 4.2°%). Furthermore, no ontogenetic pattern is recognizable for the individual malformations nor was there any cluster of any of these individual malformations seen in the other offspring of the high-dose group. The findings were assessed as incidental and not-treatment related.
Fetal external variations:
One external variation in one fetus each of test groups 0 and 1 was recorded (0 and 10 mg/kg bw/d), i.e. limb hyperextension. The incidence of this single finding was not statistically significantly different from control. The finding was not related to dose and it can be found in the historical control data at comparable or higher incidences (HCD of affected fetuses per litter: mean 0.0 % [0.0-0.7 %]). Thus, it is not considered as treatment-related and adverse.
Fetal external unclassified observations:
One unclassified external observation, i.e. pointed lower jaw, was recorded in one fetus of test group 3 (No. 93-01; 120 mg/kg bw/d). Since this finding was not confirmed during skeletal observation and occurred only in one single fetus, it is not considered biologically relevant.

Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
Fetal skeletal malformations:
Severely malformed vertebral column and/or ribs, cleft sternum, and bent ribs were observed in one fetus each of test group 2 (40 mg/kg bw/d). In case of malformed vertebral column and/or ribs and cleft sternum, there was no dose-dependency, and the incidences were within the historical control range of the rat strain (HCD). The finding bent ribs was observed in each one fetus of test groups 2 and 3 without relation to dose. Furthermore, bent ribs have been shown to be reversible postnatally. Therefore, the findings in test group 2 fetuses were not assessed as treatment-related and adverse. Test group 3 (120 mg/kg bw/d) fetuses showed 3 findings in 4 fetuses of 4 litters. The finding misshapen tuberositas deltoidea of test group 3 was seen in one individual fetus and is present in the historical control data. Generalized disturbance of ossification was observed in two fetuses of two litters and is not present in the historical control data. Although there is no ontogenetic pattern recognizable for these individual malformations, a relation to treatment cannot be excluded. The number of these malformations adds up to a statistically significantly higher value for the total skeletal malformation rate in the mid- and high-dose groups. However, the incidence of total malformations of test group 2 was within the historical control range (HCD of affected fetuses per litter: mean total malformations: 0.8%, [0.0 – 3.1]) whereas the incidence of test group 3 was slightly above.
Fetal skeletal variations:
For all test groups, skeletal variations of different bone structures were observed, with or without effects on corresponding cartilages. The observed skeletal variations were related to several parts of fetal skeletons and were neither statistically significantly nor dose-dependently changed in comparison to the concurrent control group. The overall incidences of skeletal variations were comparable to the historical control data.
Fetal skeletal unclassified cartilage observations:
Some isolated cartilage findings without impact on the respective bony structures, which were designated as unclassified cartilage observations, occurred in all test groups. The observed unclassified cartilage findings were related to the skull, the ribs and the sternum and did not show any relation to dosing. The overall incidences of skeletal unclassified cartilage observations in the substance-treated groups did not differ significantly from the concurrent control group.

Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
Fetal soft tissue malformations:
No soft tissue malformations were recorded.
Fetal soft tissue variations:
Two soft tissue variations were detected in all test groups including the control (0, 10, 40 or 120 mg/kg bw/d), i.e. dilated renal pelvis and dilated ureter. The incidences of these variations were neither statistically significantly different from control nor dose-dependent and, therefore, not considered biologically relevant. All of them can be found in the historical control data at comparable incidences.
Fetal soft tissue unclassified observations:
No soft tissue unclassified observations were recorded.


Dose descriptor:
NOAEL
Effect level:
40 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
skeletal malformations
Abnormalities:
effects observed, treatment-related
Localisation:
other: skeletal: general disturbance of ossification
Description (incidence and severity):
two fetuses of two different litters
Developmental effects observed:
yes
Lowest effective dose / conc.:
120 mg/kg bw/day (nominal)
Treatment related:
yes
Relation to maternal toxicity:
not specified
Conclusions:
Under the conditions of this prenatal developmental toxicity study, the oral administration of 2-(2-ethoxyethoxy)-2-methylpropane to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) caused adverse findings at the highest dose level of 120 mg/kg bw/d. The effects in dams consisted of a temporary reduction in food consumption and decrease in body weight during GD 6-8, a macrocytic-hypochromic, regenerative anemia in clinical pathology and an increase in spleen weights in pathology. At this dose level, in presence of maternal toxicity, fetal findings affecting skeletal structures were observed in test group 3 fetuses (120 mg/kg bw/d). Therefore, no observed adverse effect level (NOAEL) for maternal toxicity and prenatal developmental toxicity is 40 mg/kg bw/d.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
40 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
modern guideline study
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
750 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
modern guideline study, but not considered sufficient to cover the endpoint developmental toxicity alone (used as supporting information)
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

developmental toxicity - oral

In a prenatal developmental toxicity study the test substance 2-(2-ethoxyethoxy)-2-methylpropane was administered to pregnant Wistar rats daily by gavage from implantation to one day prior to the expected day of parturition (GD 6-19) to evaluate its potential maternal and prenatal developmental toxicity.

Regarding clinical examination, mean food consumption of the dams in test group 3 (120 mg/kg bw/d) was statistically significantly decreased on GD 6-8 (about 18% below control), but recovered afterwards and was comparable to the concurrent control group throughout the remaining study period (GD 8-20). Corresponding to the reduced food consumption, the mean body weight change of the high-dose dams was statistically significantly reduced on GD 6-8 (approx. 41% below control), but recovered afterwards and was comparable to the concurrent control. The reduction of food consumption and decrease of body weight change during GD 6-8 was considered as treatment-related and adverse. Test groups 1 and 2 showed no treatment-related, adverse changes.

Regarding clinical pathology, at the end of the gestation period, in dams of test group 3 (120 mg/kg bw/d), lower red blood cell (RBC) counts and mean corpuscular hemoglobin concentrations

(MCHC) as well as higher mean corpuscular volume (MCV) and absolute reticulocyte counts indicated a macrocytic-hypochromic, regenerative anemia which was considered to be treatment-related and adverse.

Regarding pathology, the target organ was the spleen. The significantly increased absolute and relative spleen weights in animals of test group 3 were regarded as treatment related. In combination with the hematologically diagnosed macrocytichypochromic, regenerative anemia, the increased spleen weight was interpreted as an adverse finding. A histopathologic examination of the spleen was not performed. Regarding the slightly, but significantly increased relative liver weights of animals in test groups 2 and 3, a treatment-related adaptive change cannot be excluded. The weight parameters lay

above the range of historical control values. A histopathologic examination was not performed. All other findings occurred either individually or were biologically equally distributed over control

and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment.

No differences of toxicological relevance between control and the treated groups were determined for any reproductive parameters, such as conception rate, mean number of corpora lutea, mean number of implantations, as well as pre- and postimplantation loss. Concerning fetal examination, fetal findings affecting skeletal structures were observed in test group 3 fetuses (120 mg/kg bw/d) in presence of maternal toxicity. Although there is no ontogenetic pattern recognizable for these individual findings, a relation to treatment cannot be excluded.

Therefore, no observed adverse effect level (NOAEL) for maternal toxicity and prenatal developmental toxicity is 40 mg/kg bw/d.

developmental toxicity - inhalation

A modern screening test via inhalation is available, but which is not considered sufficient to cover the endpoint developmental toxicity alone. Therefore, it is used as supporting information.

To evaluate the toxicity profile of 2-(2-ethoxyethoxy)-2-methylpropane after inhalation exposure, groups of ten male and ten female Wistar rats (F0 animals) per test group were exposed nose-only to dynamic atmosphere of 2-(2-ethoxyethoxy)-2-methylpropane for 6 hours per day on each day. The duration of treatment covered a 2-week pre-mating and 2-week mating period in both sexes, 3 days post-mating in males, and the entire gestation period of the females. After the lactation period and after necropsy of the pups total all parental females were exposed to the test substance on 8 days. The target concentrations were 75, 250 and 750 mg/m³. A concurrent control group was exposed to conditioned air. For adaptation to the experimental conditions all animals were transferred into chambers identical to those used in the study and exposed to fresh air on two days (6 hours per day) before start of the exposure period. 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 post-implantation loss for all F0 females. A detailed clinical observation (DCO) was performed in all animals before initial test substance exposure and, as a rule, thereafter at weekly intervals. Clinical observation was performed at least three times on exposure days and once a day during the other days. Food consumption of the F0 parents was determined once weekly during premating. In dams food consumption was determined for gestation days 0 - 7, 7 - 14, 14 - 20 and lactation days 1 - 4. During the 4 exposure days after necropsy of the pups the food consumption was determined also. Body weights of F0 parents were determined once a week, in males throughout the study and in females during premating. During gestation and lactation period, F0 females were weighed on gestation days (GD) 0, 7, 14 and 20,on the day after parturitionpostnatal day [PND] 1) and on PND 4. After the pups were sacrificed, the females that were exposed for further 8 days were weighed once weekly and once on the last exposure day. A functional observational battery (FOB) was performed and motor activity was measured in 5 parental males and females per group. The FOB of the female animals was on study day 54. The male animals were performed at the end of the exposure period on study day 26. The pups were sexed and examined for macroscopically evident changes on PND 0. They were weighed on PND 1 and on PND 4. Their viability was recorded. At necropsy on PND 4, all pups were sacrificed with CO2, under isoflurane anesthesia, and examined macroscopically for external and visceral findings. Clico-chemical and hematological examinations were performed in 5 animals per sex and grouptowards the end of the exposure period. A complete necropsy including gross pathological evaluation and weighing of selected organs was performed. Organs and tissues were examined histopathologically as required by the corresponding test guidelines. All F0 parental animals were sacrificed under pentobarbitone anesthesia by exsanguination from the abdominal aorta and vena cava and were assessed by gross pathology. Weights of selected organs were recorded and a histopathological examination was performed.

The following test substance-related adverse effects were noted:

All Test groups (up to 750 mg/m3)

No treatment-related, adverse effects were measured regarding developmental toxicity.

Conclusion:

There are two studies on developmental toxicity available. On the one hand, there is an inhalative OECD 422 available showing no adverse impact on the reproduction of rats, nor did treatment impact delivery and pup viability up to the highest concentration of 750 mg/m3. On the other hand, 2-(2-ethoxyethoxy)-2-methylpropane was applied orally in an OECD 414 to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19). Adverse findings were observed at the highest dose level of 120 mg/kg bw/d. The effects in dams consisted of a temporary reduction in food consumption and decrease in body weight during GD 6-8, a macrocytic-hypochromic, regenerative anemia in clinical pathology and an increase in spleen weights in pathology. Moreover, at this dose level, in presence of maternal toxicity, fetal findings affecting skeletal structures in two fetuses of two different litters were observed in test group 3 fetuses (120 mg/kg bw/d). Since there is no ontogenetic pattern recognizable for these individual findings a classification in cat. 2 for developmental toxicity seems approriate.

 

Toxicity to reproduction: other studies

Description of key information

no information available

Additional information

no information available

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008:

The available experimental test data is reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result the substance is should be classified as a potential reproductive toxicant (cat. 2, H361d) under Regulation (EC) No 1272/2008, as amended for the sixth time in Regulation No 605/2014.

Additional information