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EC number: 201-228-5 | CAS number: 79-81-2
- 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
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Acceptable, well-documented publication which meets basic scientific principles.
Data source
Reference
- Reference Type:
- publication
- Title:
- Vitamin A teratogenicity and risk assessment in the macaque retinoid model.
- Author:
- Hendrickx AG et al.
- Year:
- 2 000
- Bibliographic source:
- Reprod Toxicol 14: 311-323
Materials and methods
- Objective of study:
- toxicokinetics
- Principles of method if other than guideline:
- Other: no data
- GLP compliance:
- not specified
Test material
- Reference substance name:
- Retinyl palmitate
- EC Number:
- 201-228-5
- EC Name:
- Retinyl palmitate
- Cas Number:
- 79-81-2
- Molecular formula:
- C36H60O2
- IUPAC Name:
- (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraen-1-yl hexadecanoate
- Details on test material:
- Test substance: Vitamin A palmitate
(retinyl palmitate)
retinyl palmitate (CAS No. 79-81-2), coded Ro 01-5852/000, supplier: Hoffmann-LaRoche Ltd, Basel (Switzerland); according to the authors, purity was 99.9%
Constituent 1
- Radiolabelling:
- not specified
Test animals
- Species:
- monkey
- Strain:
- Macaca fascicularis
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: 3-5 kg (CRPRC), 2-5 kg (SNBL).
- Housing: individually in aluminum (CRPRC) or stainless steel (SNBL) cages.
- Diet:
CRPRC: Purina Monkey Chow (25% protein) twice daily with fruit supplementation during the treatment period. Estimated daily vitamin A intake via food consumption was 1225 IU/kg body weight (140 g of food containing 35 IU/g vitamin A; average monkey weight 4.0 kg).
SNBL: Solid diet (110 g daily of feed containing 24 IU/g vitamin A, Harlan Teklad, Harlan Sprague–Dawley, Inc.) was provided. The estimated
daily vitamin A intake via food consumption was 750 IU/kg (assuming an average monkey weight of 3.5 kg).
- Water: ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 (CRPRC), 26+/-2 (SNBL).
- Humidity (%): 60 (CRPRC), 50 +/-10 (SNBL).
- Air changes (per hr): 15 (SNBL).
- Photoperiod (hrs dark / hrs light): 12
Administration / exposure
- Route of administration:
- other: oral (nasogastric intubation)
- Vehicle:
- other: physiol. saline (SNBL), water (CRPRC)
- Details on exposure:
- Vitamin A (retinyl palmitate) was administered by nasogastric intubation at dose levels of 7500 IU/kg (4.1 mg/kg), 20000 IU/kg (11 mg/kg), 40000 IU/kg (22 mg/kg), and 80000 IU/kg (ca. 44 mg/kg) during early pregnancy(i.e. between gestational days (gd) 16 and 27).
The animals given one or two doses during this period of gestation. Control monkeys were administered the vehicle
(physiological saline or distilled water, depending on the performing institute). Hysterectomies were performed on gd 100 +/- 2, and the fetuses were examined. - Duration and frequency of treatment / exposure:
- Vitamin A (retinyl palmitate) was administered by nasogastric intubation at
dose levels of 7500 IU/kg (4.1 mg/kg), 20000 IU/kg (11 mg/kg), 40000 IU/kg
(22 mg/kg), and 80000 IU/kg (ca. 44 mg/kg) during early pregnancy (i.e. between
gestational days (gd) 16 and 27). The animals given one or two doses during
this period of gestation. Control monkeys were administered the vehicle
(physiological saline or distilled water, depending on the performing institute)
. Hysterectomies were performed on gd 100 +/- 2, and the fetuses were examined.
Doses / concentrations
- Remarks:
- Doses / Concentrations:
Males: no males included
Females: approx. 4.1, 11, 22, 44 mg/kg (7500, 20000, 40000, 80000 IU/kg)
- No. of animals per sex per dose / concentration:
- Only female animals used
Experiment 1: n=5 controls, n=4 per dose group
Experiment 2: n=8
Experiment 3: n=6 per group - Control animals:
- yes
- Positive control reference chemical:
- no data
- Details on study design:
- These investigations were part of a teratogenicity study in cynomolgus monkeys
(Macaca fascicularis) . The studies were carried out at the California Regional Primate Research
Center (CRPRC), Davis, California, and the Shin Nippon Biomedical Laboratories, Ltd., Kagoshima, Japan. - Details on dosing and sampling:
- For kinetic analysis, blood samples (1-2 ml plasma) were obtained under yellow light before dosing (0 h), and 1, 2, 3, 4.5, and 8 h after dosing
(experiments 1 and 2) or at 0, 1, 2, 3, 4.5, 8, and 24 h before the next dose (Experiment 3). - Statistics:
- The AUC for each treatment group was evaluated by descriptive statistics
(mean, SD).
Results and discussion
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- Four metabolites of Vitamin A, the retinoic acids (RA) all-trans RA, 13-cis-RA, all-trans-4-oxo-RA, and 13-cis-4-oxo-RA
were measured simultaneously using a validated reversed-phase HPLC/column switching assay.
Any other information on results incl. tables
Experiment 1:
-------------
Retinoid plasma concentrations indicated a dose-related increase in AUC 0-8 on
the last day of sampling (gd 27) for the four metabolites generated. Elevated
pre-dose plasma concentrations of retinol and the RA metabolites were observed
in the one 20000-IU/kg-female that had a malformed fetus.
Table: mean +/- SD AUC 0-8 values of retinoids in maternal plasma on gd 27
Retinoids:
R = retinol
RE = retinyl esters
AT-RA = all-trans-retinoic acid
13C-RA = 13-cis-retinoic acid
ATO-RA = all-trans-4-oxo-retinoic acid
13C-RA = 13-cis-4-oxo-retinoic acid
control 20000 IU 40000 IU
retinoid (n=5) (n=4) (n=4)
-----------------------------------------------------
R 7.8+/-1.5 17.4+/-5.6 17.4+/-2.7
RE 5.4+/-2.3 293+/-153 327+/-140
AT-RA 15.2+/-1.0 67.0+/-36.0 152+/-108
13C-RA 24.7+/-5.7 271+/-86.2 380+/-293
ATO-RA 5.9+/-4.1 46.6+/-15.6 61.8+/-41.5
13CO-RA 15.7+/-4.3 328+/-146 411+/-223
Experiment 2:
-------------
The AUC 0-8 for retinol and the four retinoic acid metabolites were higher on
gd 16 than on gd 27. The fetal outcome was related to kinetic parameters. The
plasma levels for retinol and the four metabolites were consistently higher on
gd 16 in the six females that had an adverse pregnancy outcome (n= 5 abortions
and n = 1 moderately malformed fetus). In contrast, intermediate or low values
for these parameters were observed in the two females with a mildly malformed
fetus or with a normal fetus, respectively.
AUC 0-8 of retinoids in maternal plasma
80000 IU/kg) | |||
N=8 | GD16 | GD27 | |
R | Mean | 28.9 | 15.4 |
SD | 11.8 | 10.7 | |
RE | Mean | 322 | 353 |
SD | 181 | 539 | |
AT-RA | Mean | 6100 | 45.6 |
SD | 3610 | 37.8 | |
13C-RA | Mean | 1096 | 168 |
SD | 595 | 99.7 | |
ATO-RA | Mean | 1105 | 32 |
SD | 638 | 16.7 | |
13CO-RA | Mean | 619 | 170 |
SD | 309 | 111 |
Experiment 3:
-------------
There was a dose-related increase in AUC 0-24 of the four retinoic acid
metabolites on gd 16. The AUC 0-24 values for these compounds were consistently
higher on gd 16 than on gd 27 in the 20000-IU/kg-group. There were no
comparable changes between the first and last day of treatment in the
7500-IU/kg-group. The AUC 0-24 of retinol in the two treatment groups was only
slightly higher than in the control group and did not change with dose and time.
In contrast, the AUC 0-24 of retinyl esters was 30 times higher after Vitamin
A treatment compared with controls although there was no consistent pattern
with dose or time.
AUC 0 -24 of retinoids in maternal plasma
Group 1 (control) | Group 2 (7500 IU/kg) | Group 3 (20000 IU/kg) | |||||
N=6 | GD16 | GD27 | GD16 | GD27 | GD16 | GD27 | |
R | Mean | 31.1 | 34.8 | 45.8 | 45.9 | 45.0 | 31.4 |
SD | 7.2 | 9.8 | 8.5 | 9.4 | 6.0 | 8.7 | |
RE | Mean | 1.37 | 2.6 | 55.5 | 71.1 | 88.2 | 47.1 |
SD | 0.8 | 0.8 | 40.4 | 48.5 | 66.1 | 27.4 | |
AT-RA | Mean | 60.3 | 65.0 | 265 | 238 | 1790 | 353 |
SD | 7.8 | 9.8 | 205 | 150 | 1717 | 390 | |
13C-RA | Mean | 47.1 | 46.1 | 239 | 286 | 893 | 399 |
SD | 14.9 | 11.1 | 92.5 | 60.1 | 597 | 227 | |
ATO-RA | Mean | 3.5 | 2.9 | 73.8 | 78.5 | 430 | 142 |
SD | 8.6 | 4.2 | 32.5 | 27.7 | 371 | 115 | |
13CO-RA | Mean | 9.2 | 17.6 | 193 | 274 | 765 | 427 |
SD | 13.1 | 9.6 | 113 | 139 | 567 | 284 |
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.
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