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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

A read-across screening reproduction test with the related substance 4 -ethylmorpholine in male/female Crj:CD(SD) IGS rats was performed according to OECD Guideline 421. Based on the findings, the male parental NOAEL for general toxicity was established as being 150 mg/kg/day and the female parental NOAEL for general toxicity was established as being 50 mg/kg/day based on reduced body weight gain and food consumption. The reproductive and developmental NOAEL was established as being 500 mg/kg/day. The same is assumed to be correct for the target substance.

Link to relevant study records

Referenceopen allclose all

Endpoint:
screening for reproductive / developmental toxicity
Type of 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:
guideline study with acceptable restrictions
Remarks:
read-across from related substance
Justification for type of information:
Read-across from structural analogue. Justification for this read-across approach is included in section 13.
Reason / purpose for cross-reference:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Key result
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Critical effects observed:
no
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects observed at highest dose tested.
Critical effects observed:
no
Reproductive effects observed:
no
Conclusions:
No reliable screening for reproduction/developmental toxicity with the target substance is available. Data generated with the related substance N-ethylmorpholine is used for endpoint coverage.
The NOAEL for general toxicity in parent animals are considered to be 150 mg/kg bw/day in males and 50 mg/kg bw/day in females, based on reduced body weight gain and food consumption. The NOAEL for reproductive and developmental toxicity is considered to be 500 mg/kg bw/day.
The same is assumed to be correct for the target substance.
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
The original study report is in Japanese language, although the figures and tables are in English. An English summary is available from the Japanese authorities and an extensive summary is present in the OECD HPV program files.
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): N-ethylmorpholine
- Molecular formula (if other than submission substance): C6 H13 N O
- Molecular weight (if other than submission substance): 115.18
- Smiles notation (if other than submission substance): CCN1CCOCC1
- InChl (if other than submission substance): InChI=1/C6H13NO/c1-2-7-3-5-8-6-4-7/h2-6H2,1H3
- Analytical purity: equal or more than 99%
- Impurities (identity and concentrations): 0.05% as moisture
- Lot/batch No.: 2901P0
- Stability under test conditions: The test solution was prepared and diluted to dosing concentrations by injection solvent every week. The diluted solution was confirmed to be stable for 8 days.
- Storage condition of test material: The test solution was kept in a refrigerator
Species:
rat
Strain:
other: Crj:CD(SD)IGS
Sex:
male/female
Details on test animals or test system and environmental conditions:
Animals: Four weeks old Crj:CD(SD)IGS rats bought from Charles River Japan, Inc. They were put in quarantine and acclimatization for 7 days before use.
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Vehicle: water for injection.
The test solution was prepared and diluted to dosing concentrations by injection solvent every week.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The dosing solutions were confirmed to be stable.
Duration of treatment / exposure:
Males: 42 days
Females: from 14 days before mating to day 3 of lactation
Frequency of treatment:
daily
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
vehicle
Dose / conc.:
50 mg/kg bw/day (nominal)
Dose / conc.:
150 mg/kg bw/day (nominal)
Dose / conc.:
500 mg/kg bw/day (nominal)
No. of animals per sex per dose:
13
Control animals:
yes, concurrent vehicle
Positive control:
None.
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes, on day 1, 7, 14, 21, 28, 35, 42, 43 (males). Females: on day 1, 7, 14 pre-mating, on day 0, 7, 14, 20 of pregnancy and on day 0 and 4 of lactation.

FOOD CONSUMPTION: Yes, on days 1-2, 7-8, 14-15, 29-30, 35-36, 41-42 (males). Females on days 1-2, 7-8, 14-15 pre-mating, on days 0-1, 7-8, 14-15, 20-21 of pregnancy and on days 3-4 of lactation.

ORGAN WEIGHTS: Yes

Oestrous cyclicity (parental animals):
mean length of estrous cycle during treatment period and pre-treatment period, number of animals showing 4-day cycle during pre-treatment period, changes of estrous cycle after treatment, mean times of vaginal estrus during mating period.
Sperm parameters (parental animals):
absolute and relative weights of testes and epididymides.
Litter observations:
STANDARDISATION OF LITTERS
No pups were discarded.

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, weight gain
Postmortem examinations (parental animals):
Examined
Postmortem examinations (offspring):
Examined
Statistics:
Methods by Dunnett, bartlett, Fischer, Mann-Whitney
Reproductive indices:
copulation index, fertility index, gestation index, indexes for implantation, delivery
Offspring viability indices:
indexes for birth and live birth
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
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.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
No deaths were found in males of any group. One female at 500 mg/kg bw/day died on day 2 of lactation.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
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.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
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.
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
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
Histopathological examination of reproductive organs revealed no abnormalities related to dosing.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
No adverse effects on estrous cyclicity
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
No effects on copulation index, fertility index, precoital interval, gestation length, gestation index and number of corpora lutea.
Key result
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Key result
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Critical effects observed:
no
Clinical signs:
not specified
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, treatment-related
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
Anogenital distance (AGD):
not examined
Nipple retention in male pups:
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
Slight decreases in numbers and rate of implantation were detected in the 500 mg/kg group. There were, however, no adverse effects on estrous cycle, copulation, fertility, gestation length, gestation index or number of corpora lutea. Slight decreases in numbers of pups and numbers of live pups, presumably related to decrease in implantation, were detected in the 500 mg/kg group. There were no treatment-related changes in the body weight,
external appearance, general conditions or necropsy findings in offspring of rats.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects observed at highest dose tested.
Critical effects observed:
no
Key result
Reproductive effects observed:
no
Conclusions:
The NOAELs for general toxicity in parent animals are considered to be 150 mg/kg bw/day in males and 50 mg/kg bw/day in females, based on reduced body weight gain and food consumption. The NOAEL for reproductive and developmental toxicity is considered to be 500 mg/kg bw/day.
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No reliable screening for reproduction/developmental toxicity is available with the test substance. Data generated with the related substance N-ethylmorpholine was used for endpoint coverage. In a screening study performed according to OECD 421 with 4-ethylmorpholine, rats were exposed to 0, 50, 150, 500 mg /kg. Following general toxicity was observed: 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 was accompanied by reduced food consumption in males at 500 mg/kg bw/day and females at 150 mg/kg bw/day and higher. Based on the findings, the male parental NOAEL for general toxicity was established as being 150 mg/kg/day and the female parental NOAEL for general toxicity was established as being 50 mg/kg/day based on reduced body weight gain and food consumption.


Reproductive and developmental toxicity observed: slight decreases in numbers and rate of implantation were detected in the 500 mg/kg group. There were, however, no adverse effects on estrous cycle, copulation, fertility, gestation length, gestation index or number of corpora lutea. Slight decreases in numbers of pups and numbers of live pups, presumably related to decrease in implantation, were detected in the 500 mg/kg group. There were no treatment-related changes in the body weight, external appearance, general conditions or necropsy findings in offspring of rats. The reproductive and developmental NOAEL was established as being 500 mg/kg/day. The justification for read-across within this this endpoint can be found in section 13.

Effects on developmental toxicity

Description of key information

A developmental toxicity study was performed in female Imp:Lodz rats according to a method equivalent to OECD Guideline 414 (Sitarek, 1999). 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.

Link to relevant study records
Reference
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).
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
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)
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

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

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.

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.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
600 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Sitarek (1999) studied developmental toxicity /teratogenicity (prenatal developmental toxicity study - method equivalent to OECD Guideline 414) in Imp:Lodz rats via the oral route of exposure (by gavage) at dose levels of 100, 200, 600 and 900 mg/kg/day. Treatment was given once daily at days 6 to 15 of gestation.

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.

Remarks related to this study:

1) The study was conducted in two parts, with the highest dose group (900 mg/kg/day) and a control group apparently added at a later time as an add-on, likely due to the problem that there was no toxicity observed in the original study at 600 mg/kg/day. The time "gap" between the first and second study was not provided in the published study report, and the toxicological or study-specific significance, if any, of this gap is not known.

2) Using the dossier data, the highest dose level tested in this study (900 mg/kg/day) was 75% of the oral LD50 value (1440 mg/kg/day). If a comparison is made to the oral toxicity value provided in the article (~ 2000 mg/kg), then the high dose is about 45% of the oral LD50 value. Using either comparison, the high dose used in this study, compared to the LD50 value, is still quite high.

3) The mortality of the dams at the highest dose level (3/20 animals) exceeded the customary value of 10% for "excessive" toxicity under current GHS evaluation criteria. Current GHS guidance for evaluation of reprotox studies is that dose levels that meet or exceed the 10% criteria "should not normally be considered for further evaluation".

4) In consideration of the above criteria, the study should be considered to be a negative study, with teratogenic effects noted only at doses that resulted in excessive maternal toxicity.

5) The NOAEL for this study is 600 mg/kg/day, for maternal effects and for developmental effects.

The observed effects (principally anophthalmia) were due to the maternal toxicity at 900 mg/kg/day. Apparently, there were some contemporary evaluation of the impact of maternal toxicity and developmental effects, and these were summarized by Sitarek (1999). An additional evaluation was provided in the review of Khera (1985) of which reference is made into this dossier as supporting evidence.

Justification for classification or non-classification

Based on the criteria laid down in the CLP Regulation, the substance should not be classified as reproductive toxicant.

Additional information