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EC number: 219-154-7 | CAS number: 2374-14-3
- 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:
- one-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2001
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 002
- Report date:
- 2002
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 2,4,6-trimethyl-2,4,6-tris(3,3,3-trifluoropropyl)cyclotrisiloxane
- EC Number:
- 219-154-7
- EC Name:
- 2,4,6-trimethyl-2,4,6-tris(3,3,3-trifluoropropyl)cyclotrisiloxane
- Cas Number:
- 2374-14-3
- Molecular formula:
- C12H21F9O3Si3
- IUPAC Name:
- 2,4,6-trimethyl-2,4,6-tris(3,3,3-trifluoropropyl)cyclotrisiloxane
- Reference substance name:
- 2, 4, 6-trimethyl-2, 4, 6-tris(3, 3, 3-trifluoropropyl)cyclotrisiloxane
- IUPAC Name:
- 2, 4, 6-trimethyl-2, 4, 6-tris(3, 3, 3-trifluoropropyl)cyclotrisiloxane
Constituent 1
Constituent 2
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD(SD)IGS BR
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Source: Charles River Laboratories, NC
- Age at study initiation: 6 to 7 weeks
- Weight at study initiation: Males 183 - 251g Females 146 - 194g
- Fasting period before study: No
- Housing: individually in wire mesh cages, females in plastic maternity cages with nesting material following positive evidence of mating
- Diet: Certified Rodent Lab Diet 5002, PMI Nutrition Inc., ad libitum
- Water: Reverse osmosis treated on-site drinking water ad libitum
- Acclimation period: 17 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.3 - 22.9
- Humidity (%): 31.5 - 59.1
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: To: 27 October 2000 to 3 March 2001
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: sesame oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: prepared weekly by weighing appropriate amount of test article and adding sufficient vehicle
VEHICLE
- Concentration in vehicle: 0, 0.4, 2, 10, 25/17.5 mg/mL
- Amount of vehicle: 2mL/kg - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: until positive evidence of mating or up to 14 days
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- Further matings after two unsuccessful attempts: no, after 14 days with no evidence of mating, female placed in plastic cage with nesting material
- After successful mating each pregnant female was caged: individually in plastic cage with nesting material - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Homogeneity and stability established before start of study.
Weekly for first 4 weeks then monthly analysis of formulations for test article concentration during the study - Duration of treatment / exposure:
- Administration for minimum of 70 days prior to mating.
Males dosed throughout mating and until scheduled necropsy.
Females dosed throughout mating, gestation and until lactation day 20. - Frequency of treatment:
- Once daily
- Details on study schedule:
- - Age at mating of the mated animals in the study: approximately 17 weeks
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 0.8 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 4 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 20 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 50 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 35 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: not stated
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: males weekly, females weekly until positive evidence of mating then gestation days 0, 4, 7, 11, 14 and 20 and lactation days 1, 4, 7, 14 and 21
FOOD CONSUMPTION: Yes
- Time schedule for examinations: males weekly, females weekly until positive evidence of mating then gestation days 0, 4, 7, 11, 14 and 20 and lactation days 1, 4, 7, 14 and 21
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/animal/day and g food/kg body weight/day: Yes
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No - Oestrous cyclicity (parental animals):
- Vaginal smears were prepared daily to determine the stage of the estrous cycle beginning 14 days prior to pairing and continuing until evidence of mating was observed. For females with no evidence of mating, smearing continued until the end of the mating period. The average length was calculated for complete estrous cycles (i.e. total number of returns to metestrous (M) or diestrous (D) from estrous (E) or proestrous (P). Estrous cycle length was determined by counting the number of days from the first M or D in a cycle to the first M or D in the next cycle.
- Sperm parameters (parental animals):
- Parameters examined in P male parental generations:
right testis weight, right epididymis weight, sperm motility (CASA) sperm morphology (light microscopy).
left testis and epididymis weighed and homogenized - evaluated for homogenization resistant spermatid count and sperm production rate (CASA) - Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- Maximum of 8 pups/litter (4/sex/litter when possible); excess pups were killed and discarded.
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, nipple retention (males)
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals following completion of mating period
- Maternal animals: All surviving animals on lactation day 21
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS
Males - epididymides (total and cauda), pituitary, prostate, seminal vesicles with coagulating glands and testes were weighed.
Males - coagulating glands, pituitary, prostate, seminal vesicles, testes with epididymides and vas deferens and gross lesions were preserved for possible future examination.
Females - no organs weighed
Females - gross abnormalities retained for possible future examination
Females that did not deliver or with total litter loss - if evidence of macroscopic implantation then number of implantation sites and corpora lutea recorded. If no evidence of implantation then uteri placed in 10% ammonium sulfide solution for detection of early implantation loss. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring were sacrificed on post-natal day 21
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera. Gross findings retained for possible future examination. - Statistics:
- All analyses were conducted using two-tailed tests except as noted.
The litter was used as the experimental unit.
Chi-squared test with Yates correction factor - prenatal mating and fertility indices
One-way ANOVA with Dunnett's test - pre-coital intervals, estrous cycle lengths, parental weekly gestational and lactational body weight and food consumption data, gestation lengths, sperm numbers, sperm production rates, organ weights, pup numbers, live litter sizes, pup body weight
Kruskal-Wallis test with Mann-Whitney U test - sperm motility, sperm morphology, pup sexes at birth (% males per litter), post-natal survival - Reproductive indices:
- Male Mating index
Female Fertility index
Male Fertility index - Offspring viability indices:
- Mean litter size
Mean post-natal survival
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Clinical signs noted at 50/35 and 20 mg/kg/day and attributable to treatment included impaired use of hindlimbs, reduced hindlimb resistance, hunched appearance, lacrimation, red material on nose, eyes, mouth and/or limbs, abdominal, urogenital and/or preputial areas or at the base of the tail, yellow material on various body surfaces and generally unkempt appearance. Also noted were abnormal gait, hypoactivity, shallow and/or laboured respiration and exophthalmus.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- At 50/35 mg/kg/day 5 males and 11 females were found dead and 5 males and 3 females were killed due to poor clinical condition, generally during the first 4 weeks of treatment. At 20 mg/kg/day 4 males and 7 females were found dead and 1 male and four females were killed due to poor clinical condition generally between weeks 10 and 11 of treatment.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean weekly body weight gains in males at 50/35 mg/kg/day were lower up to week 4, comparable to control thereafter until the first week of mating when losses were noted. Overall, body weight gain for 50/35 mg/kg/day males was 13.7% lower than controls over the dosing period. Reduced body weight gain was also noted for 20 mg/kg/day males during the dosing period and the overall weight gain was 5% lower than controls.
For females at 50/35 mg/kg/day mean body weight gain was lower during the first 4 weeks of treatment. Mean overall body weight gain for the gestation period was also lower for this group, the difference occurring during the last week of gestation. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Weekly food consumption for 50/35 mg/kg/day males was lower during the first 2 weeks of dosing and for the first week of dosing for females in the same group.
For females during the lactation period, lower food consumption was noted in the 50/35 and 20 mg/kg/day groups. - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- Individual variation in estrous cycle was noted in all groups. Mean estrous cycle length in treated groups was comparable to control.
- Reproductive function: sperm measures:
- no effects observed
- Description (incidence and severity):
- There was no effect of treatment.
- Reproductive performance:
- effects observed, treatment-related
- Description (incidence and severity):
- The mean number of days between pairing and coitus was higher in the 50/35 mg/kg bw/day group compared to control and historical control data (4.9 days vs 2.7 days).
There were no effects on mating and fertility indices.
The mean length of gestation at 50/35 mg/kg bw/day was higher than control and historical control (22.7 days vs 22.0 days or 22.3 days respectively).
Two females in the 50/35 mg/kg bw/day group died during delivery. While there were no other overt signs of dystocia, an number of females that died (see above) did so at or near the time of parturition.
Mean number of implantation sites was reduced in 50/35 mg/kg bw/day females
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- Fertility
- Effect level:
- 20 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: At 50/35 mg/kg/day increased number of days between pairing and coitus and increased mean gestation length, reduced mean number implantation sites, mean live litter size and number of pups born reduced.
- Dose descriptor:
- NOAEL
- Remarks:
- Parental
- Effect level:
- 0.8 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: See "Remarks"
Target system / organ toxicity (P0)
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 4 mg/kg bw/day (actual dose received)
- System:
- other: gastrointestinal; cardiovascular; musculoskeletal
- Organ:
- heart
- liver
- other: skeletal muscle
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Clinical signs of dehydrated appearance and bodies cool to touch were noted at a higher incidence at 50/35 and 30 mg/kg bw/day.
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- Total litter loss was noted for 4 females at 50/35 mg/kg bw/day and 1 female at 20 mg/kg bw/day. With the exception of 1 female at 50/35 mg/kg bw/day all litter losses occurred between lactation days 0 and 4. Furthermore, 2 females at 50/35 mg/kg bw/day and 1 at 20 mg/kg bw/day that were killed on gestation day 25 only had early resorptions in utero.
Mean live litter size and mean number of pups born in the 50/35 mg/kg bw/day group were lower than control and historical control data. A similar but less marked effect was also noted in the 20 mg/kg bw/day group.
The number of pups found dead or missing, presumed cannibalized, was higher in the 50/35 and 20 mg/kg bw/day groups. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean body weight gain was lower in 50/35 and 20 mg/kg bw/day groups from postnatal day 4.
- 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:
- no effects observed
- Description (incidence and severity):
- No findings attributable to maternal treatment with the test article.
- Histopathological findings:
- not examined
- Other effects:
- not specified
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not examined
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Remarks:
- developmental
- Generation:
- F1
- Effect level:
- 4 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Mean post-natal survival and pup weights reduced at 50/35 and 20 mg/kg/day
Target system / organ toxicity (F1)
- Critical effects observed:
- not specified
Overall reproductive toxicity
- Reproductive effects observed:
- yes
- Lowest effective dose / conc.:
- 35 mg/kg bw/day (actual dose received)
- Treatment related:
- yes
- Relation to other toxic effects:
- reproductive effects occurring together with other toxic effects, but not as a secondary non-specific consequence of other toxic effects
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
Any other information on results incl. tables
Table 1 - Survival
Dose |
Control |
0.8 |
4 |
20 |
50/35 |
Males |
|||||
Number in group |
25 |
25 |
25 |
25 |
25 |
Found dead |
0 |
0 |
0 |
4 |
5 |
Killed |
0 |
0 |
0 |
1 |
5 |
Survived until termination |
25 |
25 |
25 |
20 |
15 |
Females |
|||||
Number in group |
25 |
25 |
25 |
25 |
25 |
Found dead |
0 |
0 |
0 |
7 |
11 |
Killed |
0 |
0 |
0 |
4 |
3 |
Survived until termination |
25 |
25 |
25 |
14 |
11 |
Table 2 - Mean Gestation length (days)
Dose |
Control |
0.8 |
4 |
20 |
50/35 |
Number of animals |
20 |
22 |
23 |
15 |
15 |
Gestation length |
22.0 |
21.9 |
21.9 |
22.0 |
22.7** |
** p<0.01
Table 3 - Summary of Implantation Sites
|
Dose |
Control |
0.8 |
4 |
20 |
50/35 |
Implantation sites |
Mean |
15.4 |
16.4 |
17.0 |
14.4 |
12.1** |
Number born |
Mean |
14.8 |
15.3 |
16.0 |
13.5 |
8.7** |
Unaccounted sites |
Mean |
0.7 |
1.1 |
1.0 |
0.9 |
3.5** |
** p<0.01
Only dams that delivered 1 or more pups included in above table
Table 4 - Absolute Organ Weight (g)
|
Dose |
Control |
0.8 |
4 |
20 |
50/35 |
Prostate |
Mean |
1.10 |
1.08 |
1.04 |
0.93* |
0.86** |
Seminal vesicles |
Mean |
1.95 |
1.91 |
1.87 |
1.86 |
1.58** |
Left Testis |
Mean |
1.83 |
1.77 |
1.82 |
1.77 |
1.68 |
Right Testis |
Mean |
1.85 |
1.81 |
1.76 |
1.76 |
1.70 |
Left Epididymis |
Mean |
0.70 |
0.69 |
0.68 |
0.68 |
0.63 |
Right Epididymis |
Mean |
0.71 |
0.73 |
0.69 |
0.67 |
0.65* |
Left Cauda Epididymis |
Mean |
0.3065 |
0.3088 |
0.2933 |
0.2893 |
0.2756 |
Right Cauda Epididymis |
Mean |
0.2972 |
0.3073 |
0.2820 |
0.2758 |
0.2733 |
Pituitary |
Mean |
0.0152 |
0.0139 |
0.0145 |
0.0134* |
0.0119** |
* p<0.05 ** p<0.01
Table 5 - Litter Data
|
Dose |
Control |
0.8 |
4 |
20 |
50/35 |
Number born |
Mean |
14.8 |
15.3 |
16.0 |
14.0 |
8.7** |
Sex at birth |
Mean |
51.9 |
51.8 |
52.0 |
46.2 |
44.7 |
Live litter size |
Mean |
14.6 |
14.9 |
15.6 |
13.1 |
7.4** |
** p<0.01
Table 6 - Postnatal survival (% per litter)
|
Dose |
Control |
0.8 |
4 |
20 |
50/35 |
Birth to PND 4 (pre-selection) |
Mean |
96.6 |
95.4 |
93.3 |
82.3 |
56.8** |
PND 4 (post selection) to PND 21 |
Mean |
100.0 |
100.0 |
99.5 |
89.1** |
77.8** |
** p<0.01
N = number of litters
If dam died during interval the litter was excluded from viability calculation
Applicant's summary and conclusion
- Conclusions:
- Following administration at 0, 0.8, 4, 20 or 50/35 mg/kg/day the parental NOAEL was considered to be 0.8 mg/kg/day based on the mortality, clinical signs, food consumption, body weight effects, effects on organ weights noted at 50/35 or 20 mg/kg bw/day and pathology findings in the skeletal muscle and heart at 4, 20 or 50/35 mg/kg bw/day. The NOAEL for reproductive performance was considered to be 20 mg/kg/day based on the increased number of days between pairing and coitus and lower number of implantation sites noted at 50/35 mg/kg/day. Based on the total litter losses, reduced postnatal survival and clinical signs and lower body weight gains noted at 50/35 or 20 mg/kg/day the NOAEL for neonatal toxicity was considered to be 4 mg/kg/day.
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