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EC number: 936-831-9 | CAS number: -
- 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
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 022
- Report date:
- 2022
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: OECD 421 (Reproduction/Developmental Toxicity Screening Test)
- Version / remarks:
- 29 July 2016
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- (9-acetoxy-3,8,10-triethyl-7,8,10-trimethyl-1,5-dioxa-9-azaspiro[5.5]undec-3-yl)methyl palmitate
- Molecular formula:
- C36 H67 N O6
- IUPAC Name:
- (9-acetoxy-3,8,10-triethyl-7,8,10-trimethyl-1,5-dioxa-9-azaspiro[5.5]undec-3-yl)methyl palmitate
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Envigo RMS srl, San Pietro al Natisone (UD), Italy.
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 9 to 10 weeks old
- Weight at study initiation: 200 to 225 g for males and 175 to 200 g for females
- Housing:
The animals were housed in a limited access rodent facility. From arrival to pairing, animals were housed up to 5 of one sex to a cage, in polysulfone solid bottomed cages measuring 59.5×38×20 cm (Tecniplast Gazzada S.a.r.l., Buguggiate,Varese). Nesting material was provided inside suitable bedding bags and changed at least twice a week.
During mating, animals were housed one male to one female in clear polysulfone cages measuring 42.5×26.6×18.5 cm with a stainless steel mesh lid and floor (Tecniplast Gazzada S.a.r.l., Buguggiate, Varese). Each cage tray held absorbent material which was inspected and changed daily.
After mating, the males were re-caged as they were before mating.
The females were transferred to individual solid bottomed cages for the gestation period, birth and lactation (measuring 42.5×26.6×18.5 cm). Nesting material was provided inside suitable bedding bags. In addition, suitable nesting material (Scobis 0 Mucedola) was provided as necessary and changed at least 2 times a week.
- Diet (e.g. ad libitum): ad libitum (laboratory rodent diet (4 RF 21,Mucedola S.r.l., Via G. Galilei, 4,
20019, SettimoMilanese (MI), Italy)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C±2°C
- Humidity (%): 55%±15%
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 01.03.2021 To: 14.04.2021
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The required amount of test item was suspended in the vehicle. The preparations were made daily at concentration of 25, 75 and 250 mg/mL, unless specified otherwise based on stability data stated in the validation study (section 3.4). Concentrations were calculated and expressed in terms of test item as supplied.
VEHICLE
- Amount of vehicle (if gavage): 4 ml/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis was performed in a separate study in order to validate the analytical method and the preparation procedure and to verify the stability of the preparations (ERBC Study no. A4158). The analysis confirmed a 11 days stability at room temperature in the range from 25 to 250 mg/mL.
Samples of the preparations prepared during the current study (the first and the last week of treatment where possible) were analysed to check the homogeneity and concentration.
Chemical analysis was carried out by the Analytical Chemistry Department at ERBC. The validated software used for this activity was Analyst 1.6.2. Results of the analyseswere within the acceptability limits stated in ERBC SOPs for concentration of suspension (85-115%), - Details on mating procedure:
- - M/F ratio per cage: 1:1 (one exception since one low dose male was found dead before the start of the mating phase)
- Length of cohabitation: until positive identification occured
- Proof of pregnancy: vaginal plug / sperm in vaginal smear
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): The females were transferred to individual solid bottomed cages for the gestation period, birth and lactation (measuring 42.5×26.6×18.5 cm). Nesting material was provided inside suitable bedding bags. In addition, suitable nesting material (Scobis 0 Mucedola) was provided as necessary and changed at least 2 times a week. - Duration of treatment / exposure:
- - Males: at least 28 days. The duration of treatment covered a minimum of 2 consecutive weeks prior to pairing and thereafter through the day before necropsy.
- Females: up to 60 days. The duration of treatment covered a minimum of 2 consecutive weeks prior to pairing and thereafter during pairing, post coitum and post partum periods until Day 13 post partum or the day before sacrifice. - Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Remarks:
- Test group 1 (Control)
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Remarks:
- Test group 2
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Remarks:
- Test group 3
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- Remarks:
- Test group 4
- No. of animals per sex per dose:
- 10 animals per sex per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Dose levels have been selected in consultation with the Sponsor based on information from previous studies.
In a previous repeated-dose toxicity study (OECD 407) with a structural similar substance the NOAEL was considered to be 1000 mg/kg/day
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Mortality: Throughout the study, all animals were checked early in each working day in the morning and in the afternoon. At weekends and Public Holidays a similar procedure was followed except that the final check was carried out at approximately mid-day.
- Clinical observations: Once before commencement of treatment and at least once daily during the study, each animal was observed and any clinical signs recorded. Observations were performed at the same time interval each day, the interval was selected taking into consideration the presence of post-dose reactions. All observations were recorded for individual animals.
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: once a week
- Males: weekly from allocation to termination.
- Females: at weekly interval from allocation, where possible, to positive identification of mating and on Days 0, 7, 14 and 20 post coitum.
- Dams were weighed on Days 1, 4, 7 and 13 post partum and just prior to necropsy.
FOOD CONSUMPTION: Yes
- Time schedule: weekly during the pre-mating period, starting Day 1 of dosing up to mating.
- Individual food consumption for the females were measured on Days 7, 14 and 20 post coitum starting from Day 0 post coitum and on Days 7 and 13 post partum starting from Day 1 post partum
WATER CONSUMPTION (if drinking water study): No
CLINICAL BIOCHEMISTRY: Yes
- Anaesthetic used for blood collection (for hormone determination) : Yes (Isoflurane)
- How many animals: all parental males and females/ Pups: from each litter (1 sample for males and 1 sample for females)
- Parameter checked: T4, TSH (serum)
REPRODUCTIVE PERFORMANCE
- Mating: 1:1 (with one exception since one low dose male was found dead before the start of the mating phase)
- Parturition and gestation length: A parturition check was performed from Day 20 to Day 25 post coitum. Females which did not give birth after 25 days of post coitum period were sacrificed shortly after. Gestation length was calculated as the time between the day of successful mating (Day 0 post coitum) and the day of birth. The day of birth (when parturition was complete) was defined as Day 0 post partum. On gestation Day 22, one female (Group 3) gave birth to 8 dead pups. The delivery was not completed since the day after (Day 23 post coitum) a total of 11 pups, 8 dead and 3 alive, were counted in the cage and the dam was found dead. At necrospy, additional 3 dead foetuses were recorded in the uterus. - 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 total resorptions: Yes
- Number of early/late resorptions: No - Blood sampling:
- - Plasma: No
- Serum: Yes
- Volume collected: approximately 0.8 mL - Fetal examinations:
- - External examinations: Yes, all pups
- Soft tissue examinations: necropsy observations macroscopically
- Skeletal examinations: No
- Head examinations: No
- Sex ratio: Yes
- Pup body weight data: Yes
- Pup clinical observations. Yes - Statistics:
- Standard deviations were calculated as appropriate. For continuous variables, the significance of the differences amongst group means was assessed by Dunnett’s test or a modified t test, depending on the homogeneity of data. Statistical analysis of histopathological findings was carried out by means of the non-parametric Kolmogorov Smirnov test. The non-parametric Kruskal-Wallis analysis of variance (non-continuous variables) was used for the other parameters. Intergroup differences between the control and treated groups were assessed by the non-parametric version of theWilliams test. The criterion for statistical significance was p < 0.05. The mean values, standard deviations and statistical analysis were calculated from actual values in the computer without rounding off.
- Indices:
- Prenatal loss (%) = (no.of visible implantations − live litter size at birth) / no.of visible implantations x 100
Postnatal loss at Day 4 post partum (%) = (Live litter size at birth - live litter size at Day 4 (before culling)/ Live litter size at birth x 100
Postnatal loss at Day 13 post partum (%) = (Live litter size on Day 4 (after culling) - Live litter size on Day 13)/ Live litter size on Day 4 (after culling) x 100
Pup loss at Day 0 post partum (%) = (Total litter size - Live litter size)/ Total litter size x 100
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related clinical signs were recorded in females before pairing. During gestation, signs of difficulty to delivery were recorded in one female at 100 mg/kg/day.
No treatment-related clinical signs were recorded during post partum phase. - Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- On gestation day 22, one female at 100 mg/kg/day was sacrificed following the occurrence of important clinical signs like prolapse of the uterus, pallor, piloerection and coldness to touch. The presence of these signs was related to difficulty in delivery.
One female at 300 mg/kg/day was found dead on gestation day 23. This female gave birth 8 pups on gestation day 22 (found dead) and additional 3 live pups were found in the cage on Day 23 post coitum. Both females had a prolonged time of gestation without completing the parturition and the impaired delivery was the reason of the humane sacrifice for the low dose female (100 mg/kg/day) and the occurrence of premature death for the mid-dose female (300 mg/kg/day). The gross and microscopic evaluation did not allow to establish the cause of impaired parturition. However, since these findings occurred in single animals, they could be considered unrelated to treatment. - Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- 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:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- There were no treatment-related changes in terminal body weight when compared to controls.
Statistically significant increase in absolute and relative mean liver weight for high dose females (23% of mean relative weight) was noted and correlated microscopically with centrilobular hepatocellular hypertrophy. This was considered treatment-relatd.
Any organ weight changes were within the range of occasionally
observed and expected spontaneous changes in rats of the same age and considered unrelated to treatment.
Table included under "Any other information on results incl. tables". - Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no treatment-related macroscopic observations at the end of the treatment period. Any macroscopic observations had a comparable incidence in control and treated groups and/or are characteristically seen in untreated rats of the same age and were considered incidental and unrelated to treatment.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Microscopic observations associated with the oral administration of the test item were present in the liver of high dose females.
- In the liver, treatment-related microscopic observations consisted in centrilobular hepatocellular hypertrophy of
minimal to mild severity was present in most females (7/10) at the high dose. Hepatocyte hypertrophy
consisted of enlarged hepatocytes containing variable amounts of fine granular pale eosinophilic (ground glass) cytoplasm.
- Any other microscopic observation had a comparable incidence in control and treated groups and/or are characteristically seen in untreated rats of the same age and were considered incidental and unrelated to treatment.
Maternal developmental toxicity
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- The number of implantation sites did not show significant differences between groups as well as the pre-natal loss.
- Total litter losses by resorption:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Two females, one control and one at 100 mg/kg/day lost the litter on Day 0 post partum
- Early or late resorptions:
- not examined
- Dead fetuses:
- effects observed, non-treatment-related
- Description (incidence and severity):
- On gestation Day 22, one female (no. 51 of Group 3) gave birth to 8 dead pups. The delivery was not completed since the day after (Day 23 post coitum) a total of 11 pups, 8 dead and 3 alive, were counted in the cage and the dam was found dead. At necrospy, additional 3 dead foetuses were recorded in the uterus.
- Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- The gestation length was similar in all groups.
- Changes in number of pregnant:
- effects observed, non-treatment-related
- Description (incidence and severity):
- – 8/10 in the control group (0 mg/kg/day)
– 8/9 in the low dose group (100 mg/kg/day)
– 8/9 in the mid-dose group (300 mg/kg/day)
– 9/10 in the high dose group (1000 mg/kg/day)
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- organ weights and organ / body weight ratios
- Remarks on result:
- other: effect level based on females.
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Anogenital distance of all rodent fetuses:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The anogenital distance (normalized to the cube root of the body weigh on Day 1 post partum) did not differ in male pups of treated groups when compared to controls whereas it was significantly increased in females of all treated groups (up to 28%, respect to the control group).
Although a dose relation was evident, the statistical differences were not considered of toxicological significance but rather due to unexpected lower control, being all values in the range of the historical control data (HCD). Table included under "Any other information on results incl. tables". - External malformations:
- effects observed, non-treatment-related
- Skeletal malformations:
- not examined
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Clinical signs:
The observation of pups did not reveal treatment-related findings. Pale or small appearance, the presence of wound in the muzzle, not opened eye, or tip of tail missing were seen as single occurrences regardless the treatment groups. No nipple/aerola was recorded in any male pup.
Necropsy:
Findings at necropsy included the absence of milk in the stomach from pups sacrificed for humane kill. All autolysed organs were frequently found in decedent pups. The necropsy of culled pups (Day 4 post partum) and those sacrificed at termination (Day 14 post partum) did not show treatment-related changes.
Organ weight:
No significant changes were seen in thyroid weight from male and female pups of treated groups compared to controls.
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effects observed
Fetal abnormalities
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Developmental effects observed:
- no
Any other information on results incl. tables
Table 1: Parental liver weights
| Males | HCD | Females | HCD | |||||||
Dose level (mg/kg/day) | Control | 100 | 300 | 1000 |
| Control | 100 | 300 | 1000 |
| |
Liver | Abs. weight (g) | 12.282 | 14.248* | 14.946* | 16.092* | 14.52 | 12.234 | 12.608 | 13.924 | 15.227* | 11.29 |
Rel. weight (g) | 2.798 | 3.210* | 3.350* | 3.636* | 3.65 | 3.955 | 4.221 | 4.534 | 4.854* | 3.83 | |
* = Statistical significant from control at p<0.05 |
Table 2: Thyroid hormone measurements in male and female pups
Pups Day14 Post Partum_Males (Group mean data) | |||||
| Group | ||||
Parameter/units | 1 | 2 | 3 | 4 | |
Thyroxine nmol/L | Mean SD N | 54.9 10.1 7 | 52.3 6.5 7 | 52.5 6.9 8 | 53.3 2.8 9 |
Thyroid Stimulating Hormone ng/mL | Mean SD N | 3.80 0.65 7 | 3.60 0.68 7 | 3.83 0.72 8 | 3.67 0.85 9 |
Controls from group(s): 1 Subgroup(s): 1 * = mean value of group is significantly different from control at p < 0.05 + = mean value of group is significantly different from control at p < 0.01 | |||||
Pups Day14 Post Partum_Females (Group mean data) | |||||
| Group | ||||
Parameter/units | 1 | 2 | 3 | 4 | |
Thyroxine nmol/L | Mean SD N | 56.0 7.6 7 | 55.3 10.5 7 | 55.6 8.9 8 | 54.8 8.0 9 |
Thyroid Stimulating Hormone ng/mL | Mean SD N | 3.54 0.53 7 | 3.71 0.53 7 | 4.33 0.89 8 | 3.67 0.76 9 |
Controls from group(s): 1 Subgroup(s): 1 * = mean value of group is significantly different from control at p < 0.05 + = mean value of group is significantly different from control at p < 0.01 |
Table 3 Anogenital distance
Females_ANOGENITAL DISTANCE ON DAY 1 POST PARTUM – GROUP MEAN DATA | |||||
Anogenital Distance (normalized) mmg/g1/3)^ | |||||
| Group | ||||
| 1 | 2 | 3 | 4 | HCD |
Mean SD N | 1.07 0.12 7 | 1.28* 0.17 7 | 1.33* 0.12 8 | 1.37* 0.05 9 | 1.39
|
^ = normalised to the cube root of the body weight collected on Day 1 post partum (mm/g) Statistical analysis: Kruskall Wallis test T test if group mean differences are different from control at p < 0.05 * = mean value of group is significantly different from control | |||||
Males_ANOGENITAL DISTANCE ON DAY 1 POST PARTUM – GROUP MEAN DATA | |||||
Anogenital Distance (normalized) mmg/g1/3)^ | |||||
| Group | ||||
| 1 | 2 | 3 | 4 | HCD |
Mean SD N | 2.52 0.16 7 | 2.50 0.10 7 | 2.62 0.18 8 | 2.47 0.17 9 | 2.06
|
^ = normalised to the cube root of the body weight collected on Day 1 post partum (mm/g) Statistical analysis: Kruskall Wallis test T test if group mean differences are different from control at p < 0.05 * = mean value of group is significantly different from control |
Table 4 Historical Control Data of the Anogenital distance
Anogenital Distance- Historical Control Data | |||||
| Mean mmg/g1/3 | Max mmg/g1/3 | Min mmg/g1/3 | N |
|
AGD (mmg/g1/3) Male Pups | 2.06 | 2.96 | 1.05 | 183 | Pups |
AGD (mmg/g1/3) Female Pups | 1.39 | 8.19 | 0.55 | 155 | Pups |
Average study | |||||
AVG_study AGD (mmg/g1/3) Male Pups | 2.05 | 2.26 | 1.94 | 3 | studies |
AVG_study AGD (mmg/g1/3) Male Pups | 1.35 | 1.85 | 0.93 | 3 | studies |
Applicant's summary and conclusion
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.