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EC number: 293-878-1 | CAS number: 91648-19-0
- 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:
- Experimental start and completion dates: 14 November 2017 to 14 December 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- ECHA have agreed that a developmental toxicity study can be conduced with 1-Propanaminium, N-(3-aminopropyl)-2-hydroxy-N,N-dimethyl-3-sulfo-, N-C8 18 acyl derivs., hydroxides, inner salts. The end point will be addressed for the target substance 1-Propanaminium, N-(3-aminopropyl)-2-hydroxy-N,N-dimethyl-3-sulfo-, N-C12-14 acyl derivs., hydroxides, inner salts by reading across from this study.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 999
- Report date:
- 2019
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- OECD Guidelines for Testing Chemicals, No. 414, Prenatal Developmental Toxicity Study, 22 January 2001
- Deviations:
- yes
- Remarks:
- Randomisation was made in SPSS and not in Provantis, as indicated in the Study Plan. No impact on the results or study integrity.
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 1-Propanaminium, N-(3-aminopropyl)-2-hydroxy-N,N-dimethyl-3-sulfo-, N-(C8-18(even numbered) acyl) derivs., hydroxides, inner salts
- EC Number:
- 939-455-3
- Molecular formula:
- Molecular formula, SMILES notation, InChl and Structural formula cannot be given as the substance is a UVCB.
- IUPAC Name:
- 1-Propanaminium, N-(3-aminopropyl)-2-hydroxy-N,N-dimethyl-3-sulfo-, N-(C8-18(even numbered) acyl) derivs., hydroxides, inner salts
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source: Solvay Novecare
- Lot/batch number of test material: UP6C10X10
- Appearance: Clear liquid
- Expiration date of the lot/batch: 11 March 2018
- Purity (sultaine content): 35.4%, Correction factor: 2.82
- Purity test date: Not stated
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature (15-25°C, below 70 RH%) protected from light
- Stability under storage conditions: Stable
- Stability under test conditions: Stable for the duration of the study.
- Solubility and stability of the test substance in the vehicle: Stability in the vehicle proven for at least 21 days when stored at room temperature (20±5°C).
- Reactivity of the test substance with the vehicle (if applicable): None
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Formulated in distilled water at appropriate test concentrations
FORM AS APPLIED IN THE TEST (if different from that of starting material)
Formulated in distilled water at appropriate test concentrations
TYPE OF BIOCIDE/PESTICIDE FORMULATION (if applicable)
OTHER SPECIFICS
- measurement of pH, osmolality, and precipitate in the culture medium to which the test chemical is added: Test item pH (as received): 8.4
Test animals
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- Hannover Wistar rats (Crl:WI(Han))
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH (Sandhofer Weg 7, D-97633 Sulzfeld, Germany) from SPF colony
- Age at study initiation: Young adult female rats at least 12 weeks old at mating.
- Weight at study initiation: 200-260g (the variation did not exceed ± 20% of the mean weight at Gestation Day 0)
- Fasting period before study: Not stated
- Housing: Individual housing, Type III polycarbonate cages used during acclimatisation, Type II polycarbonate cages used during mating and gestation period
were used during the acclimatisation period.
- Diet (ad libitum): sniff® SM Autoclavable Complete Diet for Rats/Mice, Breeding and Maintenance (Ssniff Spezialdiäten GmbH, D-59494 Soest, Germany)
- Water (ad libitum): Tap water (in water bottles) as for human consumption
- Acclimation period: At least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.4 to 24.8°C (target: 22 ± 3°C)
- Humidity (%): 30-56% (target: 30-70%)
- Air changes (per hr): 15-20/hr
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6.00 a.m. to 6.00 p.m.
IN-LIFE DATES: From: To: 14 November 2017 (first mating) to 14 December 2017 (last necropsy)
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- Distilled
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Formulated in the vehicle (distilled water) at appropriate concentrations according to the dose level and volume selected. Proven stability in the vehicle (within the concentration range used) for at least 21 days when stored at room temperature (20±5°C).
VEHICLE
- Concentration in vehicle: 13.3, 40 and 120 mg/mL (dose levels selected based on a dose range finding study)
- Amount of vehicle (if gavage): 5 mL/kg
- Lot/batch no. 8130917
- Supplier: Hungaro-Gal Kft.
- Expiry date: 4 March 2018
- Storage conditions: Room temperature - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis of test item formulations for concentration was performed at the test site using a validated LC-MS method. Representative samples were taken from the test item formulations two times during the study (during the first and last week of treatment). Samples were taken in duplicate (5 mL/each), one set to analyse and one set as a back-up, if required for any confirmatory analyses. Similarly, duplicate samples were taken from the middle of the vehicle control formulation for concentration measurement.
Formulation samples were kept at room temperature until shipment. Samples (both sets) were shipped as soon as possible after collection for concentration measurement to the Principal Investigator. The validated analytical method (FPBSTUDY-172-VAL1-REPORT-01; CiToxLAB Hungary Ltd. study code: 17/133-901AN) was used for the determination of the test item content in the vehicle
All test item formulations were within the range of 94.8-104.1% of nominal concentration. No test item was detected in the vehicle control samples. Based on these results, test item formulations were considered suitable for the study purposes. - Details on mating procedure:
- - Impregnation procedure: Cohoused
- M/F ratio per cage: 1 male : 1 female
- Length of cohabitation: Approximately 2-3 hours until at least 24 sperm positivefemales/group were attained
- Further matings after two unsuccessful attempts: Not stated
- Verification of same strain and source of both sexes: Yes, Hannover Wistar rats (CRLHan) sourced from Charles River Laboratories, Research Models and Services, Germany GmbH (Sandhofer Weg 7, D-97633, Sulzfeld, Germany) from SPF colony
- Proof of pregnancy: The presence of a vaginal plug or sperm in the vaginal smear was considered as evidence of copulation (gestation day 0, GD 0). Sperm positive females were separated and caged individually - Duration of treatment / exposure:
- The control or test item dose formulations were administered to mated female rats daily by oral gavage on a 7 days/week basis, at approximately similar times, from gestation day 6 to 19 (GD 19)
- Frequency of treatment:
- Daily treatment from gestation day 6 to gestation day 19
- Duration of test:
- 20 days (Gestation day 0, no treatment on gestation days 0 to 5, daily dosing from gestation day 6 to 19 (treatment period) , necropsy on day 20)
Doses / concentrationsopen allclose all
- Dose / conc.:
- 66.7 mg/kg bw/day (nominal)
- Dose / conc.:
- 200 mg/kg bw/day (nominal)
- Dose / conc.:
- 600 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 24 mated females: Control (0)
26 mated females: Low dose - 66.7 mg/kg bw/day
26 mated females: Mid dose - 200 mg/kg bw/day
27 mated females: High dose - 600 mg/kg bw/day - Control animals:
- yes, concurrent vehicle
- Details on study design:
- Dose selection rationale: Dose levels were selected based on the available information of the chemical nature and characteristics of the test item and available results from a non-pregnant dose range finding study and developmental toxicity screening test. Based on these results, 600 mg/kg bw/day was selected as high dose.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Cage-side (general) clinical observations were made twice daily (at the beginning and end of each working day). Animals were inspected for signs of morbidity and mortality twice daily (at the beginning and end of each working day).
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: One general clinical observation was made on the first day (p.m.), on the afternoon on those days when detailed clinical observation was made in the morning. Additional general clinical observations were made for confirmatory reason on November 30, post dose, when an animal was found dead. Detailed clinical observation were made only once on necropsy days (a.m).
Detailed clinical observations were made on all animals at the onset of treatment (GD 6) then weekly. On GD 13 and/or 14, the sperm positive females were examined for the presence of vaginal bleeding or “placental sign” (intrauterine extravasation of blood as an early sign of pregnancy in rat, which was considered to confirm implantation).
BODY WEIGHT: Yes
- Time schedule for examinations: Body weight of each animal was recorded with precision on gestation day 0, 3, 6, 8, 10, 12, 14, 16, 18 and 20, or on the day of death (or when found dead).
FOOD CONSUMPTION
Food was measured with precision on gestation day 0, 3, 6, 8, 10, 12, 14, 16, 18 and 20. Food consumption was also calculated for each interval, including gestation day 0-6, 6-20 and 0-20
WATER CONSUMPTION: No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20. Caesarean section and necropsy with macroscopic examination was performed on gestation day 20.
- Organs/ Tissues examined: The dams’ viscera were examined macroscopically for any structural abnormalities or pathological changes. Overies and uterus. Placentas were examined macroscopically.
Each foetus was subjected to external examination, plus an additional examination of the great arteries. The gender of foetuses was determined
Approximately half of each litter was subjected to visceral examination, the other half processed for skeletal examination.
For the foetuses subjected to visceral examination, the abdominal and thoracic region was opened, and the thymus and great arteries examined.
For the foetuses subjected to skeletal examination, the abdominal region was opened,and the viscera and skin of foetuses removed, the cadaver was then fixed and stained.
All abnormalities (external, soft tissue and skeletal malformations, and variations) found during the foetal examinations were recorded. - 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 - 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:
- Data were collected using the software PROVANTIS v.9 (maternal data, Caesarean section and necropsy data), or were recorded on the appropriate forms from the relevant SOPs of Citoxlab Hungary Ltd. (foetal evaluation data) then tabulated with PROVANTIS v.9 or Microsoft Office Excel 2010.
The statistical evaluation of data was performed with the program package SAS v9.2 in case of Provantis v.9, or SPSS PC+4.0 (SPSS Hungary Kft, Budapest) in the case of data tabulated in Excel, by an appropriate statistical method. - Indices:
- In accordance with OECD 414 observed effects were evaluated to record all (raw) numbers used in calculating all percentages or indices
- Historical control data:
- Historical Control Data of Hannover Wistar Rats (CRL:WI(HAN)) was provided for:
Summary of Foetal Body Weight Data
Summary of External Foetal Examinations
Summary of Visceral Foetal Examinations
Summary of Skeletal Foetal Examinations
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Noisy respiration was observed in 3/23 animals in the low, 12/24 animals in the mid, and 20/25 animals in the high dose group. Piloerection was present in 10/24 animals in the mid, and all animals of the high dose group. One animal (number 4505) in the high dose showed the clinical signs of noisy or slight to moderate laboured respiration, hunched back, slightly decreased activity, red discharge around the vulva and the nose. The increased presence of noisy respiration and piloerection indicates a test item related effect and is consistent with reported signs from other gavage studies with this test item. This surfactant substance, in very small amounts, can cause local effects if there is a slight reflux from the stomach, or if test item on the gavage tube contaminates the upper oesophageal area, with some substance contaminating the upper respiratory tract. All the other symptoms were attributed as secondary to the respiratory effects. The clinical signs were considered to be caused by a local effect, not a systemic toxicity effect. Animals in the Control group were symptom free.
Clear maternal toxicity was obseved at 600 mg/kg bw/day, with clinical signs associated with a local respiratory effect, signs of stomach irritation, and lower food intake and bodyweight than controls (Average body weight on GD 20 was Ca.13% below control). In the mid dose group noisy respiration and piloerection was observed in almost half of the animals, the group had a transient lower food intake. It was concluded that slight maternal toxicity was observed at the mid dose with no adverse effect on body weight. A few animals in the low dose had respiratory effects with no consequences, this was not considered to reflect a significant maternal toxicity for the group as a whole. - Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Two high dose animals were found dead. Deaths were attributed to the strong surfactant properties of the test Item entering the upper respiratory tract as noted by the rapid onset of symptoms. It was considered likely that a small amount of test Item entered the upper respiratory tract. The deaths were not attributed to systemic toxicity of the test item.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Statistically significant body weight reduction was observed at 600 mg/kg bw/day) from GD 8 to the end of the treatment. These changes resulted in a statistically significant reduction of body weight gain, corrected body weight gain and net body weight gain values during the treatment period (GD 6-20) and the entire study (GD 0-20) when compared to the control values. GD 20 mean body weight was 13% below the control mean value, confirming an adverse maternal effect of test item.
At 200 mg/kg bw/day there was a slight but statistically significantly lower body weight gain (p<0.05) for the treatment period (GD 6-20) but no relevant statistical difference for the entire study period or for the individual weighing days. The differences seen in the Mid dose were not considered to be a clearly adverse effect of treatment.
No test item related effect on body weight was observed at 66.7 mg/kg bw/day when compared to control. Similarly, no statistically significant or biologically relevant differences were seen in the body weight gain or corrected body weight gain or net body weight gain values during the treatment period (GD 6-20) or entire study (GD 0-20) compared to the control value for this group. - Food efficiency:
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Description (incidence and severity):
- Only pertinent behavioural changes were recorded in line with guidance requirements
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- At 600 mg/kg bw/day, 12/25 animals presented diffuse or multifocal thickening of the non-glandular mucosal region of the stomach. These effects are considered to be test item related, local adverse effects, probably an irritant effect in the stomach. No macroscopic findings were observed in the control or lower treatment groups.
In the two high dose animals found dead, non-collapsed lungs were the common finding. In one animal, dark red discoloration was observed in all lung lobes (multifocal), in the stomach (in the glandular mucosa), and in the thymus. These findings are considered to be agonal changes. In one animal, multifocal thickness of the non-glandular mucosal region of the stomach was observed, which is consistent with macroscopic findings in the evaluated high dose animals. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
Maternal developmental toxicity
- Number of abortions:
- not examined
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- effects observed, non-treatment-related
- Description (incidence and severity):
- One dead foetus was present in the 200 mg/kg bw/day dose group. None were observed in either the control, low or high (66.7 or 600 mg/kg bw/day) dose groups.
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Details on maternal toxic effects:
- Clear maternal toxicity was observed at 600 mg/kg bw/day with clinical signs associated with a local respiratory effect, signs of stomach irritation, and lower food intake and bodyweight than controls. At 200 mg/kg bw/day fewer clinical signs were observed in less animals with a transient lower food intake. It was concluded that there was a slight maternal toxicity at 200 mg/kg bw/day with no adverse effect on body weight. A few animals at 66.7 mg/kg bw/day had respiratory effects with no consequences and was not considered to reflect a significant maternal toxicity.
The total number of retarded foetuses was statistical significant at 600 mg/kg bw/day, and was associated with maternal toxicity. A small increased incidence of retarded ossification at 600 mg/kg bw/day was also considered to be compatible with the observed maternal toxicity.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 66.7 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- food consumption and compound intake
- gross pathology
Maternal abnormalities
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- A statistically significantly increase of unossified or incomplete ossification in the 600 mg/kg bw/day litter correlates with the reduced foetal body weight. This is compatible with maternal toxicity with reduced body weight in the high dose.
- Reduction in number of live offspring:
- not examined
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
Effect levels (fetuses)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- Teratogenicity
- Effect level:
- >= 600 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: Based on the lack of any developmental effects in any treatment group.
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- Embryotoxicity
- Effect level:
- >= 600 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: Based on the lack of any test-item related intrauterine effect in any treatment group.
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- Foetotoxicity
- Effect level:
- >= 600 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: Based on the lack of any adverse developmental effects in any treatment group.
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
- Treatment related:
- no
Any other information on results incl. tables
Table 1. Summary of pregnancy data
Parameters
| Dose (mg/kg bw/day)
| |||
| 0 | 66.7 | 200 | 600 |
Number of mated females | 24 | 26 | 26 | 27 |
Pre-terminal death or euthanasia | 0 | 0 | 0 | 2 |
Number of non-pregnant females | 1 | 3 | 2 | 0 |
Number of females with ≤ 5 implantation sites | 0 | 0 | 1 | 0 |
Number of evaluated females on GD20 (Caesarean section) | 23 | 23 | 24 | 25 |
Table 2. Summary of the intrauterine evaluation
Parameters | Dose (mg/kg bw/day) | stats. | |||
0 | 66.7 | 200 | 600 | ||
Number of evaluated dams | 23 | 23 | 24 | 25 | NS |
Mean number of corpora lutea | 12.04 | 11.78 | 11.67 | 11.24 | NS |
Preimplantation loss, mean | 1.04 | 1.70 | 1.75 | 1.24 | NS |
Preimplantation loss (%), mean | 8.79 | 14.09 | 15.25 | 10.60 | NS |
Mean number of implantations | 11.0 | 10.09 | 9.92 | 10.0 | NS |
Early embryonic loss, mean | 0.17 | 0.26 | 0.17 | 0.20 | NS |
Early embryonic loss (%), mean | 1.48 | 2.25 | 2.25 | 2.15 | NS |
Late embryonic loss, mean | 0.22 | 0.00 | 0.13 | 0.08 | NS |
Late embryonic loss (%), mean | 1.80 | 0.00 | 1.50 | 0.73 | NS |
Dead foetuses, mean | 0.00 | 0.00 | 0.04 | 0.00 | NS |
Dead foetuses (%), mean | 0.00 | 0.00 | 0.38 | 0.00 | NS |
Post-implantation loss, mean | 0.00 | 0.26 | 0.33 | 0.28 | NS |
Post-implantation loss (%), mean | 3.28 | 2.55 | 4.14 | 2.89 | NS |
Total intrauterine mortality, mean | 1.43 | 1.96 | 2.08 | 1.52 | NS |
Total intrauterine mortality (%), mean | 11.97 | 16.34 | 18.36 | 13.35 | NS |
Viable foetuses, mean | 10.61 | 9.83 | 9.58 | 9.72 | NS |
Notes: Most important parameters are shown in bold.
NS: Statistically not significant when compared to the vehicle control.
Table 3. Examination of viable foetuses
Parameters | Dose (mg/kg bw/day) | Stats. | |||
0 | 66.7 | 200 | 600 | ||
Number of examined litters | 23 | 23 | 24 | 25 | NS |
Viable foetuses, mean | 10.61 | 9.83 | 9.58 | 9.72 | NS |
Male foetuses, mean | 5.13 | 4.91 | 4.71 | 5.24 | NS |
Female foetuses, mean | 5.48 | 4.91 | 4.88 | 4.48 | NS |
Total number of foetuses | 244 | 226 | 230 | 243 | NS |
Total number of male foetuses | 118 | 113 | 113 | 131 | NS |
Total number of female foetuses | 126 | 113 | 117 | 112 | NS |
Sex distribution (% of males / females) | 49/51 | 50/50 | 50/50 | 53/47 | NS |
Mean foetal weight / litter (g) | 3.43 | 3.49 | 3.51 | 3.45 | NS |
Number of foetuses with retarded body weight | 10 | 17 | 12 | 33** | NS |
Number of affected litters (with runts) | 8 | 8 | 6 | 11 | NS |
Notes: Most important parameters are shown in bold.
NS: Statistically not significant when compared to the vehicle control.
CH2: Chi Square test; **= p<0.01
Table 4. Summary table of the external abnormalities
Parameters | Dose (mg/kg bw/day) | HC data | |||
0 | 66.7 | 200 | 600 | ||
Total number of examined litters | 23 | 23 | 24 | 25 | 670 |
Total number of examined foetuses | 244 | 226 | 230 | 243 | 6889 |
Total number of intact (normal) foetuses | 244 | 226 | 230 | 243 | -- |
HC: historical control
Table 5. Summary table of the visceral abnormalities
Parameters | Dose (mg/kg bw/day) | HC data | |||
0 | 66.7 | 200 | 600 | ||
Total number of examined litters | 23 | 23 | 24 | 25 | 670 |
Total number of examined foetuses | 121 | 114 | 115 | 121 | 3450 |
Total number of intact (normal) foetuses | 116 | 108 | 109 | 121* | -- |
Total number of foetuses / litters with malformation | 1/1 | 0/0 | 2/2 | 0/0 | -- |
Total number of foetuses / litters with variation | 4/4 | 6/6 | 4/3 | 0/0* | -- |
Notes: Numbers represent the number of abnormalities / number of affected litters.
HC: historical control
*= p<0.05; Chi Square test
Table 6. Details of the visceral abnormalities
Parameters | Dose (mg/kg bw/day) | HC data | |||||
0 | 66.7 | 200 | 600 | ||||
Total number of examined litters | 23 | 23 | 24 | 25 | 670 | ||
Total number of examined foetuses | 121 | 114 | 115 | 121 | 3450 | ||
Visceral malformations | |||||||
Kidney, misshapen (Small) | litter incidence | n | 1 | 0 | 0 | 0 | 1 |
% | 4.3 | 0.0 | 0.0 | 0.0 | 0.149 | ||
Foetal incidence | n | 1 | 0 | 0 | 0 | 1 | |
% | 0.826 | 0.000 | 0.000 | 0.000 | 0.029 | ||
Abnormal Lung Lobes | litter incidence | n | 0 | 0 | 1 | 0 | 1 |
% | 0.0 | 0.0 | 4.2 | 0.0 | 0.149 | ||
Foetal incidence | n | 0 | 0 | 1 | 0 | 1 | |
% | 0.000 | 0.000 | 0.870 | 0.000 | 0.029 | ||
Testis, malpositioned | litter incidence | n | 0 | 0 | 1 | 0 | -- |
% | 0.0 | 0.0 | 4.2 | 0.0 | -- | ||
Foetal incidence | n | 0 | 0 | 1 | 0 | -- | |
% | 0.000 | 0.000 | 0.870 | 0.000 | -- | ||
Visceral variations | |||||||
Brachiocephalic trunk, short | litter incidence | n | 2 | 1 | 0 | 0 | 45 |
% | 8.7 | 4.3 | 0.0 | 0.0 | 6.7 | ||
Foetal incidence | n | 2 | 1 | 0 | 0 | 53 | |
% | 1.653 | 0.877 | 0.000 | 0.000 | 1.536 | ||
Renal papilla, absent | litter incidence | n | 0 | 0 | 1 | 0 | -- |
% | 0.0 | 0.0 | 4.2 | 0.0 | -- | ||
Foetal incidence | n | 0 | 0 | 1 | 0 | -- | |
% | 0.000 | 0.000 | 0.870 | 0.000 | -- | ||
Renal pelvis, dilated | litter incidence | n | 0 | 0 | 1 | 0 | -- |
% | 0.0 | 0.0 | 4.2 | 0.0 | -- | ||
Foetal incidence | n | 0 | 0 | 1 | 0 | -- | |
% | 0.000 | 0.000 | 0.870 | 0.000 | -- | ||
Carotid artery, malpositioned | litter incidence | n | 0 | 0 | 1 | 0 | 1 |
% | 0.0 | 0.0 | 4.2 | 0.0 | 0.149 | ||
Foetal incidence | n | 0 | 0 | 1 | 0 | 1 | |
% | 0.000 | 0.000 | 0.870 | 0.000 | 0.029 |
Notes: Numbers represent the number (n) or ratio (%) of abnormalities.
HC: historical control (data provided where considered useful)
No statistically significant differences were noted compared to the control group.
Parameters | Dose (mg/kg bw/day) | HC data | |||||
0 | 66.7 | 200 | 600 | ||||
Total number of examined litters | 23 | 23 | 24 | 25 | 670 | ||
Total number of examined foetuses | 121 | 114 | 115 | 121 | 3450 | ||
Visceral variations | |||||||
Kidney, malpositioned | litter incidence | n | 0 | 1 | 0 | 0 | 1 |
% | 0.0 | 4.3 | 0.0 | 0.0 | 0.149 | ||
Foetal incidence | n | 0 | 1 | 0 | 0 | 1 | |
% | 0.000 | 0.877 | 0.000 | 0.000 | 0.029 | ||
Adrenal gland, malpositioned | litter incidence | n | 0 | 1 | 0 | 0 | 1 |
% | 0.0 | 4.3 | 0.0 | 0.0 | 0.149 | ||
Foetal incidence | n | 0 | 1 | 0 | 0 | 1 | |
% | 0.000 | 0.877 | 0.000 | 0.000 | 0.029 | ||
Ureter convoluted | litter incidence | n | 0 | 0 | 1 | 0 | 7 |
% | 0.000 | 0.000 | 4.167 | 0.000 | 1.045 | ||
Foetal incidence | n | 0 | 0 | 1 | 0 | 7 | |
% | 0.000 | 0.000 | 0.870 | 0.000 | 0.203 | ||
Thymic cord | litter incidence | n | 0 | 3 | 1 | 0 | 69 |
% | 0.000 | 13.043 | 4.167 | 0.000 | 10.299 | ||
Foetal incidence | n | 0 | 3 | 3 | 0 | 82 | |
% | 0.000 | 2.632 | 1.739 | 0.000 | 2.377 | ||
Renal papilla, small | litter incidence | n | 2 | 1 | 0 | 0 | 20 |
% | 8.7 | 4.3 | 0.0 | 0.0 | 2.985 | ||
Foetal incidence | n | 2 | 1 | 0 | 0 | 22 | |
% | 1.653 | 0.877 | 0.000 | 0.000 | 0.638 |
Notes: Numbers represent the number (n) or ratio (%) of abnormalities.
HC: historical control (data provided where considered useful)
No statistically significant differences were noted compared to the control group.
Table 7. Summary table of the skeletal abnormalities
Parameters | Dose (mg/kg bw/day) | HC data | |||
0 | 66.7 | 200 | 600 | ||
Total number of examined litters | 23 | 23 | 24 | 25 | 669 |
Total number of examined foetuses | 123 | 112 | 115 | 122 | 3435 |
Total number of intact (normal) foetuses | 111 | 93 | 98 | 90 CH** | -- |
Total number of foetuses / litters with malformation | 2/2 | 0/0 | 1/1 | 1/1 | -- |
Total number of foetuses / litters with variation | 10/7 | 19CH*/11 | 16/9 | 31CH/15 | -- |
Notes: Numbers represent the number of abnormalities / number of affected litters.
HC: historical control
CH: Chi2 test; * = p < 0.05 ** = p < 0.01
Table 8. Details of the skeletal abnormalities
Parameters | Dose (mg/kg bw/day) | HC data | |||||
0 | 66.7 | 200 | 600 | ||||
Total number of examined litters | 23 | 23 | 24 | 25 | 669 | ||
Total number of examined foetuses | 123 | 112 | 115 | 122 | 3435 | ||
Skeletal malformations | |||||||
Malformed Vertebrae (Split, Fused) | litter incidence | n | 0 | 0 | 1 | 0 | 3 |
% | 0.0 | 0.0 | 4.2 | 0.0 | 0.448 | ||
Foetal incidence | n | 0 | 0 | 1 | 0 | 3 | |
% | 0.000 | 0.000 | 0.870 | 0.000 | 0.087 | ||
Rib, Fused | litter incidence | n | 0 | 0 | 0 | 1 | -- |
% | 0.000 | 0.000 | 0.000 | 4.000 | -- | ||
Foetal incidence | n | 0 | 0 | 0 | 1 | -- | |
% | 0.000 | 0.000 | 0.000 | 0.820 | -- | ||
Transverse process fused; Pelvic girdle, malpositioned# | litter incidence | n | 2 | 0 | 0 | 0 | 6 |
% | 8.696 | 0.000 | 0.000 | 0.000 | 0.897 | ||
Foetal incidence | n | 2 | 0 | 0 | 0 | 6 | |
% | 1.626 | 0.000 | 0.000 | 0.000 | 0.175 |
Notes: Numbers represent the number (n) or ratio (%) of abnormalities.
HC: historical control (data provided where considered useful)
No statistically significant differences were noted compared to the control group.
#: Historical control database contains Transverse processes, fused
Table 8. Details of the skeletal abnormalities (continued)
Parameters | Dose (mg/kg bw/day) | HC data | |||||
0 | 66.7 | 200 | 600 | ||||
Total number of examined litters | 23 | 23 | 24 | 25 | 669 | ||
Total number of examined foetuses | 123 | 112 | 115 | 122 | 3435 | ||
Skeletal malformations | |||||||
Skull: 3 or More Bones, Incomplete Ossification | litter incidence | n | 1 | 3 | 1 | 4 | 123 |
% | 4.3 | 13.0 | 4.2 | 16.0 | 18.358 | ||
Foetal incidence | n | 1 | 5 | 1 | 5 | 153 | |
% | 0.813 | 4.464 | 0.870 | 4.098 | 4.454 | ||
Skull: Hyoid, body, unossified | litter incidence | n | 0 | 1 | 0 | 1 | -- |
% | 0.000 | 4.348 | 0.000 | 4.000 | -- | ||
Foetal incidence | n | 0 | 1 | 0 | 3 | -- | |
% | 0.000 | 0.893 | 0.000 | 2.459 | -- | ||
Sternum: Ossified Sternebra (4 or less) # | litter incidence | n | 5 | 5 | 5 | 9 | 269 |
% | 21.7 | 21.7 | 20.8 | 36.0 | 40.2 | ||
Foetal incidence | n | 5 | 7 | 10 | 18CH** | 385 | |
% | 4.065 | 6.250 | 8.696 | 14.554 | 11.208 | ||
Ribs: Wavy | litter incidence | n | 2 | 6 | 2 | 7 | 198 |
% | 8.7 | 26.1 | 8.3 | 28.0 | 29.596 | ||
Foetal incidence | n | 3 | 10CH* | 3 | 11CH* | 311 | |
% | 2.439 | 8.929 | 2.609 | 9.016 | 5.054 | ||
Ribs: Rib or Cartilage Interrupted | litter incidence | n | 1 | 0 | 0 | 2 | 4 |
% | 4.348 | 0.000 | 0.000 | 8.000 | 0.598 | ||
Foetal incidence | n | 1 | 0 | 0 | 2 | 6 | |
% | 0.813 | 0.000 | 0.000 | 1.639 | 0.175 | ||
Vertebrae: 2 or More Dumbbell or Asymmetric Ossification | litter incidence | n | 0 | 1 | 1 | 1 | 85 |
% | 0.000 | 4.348 | 4.167 | 4.000 | 12.706 | ||
Foetal incidence | n | 0 | 1 | 2 | 1 | 92 | |
% | 0.000 | 0.893 | 1.739 | 0.820 | 2.697 | ||
Vertebrae: Sacral Unossified | litter incidence | n | 0 | 0 | 1 | 0 | -- |
% | 0.000 | 0.000 | 4.167 | 0.000 | -- | ||
Foetal incidence | n | 0 | 0 | 1 | 0 | -- | |
% | 0.000 | 0.000 | 0.870 | 0.000 | -- | ||
Bipartite Ossification | litter incidence | n | 0 | 0 | 2 | 0 | 27 |
% | 0.000 | 0.000 | 8.333 | 0.000 | 4.036 | ||
Foetal incidence | n | 0 | 0 | 2 | 0 | 27 | |
% | 0.000 | 0.000 | 1.739 | 0.000 | 0.786 | ||
Pubis unossified | litter incidence | n | 0 | 0 | 1 | 1 | 6 |
% | 0.000 | 0.000 | 4.167 | 4.000 | 0.897 | ||
Foetal incidence | n | 0 | 0 | 1 | 1 | 6 | |
% | 0.000 | 0.000 | 0.870 | 0.820 | 0.175 | ||
Limbs (C/T): Tarsal ≤3 | litter incidence | n | 1 | 1 | 1 | 1 | 34 |
% | 4.348 | 4.348 | 4.167 | 4.000 | 5.082 | ||
Foetal incidence | n | 1 | 1 | 2 | 1 | 49 | |
% | 0.813 | 0.893 | 1.739 | 0.820 | 1.426 |
Notes: Numbers represent the number (n) or ratio (%) of abnormalities.
HC: historical control (data provided where considered useful)
#: Ossified sternebra (3 or less) is recorded in the historical control database
CH: Chi2 test; * = p < 0.05; ** = p < 0.01
Table 9. Summary of Bodyweight Data
Female |
| Day(s) Relative to Start Date | |||||||||
0 | 3 | 6 | 8 | 10 | 12 | 14 | 16 | 18 | 20 | ||
0 | Mean | 221.6 R | 230.3 R | 242.6 R | 248.4 | 254.6 | 265.7 | 273.6 | 286.0 | 308.8 | 334.6 |
66.7 mg/kg bw/day | Mean | 221.3 | 232.0 | 241.8 | 245.9 | 252.1 | 259.8 | 269.4 | 281.5 | 303.3 | 328.5 |
200 mg/kg bw/day | Mean | 222.8 | 232.7 | 244.2 | 246.4 | 251.3 | 257.8 | 266.1 | 278.8 | 298.1 | 321.3 |
600 mg/kg bw/day | Mean | 222.1 | 231.1 | 240.6 | 233.8uu | 235.7dd | 242.8dd | 250.1dd | 260.9dd | 272.1dd | 290.8dd |
Statistical Test: Citoxlab DT Transformation: Automatic
Comments and Markers
Measurement Group Sex Day Marker Comment
Bodyweight. 1CG Female 0 R Automatic Transformation: Rank
Bodyweight. 1CG Female 3 R Automatic Transformation: Rank
Bodyweight. 1CG Female 6 R Automatic Transformation: Rank
Bodyweight. 1CG Female 8 R,kk Automatic Transformation: Rank, (All Groups) Test: Kruskal-Wallis p < 0.01
Bodyweight. 1CG Female 10 I,aa Automatic Transformation: Identity (No Transformation), (All Groups) Test: Analysis of Variance p < 0.01
Bodyweight. 1CG Female 12 I,aa Automatic Transformation: Identity (No Transformation), (All Groups) Test: Analysis of Variance p < 0.01
Bodyweight. 1CG Female 14 I,aa Automatic Transformation: Identity (No Transformation), (All Groups) Test: Analysis of Variance p < 0.01
Bodyweight. 4HDG Female 8 uu Test: Dunn 2 Sided p < 0.01
Bodyweight. 4HDG Female 10 dd Test: Dunnett 2 Sided p < 0.01
Bodyweight. 4HDG Female 12 dd Test: Dunnett 2 Sided p < 0.01
Bodyweight. 4HDG Female 14 dd Test: Dunnett 2 Sided p < 0.01
Bodyweight. 1CG Female 16 I,aa Automatic Transformation: Identity (No Transformation), (All Groups) Test: Analysis of Variance p < 0.01
Bodyweight. 1CG Female 18 I,aa Automatic Transformation: Identity (No Transformation), (All Groups) Test: Analysis of Variance p < 0.01
Bodyweight. 1CG Female 20 I,aa Automatic Transformation: Identity (No Transformation), (All Groups) Test: Analysis of Variance p < 0.01
Bodyweight. 4HDG Female 16 dd Test: Dunnett 2 Sided p < 0.01
Bodyweight. 4HDG Female 18 dd Test: Dunnett 2 Sided p < 0.01
Bodyweight. 4HDG Female 20 dd Test: Dunnett 2 Sided p < 0.01
Table 10. Selected body weight parameters
Parameters | Dose (mg/kg bw/day) | Stats. | |||
0 | 66.7 | 200 | 600 | ||
Number of evaluated dams | 23 | 23 | 24 | 25 | - |
Body weight on GD20 (g) | 334.6 | 328.5 | 321.3 | 290.8** | D |
Body weight gain GD6-20 (g) | 92.0 | 86.7 | 77.1* | 50.2** | D |
Body weight gain GD0-20 (g) | 113.0 | 107.1 | 98.5 | 68.7** | U |
Corrected body weight on GD20 (g) | 271.2 | 269.0 | 262.4 | 237.0** | U |
Corrected body weight gain GD0-20 (g) | 49.6 | 47.6 | 39.6 | 14.9** | U |
Net body weight gain GD6-20 (g) | 28.6 | 27.1 | 18.2* | -3.6** | U |
Notes: Body weight data were rounded to one decimal place. Corrected and net weight / weight gains refer to body weight values minus the weight of the gravid uterus.
*= p<0.05; **= p<0.01; D: Dunnett two sided test.; U: Dunn two sided test
Applicant's summary and conclusion
- Conclusions:
- C8-18 alkylamidopropyl hydroxysultaine, when administered daily by oral gavage to pregnant Hannover Wistar rats from gestation days 6 to 19 at 600 mg/kg bw/day induced maternal toxicity, with clinical signs associated with a local respiratory effect, reduced food intake, reduced body weight and body weight gain, and thickening of the non-glandular mucosal region of the stomach. All maternal changes at 600 mg/kg bw/day were compatible with being related to local irritancy of the test item, with no evidence of any direct systemic toxicity. The 200 mg/kg bw/day had lesser signs with no adverse effect on body weight, there was evidence of slight maternal toxicity. A few animals at 66.7 mg/kg bw/day had respiratory effects with no consequences, this was not considered to reflect a significant maternal toxicity.
At 600 mg/kg bw/day, the incidence of runts was higher, and the incidence of retarded ossification were statistically higher compared to the control group; these observations were attributed to maternal toxicity. Theese effects were not evident at lower dose groups. There were no malformations or developmental effects attributed to test item at any dose level.
The following no-observed-adverse-effect (NOAEL) levels were derived:
NOAELmaternal toxicity: 66.7 mg/kg bw/day, based on significant maternal effects at 600 mg/kg bw/day and clinical signs of local effects at 200 mg/kg bw/day. The maternal effects were all attributed to local effects, there was no evidence of direct systemic toxicity in any group.
NOAELembryotoxicity: 600 mg/kg bw/day, based on the lack of any test-item related intrauterine effect in any treatment group.
NOAELfoetotoxicity: 600 mg/kg bw/day, based on the lack of any adverse developmental effects in any treatment group.
NOAELteratogenecity: 600 mg/kg bw/day, based on the lack of any developmental effects in any treatment group. - Executive summary:
A developmental toxicity study was performed to assess the effects of the test item C8-18 alkylamidopropyl hydroxysultaine on the embryonic and foetal development (inclusive of organogenesis period) of Hannover Wistar rats in their first pregnancy. The study was perfomed in accordence with OECD 414. The dams (one control and three test item treated groups) were treated daily by oral (gavage) at a dose volume of 5 mL/kg bw from gestation day 6 up to and including gestation day 19. Control dams were treated with the vehicle (distilled water). Caesarean sections, necropsy of dams and examination of uterine contents were performed on gestation day 20. Doses were selected based on available information of the test item chemical nature and characteristics and available results froma a dose range finding study and developmental toxicity screening test. Doses of 66.7, 200 and 600 mg/kg bw/day were selected based overt toxicity at 800 mg/kg bw/day in previous testing. Test item formulations were analysed for concentration twice during the treatment period using LC-MS. Simultaneously, vehicle control formulations were analysed. Parameters monitored included mortality and clinical observations, body weight, body weight gain and individual food consumption. Maternal reproductive parameters associated with uterine examination were evaluated, and the foetuses were weighed and examined for external, visceral and skeletal abnormalities. Placentas were examined macroscopically. The number of confirmed pregnant, evaluated dams was 23 in both the control and 66.7 mg/kg bw/day groups, 24 at 200 mg/kg bw/day and 25 at 600 mg/kg bw/day) dose groups, respectively. No histopathology evaluation was performed.
Based on the above the following no-observed-adverse-effect (NOAEL) levels were derived:
NOAELmaternal toxicity: 66.7 mg/kg bw/day, based on significant maternal effects at 600 mg/kg bw/day and clinical signs of local effects at 200 mg/kg bw/day. The maternal effects were all attributed to local effects, there was no evidence of direct systemic toxicity in any group.
NOAELembryotoxicity: 600 mg/kg bw/day, based on the lack of any test-item related intrauterine effect in any treatment group.
NOAELfoetotoxicity: 600 mg/kg bw/day, based on the lack of any adverse developmental effects in any treatment group.
NOAELteratogenecity: 600 mg/kg bw/day, based on the lack of any developmental effects in any treatment group.
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