Registration Dossier
Registration Dossier
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EC number: 701-303-7 | CAS number: -
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2015
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP and Guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 015
- Report date:
- 2015
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.31 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Ethylenediamine, ethoxylated and propoxylated
- EC Number:
- 500-047-1
- EC Name:
- Ethylenediamine, ethoxylated and propoxylated
- Cas Number:
- 26316-40-5
- Molecular formula:
- (C2H4O)m (C3H6O)n C2H8N2 sum of n+m: >1 -<8.5
- IUPAC Name:
- Ethylenediamine, ethoxylated and propoxylated
- Test material form:
- not specified
- Details on test material:
- - Name of test material (as cited in study report): Ethylenediamine, ethoxylated and propoxylated (>1 – <8.5 mol of EO and PO)
- Analytical purity: 99.8%
- Lot/batch No.: F359EB7L12
- Stability under test conditions: at least 24 days
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD(SD)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River
- Age at study initiation: sexually mature adult
- Weight at study initiation: 200-250 g
- Housing: 1/cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 4 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 (range of 20-26)
- Humidity (%): 50 (range of 30-70)
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Dosing solutions were prepared by mixing the test material in ultrapure water at concentrations of 0, 25, 75 or 250 mg/ml and administered at a dose volume of 4 ml/kg body weight. Dose volumes were adjusted daily based on individual body weights. The control rats were dosed with ultrapure water at 4 ml/kg body weight. Dose solutions were prepared periodically throughout the study based on the established stability.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Dose confirmation of dose solutions from the first mix was performed pre-exposure. The homogeneity of the low- and high-dose test solutions was determined concurrent with dose confirmation. The method used for analyzing the test material in ultrapure water was liquid chromatography-mass spectrometry (LC/MS).
- Details on mating procedure:
- - Impregnation procedure: purchased timed pregnant
- Duration of treatment / exposure:
- GD 6-20
- Frequency of treatment:
- once daily, 7 days/week
- Duration of test:
- up to GD 21
- No. of animals per sex per dose:
- 24/dose level
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Dose levels for this study were selected on the basis of the developmental toxicity probe study. Oral administration of Ethylenediamine, ethoxylated and propoxylated (>1 – <8.5 mol of EO and PO) to time-mated Crl:CD(SD) rats up to and including the limit dose of 1000 mg/kg/day resulted in no maternal toxicity and no indication of embryo/fetal lethality; therefore, no observable toxicity was expected. The high-dose of 1000 mg/kg/day represents a limit dose as defined in the Health Effects Test Guideline of the United States Environmental Protection Agency (OPPTS 870.3700 Prenatal Developmental Toxicity Study). The lower dose levels were selected to provide dose response data for any toxicity that may have been observed among the high-dose group rats and to establish a no-observed-effect level (NOEL).
- Rationale for animal assignment: Animals were stratified by GD 0 body weight and then randomly assigned to treatment groups using a computer program designed to increase the probability of uniform mean group weights and standard deviations at the start of the study.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- All rats were observed in their cages for significant clinical abnormalities clearly visible upon a limited examination and to monitor the general health of the animals.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At least once daily; approximately 1 hour after dosing.
BODY WEIGHT: Yes
- Time schedule for examinations: Recorded on GD 0 by the supplier and daily from GD 6-21. Statistical analysis of body weights was performed using data collected on GD 0, 6, 9, 12, 15, 18, and 21. Statistical analysis of body weight gains was conducted for the following intervals: GD 0-6, 6-9, 9-12, 12-15, 15-18, 18-21, 6-21, and 0-21.
FOOD CONSUMPTION: Yes, recorded every 3 days from GD 3-21.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Organs examined: The maternal necropsy included an examination of the external tissues and all orifices. The skin was reflected from the carcass, the thoracic and abdominal cavities were opened and the viscera were examined. The stomach, liver, and kidneys were dissected from the carcass and were incised. Any obvious gross pathologic alterations were recorded.
OTHER: The weight of the liver, kidneys, and gravid uterus were recorded. The ratios of liver and kidney weights to terminal body weight were calculated. Representative portions of liver, kidneys, and gross lesions were preserved in neutral, phosphate-buffered 10% formalin. Miccoscopic examination of the liver, kidneys, and gross lesions was not conducted. - 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
OTHER: The uteri of females lacking visible implantations was stained with a 10% aqueous solution of sodium sulfide based on (Kopf et al., 1964) and examined for evidence of early resorptions in order to verify pregnancy status. - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [ half per litter]
- Skeletal examinations: Yes: [ half per litter]
- Head examinations: Yes: [half per litter] - Statistics:
- Maternal body weights, maternal body weight gains, maternal organ weights, gravid uterine weights, fetal body weights, feed consumption: Bartlett's test, parametric or non-parametric ANOVA, Dunnett's test or Wilcoxon Rank-Sum test with Bonferroni's correction
Frequency of pre- and post-implantation loss and fetal alterations: censored Wilcoxon test with Bonferroni's correction
Number of corpora lutea, implantations, and litter size: non-parametric ANOVA, Wilcoxon Rank-Sum test with Bonferroni's correction
Pregnancy rates: Fisher exact probability test with Bonferroni's correction
Fetal sex ratios: binomial distribution test
Statistical outliers were identified using a sequential method and, if excluded, were excluded for sound scientific reasons. - Indices:
- Pre/post-implantation loss
- Historical control data:
- Yes
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- Clinical and cage-side examinations performed on all animals revealed no treatment-related findings. Observations were sporadic and transient and were therefore considered unrelated to treatment. See 'Overall remarks, attachments' below for data.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- There were no deaths. See 'Overall remarks, attachments' below for data.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related differences in the body weights or body weight gains in any of the treated groups when compared to controls. See 'Overall remarks, attachments' below for data.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- There were no treatment-related differences in the amount of feed consumed in any of the treated groups when compared to controls. See 'Overall remarks, attachments' below for data.
- 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
- Description (incidence and severity):
- There were no treatment-related differences in any of the measured parameters in any of the treated groups when compared to controls. See 'Overall remarks, attachments' below for data.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related gross pathologic observations.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- See 'Overall remarks, attachments' below for data.
- Pre- and post-implantation loss:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no treatment-related effects on numbers of implantations, percent pre-implantation loss, percent postimplantation loss, in any of the treated groups compared to controls. Mean percent post-implantation loss was statistically identified as higher in the 1000 mg/kg/day group when compared to the control group; however, this value was well within the range of historical control data and, therefore, was not considered treatment related. See 'any other information on results incl. tables' and 'Overall remarks, attachments' below for data.
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related effects on resorption rates. See 'Overall remarks, attachments' below for data.
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- See 'Overall remarks, attachments' below for data.
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- See 'Overall remarks, attachments' below for data.
- Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- See 'Overall remarks, attachments' below for data.
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): See 'Overall remarks, attachments' below for data. - Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- See 'Overall remarks, attachments' below for data.
- Other effects:
- not specified
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
Details on maternal toxic effects:
Clinical and cage-side examinations performed on all animals revealed no treatment-related findings. Observations were sporadic and transient and were therefore considered unrelated to treatment.
There were no treatment-related differences in the body weights or body weight gains in any of the treated groups when compared to controls.
There were no treatment-related differences in teh amount of feed consumed in any of the treated groups when compared to controls.
There were no treatment-related differences in terminal body, liver, or kidney weights in any of the treated groups when compared to controls.
There were no treatment-related gross pathological observations.
There were no treatment-related effects on pregnancy rates, resorption rates, litter size, numbers of corpora lutea or implantations, percent pre-implantation loss, percent post-implantation loss, fetal sex ratios, fetal body weights or gravid uterine weights in any of the treated groups compared to controls. Mean percent post-implantation loss was statistically identified as higher in the 1000 mg/kg/day group when compared to the control group; however, this value was well within the range of historical control data and, therefore, was not considered treatment related. See 'any other information on results incl. tables' and 'Overall remarks, attachments' below for data.
Effect levels (maternal animals)
open allclose all
- Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day
- Basis for effect level:
- other: developmental toxicity
Maternal abnormalities
- Abnormalities:
- not specified
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- There were no treatment related effects on fetal body weights. See 'Overall remarks, attachments' below for data.
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): See 'Overall remarks, attachments' below for data. - Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- See 'Overall remarks, attachments' below for data.
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- See 'Overall remarks, attachments' below for data.
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- See 'Overall remarks, attachments' below for data.
- Changes in postnatal survival:
- no effects observed
- Description (incidence and severity):
- See 'Overall remarks, attachments' below for data.
- External malformations:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related external alterations in any dose group. Incidental findings bearing no relationship to treatment included the malformations of agnathia and astomia in a single control fetus. See 'any other information on results incl. tables' and 'Overall remarks, attachments' below for data.
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no statically significant or treatment-related skeletal alterations in any dose group. Incidental findings bearing no relationship to treatment included the malformations sternoschisis and fused ribs and the variations delayed ossification (DO) interparietal, supernumerary skull bone, DO cervical centra, extra site of ossification sternebrae, irregular pattern of ossification sternebrae, extra 1st lumbar rib, DO thoracic centra, and DO pubis. Given that these observations occurred in the control group, at low frequencies, and/or lacked a dose response, these observations were considered spurious and unrelated to treatment. See 'any other information on results incl. tables' and 'Overall remarks, attachments' below for data.
- Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no treatment-related visceral alterations in any dose group. Incidental findings bearing no relationship to treatment included the malformations situs inversus, retroesophageal aortic arch, and hydronephosis and the variations fused lung, hemorrhage adrenal, pale liver, and supernumerary hepatic liver lobule. Given that these observations occurred in the control group, at low frequencies, and/or lacked a dose response, these observations were considered spurious and unrelated to treatment. See 'any other information on results incl. tables' and 'Overall remarks, attachments' below for data.
- Other effects:
- no effects observed
- Description (incidence and severity):
- Craniofacial Examination
There were no treatment-related craniofacial alterations in any dose group. Incidental findings bearing no relationship to treatment included the malformation
microphthalmia in a single control fetus. - Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
There were no statisticaly signficant differences in the incidence of any fetal alteration in any of the treatment groups compared to controls. The small number of alterations observed in fetuses from dams administered Ethylenediamine, ethoxylated and propoxylated either occurred at low frequences, were within recent historical control values, and/or were not dose related.
Effect levels (fetuses)
- Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day
- Basis for effect level:
- other: embryofetal development
Fetal abnormalities
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Developmental effects observed:
- no
Any other information on results incl. tables
Post-implantation Loss:
| Dose Level (mg/kg/day) | 0 | 100 | 300 | 1000 |
| Mean % Post-implantation Loss | 3.3 +/- 3.7 | 3.5 +/- 7.7 | 2.2 +/- 3.9 | 6.2* +/- 5.1 |
*Statistically different from control mean by Consored Wilcoxon's test alpha =0.05
Historal Control Post-implantation Loss:
(D=Dietary, G=Gavage)
Study Route Year |
1 D 2010 |
2 D 2010 |
3 D 2010 |
4 D 2012 |
5 D 2012 |
6 D 2014 |
7 G 2014 |
8 D 2014 |
9 G 2014 |
10 G 2015 |
11 G 2015 |
12 D 2015 |
13 G 2015 |
| Mean % Post-implantation Loss | 1.9 +/- 4.3 | 1.4 +/-2.8 | 2.2 +/-3.4 | 4.1 +/-9.8 | 2.0 +/-3.5 | 4.0 +/-6.5 | 5.1 +/-4.0 | 4.2 +/-6.0 | 3.9 +/-11.1 | 3.4 +/-4.9 | 8.8 +/-16.8 | 2.3 +/-5.3 | 3.7 +/-5.9 |
D=Dietary, G=Gavage
Bold type indicates the highest observed value for the endpoint.
Incidences of External Malformations
| Dose (mg/kg/day) | 0 | 100 | 300 | 1000 | |
| Agnathia | F L |
1/303a 1/22 |
0/326 0/24 |
0/303 0/22 |
0/303 0/22 |
| Astomia | F L |
1/303a 1/22 |
0/326 0/24 |
0/303 0/22 |
0/303 0/23 |
F = fetuses; L = litters
aMalformations denoted with the same superscript were noted in a single fetus.
Incidences of External Malformations:
| Dose (mg/kg/day) | 0 | 100 | 300 | 1000 | |
| Microphthalmia | F L |
1/153 1/22 |
0/160 0/24 |
0/150 0/22 |
0/151 0/23 |
F=fetuses; L= litters
Incidences of Visceral Malformations:
| Dose (mg/kg/day) | 0 | 100 | 300 | 1000 | |
| Situs Inversus | F L |
0/153 0/22 |
0/160 0/24 |
1/150 1/22 |
0/151 0/23 |
| Retroesophageal Aortic Arch | F L |
0/153 0/22 |
0/160 0/24 |
0/150 0/22 |
1/151 1/23 |
| Hydronephrosis | F L |
1/153 0/22 |
1/160 1/24 |
1/150 0/22 |
0/151 0/23 |
F=fetuses; L=litters
Incidences of Accessory Blood Vessel Kidney:
| Dose (mg/kg/day) | 0 | 100 | 300 | 1000 | |
| Accessory Blood Vessel Kidney | F L |
1/153 (0.7%) 1/22 (4.5%) |
1/160 (0.6%) 1/24(4.2%) |
4/150 (2.7%) 2/22 (9.1%) |
3/151 (2.0%) 3/23 (13.0%) |
F=fetuses; L=litters
Historical Control Data for Accessory Blood Vessel Kidney:
Study Route Year |
1 D 2010 |
2 D 2010 |
3 D 2010 |
4 D 2012 |
5 D 2012 |
6 D 2014 |
7 G 2014 |
8 D |
9 G 2014 |
10 G 2015 |
11 G 2015 |
12 D 2015 |
13 G 2015 |
|
| Accessory Blood Vessel Kidney | F L |
0/138 (0.0%) 0/22 (0.0%) |
0/168 (0.0%) 0/24 (0.0%) |
0/179 (0.0%) 0/26 (0.0) |
0/123 (0.0%) 0/22 (0.0%) |
0/150 (0.0%) 0/24 (0.0%) |
0/137 (0.0%) 0/23 (0.0%) |
0/136 (0.0%) 0/23 (0.0%) |
0/133 (0.0%) 0/24 (0.0%) |
0/140 (0.0%) 0/24 (0.0%) |
0/148 (0.0%)
0/24 (0.0%) |
0/124 (0.0%) 0/21 (0.0%) |
0/153 (0.0%) 0/23 (0.0%) |
3/146 (2.1%) 3/24 (12.5%) |
D=Dietary, G=Gavage
F = fetuses; L = litters
Bold type indicates the highest observed value for the endpoint.
Incidences of Skeletal Malformations
| Dose (mg/kg/day) | 0 | 100 | 300 | 1000 | |
| Sternoschisis | F L |
1/150 1/22 |
0/166 0/24 |
0/153 0/22 |
0/152 0/23 |
| Fused Ribs | F L |
0/150 0/22 |
1/166 1/24 |
0/153 0/22 |
0/152 0/23 |
F=fetuses; L=litters
Incidences of Selected Skeletal Variations:
| Dose (mg/kg/day) | 0 | 100 | 300 | 1000 | |
| DO Sternebrae | F L |
0/150 (0.0%) 0/22 (0.0%) |
1/166 (0.6%) 1/24 (4.2%) |
3/153 (2.0%) 1/22 (4.5%) |
3/152 (2.0%) 3/23 (13.0%) |
| Class I Wavy Ribs | F L |
0/150 (0.0%) 0/22 (0.0%) |
1/166 (0.6%) 1/24 (0.0%) |
0/153 (0.0%) 0/22 (0.0%) |
2/152 (1.3%) 2/23 (8.7%) |
| Class II Wavy Ribs | F L |
0/150 (0.0%) 0/22 (0.0.0%) |
1/166 (0.6%) 1/24 (4.2%) |
0/153 (0.0%) 0/22 (0.0%) |
1/152 (0.7%) 1/23 (4.3%) |
| Calloused Ribs | F L |
1/150 (0.7%) 1/22 (4.5%) |
2/166 (1.2%) 1/24 (4.2%) |
1/153 (0.7%) 1/24 (4.5%) |
2/152 (1.3%) 2/23 (8.7%) |
F=fetuses; L=litters
Historical Control Data for Selected Skeletal Variations:
Study Route Year |
1 D 2010 |
2 D 2010 |
3 D 2010 |
4 D 2012 |
5 D 2012 |
6 D 2014 |
7 G 2014 |
8 D 2014 |
9 G 2014 |
10 G 2015 |
11 G 2015 |
12 D 2015 |
13 G 2015 |
|
| DO Sternebrae | F L |
1/138 (0.7%) 1/22 (4.5%) |
2/152 (1.3%) 2/24 (8.3%) |
3/180 (1.7%) 2/26 (7.7%) |
2/131 (1.5%) 2/22 (9.1%) |
2/151 (1.3%) 2/24 (8.3%) |
1/139 (0.7%) 1/23 (4.3%) |
0/135 (0.0%) 0/23 (0.0%) |
1/134 (0.7%) 1/24 (4.2%) |
0/145 (0.0%) 0/24 (0.0%) |
2/151 (1.3%) 2/24 (8.3%) |
0/125 (0.0%) 0/21 (0.0%) |
0/152 (0.0%) 0/23 (0.0%) |
2/147 (1.4%) 2/24 (8.3%) |
| Class I Wavy Ribs | F L |
0/138 (0.0%) 0/22 (0.0%) |
0/152 (0.0%) 0/24 (0.0%) |
2/180 (1.1%) 2/26 (7.7%) |
1/131 (0.8%) 1/22 (4.5%) |
2/151 (1.3%) 2/24 (8.3%) |
0/139 (0.0%) 0/23 (0.0%) |
1/135 (0.7%) 1/23 (4.3%) |
4/134 (30%) 1/24 (4.2%) |
0/145 (0.0%) 0/24 (0.0%) |
0/151 (0.0%) 0/24 (0.0%) |
0/125 (0.0%) 0/21 (0.0%) |
1/152 (0.7%) 1/23 (4.3%) |
2/147 (1.4%) 2/24 (8.3%) |
Class II Wavy Ribs |
F L |
0/138 (0.0%) 0/22 (0.0%) |
0/152 (0.0%) 0/24 (0.0%) |
0/180 (0.0%) 0/26 (0.0%) |
0/131 (0.8%) 0/22 (0.0%) |
0/151 (0.0%) 0/24 (0.0%) |
0/139 (0.0%) 0/23 (0.0%) |
0/135 (0.0%) 0/23 (0.0%) |
1/134 (0.7%) 1/24 (4.2%) |
0/145 (0.0%) 0/24 (0.0%) |
0/151 (0.0%) 0/24 (0.0%) |
0/125 (0.0%) 0/21 (0.0%) |
0/152 (0.0%) 0/23 (0.0%) |
2/147 (1.4%) 2/24 (8.3%) |
Calloused Ribs |
F L |
0/138 (0.0%) 0/22 (0.0%) |
0/152 (0.0%) 0/24 (0.0%) |
1/180 (0.6%) 1/26 (3.8%) |
0/131 (0.8%) 0/22 (0.0%) |
1/151 (0.7%) 1/24 (4.2%) |
0/139 (0.0%) 0/23 (0.0%) |
3/135 (2.2%) 3/23 (13.0%) |
4/134 (30%) 1/24 (4.2%) |
0/145 (0.0%) 0/24 (0.0%) |
0/151 (0.0%) 0/24 (0.0%) |
0/125 (0.0%) 0/21 (0.0%) |
0/152 (0.0%) 0/23 (0.0%) |
2/147 (1.4%) 2/24 (8.3%) |
D=Dietary, G=Gavage
F = fetuses; L = litters
Bold type indicates the highest observed value for the endpoint.
Applicant's summary and conclusion
- Conclusions:
- Gavage administration of Ethylenediamine, ethoxylated and propoxylated (>1-<8.5 mol of EO and PO) up to, and including the limit dose of 1000 mg/kg/day, resulted in no treatment-related maternal toxicity and no indication of embryo/fetal toxicity or teratogenicity. Therefore, under the conditions of this study, the no-observed-effect level (NOEL) for maternal toxicity and developmental toxicity was the limit dose of 1000 mg/kg/day.
- Executive summary:
The purpose of this study was to evaluate the maternal and developmental toxicity of Ethylenediamine, ethoxylated and propoxylated (>1-<8.5 mol of EO and PO) in Crl:CD(SD) rats following repeated gavage administration.
Groups of 24 time-mated female rats were administered Ethylenediamine, ethoxylated and propoxylated (>1-<8.5 mol of EO and PO) in ultrapure water by gavage at dose levels of 0, 100, 300, or 1000 mg/kg/day on gestation day (GD) 6 through 20. In-life maternal study parameters included clinical observations, body weight, body weight gain and feed consumption. On GD 21, all rats were euthanized and examined for gross pathologic alterations. Liver, kidneys and gravid uterine weights were recorded, along with the number of corpora lutea, uterine implantations, resorptions and live/dead fetuses. All fetuses were weighed, sexed and examined for external alterations. Approximately one half of the fetuses were examined for visceral and craniofacial alterations while skeletal examinations were conducted on the remaining fetuses.
Gavage administration of Ethylenediamine, ethoxylated and propoxylated (>1-<8.5 mol of EO and PO) up to, and including the limit dose of 1000 mg/kg/day, resulted in no treatment-related maternal toxicity and no indication of embryo/fetal toxicity or teratogenicity.
Therefore, under the conditions of this study, the no-observed-effect level (NOEL) for maternal toxicity and developmental toxicity was the limit dose of 1000 mg/kg/day.
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