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EC number: 931-275-3 | CAS number: 1125503-33-4
- 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:
- 2016-09-02 to 2017-02-21
- Reliability:
- 1 (reliable without restriction)
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 017
- Report date:
- 2017
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- Adopted by the Council on 22nd January 2001
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- [See concordance under 1.1. of the CSR]
- IUPAC Name:
- [See concordance under 1.1. of the CSR]
- Details on test material:
- SOURCE OF TEST MATERIAL
- lot/batch No.of test material: ESD0021175
- Expiration date of the lot/batch: 2017-11-27
- Apperance: colourless waxy solid
- Storage condition of test material: Refrigerator (2 to 8 °C)
- Purity: 35% (w/v) solution in water
- Date of arrival: 14 September 1989
- Storage conditions: room temperature
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- lot/batch No.of test material: ESD0021175
- Expiration date of the lot/batch: 2017-11-27
- Apperance: colourless waxy solid
- Storage condition of test material: Refrigerator (2 to 8 °C)
Test animals
- Species:
- rat
- Strain:
- Wistar
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: Distilled water
- Details on exposure:
- The dose formulations were prepared shortly before each dosing.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of the dose formulations from one set per dose group will be taken immediately after preparation once before commencement of dosing i.e. on day 5 of gestation and on day 19 of gestation (i.e. day 1 and day 15 of treatment) or homogeneity (mean of homogeneity will be given as dose concentration). On day 11 of gestation (e.e. day 7 of treatment), samples of all dose formulations will be analysed for dose concentrations by analysing triplicate samples.
Analysis was performed according to the validated analytical method provided by the sponsor. - Details on mating procedure:
- - Impregnation procedure: cohoused
- M/F ratio per cage: one male: one female
- Length of cohabitation: maximum period of fourteen days
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- Proof of pregnancy: Each female examined for presence of vaginal plug or sperm in vaginal smear referred to as day 0 of gestation - Duration of treatment / exposure:
- day 5 of Gestation to day 19 of Gestation
- Frequency of treatment:
- daily
- Duration of test:
- Animals were sacrificed on day 20 of gestation by cesariean section.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 20 mg/kg bw/day (nominal)
- Dose / conc.:
- 40 mg/kg bw/day (nominal)
- Dose / conc.:
- 80 mg/kg bw/day (nominal)
- Dose / conc.:
- 120 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- females: 24 / group
males: 50 males in total were used for mating - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
Based on the results from a dose range finding study in Wistar rats with the test substance (RCC study number 6265), conducted at RCC Laboratories India Private Limited, the 4 doses were selected.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
Once on day of receipt and twice daily thereafter. Once on day of necropsy
-
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
Acclimatization period once daily. Twice daily on initial 3 days after treatment; once daily thereafter
BODY WEIGHT: Yes
Time schedule for examinations:
- Acclimatization Period: Once weekly
- Premating: On first day of pairing and weekly thereafter (if any)
- Gestation: On gestation day 0, 3, 5, 8, 11, 14, 17, 19 and 20 and at death, if any
FOOD CONSUMPTION GESTATION: Yes
- on Gestation day 3, 5, 8, 11, 14, 17 and 19
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
All animals including those found dead or sacrificed in moribund condition were subject of complete gross necropsy.
- Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes (not obtained from animals found dead during study)
- 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: half per littera
- Skeletal examinations: Yes: half per litter - Statistics:
- The following statistical methods were used to analyze the body weight, body weight change, feed consumption, reproduction and external, visceral and skeletal alterations/variations.
•Data were summarized in tabular form. Statistical analysis were performed using statplus program. Values were given as mean ± standard deviation (SD).
•All the data were checked for Normality with Shapiro-Wilk W test.
•All the data were checked for Homogeneity with Bartlett Chi-Square test.
•Data were subjected to perform Analysis of Variance (ANOVA) for continuous data.
•Discontinuous data were subjected to nonparametric test (Mann-Whitney U-Test). - Indices:
- The following formulae were used for calculating the indices:
Pre–implantation loss (%)
(Number of Corpora Lutea - number of implantation sites) / Number of Corpora Lutea x 100
Post–implantation loss (%)
(Number of implantation sites - Total number of live foetuses) / Number of implantation sites x 100
Sex Ratio (% males)
Number of male foetuses (Day 0) / Total number of foetuses (Day 0) x 100
Variation Incidence (%)
Number of foetuses with variation/ Total Number of foetuses examined x 100
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- No clinical signs observed in all females up to 80 mg/kg bw/d. Prior to death of all group 120 mg/kg bw/d animals, these animals showed diarrhoea, dullness and piloerection. Two animals additionally showed epistaxis.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- No Mortalities observed up to the dose of 80 mg/kg bw/d. All females of 120 mg/kg bw dose group died beginning on treament day 4 until day 12 of treatment. Prior to death, all animals showed diarrhoea, dullness and piloerection. Two animals additionally showed epistaxis.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No significant difference was observed in the body weight and body weight gain (%) of pregnant females in low, intermediate and medium high dose group animals as compared with control group animals.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No significant difference was observed in the feed consumption of pregnant females in low, intermediate and medium high dose group animals when compared with control group animals.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- Ophthalmoscopy did not reveal any abnormalities during last week in all animals of groups 1 and 4. In the last week of treatment, all the animals in group 5 were found dead. Hence, ophthalmoscopy was performed for group 4 animals.
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- Hematological parameters such as Erythrocyte count (RBC), Hemoglobin (Hb), Hematocrit (PCV), Mean corpuscular volume (MCV), Mean corpuscular hemoglobin (MCH), Mean corpuscular hemoglobin concentration (MCHC), Platelet (thrombocyte) count (PLT), Total leucocyte count (WBC), Differential leukocyte count (DC), Prothrombin time (PT) and Activated Partial Thromboplastin time (APTT) did not show any toxicologically relevant findings in the treated groups when compared with control group.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- Clinical biochemistry parameters like Glucose (GLU), Urea, Creatinine (CREA), Triglycerides (TRIGL), Alkaline phosphatase (ALP), Bilirubin (BIL), Sodium (Na), Potassium (K), Chloride (Cl), Total protein (TPO), Albumin (ALB), Globulin (GLB) and Albumin and Globulin ratio (A/G) did not show any toxicologically relevant findings in treatment groups when compared with control group. Where as in cholesterol, there was significant decrease in medium high as compared with intermediate dose. In aspartate aminotransferase, there was significant increase in medium high as compared with intermediate dose and significant decrease in intermediate dose as compared with low dose. In alanine aminotransferase, there was significant increase in low, intermediate and medium high dose as compared with control and significant increase in medium high as compared with low and intermediate dose.
The significant changes observed in the clinical pathology parameters were marginal and could not be attributed to the test item administration as these values were within clinical and biological variation. - 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:
- effects observed, treatment-related
- Description (incidence and severity):
- No test item-related macroscopic findings were observed at necropsy on day 20 of gestation in any of the animals up to 80 mg/kg bw/d. All Females of 120 mg/kg bw dose group died beginning on treatment day 4 until day 12 of treatment. Findings at necropsy of 120 mg/kg bw/d dose group females: Thymus - small in size, slightly; Adrenals – enlarged, slightly; Spleen – enlarged, slightly; Stomach – distended, moderately to markedly; Fore stomach raised whitish foci, moderately to markedly; Ulceration moderately to markedly; Mucous membrane peeled off in some females; Glandular stomach – reddened, slightly to moderately.
- 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
- Description (incidence and severity):
- No abortions occurred during the treatment period.
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- No significant difference was observed in the gravid uterine weight, corpora lutea count, in early and late resorption and number of live foetuses as well as in pre and post implantation losses between control and treated groups.
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- No significant difference was observed in the gravid uterine weight, corpora lutea count, in early and late resorption and number of live foetuses as well as in pre and post implantation losses between control and treated groups. No litter loss occurred
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- No significant difference was observed in the gravid uterine weight, corpora lutea count, in early and late resorption and number of live foetuses as well as in pre and post implantation losses between control and treated groups.
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- With the exception of one dead fetus out of 170 fetuses at the 80 mg/kg bw/d dose group, no dead fetuses were observed in any of the dose groups (0, 20, 40, 80 mg/kg bw/d).
- Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- Due to the study design of an OECD 414 study, pregnancy is terminated by caesarian section at day 20 of gestation. No changes were observed at any dose group.
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): Due to the study design of an OECD 414 study, pregnancy is terminated by caesarian section at day 20 of gestation. - Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- All female animals of control, low, intermediate, medium high and high dose groups showed positive evidence of mating. At necropsy, three females each in control and 40 mg/kg bw/d group, four females in 20 mg/kg bw/d dose group and two females in the 80 mg/kg bw/d dose group were found non pregnant. In high dose group (i.e. 120 mg/kg bw/d) three animals were found non pregnant during necropsy.
- Other effects:
- no effects observed
- Details on maternal toxic effects:
- All Females of 120 mg/kg bw dose group died beginning on treatment day 4 until day 12 of treatment. Findings at necropsy of 120 mg/kg bw/d dose group females: Thymus - small in size, slightly; Adrenals – enlarged, slightly; Spleen – enlarged, slightly; Stomach – distended, moderately to markedly; Fore stomach raised whitish foci, moderately to markedly; Ulceration moderately to markedly; Mucous membrane peeled off in some females; Glandular stomach – reddened, slightly to moderately. At necropsy no abnormality was detected in all females of dose groups 0, 20, 40, 80 mg/kg bw/d.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 80 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- mortality
- Remarks on result:
- other:
- Remarks:
- At high dose of 120 mg/kg bw/d all dams died
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
- Localisation:
- other: none
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- At time of ceasarian section and thus time point of weighing all foetuses, no significant difference was observed in foetal weight between control and treated groups. Foetal body wheight change is not an aim of the study design.
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): At time of ceasarian section which is part of the OECD 414 study design and thus time point of weighing all foetuses, no significant difference was observed in foetal weight between control and treated groups. Foetal body wheight change is not an aim of the study design. - Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- No reduction of live foetuses was observed throughout the dose groups 0, 20, 40 and 80 mg/kg bw/d. The high dose group (i.e. 120 mg/kg bw/d) could not be evaluated as all dams of this dosing group died until treatment day 12.
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- Sex ratio was calculated as percent (%) male and no significant difference was observed in sex ratio in treated groups.
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- No changes in litter size and litter weights could be determined in all treated groups compared to control group.
- Changes in postnatal survival:
- not specified
- Description (incidence and severity):
- Postnatal survival is not an aim of the study design of an OECD 414 study.
- External malformations:
- no effects observed
- Description (incidence and severity):
- There were no test item related variations/malformations observed in foetuses subjected for external and visceral (soft tissue) examination.
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- The number of foetuses showing skeletal variation in treatment groups were comparable with control group. There were no test item related skeletal variations/malformations in any of the treated group. Most of the observations recorded were minor abnormalities and considered as routine variables.
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- There were no test item related variations/malformations observed in foetuses subjected for external and visceral (soft tissue) examination.
- Other effects:
- no effects observed
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- <= 80 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: HYEQS did not produce any malformations and no maternal or embryo-fetal toxicity up to the medium high dose of 80 mg/kg bw/d.
- Remarks on result:
- other:
- Remarks:
- At high dose of 120 mg/kg bw/d all dams died
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
Tab. 1 Mortality and Clinical Signs Females - Summary
Group |
G1 |
G2 |
G3 |
G4 |
G5 |
||
Dose (mg/kg bw) |
0 |
20 |
40 |
80 |
120 |
||
Mortality |
0/24 |
0/24 |
0/24 |
0/24 |
24/24 |
||
Clinical signs |
0/24 |
0/24 |
0/24 |
0/24 |
Dullness |
- |
(24/24) |
Diarrhoea |
- |
(24/24) |
|||||
Piloerection |
- |
(24/24) |
|||||
Epistaxis |
- |
(02/24) |
Tab. 2 Pregnancy Status - Summary
Group |
G1 |
G2 |
G3 |
G4 |
G5* |
Dose (mg/kg bw) |
0 |
20 |
40 |
80 |
120 |
Females mated |
24 |
24 |
24 |
24 |
24 |
Pregnant females |
21 |
20 |
21 |
22 |
21 |
* All the animals were found dead between day 8 and 16 of gestation period (i.e. day 4 and day 12 of treatment)
Tab. 3 Body weight (G) dams - Summary
Group |
Body weights (G) |
||||||||
Gestation Day |
|||||||||
|
0 |
3 |
5 |
8 |
11 |
14 |
17 |
20 |
|
Group 1 |
Mean |
253.6 |
261.8 |
269.0 |
276.5 |
288.0 |
303.2 |
319.1 |
329.4 |
SD |
7.44 |
8.67 |
10.44 |
11.42 |
13.34 |
15.01 |
14.82 |
14.04 |
|
N |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
|
Group 2 |
Mean |
255.8 |
261.7 |
267.7 |
274.7 |
283.8 |
297.0 |
313.5 |
327.1 |
SD |
9.27 |
9.25 |
9.80 |
11.75 |
13.47 |
13.35 |
14.11 |
15.30 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
|
Group 3 |
Mean |
256.8 |
262.6 |
268.5 |
275.1 |
286.2 |
302.3 |
322.6 |
338.4 |
SD |
8.25 |
6.97 |
6.68 |
7.87 |
7.35 |
10.08 |
11.49 |
15.02 |
|
N |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
|
Group 4 |
Mean |
265.0 |
262.5 |
269.7 |
277.3 |
287.8 |
301.0 |
319.1 |
333.4 |
SD |
8.14 |
7.91 |
9.44 |
11.30 |
12.41 |
13.04 |
14.59 |
16.26 |
|
N |
22 |
22 |
22 |
22 |
22 |
22 |
22 |
22 |
Tab. 4 Body weight Gain (%) dams - Summary
Group |
Body weights Gain (%) |
||||||||
Gestation Day |
|||||||||
- |
0 |
3 |
5 |
8 |
11 |
14 |
17 |
20 |
|
Group 1 |
Mean |
0.0 |
3.2 |
6.1 |
9.0 |
13.6 |
19.6 |
25.9 |
29.9 |
SD |
0.00 |
1.91 |
3.38 |
4.31 |
4.78 |
5.44 |
5.52 |
5.38 |
|
N |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
|
Group 2 |
Mean |
0.00 |
2.3 |
4.7 |
7.5 |
11.0 |
16.2 |
22.7 |
28.0 |
SD |
0.00 |
1.47 |
2.66 |
3.90 |
4.52 |
4.56 |
5.93 |
7.10 |
|
N |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
|
Group 3 |
Mean |
0.0 |
2.3 |
4.6 |
7.2 |
11.5 |
17.8 |
25.7 |
31.9 |
SD |
0.00 |
1.30 |
2.54 |
3.90 |
3.92 |
5.21 |
6.42 |
7.73 |
|
N |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
21 |
|
Group 4 |
Mean |
0.0 |
2.6 |
5.4 |
8.4 |
12.5 |
17.6 |
24.8 |
30.4 |
SD |
0.00 |
1.77 |
3.18 |
4.51 |
5.07 |
5.51 |
7.15 |
8.75 |
|
N |
22 |
22 |
22 |
22 |
22 |
22 |
22 |
22 |
Caesarean Data
Tab. 5 Maternal Data - Summary
Parameter |
Group |
G1 |
G2 |
G3 |
G4 |
Dose (mg/kg bw) |
0 |
20 |
40 |
80 |
|
No. of Dams |
21 |
20 |
21 |
22 |
|
Gravid Uterine Weight (G) |
Mean |
41.5978 |
38.2861 |
50.8140 |
41.9012 |
SD |
19.0702 |
20.3954 |
15.4402 |
20.3170 |
|
Total Foetuses |
Number |
163 |
136 |
183 |
170 |
Mean |
7.76 |
6.80 |
8.71 |
7.73 |
|
SD |
3.83 |
4.09 |
3.15 |
4.08 |
|
No. of CL |
Mean |
12.48 |
11.60 |
12.14 |
11.05 |
SD |
3.37 |
2.64 |
2.52 |
4.71 |
|
No. of Implantation |
Mean |
8.48 |
7.90 |
9.48 |
8.82 |
SD |
3.92 |
4.36 |
3.03 |
4.26 |
|
Early Resorption |
Mean |
0.67 |
0.90 |
0.76 |
1.09 |
SD |
0.86 |
1.12 |
1.22 |
1.31 |
|
Late Resorption |
Mean |
0.05 |
0.20 |
0.00 |
0.00 |
SD |
0.22 |
0.89 |
0.00 |
0.00 |
|
Pre implantation loss |
Mean |
4.0 |
3.7 |
2.7 |
2.2 |
SD |
3.44 |
3.34 |
3.26 |
2.20 |
|
% |
30.85 |
34.23 |
20.75 |
18.38 |
|
Post implantation loss |
Mean |
0.7 |
1.1 |
0.8 |
1.1 |
SD |
0.90 |
1.29 |
1.22 |
1.39 |
|
% |
9.07 |
14.19 |
8.75 |
14.75 |
|
Total Number of resorption/s |
Number |
15 |
22 |
16 |
24 |
Pup Data
Tab 6 Litter data – Summary
Parameter |
Group |
G1 |
G2 |
G3 |
G4 |
Dose (mg/kg body weight) |
0 |
20 |
40 |
80 |
|
No. of Dams |
24 |
24 |
24 |
24 |
|
No. of Litters |
21 |
20 |
21 |
22 |
|
Total No. of Foetuses |
163 |
136 |
183 |
170 |
|
Mean Litter Size |
7.76 |
6.80 |
8.71 |
7.73 |
|
No. of live foetuses |
Number |
163 |
136 |
183 |
169 |
Mean |
7.76 |
6.80 |
8.71 |
7.68 |
|
SD |
3.83 |
4.09 |
3.15 |
4.09 |
|
(%) |
100 |
100 |
100 |
99.4 |
|
No. of dead foetuses |
Number |
0 |
0 |
0 |
1 |
Mean |
0.00 |
0.00 |
0.00 |
0.05 |
|
SD |
0.00 |
0.00 |
0.00 |
0.21 |
|
No. of live male foetuses |
Number |
70 |
72 |
80 |
84 |
Mean |
3.33 |
3.60 |
3.81 |
3.82 |
|
SD |
1.85 |
2.48 |
1.91 |
2.56 |
|
No. of live female foetuses |
Number |
93 |
64 |
103 |
85 |
Mean |
4.43 |
3.20 |
4.90 |
3.86 |
|
SD |
2.60 |
1.91 |
2.26 |
2.53 |
Tab.7 Group Mean Foetal weight
Group |
Foetal weight / Litter (G) |
Foetal weight (G) |
||
Male |
Female |
|||
Group 1 |
Mean |
3.5834 |
3.6996 |
3.4960 |
SD |
0.6132 |
0.6325 |
0.5866 |
|
N |
163 |
70 |
93 |
|
Group 2 |
Mean |
3.6514 |
3.7097 |
3.5859 |
SD |
0.5052 |
0.5193 |
0.4845 |
|
N |
136 |
72 |
64 |
|
Group 3 |
Mean |
3.8994 |
4.0176 |
3.8076 |
SD |
0.6315 |
0.5102 |
0.7004 |
|
N |
183 |
80 |
103 |
|
Group 4 |
Mean |
3.7112 |
3.7236 |
3.6990 |
SD |
0.5006 |
0.4952 |
0.5085 |
|
N |
170 |
84 |
86 |
Tab. 8 Group Mean Sex Ratio
Group |
Sex ratio (%) Male |
Sex ratio (%) Female |
|
Group 1 |
Mean |
41.75 |
58.25 |
SD |
15.73 |
15.73 |
|
N |
163 |
||
Group 2 |
Mean |
47.02 |
52.98 |
SD |
25.65 |
25.65 |
|
N |
136 |
||
Group 3 |
Mean |
41.50 |
58.50 |
SD |
19.44 |
19.44 |
|
N |
183 |
||
Group 4 |
Mean |
44.38 |
51.31 |
SD |
23.66 |
24.21 |
|
N |
170 |
Effects on Embryos/Foetuses
Tab. 9 External findings - Summary
Group |
G1 |
G2 |
G3 |
G4 |
|
Dose (mg/kg body weight) |
0 |
20 |
40 |
80 |
|
No. of Litter Examined |
21 |
20 |
21 |
22 |
|
No. of Foetuses Examined |
163 |
136 |
183 |
170 |
|
Variation Incidence – Number (%) |
|||||
No. of Foetus with Variations |
Total Variations |
1(0.61) |
1(0.74) |
2(1.10) |
1(0.59) |
Body Small in size |
1(0.61) |
1(0.74) |
1(0.55) |
1(0.59) |
|
Body Pale |
0(0.00) |
0(0.00) |
1(0.55) |
0(0.00) |
Tab. 10 Visceral Findings - Summary
Group |
G1 |
G2 |
G3 |
G4 |
|
Dose (mg/kg body weight) |
0 |
20 |
40 |
80 |
|
No. of Litter Examined |
21 |
20 |
21 |
22 |
|
No. of Foetuses Examined |
76 |
63 |
87 |
81 |
|
Variation Incidence – Number (%) |
|||||
No. of Foetus with Variations |
Total Variations |
7(9.21) |
1(1.59) |
0(0.00) |
2(2.47) |
Ureters: Convoluted |
4(5.26) |
0(0.00) |
0(0.00) |
2(2.47) |
|
Spleen: Pale |
2(2.63) |
0(0.00) |
0(0.00) |
0(0.00) |
|
Spleen: Small in size |
1(1.32) |
1(1.59) |
0(0.00) |
0(0.00) |
Tab. 11 Skeletal Findings - Summary
Group |
G1 |
G2 |
G3 |
G4 |
|||||
Dose (mg/kg body weight) |
0 |
20 |
40 |
80 |
|||||
No. of Litter Examined |
21 |
20 |
21 |
22 |
|||||
No. of Foetuses Examined |
87 |
73 |
96 |
89 |
|||||
Variation Incidence – Number (%) |
|||||||||
Nasal |
|||||||||
Not ossified |
1(1.16) |
0(0.00) |
0(0.00) |
0(0.00) |
|||||
Premaxilla |
|||||||||
Not Ossified |
1(1.16) |
0(0.00) |
0(0.00) |
0(0.00) |
|||||
Mandible |
|||||||||
Short |
1(1.16) |
0(0.00) |
0(0.00) |
0(0.00) |
|||||
Exoccipital |
|||||||||
Not ossified |
1(1.16) |
0(0.00) |
0(0.00) |
0(0.00) |
|||||
Interparietal |
|||||||||
Incompletely ossified |
1(1.16) |
0(0.00) |
0(0.00) |
0(0.00) |
|||||
Supraoccipital |
|||||||||
Not ossified |
1(1.16) |
0(0.00) |
0(0.00) |
0(0.00) |
|||||
Hyoid |
|||||||||
Incompletely ossified |
1(1.16) |
0(0.00) |
1(1.04) |
0(0.00) |
|||||
Vertebrae - Thoracic |
|||||||||
Dumbbell shaped |
7(8.14) |
13(17.81) |
14(14.58) |
14(15.73) |
|||||
Bipartite |
2(2.33) |
0(0.00) |
2(2.08) |
5(5.62) |
|||||
Cervical |
|||||||||
Not ossified |
1(1.16) |
0(0.00) |
0(0.00) |
0(0.00) |
|||||
Caudal |
|||||||||
Not ossified |
1(1.16) |
0(0.00) |
0(0.00) |
0(0.00) |
|||||
Lumbar |
|||||||||
Dumbbell shaped |
1(1.16) |
0(0.00) |
0(0.00) |
0(0.00) |
|||||
Hemivertebra |
0(0.00) |
1(1.37) |
0(0.00) |
0(0.00) |
|||||
Misaligned |
0(0.00) |
1(1.37) |
0(0.00) |
0(0.00) |
|||||
Sacral |
|||||||||
Dumbbell shaped |
0(0.00) |
1(1.37) |
0(0.00) |
0(0.00) |
|||||
Sternal Centers |
|||||||||
Not ossified |
9(10.47) |
2(2.74) |
2(2.08) |
2(2.25) |
|||||
Manubrium |
|||||||||
Not ossified |
0(0.00) |
0(0.00) |
1(1.04) |
0(0.00) |
|||||
Xyphiod |
|||||||||
Not ossified |
6(6.98) |
2(2.74) |
4(4.17) |
1(1.12) |
|||||
Ribs (Left) |
|||||||||
Waviness |
0(0.00) |
0(0.00) |
2(2.08) |
3(3.37) |
|||||
Supernumerary |
12(13.95) |
11(15.07) |
14(14.58) |
11(12.36) |
|||||
Ribs (Right) |
|||||||||
Waviness |
0(0.00) |
1(1.37) |
2(2.08) |
5(5.62) |
|||||
Supernumerary |
11(12.79) |
11(15.07) |
11(11.46) |
12(13.48) |
|||||
Ischium (Left) |
|||||||||
Not ossified |
1(1.16) |
0(0.00) |
0(0.00) |
0(0.00) |
|||||
Ischium (Right) |
|||||||||
Not ossified |
1(1.16) |
0(0.00) |
0(0.00) |
0(0.00) |
|||||
Pubis (Left) |
|||||||||
Not ossified |
2(2.33) |
0(0.00) |
0(0.00) |
0(0.00) |
|||||
Pubis (Right) |
|||||||||
Not ossified |
1(1.16) |
0(0.00) |
0(0.00) |
0(0.00) |
|||||
Individual Macroscopic Findings Females
Group / Dose |
Dam Number |
Necropsy Findings |
|||
1/ 0 mg/kg
|
01 |
No Abnormality Detected |
|||
02 |
No Abnormality Detected |
||||
03 |
No Abnormality Detected |
||||
04 |
No Abnormality Detected |
||||
05 |
No Abnormality Detected |
||||
06 |
No Abnormality Detected |
||||
07 |
No Abnormality Detected |
||||
08 |
No Abnormality Detected |
||||
09 |
No Abnormality Detected |
||||
10 |
No Abnormality Detected |
||||
11 |
No Abnormality Detected |
||||
12 |
No Abnormality Detected |
||||
13 |
No Abnormality Detected |
||||
14 |
No Abnormality Detected |
||||
15 |
No Abnormality Detected |
||||
16 |
No Abnormality Detected |
||||
17 |
No Abnormality Detected |
||||
18 |
No Abnormality Detected |
||||
19 |
No Abnormality Detected |
||||
20 |
No Abnormality Detected |
||||
21 |
No Abnormality Detected |
||||
22 |
No Abnormality Detected |
||||
23 |
No Abnormality Detected |
||||
24 |
No Abnormality Detected |
||||
Group / Dose |
Dam Number |
Necropsy Findings |
|||
2/ 20 mg/kg
|
25 |
No Abnormality Detected |
|||
26 |
No Abnormality Detected |
||||
27 |
No Abnormality Detected |
||||
28 |
No Abnormality Detected |
||||
29 |
No Abnormality Detected |
||||
30 |
No Abnormality Detected |
||||
31 |
No Abnormality Detected |
||||
32 |
No Abnormality Detected |
||||
33 |
No Abnormality Detected |
||||
34 |
No Abnormality Detected |
||||
35 |
No Abnormality Detected |
||||
36 |
No Abnormality Detected |
||||
37 |
No Abnormality Detected |
||||
38 |
No Abnormality Detected |
||||
39 |
No Abnormality Detected |
||||
40 |
No Abnormality Detected |
||||
41 |
No Abnormality Detected |
||||
42 |
No Abnormality Detected |
||||
43 |
No Abnormality Detected |
||||
44 |
No Abnormality Detected |
||||
45 |
No Abnormality Detected |
||||
46 |
No Abnormality Detected |
||||
47 |
No Abnormality Detected |
||||
48 |
No Abnormality Detected |
||||
Group / Dose |
Dam Number |
Necropsy Findings |
|||
2/ 20 mg/kg
|
25 |
No Abnormality Detected |
|||
26 |
No Abnormality Detected |
||||
27 |
No Abnormality Detected |
||||
28 |
No Abnormality Detected |
||||
29 |
No Abnormality Detected |
||||
30 |
No Abnormality Detected |
||||
31 |
No Abnormality Detected |
||||
32 |
No Abnormality Detected |
||||
33 |
No Abnormality Detected |
||||
34 |
No Abnormality Detected |
||||
35 |
No Abnormality Detected |
||||
36 |
No Abnormality Detected |
||||
37 |
No Abnormality Detected |
||||
38 |
No Abnormality Detected |
||||
39 |
No Abnormality Detected |
||||
40 |
No Abnormality Detected |
||||
41 |
No Abnormality Detected |
||||
42 |
No Abnormality Detected |
||||
43 |
No Abnormality Detected |
||||
44 |
No Abnormality Detected |
||||
45 |
No Abnormality Detected |
||||
46 |
No Abnormality Detected |
||||
47 |
No Abnormality Detected |
||||
48 |
No Abnormality Detected |
||||
|
Group / Dose |
Dam Number |
Necropsy Findings |
||
|
5/ 120 mg/kg
|
97 |
External: |
Perineum soiled; Rigor mortis present |
|
|
Internal:
|
Urinary bladder - distended, slightly; Adrenals - enlarged, slightly; Stomach - distended moderately; Fore stomach raised whitish foci; Ulcers, slightly; Glandular stomach – reddened, slightly |
|||
|
98 |
External: |
Perineum soiled; Rigor mortis present |
||
|
Internal:
|
Urinary bladder - distended, slightly; Adrenals - enlarged, slightly; Stomach - distended moderately; Fore stomach raised whitish foci moderately; Ulcers slightly; Glandular stomach – reddened, slightly |
|||
|
99 |
External: |
Perineum soiled; Rigor mortis present |
||
|
Internal:
|
Thymus - small in size, slightly; Stomach – distended, slightly; Fore stomach raised whitish foci markedly; reddish fluid content present; Ulceration, moderately; Glandular stomach – reddened, slightly |
|||
|
100 |
External: |
Perineum soiled; Rigor mortis present |
||
|
Internal:
|
Thymus - small in size, slightly; Adrenals – enlarged, slightly; Spleen – enlarged, slightly; Stomach - distended slightly; Fore stomach raised whitish foci moderately; Ulceration, moderately; Glandular stomach – reddened, slightly |
|||
|
101 |
External: |
Perineum soiled; Rigor mortis present |
||
|
Internal:
|
Thymus - small in size, slightly; Lungs – reddened, slightly; Spleen - enlarged in size, slightly; Stomach – distended, slightly; Fore stomach raised whitish foci moderately; Ulceration, moderately; Glandular stomach – reddened, moderately |
|||
|
5/ 120 mg/kg
|
102 |
External: |
Perineum soiled; Rigor mortis present |
|
|
Internal:
|
Thymus - small in size. slightly; Stomach - distended slightly; Fore stomach raised whitish foci markedly; reddish fluid content, present; Ulceration, moderately; Glandular stomach – reddened, slightly |
|||
|
103 |
External: |
Perineum soiled; Rigor mortis present |
||
|
Internal:
|
Thymus - small in size, slightly; Adrenals – enlarged, slightly; Spleen – enlarged, slightly; Stomach – distended, slightly; Fore stomach raised whitish foci moderately; Ulceration, moderately; Mucous membrane peeled off; Glandular stomach – reddened, moderately |
|||
|
104 |
External: |
Perineum soiled; Rigor mortis present |
||
|
Internal:
|
Thymus - small in size, slightly; Adrenals - enlarged slightly; Spleen – enlarged, slightly; Stomach – distended, slightly; Fore stomach raised whitish foci moderately; Ulceration, moderately; Glandular stomach – reddened, slightly |
|||
|
105 |
External: |
Perineum soiled |
||
|
Internal:
|
Lungs reddened all lobes slightly; Autolytic changes were set in |
|||
|
106 |
External: |
Perineum soiled; Rigor mortis present |
||
|
Internal:
|
Thymus - small in size, slightly; Adrenals – enlarged, slightly; Spleen – enlarged, slightly; Stomach – distended, slightly; Fore stomach raised whitish foci markedly; Ulceration, markedly; Glandular stomach – reddened, moderately |
|||
|
5/ 120 mg/kg
|
107 |
External: |
Perineum soiled; Rigor mortis present |
|
|
Internal:
|
Thymus - small in size, slightly; Adrenals – enlarged, slightly; Spleen – enlarged, slightly; Stomach – distended, moderately; Fore stomach raised whitish foci markedly; Ulceration markedly; Mucous membrane peeled off; Glandular stomach – reddened, moderately |
|||
|
108 |
External: |
Perineum soiled |
||
|
Internal:
|
Thymus - small in size, slightly; Adrenals – enlarged, slightly; Spleen – enlarged, slightly; Stomach – distended, moderately; Fore stomach raised whitish foci markedly; Ulceration, markedly; Glandular stomach – reddened, moderately |
|||
|
109 |
External: |
Perineum soiled |
||
|
Internal:
|
Thymus - small in size, slightly; Adrenals – enlarged, slightly; Spleen – enlarged, slightly; Stomach - distended moderately; Fore stomach raised whitish foci markedly; Ulceration, markedly; Glandular stomach - reddened moderately; Autolytic changes were set in |
|||
|
110 |
External: |
Perineum soiled; Rigor mortis present |
||
|
Internal:
|
Thymus – small in size, slightly; Adrenals – enlarged, slightly; Spleen – enlarged, slightly; Stomach – distended, slightly; Fore stomach raised whitish foci moderately; Ulceration, moderately; Glandular stomach – reddened, slightly |
|||
|
5/ 120 mg/kg
|
111 |
External: |
Perineum soiled |
|
|
Internal:
|
Thymus - small in size, slightly; Adrenals – enlarged, slightly; Spleen – enlarged, slightly; Stomach – distended, moderately; Fore stomach raised whitish foci markedly; Ulceration, markedly; Glandular stomach –reddened, moderately; Autolytic changes were set in |
|||
|
112 |
External: |
Perineum soiled; Rigor mortis present |
||
|
Internal:
|
Thymus - small in size, slightly; Stomach – distended, slightly; Fore stomach raised whitish foci markedly; reddish fluid content present; Ulceration moderately; Glandular stomach – reddened, slightly |
|||
|
113 |
External: |
Perineum soiled; Rigor mortis present |
||
|
Internal:
|
Thymus - small in size, slightly; Stomach – distended, slightly; Fore stomach raised whitish foci markedly; Ulceration, moderately; Glandular stomach – reddened, slightly |
|||
|
114 |
External: |
Perineum soiled |
||
|
Internal:
|
Thymus - small in size, slightly; Adrenals - enlarged in size, slightly; Stomach - non glandular mucosa thickened slightly; raised whitish foci moderately; Ulceration slightly; Glandular stomach - reddened slightly |
|||
|
115 |
External: |
Perineum soiled; Rigor mortis present |
||
|
Internal:
|
Thymus - small in size, slightly; Stomach – distended, slightly; Fore stomach raised whitish foci markedly; Ulceration moderately; Glandular stomach - reddened slightly |
|||
|
5/ 120 mg/kg
|
116 |
External: |
Perineum soiled; Rigor mortis present |
|
|
Internal:
|
Thymus - small in size, slightly; Adrenals – enlarged, slightly; Spleen - enlarged in size, slightly; Stomach - distended moderately; Fore stomach raised whitish foci markedly; Ulceration, markedly; Glandular stomach - reddened moderately |
|||
|
117 |
External: |
Perineum soiled |
||
|
Internal:
|
Thymus - small in size, slightly; Adrenals - enlarged in size, slightly; Stomach - non glandular mucosa thickened slightly; raised whitish foci moderately; Ulceration, moderately; Glandular stomach - reddened slightly |
|||
|
118 |
External: |
Perineum soiled |
||
|
Internal:
|
Thymus - small in size, slightly; Adrenals – enlarged, slightly; Spleen – enlarged, slightly; Stomach – distended, moderately; Fore stomach raised whitish foci markedly; Ulceration, markedly; Glandular stomach - reddened moderately; Autolytic changes were set in |
|||
|
119 |
External: |
Perineum soiled; Rigor mortis present; Nostrils reddish discharge slightly |
||
|
Internal:
|
Thymus - small in size, moderately; Adrenals – enlarged, slightly; Stomach – distended, moderately; Fore stomach raised whitish foci moderately; Ulceration, moderately; Glandular & non glandular – reddened, moderately |
|||
|
120 |
External: |
Perineum soiled; Rigor mortis present; Nostrils reddish discharge slightly |
||
|
Internal:
|
Thymus - small in size, moderately; Adrenals – enlarged, slightly; Stomach – distended, moderately; Fore stomach raised whitish foci moderately; Ulceration, moderately; Glandular & non glandular – reddened, moderately |
|||
Applicant's summary and conclusion
- Conclusions:
- Pregnant females (24/dose group) were dosed by oral gavage at 0, 20, 40, 80 and 120 mg/kg bw /d solved in water as vehicle beginning at day 6 of pregnancy up to day 19 of pregnancy. On day 20 all females were sacrificed by caesarian section. Fetuses were counted, weighted, sex determined and divided in two groups by randomization. One group of fetuses was selected for visceral examination the second group was prepared for skeletal examination.
Dullness, diarrhoea, piloerection and epistaxis (two females) were observed in 24 out of 24 female animals treated at 120 mg/kg body weight (high dose). All animals of the high dose group died during day 8 to day 16 of gestation (i.e. between day 4 and day 12 of treatment). Gross pathological local findings of the decedent dams at stomach, fore-stomach and glandular stomach are considered a direct consequence of the chemical property of the test substance, namely being a cationic surfactant. These findings are:
- Stomach – distended, moderately to markedly;
- Fore stomach raised whitish foci, moderately to markedly;
- Ulceration moderately to markedly;
- Mucous membrane peeled off in some females;
- Glandular stomach – reddened, slightly to moderately.
No mortality or clinical signs of toxicity or macroscopic changes were observed in all animals dosed up to 80 mg/kg bw/d.
The evaluation of the reproductive organs of all dams dosed up to 80 mg/kg bw/d, pre- and post-implantation loss, gravid uterine weight, litter size, viability of the fetuses, foetus weight per litter and foetus weight, sex ratio of the fetuses and the external, visceral and skeletal examination of the fetuses revealed that HYEQS did not produce any malformations and no maternal or embryo-fetal toxicity up to the dose of 80 mg/kg body weight. Hence, under the present experimental conditions, HYEQS is not a teratogen. - Executive summary:
Pregnant females (24/dose group) were dosed by oral gavage at 0, 20, 40, 80 and 120 mg/kg bw /d solved in water as vehicle beginning at day 6 of pregnancy up to day 19 of pregnancy. On day 20 all females were sacrificed by caesarian section. Fetuses were counted, weighted, sex determined and divided in two groups by randomization. One group of fetuses was selected for visceral examination the second group was prepared for skeletal examination.
Dullness, diarrhoea, piloerection and epistaxis (two females) were observed in 24 out of 24 female animals treated at 120 mg/kg body weight (high dose). All animals of the high dose group died during day 8 to day 16 of gestation (i.e. between day 4 and day 12 of treatment). Gross pathological local findings at stomach, forestomach and glandular stomach are considered a direct consequence of the chemical property of the test substance. No mortality or clinical signs of toxicity were observed in all animals dosed up to 80 mg/kg bw/d.
The evaluation of the reproductive organs of the dams, pre- and post-implantation loss, gravid uterine weight, litter size, viability of the foetuses, foetus weight per litter and foetus weight, sex ratio of the foetuses and the external, visceral and skeletal examination of the foetuses revealed that HYEQS did not produce any malformations and no maternal or embryo-fetal toxicity up to the dose of 80 mg/kg bw/d. Hence, under the present experimental conditions HYEQS is not a teratogen.
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