Registration Dossier - ECHA (2024)

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The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEMhere.

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REACH

EC number: 203-640-0 |CAS number: 109-02-4

  • General information
  • Ecotoxicological information
  • Toxicological information
  • Analytical methods
  • Guidance on safe use
  • Assessment reports
  • Reference substances
  • Substance Identity
  • Administrative Information

Registration Dossier - ECHA (1)

Toxicological information

Developmental toxicity / teratogenicity

  • Administrative data
  • Data source
  • Materials and methods
  • Results and discussion
  • Applicant's summary and conclusion

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
deviation: exposure to test substance only during period of organogenesis (from day 6 to 15 of gestation) instead of until day 20 of gestation (day before caesarean section).

Data source

Referenceopen allclose all

Reference 1

Reference Type:
publication
Title:
Unnamed
Year:
1 999

Reference 2

Reference Type:
publication
Title:
Maternal toxicity: a possible etiological factor in embryo-fetal deaths and fetal malformations or rodent-rabbit species
Author:
Khera KS
Year:
1 985
Bibliographic source:
Teratology 31(1): 129-53

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
only exposure during period of organogenesis (from day 6 to 15 of gestation); body weight and food consumption not recorded at 3-day intervals, no determination of sex of foetus.
GLP compliance:
no
Limit test:
no

Test material

Test material information

Constituent 1

Registration Dossier - ECHA (2)

Reference substance name:
4-methylmorpholine
EC Number:
203-640-0
EC Name:
4-methylmorpholine
Cas Number:
109-02-4
Molecular formula:
C5H11NO
IUPAC Name:
4-methylmorpholine
Test material form:
liquid
Specific details on test material used for the study:
- Name of test material (as cited in study report): N-methylmorpholine
- Composition of test material, percentage of components: 99% of N-methylmorpholine and 1% of water (determined by chromatographic analysis)

Test animals

Species:
rat
Strain:
other: Imp: Lodz
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Institute's own breeding colony
- Age at study initiation: approximately 3 months old (females), males were 4 months old
- Weight at study initiation: 199 - 213 g (females); 320-340 g (males)
- Housing: The rats were housed in quarters
- Diet (e.g. ad libitum): commercial pelleted chow (Fodder Factory, Motycz, Poland), ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): approximately 22°C
- Humidity (%): 45-55%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
N-methylmorpholine was dissolved in water.
Analytical verification of doses or concentrations:
no
Details on mating procedure:
Approximately 3-month-old female rats were mated overnight with 4-month-old male rats. The day on which sperm was observed in the vagin*l smears was designated as day 0 of gestation.
Duration of treatment / exposure:
From days 6 to 15 of gestation
Frequency of treatment:
Daily
Duration of test:
Until day 20 of gestation, all surviving females were sacrificed under ether anesthesia on day 20 of gestation.
No. of animals per sex per dose:
20-23 female animals/group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: 5%, 10%, 30% and 45% of LD50

Examinations

Maternal examinations:
The general behaviour of the dams was observed every day. Body weights were measured on days 0, 3, 10, 17 and 20 of gestation and food and water consumption on days 3, 10, and 17 of gestation. All surviving females were sacrificed under ether anesthesia on days 20 of gestation.
The liver, kidneys, adrenals, ovaries, and spleen of the mothers were removed and weighed. Haemoglobin (cyanomethaemoglobin method) and haematocrit values were determined in maternal blood.
Ovaries and uterine content:
The uterus was opened and the number of live fetuses, dead fetuses, and early and late resorption sites were recorded. A site was judged as a late resorption when macroscopic discrimination between fetal residues and placental material was possible. When this discrimination could not be made, the site was judged to be an early resorption. Total implantations were calculated as the sum of the number of fetuses and resorption sites in each pregnant female rat.
Fetal examinations:
Live fetuses were measured for body weight and crown-rump length and examined for external malformations. Approximately half of the live fetuses from each litter were preserved in 95% ethanol for subsequent skeletal examination after staining with Alizarin S. The remaining fetuses were fixed in Bouin's solution for visceral examination.
Statistics:
In the case of hom*ogenecity of variance, one-way analysis of variance and Dunnett's test were used; in the case of heterogenicity, the Kruskal-Wallis analysis of variance was followed by a non-parametric test. Frequency data were analysed with Fischer's extact probability test. The effect of N-methylmorpholine on food and water consumption and maternal body weight gain was evaluated by a two-way analysis of variance and Scheffe's test for multiple comparison.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
No significant differences in appearance and behaviour between exposed and control pregnant females.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
In the 900 mg/kg dose group, 3 pregnant females died, whereas 1 animal died in the 600 mg/kg dose group.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The maternal toxicity of the test substance in the group receiving the highest dose of the chemical (900 mg/kg) was manifested by a significantly lower body weight gain, which was found on day 17 of gestation and only slightly on day 20 of gestation but significantly lower body weight gain during pregnancy in the 600 mg/kg group.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Integral toxicity indices, such as daily food and water intake or absolute and relative organ weights, indicate that the test substance at 900 mg/kg bw is toxic to pregnant females.
The daily food consumption was significantly lower in the group receiving the highest doses compared to the control group (17.6 g/rat vs 23.3 g/rat at 17th GD) and relative weights of kidneys, adrenals, and spleen were significantly increased.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Integral toxicity indices, such as daily food and water intake or absolute and relative organ weights, indicate that the test substance at 900 mg/kg bw is toxic to pregnant females.
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
No differences in haematological values.
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No significant differences in appearance and behaviour between exposed and control pregnant females.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Integral toxicity indices, such as daily food and water intake or absolute and relative organ weights, indicate that the test substance at 900 mg/kg bw is toxic to pregnant females. The daily food consumption was significantly lower in the group receiving the highest doses compared to the control group (17.6 g/rat vs 23.3 g/rat at 17th GD) and relative weights of kidneys, adrenals, and spleen were significantly increased.
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not specified

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
In the 900 mg/kg dose group, 3 pregnant females died, whereas 1 animal died in the 600 mg/kg dose group.
No significant differences in appearance and behaviour between epxosed and control pregnant females. No differences in haematological values.
The maternal toxicity of N-methylmorpholine in the group receiving the highest dose of the chemical (900 mg/kg) was manifested by a significantly lower body weight gain, which was found on day 17 of gestation and only slightly on day 20 of gestation but significantly lower body weight gain during pregnancy in the 600 mg/kg group.
Integral toxicity indices, such as daily food and water intake or absolute and relative organ weights, indicate that N-methylmorpholine at 900 mg/kg bw is toxic to pregnant females. The daily food consumption was significantly lower in the group receiving the highest doses compared to the control group (17.6 g/rat vs 23.3 g/rat at 17th GD) and relative weights of kidneys, adrenals, and spleen were significantly increased.
No significant alterations in maternal parameters were observed in the 100-600 mg/kg dose groups.

Effect levels (maternal animals)

open allclose all

1

Key result
Dose descriptor:
NOAEL
Remarks:
maternal toxicity
Effect level:
600 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake
organ weights and organ / body weight ratios

2

Key result
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Effect level:
600 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Maternal abnormalities

Key result
Abnormalities:
effects observed, treatment-related
Localisation:
not specified

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
The test substance exhibits a fetotoxic effect causing a decrease in both the weight and body length of the fetuses from the pregnant female rats exposed to the highest dose of this chemical. This fetotoxic activity of the test substance at the highest dose was manifested in delayed ossification. In the group of fetuses prenatally exposed to the chemical at 900 mg/kg bw, significantly higher frequency of delayed ossification of cranium, shoulder girdle bones (incomplete development of skull bones and scapular bones), and increased frequency of wavy ribs was found. Abnormal development, leading to significantly increased frequency of fetuses with enlarged cerebral ventricles and subarachnoid spaces in the highest exposure group was observed. The cerebral ventricles were classified as enlarged when they were a minimum of five times greater than the ventricles of control fetuses, and the internal hydrocephalus was diagnosed when a minimum of ten times greater than control. Unilateral enlargement of the renal pelvis was significantly increased only in 200 mg group fetuses but was not dependent on the dose of N-methylmorpholine. When the enlargement of renal pelvis was more ten times than control it was classified as hydronephrosis.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
900 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
external malformations
skeletal malformations

Fetal abnormalities

Key result
Abnormalities:
effects observed, treatment-related
Localisation:
other: see below
Description (incidence and severity):
N-methylmorpholine exhibits a fetotoxic effect causing a decrease in both the weight and body length of the fetuses from the pregnant female rats exposed to the highest dose of this chemical. This fetotoxic activity of N-methylmorpholine at the highest dose was manifested in delayed ossification. In the group of fetuses prenatally exposed to the chemical at 900 mg/kg bw, significantly higher frequency of delayed ossification of cranium, shoulder girdle bones (incomplete development of skull bones and scapular bones), and increased frequency of wavy ribs was found. Abnormal development, leading to significantly increased frequency of fetuses with enlarged cerebral ventricles and subarachnoid spaces in the highest exposure group was observed. The cerebral ventricles were classified as enlarged when they were a minimum of five times greater than the ventricles of control fetuses, and the internal hydrocephalus was diagnosed when a minimum of ten times greater than control. Unilateral enlargement of the renal pelvis was significantly increased only in 200 mg group fetuses but was not dependent on the dose of N-methylmorpholine. When the enlargement of renal pelvis was more ten times than control it was classified as hydronephrosis.

Overall developmental toxicity

Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
600 mg/kg bw/day (nominal)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects

Any other information on results incl. tables

In the studies mentioned in the publication of Khera (1985), only nine chemicals (four each in hamsters and rabbits and one in rats) were reported to induce embryo-fetal deaths at apparently nonmaternotoxic doses. These findings tend to suggest a contributory role for maternal toxicity in the induction of embryo-fetal deaths. The previously reported hypothesis that certain fetal defects in mice may perhaps be caused by maternal toxicity was also found to be true in a review of data on hamsters, rats and rabbits. Salient maternal toxicity-associated fetal malformations were exencephaly, encephalocele, micro-or anophthalmia, and fused ribs in hamsters and defective (fused, missing, or extra) ribs, vertebrae, and sternebrae, ex-, an-, or microphthalmia, and cleft palate in rats and rabbits. These malformations occurred at low frequencies, generally with no readily apparent dose-response relationship. Presumptive evidence indicates that embryo-fetal deaths, and the above-mentioned fetal malformations in experimental animals, which in published literature are presently attributed to chemical induction for a large number of chemicals, may be a consequence of maternal toxicity per se.

Applicant's summary and conclusion

Conclusions:
The substance is teratogenic but only at one dose (900 mg/kg), which was also maternotoxic. The principle fetal malformations were anophthalmia, internal hydrocephalus, and hydronephrosis. The maternal toxicity at this dose consisted of reduced food consumption, reduced body-weight gains, and increased relative weights of kidneys, adrenals, and spleen. No adverse maternal or fetal findings were observed at 600 mg/kg or lower doses of the compound.

Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.

Registration Dossier - ECHA (3)

Registration Dossier - ECHA (2024)
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