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EC number: 800-906-3 | CAS number: 1402434-48-3
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Acceptable, well-documented and cited in the peer-reviewed regulatory agency.
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 2 004
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- not applicable
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 4-ethylmorpholine
- EC Number:
- 202-885-0
- EC Name:
- 4-ethylmorpholine
- Cas Number:
- 100-74-3
- IUPAC Name:
- 4-ethylmorpholine
- Reference substance name:
- Morpholine, 4-ethyl-
- IUPAC Name:
- Morpholine, 4-ethyl-
- Details on test material:
- - Name of test material (as cited in study report): N-ethylmorpholine
- Analytical purity: Equal or more than 99 %
- Impurities (identity and concentrations): 0.05% as moisture
- Lot/batch No.: 2901P0
Constituent 1
Constituent 2
Test animals
- Species:
- rat
- Strain:
- other: Crj:CD(SD)IGS
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Four weeks old Crj:CD(SD)IGS rats bought from Charles River Japan, Inc. They were put in quarantine and acclimatization for 7 d before use.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- The test solution was prepared and diluted to dosing concentrations by injection solvent every week. They were kept in a refrigerator. The diluted solution was also confirmed to be stable for 8 d.
- Duration of treatment / exposure:
- Males: 42 d
Females: From 14 d before mating to Day 3 of lactation - Frequency of treatment:
- Once daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0 (vehicle), 50, 150, 500 mg/kg bw/day
Basis:
nominal conc.
- No. of animals per sex per dose:
- 13/sex/dose
- Control animals:
- yes, concurrent vehicle
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes - Oestrous cyclicity (parental animals):
- Yes
- Sperm parameters (parental animals):
- Parameters examined in P male parental generations: Testis weight, epididymis weight, histopathological examination of reproductive organs
- Litter observations:
- PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: Number and sex of pups, stillbirths, live births, viability index - Postmortem examinations (parental animals):
- Terminal killing: Males at Day 43; females at Day 4 of lactation.
- Postmortem examinations (offspring):
- Necropsy was perfomed.
- Statistics:
- Statistical analysis of offspring was carried out using the litter as the experimental unit. Bartlett's test of homogeneity of variance was used to determine if the groups had equivalent at the 5% level of significance. If variance was equivalent, the groups were compared by one-way analysis of variance. If significant
differences were found, Dunnett's test was performed. If the groups did not have equivalent variances, the Kruskal-Wallis test was used to assess the overall effects. Whenever significant differences were noted, Dunnett-type test was performed. Mann-Whitney U-test or Fisher's exact test was also used. - Reproductive indices:
- Copulation index and fertility index
- Offspring viability indices:
- Gestation index , implantation index, delivery index , birth index , live birth index , sex ratio and viability index
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
Details on results (P0)
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- (for reproductive toxicity)
- Effect level:
- 500 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
- Dose descriptor:
- NOAEL
- Remarks:
- (for systemic toxicity)
- Effect level:
- 150 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Based on observed clinical signs such as salivation as well as decrease in body weight and food consumption at higher doses.
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Gross pathological findings:
- no effects observed
Details on results (F1)
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Table 1. Body weight changes of rats treated orally with N-ethylmorpholine in preliminary reproduction toxicity screening test:
Dose (mg/kg/ bw/day) |
0 |
50 |
150 |
500 |
Male |
13 |
13 |
13
|
13 |
Terminal body weight (g) +/-S.D. |
497.0 |
494.0 30.9 |
488.0 38.9 |
457.5* 31.7 |
Female |
13 |
13 |
13
|
13 |
Days 14 of administration (g) |
266.5 13.1 |
263.6 15.7 |
263.4 17.8 |
259.5 17.5 |
No. of animals |
12 |
12 |
12 |
12 |
Days 20 of pregnancy (g) +/-S.D. |
428.5 33.1 |
423.2 29.8 |
410.6 27.2 |
386.1* 42.1 |
No. of animals |
12 |
12 |
12 |
12 |
Days 4 of lactation (g) +/-S.D. |
345.6 22.8 |
338.4 26.9 |
330.1 19.3 |
329.7 24.5 |
Significant difference from control group; *p=<0.05,**p=<0.01
Table 2. Food consumption of rats treated orally with N-ethylmorpholine in preliminary reproduction toxicity screening test
Dose (mg/kg/ bw/day) |
0 |
50 |
150 |
500 |
Male |
13 |
13 |
13
|
13 |
Days of administration (g) |
||||
1-2 +/-S.D. |
27.8 1.9 |
26.9 2.3 |
25.4 3.7 |
21.3** 2.7 |
7-8 +/-S.D. |
25.1 1.9 |
25.8 1.5 |
25.3 2.8 |
22.1** 1.7 |
14-15 +/-S.D. |
27.1 2.9 |
27.7 8.2 |
26.6 2.9 |
24.3* 3.2 |
29-30 +/-S.D. |
28.7 2.4 |
29.5 2.1 |
28.0 2.7 |
24.2** 1.7 |
35-36 +/-S.D. |
29.9 7.5 |
26.7 3.3 |
27.7 3.0 |
27.2 6.4 |
41-42 +/-S.D. |
29.6 3.3 |
29.4 3.4 |
28.9 4.1 |
26.2* 2.0 |
Female |
13 |
13 |
13 |
13 |
Days of administration (g) |
||||
1-2 +/-S.D. |
20.7 1.9 |
18.5 3.5 |
16.6** 3.4 |
16.5** 3.7 |
7-8 +/-S.D. |
19.7 3.7 |
19.4 3.9 |
20.2 2.9 |
19.9 3.5 |
14-15 +/-S.D. |
19.9 3.7 |
20.4 2.6 |
19.7 2.3 |
19.4 1.8 |
No. of animals |
12 |
12 |
12 |
12 |
Days of pregnancy (g) |
||||
0-1 +/-S.D. |
21.0 2.6 |
21.1 1.9 |
19.4 2.7 |
18.4* 2.9 |
7-8 +/-S.D. |
28.9 3.6 |
28.5 3.0 |
25.5* 3.4 |
23.2** 3.2 |
14-15 +/-S.D. |
28.6 3.4 |
26.8 2.8 |
26.3 2.0 |
24.7* 4.3 |
20-21 +/-S.D. |
19.3 3.5 |
21.0 2.4 |
20.8 4.0 |
18.7 2.5 |
No. of animals |
12 |
12 |
12 |
9 |
Days 4 of lactation (g) |
||||
3-4 +/-S.D. |
47.1 6.7 |
49.4 4.6 |
43.3 4.3 |
41.4 8.8 |
Significant difference from control group; *p=<0.05,**p=<0.01
Table 3. Estrous cycle and reproductive performance in rats treated orally with N-ethylmorpholine in preliminary reproduction toxicity screening test
Dose (mg/kg/ bw/day) |
0 |
50 |
150 |
500 |
|
Estrous cycle |
|||||
Type of cycle during treatment period |
|||||
4-day cycle |
13 |
13 |
12 |
12 |
|
4,5-day cycle |
0 |
0 |
1 |
1 |
|
Length of estrous cycle in days |
4.0 0.0 |
4.0 0.0 |
4.0 0.1 |
4.0 0.1 |
|
Reproductive performance |
|||||
Number of mated pairs |
13 |
13 |
13 |
13 |
|
Number of copulated pairs |
13 |
13 |
12 |
12 |
|
Copulation index (%) |
100.0 |
100.0 |
92.3 |
92.3 |
|
Number of pregnant animals |
12 |
12 |
12 |
11 |
|
Fertility index (%) |
92.3 |
92.3 |
100.0 |
91.7 |
|
Pairing days until copulation |
2.3 1.1 |
2.2 1.1 |
3.3 1.7 |
2.6 1.3 |
|
Frequency of vaginal estrus |
1.0 0.0 |
1.0 0.0 |
1.1 0.3 |
1.0 0.0 |
|
Copulation index = (Number of copulated
pairs/Number of mated pairs) X 100
Fertility index = (Number of pregnant animals/Number of copulated pairs)
X 100
Table 4. Summary of development
of pups from dams treated orally with N-ethylmorpholine in preliminary
reproduction toxicity screening test
Dose (mg/kg/ bw/day) |
0 |
50 |
150 |
500 |
Number of pregnant females |
12 |
12 |
12 |
11 |
Gestation index (%) |
100.0 |
100.0 |
100.0 |
90.9 |
Gestation length in days +/-S.D. |
22.7 0.5 |
22.3 0.7 |
22.3 0.5 |
22.8 0.6 |
Number of corpora lutea +/-S.D. |
16.2 2.0 |
16.9 1.8 |
15.7 1.9 |
16.0 3.0 |
Number of implantation sites +/-S.D. |
15.6 2.6 |
16.1 1.7 |
14.8 1.8 |
13.1 4.7 |
Implantation index (%) +/-S.D. |
95.9 7.4 |
95.2 4.9 |
94.9 6.1 |
80.6 26.6 |
Day 0 of lactation |
||||
Number of pups born +/-S.D. |
14.2 2.8 |
15.1 1.2 |
13.8 1.6 |
11.4 4.9 |
Delivery index (%) +/-S.D. |
90.6 9.3 |
94.1 6.0 |
93.1 7.7 |
84.6 15.8 |
Number of pups alive +/-S.D. |
13.7 2.9 |
15.0 1.3 |
13.7 1.7 |
10.0 5.4 |
Birth index (%) +/-S.D. |
87.4 9.7 |
93.6 5.7 |
92.5 8.0 |
71.2 32.7 |
Live birth index (%) +/-S.D. |
96.5 5.6 |
99.4 1.9 |
99.4 2.2 |
83.5 35.6 |
Sex ratio on day 0 (%) +/-S.D. |
52.4 13.2 |
47.9 8.0 |
48.9 12.6 |
54.2 26.3 |
Day 4 of lactation |
||||
Number of pups alive +/-S.D. |
13.6 2.8 |
15.0 1.3 |
13.5 1.7 |
11.6 3.9 |
Viability index (%) +/-S.D. |
99.5 1.7 |
100.0 0.0 |
98.8 2.8 |
98.1 3.8 |
Sex ratio on day 4 (%) +/-S.D. |
52.6 13.1 |
47.9 8.0 |
49.5 12.6 |
58.5 25.9 |
Gestation
index = (Number of females with live pups/ Number of pregnant females) X
100
Implantation index = (Number of implantation sites/ Number of corpora
lutea) X 100
Delivery index = (Number of pups born/Number of implantation sites) X 100
Birth index = (Number of live pups on day 0/Number of implantation
sites) X 100
Live birth index = (Number of live pups on day 0/Number of pups born) X
100
Sex ratio = (Number of male live pups/Number of female live pups) X 100
Viability index = (Number of live pups on day 4/Number of live pups on
day 0)
Applicant's summary and conclusion
- Conclusions:
- Based on the absence of any adverse effects of the read-across substance, ethylmorpholine on reproductive and developmental parameter, the NOAEL for reproductive and developmental toxicity is considered to be 500 mg/kg bw/day. Further, based on clinical signs and decreased body weight gain and food consumption, the LOAEL and NOAEL for general toxicity in parent animals are considered to be 150 and 50 mg/kg bw/day, respectively.
- Executive summary:
The toxicity to reproduction of the read-across substance, 4-ethylmorpholine was tested in a reproduction / developmental toxicity screening test according to the OECD Guideline 421 in compliance with GLP.
Drj:CD(SD)IGD rats (13 animals/sex/dose) were given test substance by gavage at 0 (vehicle: water), 50, 150 or 500 mg/kg bw/day. Males were dosed for a total of 42 d beginning 14 d before mating. Females were dosed from 14 d before mating to Day 3 of lactation throughout the mating and pregnancy period.
No deaths were found in males of any group. One female at 500 mg/kg bw/day died on Day 2 of lactation. Tremor was observed in the female which died, and transient salivation after dosing was observed in males and females at 150 mg/kg bw/day and higher. Decrease in body weight gain accompanied by reduced food consumption was detected in males at 500 mg/kg bw/day and females at 150 mg/kg bw/day and higher. Body weight gains on Days 1-7, Days 21 -28 and Days 35-43 of administration in males at 500 mg/kg bw/day, on Days 1-7 of administration, Days 7-14 and Days 14-21 of pregnancy and Days 0-4 of lactation in females at 500 mg/kg bw/day, and Days 1-7 of administration, Days 0-7 of pregnancy and Days 0-4 of lactation in females at 150 mg/kg bw/day were found. Absolute and relative weights of the testes and epididymides in the groups treated with this chemical were not different from the control group. Necropsy and histopathological examinations revealed no changes related to the administration of this chemical. Histopathological examinations of the testes, epididymides and ovaries revealed no toxicological changes. There were no adverse effects on estrous cyclicity, copulation index, fertility index, precoital interval, gestation length, gestation index or number of corpora lutea. No significant changes were observed in numbers of implantations and pups and live pups, and in indexes for implantation, delivery, birth and live birth. There were no treatment- related changes in body weight, external appearance or necropsy findings in offspring of rats.
Based on the absence of any adverse effects on reproductive and developmental parameter, the NOAEL for reproductive and developmental toxicity is considered to be 500 mg/kg bw/day. Further, based on clinical signs and decreased body weight gain and food consumption, the LOAEL and NOAEL for general toxicity in parent animals are considered to be 150 and 50 mg/kg bw/day, respectively.
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