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EC number: 276-696-7 | CAS number: 72490-01-8
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 23 Aug 1982 to 24 Sep 1982 (Experiment A), 18 Jul 1983 to 19 Aug 1983 (Experiment B)
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 984
- Report date:
- 1984
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 1981 and 2001
- Qualifier:
- according to guideline
- Guideline:
- other: Food and Drug Administration. Guidelines for Reproduction Studies for Safety Evaluation of Drugs for Human Use
- Version / remarks:
- 1966
- Qualifier:
- according to guideline
- Guideline:
- other: Committee on Safety of Medicines. Guidelines on Reproduction Studies for Guidance of Applicants for Product Licences and Clinical Trial Certificates, June.
- Version / remarks:
- 1974
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Ethyl [2-(4-phenoxyphenoxy)ethyl]carbamate
- EC Number:
- 276-696-7
- EC Name:
- Ethyl [2-(4-phenoxyphenoxy)ethyl]carbamate
- Cas Number:
- 72490-01-8
- Molecular formula:
- C17 H19 N O4
- IUPAC Name:
- ethyl [2-(4-phenoxyphenoxy)ethyl]carbamate
Constituent 1
Test animals
- Species:
- rabbit
- Strain:
- other: Swiss Hare
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: Experiment A, 2440-3500 g and experiment B, 2250-3530 g
- Housing: The animals were individually housed in stainless steel cages
- Diet: Diet cubes ad libitum
- Water: Tap water ad libitum
- Acclimation period: Minimum of 4 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18
- Humidity (%): 50
- Air changes: Fully air- conditioned
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: 23 Aug 1982 to 24 Sep 1982 (Experiment A), 18 Jul 1983 to 19 Aug 1983 (Experiment B)
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: SSV (4% carboxymethylcellulose, 0.9% NaCl, 0.5% benzylalcohol, 0.4% Tween 80 in water)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test substance was formulated freshly each week in the vehicle. High shear mixing was used during formulation and the suspension was kept homogeneous during dosing by the use of a magneto stirrer
VEHICLE
- Amount of vehicle: 5 mL/kg - Analytical verification of doses or concentrations:
- yes
- Details on mating procedure:
- - Impregnation procedure: Cohoused
- M/F ratio per cage: 1:1
- Proof of pregnancy: sperm in vaginal smear referred to as day 1 of pregnancy - Duration of treatment / exposure:
- From day 7 to 19 inclusive of gestation
- Frequency of treatment:
- Once daily
- Duration of test:
- Until day 30 of gestation
Doses / concentrationsopen allclose all
- Dose / conc.:
- 30 mg/kg bw/day (actual dose received)
- Remarks:
- Experiment A, group II
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Remarks:
- Experiment A, group III
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Remarks:
- Experiment A, group IV
- Dose / conc.:
- 200 mg/kg bw/day (actual dose received)
- Remarks:
- Experiment B, group II
- No. of animals per sex per dose:
- Experiment A: 20 mated females
Experiment B: 35 mated females - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: In a range finding study for maternal sensitivity and embryotoxicity, the substance doses of 100 and 300 mg/kg bw/day were administered to pregnant rabbits. Based on these results, dosages of 30, 100 and 300 mg/kg bw/day were selected for the principle study
- Foetuses from a necropsy subgroup were removed by ovariohysterectomy one day before parturition and processed for skeletal and visceral examinations. Additionally, dams from a rearing subgroup were allowed to deliver naturally and to raise their young until weaning. All females with litters were necropsied after the 23rd day of lactation and the uteri were examined for implantation sites. The offspring was examined externally.
- Accurate interpretation of the findings from the principle study was increasingly complicated by the appearance of some malformations mainly in the 300 mg/kg dose group which rendered inconclusive results. Therefore, a supplementary study was conducted with increased numbers of females using a dose of 200 mg/kg in an attempt to reproduce the same effects and to establish the relevance of the malformations that arose in the 300 mg/kg group. The same treatment schedule was used as in the principle study and included a separate control group.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS:
- Time schedule: Daily, all changes in behaviour, general condition, signs of pharmacological action, etc., rabbits which during the experiment were autopsied
BODY WEIGHT:
- Time schedule for examinations: On day of gestation 1, 7, 20 and 30
- Ovaries and uterine content:
- The ovaries and uterine content was examined after termination:
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, all per litter
- Skeletal examinations: Yes, all per litter
- All the young were tested for their 24h viability in an incubator at 34 °C - Statistics:
- 1. Descriptive statistics:
- In the tables for each group, median and interquartile- range are indicated. The median has the property, that 50 % of all values in the group are smaller and 50 % are larger than the median. The interquartile range contains 50 % of the values in the group, excluding the 25 % smallest and the 25 % largest values.
Exp. A: Statistical evaluations employed the T-TEST for independent samples and/or the CHI—SQUARE—TEST. The data presented in the tables are calculated mean values and standard deviations.
2. Significance tests:
- Trend set: All groups together are tested by a simultaneous test against trend (Jonckheere-test) or Armitage-test as indicated in the table. In case of a significant result, the correspondent interpretation (‘’*’’ for 5 % > p ≥ 1 % and ‘’**’’ for p < 1 % is attached to the highest dosage group. The test is then repeated without the already "significant" highest dosage group and again interpreted as before.
- Simultaneous test without ordered alternative: In the case of a non-significant result of the trend test, the same (remaining) groups are tested by a simultaneous test without trend alternative (Kruskal-Wallis-test and Chi^2-test as indicated in the table). If this test again is not significant (p= 1%) the test procedure ends: all remaining groups are not significantly different from control. P is chosen as 1% for this test to keep the total error probability near 5%
- Two sample tests for each dosage group against control: In the case of a significant result for test b), all dosages groups are separately tested against control by means of a two sample test (U-test or Fisher-test as indicated) the interpretations mean: ‘’#’’: 5% > p ≥ 1% and ‘’##’’: p<1%
3. Experimental unit: The dam is considered the independent experimental unit within all significant tests
4. Relative numbers: (relative number = absolute number/number of implantations)
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Two dams at 100 mg/kg bw/d died on day 12 and 19 (cause of death unknown).
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weight gain was reduced in dams at 300 mg/kg bw/d during the treatment period (80% of control) and at 200 mg/kg bw/d from the treatment period till necropsy (76-90% of control).
- 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
- Endocrine findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Other effects:
- no effects observed
Effect levels (maternal animals)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- Systemic
- Effect level:
- 100 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- Developmental
- Effect level:
- 300 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Anogenital distance of all rodent fetuses:
- not examined
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Skeletal examination of the neonates by radiography and/or Alizarin Red staining revealed no compound- related effects on any of the measured ossification parameters and all findings from the treatment group of both the principle and supplementary studies compared favorably to the respective controls.
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- The examination for soft tissue abnormalities revealed no indication of any drug-related deviation in any dose group
- Other effects:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- In the principle study (A) macroscopic examination of the foetuses at necropsy from the control group revealed one foetus with a hypoplastic tail. A dose of 30 mg/kg revealed one foetus with a hypoplastic tail and two additional litter mates with tails missing. From a dose of 100 mg/kg there were two foetuses with missing tails, one foetus with an open eye and one foetus with spina bifida. The malformations at the highest dose of 300 mg/kg included two cases of spina bifida with hypoplastic tails, one single case from both spina bifida and open eyes, a single foetal resorption with omphalocele and two cases of hypoplastic tail. From the supplementary study (B) with 200 mg/kg the only observed malformation was localized in a foetal resorption which had open eyes and a reduction malformation of the right arm. Contrary to results in study A, the control group of study B contained malformations in which the type and incidence is
analogous to those found in the 300 mg/kg dose group. These included two foetuses with ectopy; one of which had a missing tail, one foetus with an eye open, a foetus with omphalocele and a foetus with hypoplastic tail. Although the malformations arising from study. A were considered as being questionably compound-related, further investigation has undoubtedly shown that an association with the test substance can be excluded. That the observed malformations in study A are not compound- related is mainly the result of substantiating evidence collected from the supplementary study (B). It was assumed that a reproducible pattern of the same types of malformations would have appeared in the 200 mg/kg if those seen in the 300 mg/kg group were actually relevant. But neither pattern nor associated malformations Were established and no relationship exist in the results between the two dose groups. Furthermore, though the incidence of malformations of increased in the 300 mg/kg dose group the same type of malformations are often observed among historical controls but in particular among the controls in the supplementary study. In addition there were also no malformations noted among the foetuses in the preliminary study at doses of 100 and 300 mg/kg. Therefore, in view of the various supporting
data, all of the observed malformations originating in the principle study are considered only to be arbitrary findings
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 300 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
Table 1. Results experiment A
Dose (mg/kg bw/day) |
0 |
30 |
100 |
300 |
dr |
Maternal effects Mortality (n=20) Clinical signs Pregnant animals Body weight gain Food consumption Uterus weight Pathology macroscopy |
0
18 |
0 2 No treatment-related findings 20 17
Not performed Not determined
Not performed |
0
20
dc |
|
|
Litter response |
|
|
|
|
|
Number of dams |
18 |
20 |
17 |
20 |
|
examined |
|
|
|
||
Corpora lutea/dam |
|
No treatment-related findings |
|
||
Total number of resorptions/dam |
2.2 |
2.1 |
1.2 |
2.8 |
|
|
|
|
|
||
Number of resorptions/group |
|
|
|
||
- embryonic |
38 |
41 |
14 |
50 |
|
- foetal |
1 |
2 |
6 |
5 |
|
Dams with live foetuses |
17 |
17 |
17 |
18 |
|
|
|
||||
Live foetuses/dam |
6.8 |
5.0 |
6.4 |
6.3 |
|
Dead foetuses |
0 |
0 |
0 |
0 |
|
Foetal weight |
41.8 |
44.3 |
44.6 |
43.6 |
|
Post-implantation loss/dam1 |
2.1 |
2.2 |
1.2 |
2.7 |
|
|
|
Dose (mg/kg bw/day) |
0 |
30 |
100 |
300 |
dr |
Sex ratio |
No treatment-related findings |
|
|||
Mean crown-rump length |
No treatment-related findings |
||||
Survival rate 24 h |
No treatment-related findings |
||||
Examination of the foetuses |
122
0
1 (0.8%) |
101 109
0 1 (0.9%) 1 0 (1.0%) No treatment-related findings No treatment-related findings |
126
3 (2.4%) 4 (3.2%) |
|
|
Total no foetuses |
|||||
External observations - spina bifida, sacral region - hypoplastic tail |
|||||
Skeletal findings |
|||||
Visceral findings |
dr: dose related
dc/ic: statistically significantly decreased/increased compared to the controls
d/i: decreased/increased, but not statistically significantly compared to the controls
a/r: absolute/relative organ weight
1: as calculated by the reviewer; no statistical analysis performed
Table 2. Results experiment B
Dose (mg/kg bw/day) |
0 |
200 |
dr |
||
Maternal effects Mortality Clinical signs Pregnant animals Body weight gain Food consumption Uterus weight Pathology macroscopy |
35 |
None No treatment-related findings
Not performed Not determined
Not performed |
33 d |
|
|
Litter response |
|
|
|
|
|
Number of dams examined |
35 |
|
33 |
||
Corpora lutea/dam |
|
No treatment-related findings |
|
||
Total number of resorptions/dam |
1.0 |
|
1.0 |
Dose (mg/kg bw/day) |
0 |
200 |
dr |
||
Number of resorptions/group - embryonic - foetal |
34 11 |
28 3 |
|
||
Dams with live foetuses |
35 |
33 |
|||
Live foetuses/dam |
7.0 |
8.0 |
|||
Foetal weight |
42.4 |
41.6 |
|||
Post-implantation loss/dam1 |
2.0 |
1.0 |
|||
Sex ratio |
No treatment-related findings |
||||
Mean crown-rump length |
No treatment-related findings |
||||
Survival rate 24 h |
No treatment-related findings |
||||
Examination of the foetuses |
349
0
1 (0.3%) |
No treatment-related findings No treatment-related findings |
234
0
0 |
|
|
Total no foetuses |
|||||
External observations - spina bifida, sacralregion - hypoplastic tail |
|||||
Skeletal findings |
|||||
Visceral findings |
Table 3. Historical control data from Hoffmann LaRoche, between 1977 and 1988
|
Control Gronp |
Foetuses with Finding |
|||||
N of Litters |
N of foetuses |
hypoplasfictail |
missing tail |
open eyes |
spina bifida |
ompha /ocoele |
|
TOTAL |
539 |
3656 |
3 |
2 |
2 |
2 |
2 |
% of litters affected (range) |
0-13.3 |
0-6.7 |
0-5.3 |
0-5.6 |
0-6.7 |
||
% of fetuses affected (range) |
0-2.3 |
0-1.1 |
0-1.0 |
0-0.8 |
0-1.1 |
Applicant's summary and conclusion
- Conclusions:
- Based on decreased body weight, the NOAEL for maternal toxicity was set at 100 mg/kg bw/day. Based on no effects on foetal development the NOAEL for developmental toxicity was set at ≥ 300 mg/kg bw/day.
- Executive summary:
The test substance was tested for embryotoxic and teratogenic action in 20 mated (principle study) and 35 (supplementary study) female Swiss hare rabbits according to OECD TG 414 and GLP principles. In the principle study, doses of 30, 100 and 300 mg/kg bw/day were administered by oral gavage to pregnant animals from day 7 to 19 inclusive of gestation. A control group received the vehicle (SSV, 4% carboxymethylcellulose, 0.9% NaCl, 0.5% benzylalcohol, 0.4% Tween 80 in water) for the same treatment period. All females were sacrificed at day 30 of gestation. Foetuses were removed by ovariohysterectomy tested for viability (24 h) and examined for macroscopic, skeletal and soft tissue anomalies. Accurate interpretation of the findings of the principle study was increasingly complicated by the appearance of some malformations in the 300 mg/kg dose group which rendered inconclusive results. Therefore, a supplementary study was conducted with increased number of females using a dose of 200 mg/kg bw/day in an attempt to reproduce the same effects and to establish the relevance of the malformations that occurred in the 300 mg/kg group. The same treatment schedule was used as in the principle study and included a separate control group. Throughout the summary the principle and supplementary study will be referred as A and B.
Results showed a moderately reduced body weight development during the treatment period among females of the 200 and 300 mg/kg dose groups, but not a highly significant effect. There were no detectable effects on the measured reproductive parameters, on the course and outcome of pregnancy nor on the 24 hour survivability of the neonates in either study. In the principle study (A) beginning with a dose of 100 mg/kg, some morphological malformations appeared mainly as open eyes, spina bifida and/or short or missing tail. The incidence was low and compared favourably to the frequency of these malformations in observed historical control data of this rabbit strain. In spite of no effects seen in the preliminary study at a dose of 300 mg/kg, malformations did appear at this dose level in the principle study. The malformations were similar to those observed in the 100 mg/kg group but the incidence was somewhat higher than recognized in historical controls thus, complicating an accurate interpretation of the results. In the supplementary study (B) using a dose of 200 mg/kg, it was assumed that a pattern of the same types of malformations would appear if the effects seen in the 300 mg/kg group were relevant. However, the results from this study show that no pattern or associated malformation was established between the two doses and only one malformation was present and localized in a foetal resorption. Furthermore, in contrast to the single malformation from the control group of the principle study (A), the malformations seen in the control group of the study supplementary study (B) appeared more frequently and were analogous in both type and incidence to the malformations seen in the 300 mg/kg dose group. Therefore, in view of all substantiating evidence with particular emphasis on the high incidence of malformations seen in the controls of the supplementary study, all malformations seen in the principle study (A) of the 300 mg/kg group are considered to be arbitrary findings and not test substance-related. Examination of the foetuses for skeletal and soft tissue anomalies did not reveal any effects considered to be test substance-related from any dose group.
In conclusion, based on decreased body weight, the NOAEL for maternal toxicity was set at 100 mg/kg bw/day. Based on no effects on foetal development the NOAEL for developmental toxicity was set at ≥ 300 mg/kg bw/day.
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