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EC number: 258-004-5 | CAS number: 52556-42-0
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 16.11.2012 - 03.05.2013
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
- Report date:
- 2013
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Sodium 3-(allyloxy)-2-hydroxypropanesulphonate
- EC Number:
- 258-004-5
- EC Name:
- Sodium 3-(allyloxy)-2-hydroxypropanesulphonate
- Cas Number:
- 52556-42-0
- Molecular formula:
- C6H12O5S.Na
- IUPAC Name:
- sodium 2-hydroxy-3-(prop-2-en-1-yloxy)propane-1-sulfonate
- Reference substance name:
- Sodium hydroxide
- EC Number:
- 215-185-5
- EC Name:
- Sodium hydroxide
- Cas Number:
- 1310-73-2
- Molecular formula:
- HNaO
- IUPAC Name:
- sodium hydroxide
- Reference substance name:
- 3-(allyloxy)propane-1,2-diol
- EC Number:
- 204-620-4
- EC Name:
- 3-(allyloxy)propane-1,2-diol
- Cas Number:
- 123-34-2
- Molecular formula:
- C6H12O3
- IUPAC Name:
- 3-(allyloxy)propane-1,2-diol
- Reference substance name:
- disodium 2-hydroxy-3-(3-sulfonatopropoxy)propane-1-sulfonate
- Molecular formula:
- C6H12Na2O8S2
- IUPAC Name:
- disodium 2-hydroxy-3-(3-sulfonatopropoxy)propane-1-sulfonate
- Test material form:
- solid - liquid: aqueous solution
- Details on test material:
- light yellow liquid
Constituent 1
additive 1
impurity 1
impurity 2
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: charls River, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: 10 - 11 weeks
- Weight at study initiation: 274 - 309 g (males); 174 - 199 g (females)
- Fasting period before study: no
- Housing: males in groups of three, females individual
- Diet : Mainenance diet for rats and mice, No. 1324 TPF, ad libitum
- Water : sterilised community tap water, ad libitum
- Acclimation period: 9-10 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 3 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 h/12h
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test item has been delivered as a 35,2% aqueous solution and a relative density of 1,17 g/cm3. Dosing referred to the effective content of the active ingredient (HAPS). The raw solution also contained 3,7% NaOH increasing the pH up to 13,2, causing severe corrosive effects during application. Thus, the composition was neutralised to a pH of 7 with concentrated HCl. For preparation of the application solutions the neutralised test solution was diluted with autoclaved community tap water. The test item preparation was intended for an application volume of 4 ml per kg body weight.
All material data sheets were stored with the raw data. - Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: up to 14 deays
- 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: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- Males were dosed daily for 42 to 57 days, including the day before the scheduled termination of the in-life phase. This included two weeks of dosing prior to mating and continued throughout the mating period until approximately four weeks post-mating. Females were dosed two weeks prior to mating, covering at least twocomplete oestrous cycles, the variable time to conception, the duration of pregnancy and at least four days after delivery, up to and including the day before scheduled termination of the in-life phase. Therefore the duration of the study following acclimatisation depended on the female performance and was at least 47 days: 14 days pre-mating, up to 14 days until mating, an average of 21 days of gestation, and between 8 and 14 days of lactation.
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Dose / conc.:
- 62.5 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 12
- Control animals:
- yes
- Positive control:
- no
Examinations
- Parental animals: Observations and examinations:
- 1. Viability / fatalities Daily
2. General clinical signs / behaviour Daily
3. Body weight Once weekly (including once before beginning
of application)
4. Group/Individual food consumption Once weekly (including once before beginning
of application)
5. Group/Individual water consumption Once weekly (including once before beginning
of application) - Oestrous cyclicity (parental animals):
- yes
- Sperm parameters (parental animals):
- yes
- Litter observations:
- yes
- Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals
- Maternal animals: All surviving animals
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera
HISTOPATHOLOGY / ORGAN WEIGHTS
Tissues [ovaries, testes, epididymis of the highest dose group and the control group] were prepared for microscopic examination and weighed, respectively. - Postmortem examinations (offspring):
- - External examinations: Yes: all per litter
- Skeletal examinations: Yes - Statistics:
- Statistical Analysis
Spread sheet calculations were performed using Microsoft® Excel® 2011 for Mac.
Food- and water consumption of male animals were documented sorted by experimental groups, whereas the body weight was documented for each animal individually. Body weight, food- and water consumption, litter size and litter weight were documented for each female animal individually.
Descriptive statistics
The arithmetic mean, standard deviation and median were calculated for all grouped numerical data originating from monitoring the body weight, food- and water consumption, organ weights (gross pathology) and litter size and weight (for details see appendix). Where appropriate, detailed column statistics were applied (minimum / maximum data, 25% quantiles, standard error, upper and lower confidence interval 95%).
Inductive statistics
If appropriate, the respective test item groups were compared to the vehicle group by assessing statistical significance using a two-tailed unpaired Student´s t-test. For allcalculations, the significance level was set to 0,05. - Reproductive indices:
- examination of reproductive organs
- Offspring viability indices:
- bodyweight
sex ratio
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Mild discomfort throughout the whole application period was observed for the male animals treated with the high dose of the test item (wiping of nose and mouth through the cage bedding, salivation after application, bleeding of mucous membranes at nose and mouth, respiratory sounds). Due to the solely appearance of the symptoms in the animals treated with the high dose of the test item, it could be estimated with high probability that the test item induced slight irritating effects after application of the highest concentration. Hence, a test item related effect could not be excluded.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Due to the high incidence and the exclusive occurrence within the animals treated with the high dose, a test item related effect could not be excluded. Death could be a result of reflux after gavage dosing leading to an accidental aspiration of dose formulation. Even very small
amounts of irritant test formulations can result in life-threatening respiratory symptoms and death. - Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No significant differences were observed between all test item treated male animals and the vehicle control animals. Generally, no signs for a direct test item related effect on the body weight of the female animals could be observed during the first two exposure weeks. Nonetheless, a test item related effect at a later time point could be masked by the variances in body weight resulting from the different number of females achieving pregnancy per dose group.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- No significant differences in food consumption could be observed for all test item treated animals throughout the whole in-life phase. Individual fluctuations were most likely effects of natural origin. On the contrary, an increased water intake of all animals (male and female) treated with the highest dose of the test item could be observed throughout the whole in-life phase when compared to their respective vehicle control animals. Additionally, single fluctuations were observed for the male animals of the medium dose group.
In summary, no significant differences in food consumption could be observed for the test item treated animals throughout the whole in-life phase. Individual fluctuations were most likely effects of natural origin. - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Summarised, an increased water intake of all animals (male and female) treated with the highest dose of the test item could be observed throughout the whole in-life phase when compared to their respective vehicle control animals. Additionally, single fluctuations were observed for the male animals of the medium dose group.
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- A minimal to slight ovarian hypertrophy/hyperplasia characterised by the presence of many, partly cystic corpora lutea, several tertiary follicles and an increase in the number of interstitial cells was noted in the female animals treated with the high dose of the test item. Although these findings could be due to the infertile state and estrus cycle of the ovaries, a relationship to the treatment with the test item could not excluded.
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Description (incidence and severity):
- Effects of the spermatogenesis may not have had an adequate time to become evident (such as reduced sperm counts affecting the fertility), as chemical exposure did not cover a complete cycle of spermatogenesis in male test animals.
- Reproductive performance:
- effects observed, treatment-related
- Description (incidence and severity):
- Regarding the reproduction and developmental parameters gathered in this study, the test item prevented or significantly reduced the achievement of pregnancy in all tested dose levels. The presence of corpora lutea after first pairing indicated that an implantation of the zygote took place but embryonic development did not occur or was aborted during the first days of gestation. The absence of corpora lutea after second pairing then indicated that, with prolonged dosing the implantation of the zygote or the ovarian maturation were impaired by the test item. Nonetheless, based on the results of the study a specific physiological cause of the toxic effect could not be identified.
Effect levels (P0)
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- ca. 62.5 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: lack of achieving pregnancy
Target system / organ toxicity (P0)
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 62.5 mg/kg bw/day (nominal)
- System:
- female reproductive system
- Organ:
- ovary
- uterus
- Treatment related:
- yes
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Histopathological findings:
- not examined
- Other effects:
- no effects observed
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not examined
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Details on results (F1)
Effect levels (F1)
- Key result
- Dose descriptor:
- LOAEL
- Generation:
- F1
- Effect level:
- 65.2 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- yes
- Lowest effective dose / conc.:
- 62.5 mg/kg bw/day (nominal)
- Treatment related:
- yes
- Relation to other toxic effects:
- reproductive effects in the absence of other toxic effects
- Dose response relationship:
- not specified
Applicant's summary and conclusion
- Conclusions:
- A daily oral administration of the test item Sodium 3-(allyloxy)-2- hydroxypropanesulphonate (HAPS) to male Wistar rats at dose levels of 62,5 mg, 250 mg and 1000 mg/kg body weight over a time period of 42 to 57 days did not produce any pathological evidence for toxic effects on the reproduction performance of male rats.
However, effects of the spermatogenesis may not have had an adequate time to become evident (such as reduced sperm counts affecting the fertility), as chemical exposure did not cover a complete cycle of spermatogenesis in male test animals. Therefore, and due to the lack of pregnancies in the
test item treated female animals, an effect of the test item on the spermatogenesis could not be excluded.
The study has shown that a daily oral administration of the test item at a dosage of 250 mg/kg body weight results in a prevention of pregnancies in female Wistar rats. At a dosage of 62,5 mg/kg, this effect was still apparent in the majority of the animals of this group. Five of 12 animals were able to achieve pregnancy but only 2 of these animals had a normal litter size and development. Hence, a daily oral administration of the test item to female Wistar rats at dose levels above 62,5 mg/kg body weight over a time period of 47 to 76 days produced severe pathological evidence for toxic effects on the reproductionv performanceof female rats regarding the achievement of pregnancy, litter size and survival rate of pups. It must therefore be assumed that the NOAEL regarding reproduction and development of the test item is significantly below the herein used lowest dose of 62,5 mg/kg. - Executive summary:
In the present study toxic effects of the test item Sodium 3-(allyloxy)-2- hydroxypropanesulphonate (HAPS) at a maximum dose of 1000 mg/kg body weight on the development and reproduction of Wistar rats after oral administration were under examination.
General clinical signs
Mild discomfort throughout the whole application period was observed for the male animals treated with the high dose of the test item (wiping of nose and mouth through the cage bedding, salivation after application, bleeding of mucous membranes at nose and mouth, respiratory sounds). Due to the solely appearance of the symptoms in the animals treated with the high dose of the test item, it could be estimated with high probability that the test item induced slight irritating effects after application of the highest concentration. Hence, a test item related effect could not be excluded.
Body weight, food and water consumption
No significant differences were observed between all test item treated male animals and the vehicle control animals. Generally, no signs for a direct test item related effect on the body weight of the female animals could be observed during the first two exposure weeks. Nonetheless, a test item related effect at a later time point could be masked by the variances in body weight resulting from the different number of females achieving pregnancy per dose group.
No significant differences in food consumption could be observed for all test item treated animals throughout the whole in-life phase. Individual fluctuations were most likely effects of natural origin. On the contrary, an increased water intake of all animals (male and female) phase when compared to their respective vehicle control animals. Additionally, single fluctuations were observed for the male animals of the medium dose group.
Necropsy
No test item related prevalent findings were observed during necropsy, neither for male nor for female animals. None of the irregular findings detected at the necropsy could be related to the administration of the test item. They were regarded to be spontaneous in nature.
Histology
The ovaries, testes, and epididymis from a total of 51 adult rats (high dose: 10 male/ 6 female; satellite group: 11 female; vehicle control: 12 male/ 12 female) and all other organs showing macroscopic lesions were examined histopathologically. The morphology of the ovaries of the infertile treated females of the high dose group (including animals of the satellite group) was slightly different from those examined in the dams of the vehicle control group. In the main, a minimal to slight ovarian hypertrophy/hyperplasia characterised by the presence of many, partly cystic corpora lutea, several tertiary follicles and an increase in the number of interstitial cells was noted in the treated females. These findings may be due to the infertile state and estrus cycle of the ovaries. However, a relationship to the treatment with the test item could not excluded. All other microscopic findings recorded in the reproductive organs (epididymides, testes, ovaries, uterus horn and some other macroscopic alterations) of the examined animals were considered to be due to the actual estrus cycle or were spontaneous in nature. These findings were within the normal background pathology commonly seen in rats of this age. The differences noted were regarded as random events. After consultation with the Sponsor, an examination of the medium and low dose animals was not performed.
Reproduction and Development
Regarding the reproduction and developmental parameters gathered in this study, the test item prevented or significantly reduced the achievement of pregnancy in all tested dose levels. The presence of corpora lutea after first pairing indicated that an implantation of the zygote took place but embryonic development did not occur or was aborted during the first days of gestation. The absence of corpora lutea after second pairing then indicated that, with prolonged dosing the implantation of the zygote or the ovarian maturation were impaired by the test item. Nonetheless, based on the results of the study a specific physiological cause of the toxic effect could not be identified.
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