Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 200-815-3 | CAS number: 74-85-1
- 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:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
Data source
Reference
- Reference Type:
- publication
- Title:
- Ethylene Oxide in Blood of Ethylene-Exposed B6C3F1 Mice, Fischer 344 Rats, and Humans
- Author:
- Filser, J.G., Kessler, W., Artati, A., Erbach, E., Faller, T., Kreuzer, P.E., Li, Q., Lichtmannegger, J., Numtip, W., Klein, D., Pütz, C., Semder, B., Csanády, G.A.
- Year:
- 2 013
- Bibliographic source:
- Toxicological Sciences 136(2), 344-358 2013
Materials and methods
- Objective of study:
- metabolism
- toxicokinetics
Test guideline
- Qualifier:
- no guideline followed
- GLP compliance:
- not specified
Test material
- Reference substance name:
- Ethylene
- EC Number:
- 200-815-3
- EC Name:
- Ethylene
- Cas Number:
- 74-85-1
- Molecular formula:
- C2H4
- IUPAC Name:
- ethene
- Reference substance name:
- Ethylene oxide
- EC Number:
- 200-849-9
- EC Name:
- Ethylene oxide
- Cas Number:
- 75-21-8
- Molecular formula:
- C2H4O
- IUPAC Name:
- oxirane
- Details on test material:
- - Name of test material (as cited in study report): Ethylene (ET) 3.5 and Ethylene Oxide (EO) 3.0
- Physical state: gas
- Other: purchased from Linde, Unterschleißheim, Germany.
Constituent 1
Constituent 2
- Radiolabelling:
- no
Test animals
- Species:
- other: mouse and rat
- Strain:
- other: B6C3F1 (mice) and Fischer 344 (rats)
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Species: Fischer 344/N rats
- Source: Charles River Wiga Deutschland, Sulzfeld, Germany
- Weight at study initiation: 230–290g
TEST ANIMALS
- Species: B6C3F1 mice
- Source: Charles River Wiga Deutschland, Sulzfeld, Germany
- Weight at study initiation: 23–30g
CONDITIONS (Rodents)
- Housing: 2 rats in a Macrolon type III cage in an IVC top flow system (Tecniplast, Buguggiate, Italy) which provided clean air
- Diet: ad libitum (chow Nr. 1324, Altromin, Lage, Germany)
- Water: ad libitum (tap)
- Acclimation period: 5+ days
- Photoperiod (hrs dark / hrs light): 12-h light/dark cycle
Other details
The animal tests followed the Guide for the Care and Use of Laboratory Animals (National Research Council, 1996).
Human Volunteers
- General Description: Good physical condition, nonsmoking
- Sex: males
- Group size: 4 individuals
- Profession: toxicologists
Other details
The study protocol was reviewed and approved by the Ethics Committee of the Medical Faculty of the Technische Universität München.
Administration / exposure
- Route of administration:
- inhalation: gas
- Vehicle:
- other: Synthetic air 5.5
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE
Animals were exposed in closed all-glass chambers (see Filser (1992) Arch. Toxicol 66, 1-10 for details). Exhaled carbon dioxide was trapped using soda lime, and replaced using pure oxygen.
Studies in rodents – EO measurements in exhaled air:
Animals exposed whole body for 6 hr
- mice: n = 5, chamber volume = 2.8 l
- rats: n = 2, chamber volume = 6.6 l.
Target concentrations of ET in air were:
- mice: 0, 1, 3, 10 or 30 ppm
- rats: 0, 1 or 3 ppm
Studies in rodents – EO measurements in blood:
Mice and rats were exposed either whole body (63 l glass sphere) or nose only (flow through chamber, mouse = 290 ml volume, rat = 750 ml volume)
Target concentrations of ET in air were:
- whole body = 0, 30, 100 (mice only), 130 (rats only), 300, 1000, 10000 ppm (6 hr exposure period)
- nose only = 0, 100 (mice only), 300, 1000 or 10000 ppm (45 min exposure period)
Studies in volunteers:
Three volunteers (A, B, C) were exposed to target concentrations of 5, 20 or 50 ppm ET for 4 hr; a fourth volunteer (D) was exposed to 5 or 20 ppm ET for the same period.
Volunteers were exposed to increasing concentrations of ET with a 2-d gap between exposures.
Methods described elsewhere (Filser et al. (2000) Toxicol. Appl. Pharmacol. 169, 40-51; Filser et al. (2008) Toxicol. Sci. 102, 219-231) - Duration and frequency of treatment / exposure:
- Animals - 45 min or 6 h
Humans volunteers - 4h
Doses / concentrations
- Remarks:
- Doses / Concentrations:
Whole body : 30, 100 (mice only), 130 (rats only), 300, 1000, and 10 000 ppm.
Nose only : 100 (mice only), 300, 1000, or 10 000 ppm.
Volunteers A, B, and C to 3 ET target concentrations: 5, 20, and 50 ppm. Volunteer D to 2 ET target concentrations: 5 and 20 ppm.
- No. of animals per sex per dose / concentration:
- 2 mice
5 rats - Control animals:
- yes, concurrent no treatment
- Details on dosing and sampling:
- ET monitoring
- Sample taken from: Air in chamber and ambient air
- Frequency of measurement: 10-20 minutes
- Method type(s) for identification: Gas chromatograph (GC) with flame ionisation detector (FID)
- Limit of Detection: 0.07 ppm
EO monitoring
- Sample taken from: Air in chamber and ambient air
- Frequency of measurement: Graphical information indicates that levels of EO in exhaled air were monitored every 30-60 minutes
- Method type(s) for identification: GC/FID and GC coupled with mass-selective detector (MSD)
- Limit of Detection: 0.2 ppm (GC/FID); 0.45 ppb (mice), 4 ppb (rats) (GC/MDS)
Humans
ET monitoring
- Samples taken from: Air at the point of flow into the mask and exhaled air
- Method for identification: GC/FID
- Measurement time points: 1 minute after exposure initiation, then every 10 to 15 minutes (inflowing air); every 0.5h (gas bag air)
- Limit of Detection: 0.07 ppm
EO monitoring
- Samples taken from: Exhaled air
- Method for identification: GC/MSD
- Measurement time points: before initiation of exposure to ET and every hour until exposure termination
- Limit of Detection: 0.8 ppb
METABOLITE CHARACTERISATION STUDIES
EO detection
Rodents
- Tissues and body fluids sampled: blood
- Time and frequency of sampling: Graphical information indicates that levels of EO in blood were monitored 15, 30, 45 and 60 minutes after the start of exposure, and also at 2 and 6 hours
- Method type(s) for identification: GC/MSD
- Limits of detection and quantification: EO = 80 nmol/l
- Other: Predicted levels of EO in blood following ET exposure were calculated using the function: EO concentrations at plateau (ppm) x blood-to-air partition coefficient of EO/ 25.13 (the molar volume [l] of an ideal gas at 25°C and 740 torr)
Humans
- Tissues and body fluids sampled: blood
- Time and frequency of sampling: before initiation of exposure and every hour until exposure termination
- Method type(s) for identification: GC/MSD
- Limits of detection and quantification: 3-5 nmol/l - Statistics:
- Linear regression analysis and standard errors of the means of slopes (SEMs), arithmetic means and SDs, as well as one-way ANOVA followed by Bonferroni’s post test for multiple comparisons were calculated using Prism 5 for Mac OSX (GraphPad Software, San Diego, California). A statistically significant difference was defined as p ≤ .05.
Results and discussion
Main ADME results
- Type:
- metabolism
- Results:
- Formation of ethylene oxide from ethylene followed the relationship rat>mouse>human
Any other information on results incl. tables
Conversion of ethylene to ethylene oxide in vivo
Studies in rodents
No background EO was detected in blood from unexposed rats and mice (limit of detection = 80 nmol/l).
Graphical data indicated that at lower ET exposures (<30 ppm), levels of EO in blood and exhaled air increased over time and reached a plateau after about 2 hr exposure; half-lives of approx. 8.9 min and 15 min were calculated for mice and rats, respectively, exposed to 30 ppm ET.
At higher exposures (>30 ppm ET), levels of EO in blood peaked following approx. 30 min exposure and then decreased to a plateau after around 2 hr. (No information collected on levels of EO in exhaled air at these higher ET exposure.)
Steady state concentrations of EO in blood (calculated from EO exhalation data) were approx. 2-fold higher in rats compared to mice:
ET in air ppm |
EO in blood (umol/l) Mean ± SD |
|
Mouse |
Rat |
|
1 |
0.007 ± 0.002 |
0.016 ± 0.001 |
3 |
0.018 ± 0.003 |
0.044 ± 0.004 |
10 |
0.077 ± 0.004 |
not done |
30 |
0.198 ± 0.024 |
not done |
A similar relationship was apparent for the direct estimation of levels of EO in blood for mice (0.203 ± 0.026 umol/l) and rats (0.469 ± 0.074 umol/l) exposed to 30 ppm ET.
The extent of conversion of ET to EO was calculated as:
Mouse = 0.041 ± 0.001 umol EO/l blood per ppm ET in air
Rat = 0.092 ± 0.001 umol EO/l blood per ppm ET in air
Studies in humans
There was no statistically significant difference between the concentration of ET in inhaled and exhaled air for 4 volunteers exposed to 5, 20 or 50 ppm ET, however, the level of ET in exhaled air was generally around 6% lower than that of inhaled air.
Levels of EO in human venous blood were as follows:
Volunteer |
ET exposure (ppm) |
EO in blood (nmol/l) Mean ± SEM |
|
Calculated |
Measured |
||
A |
5 |
10 ± 1.5 |
7 ± 0.8 |
20 |
25 ± 5.7 |
24 ± 0.3 |
|
50 |
59 ± 10.1 |
58 ± 3.4 |
|
B |
5 |
8 ± 1.1 |
7 ± 0.5 |
20 |
28 ± 4.0 |
36 ± 7.3 |
|
50 |
97 ± 8.2 |
81 ± 2.9 |
|
C |
5 |
5 ± 0.6 |
6.5 ± 0.6 |
20 |
27 ± 1.7 |
33 ± 0.9 |
|
50 |
58 ± 9.4 |
71 ± 12.2 |
|
D |
5 |
6 ± 0.1 |
7 ± 0.7 |
20 |
33 ± 4.3 |
42 ± 9.6 |
Concentrations of metabolically formed EO after approx. 2 hr (pseudo-steady state) were used to calculate the extent of conversion of ET to EO. Results were as follows:
Volunteer |
nmol EO/l blood per ppm ET in air |
A |
1.16 a |
B |
1.74 b |
C |
1.34 a |
D |
1.75 b |
Mean |
1.431 ± 0.002 |
a = results not statistically significantly different
b = results not statistically significantly different
Values for volunteers A and C differed significantly from those of volunteers B and D.
Haemoglobin and DNA adduct comparison:
In mice, the model underestimated the HB adducts by approximately 2-4 fold, and 2 out of 4 DNA adduct levels were underestimated by up to 1.3 fold.
In rats, all of the HB adduct levels were underestimated by approximately 1-6 fold. The DNA adduct levels were all overestimated by approximately 1.6 fold.
In humans, the calculated value was approximately 1.2 times higher than the single reported measured value. DNA adduct levels could not be compared due to lack of reported data.
Summary
At ET concentrations up to 30 ppm, EO concentrations in blood from rodents (quantified in the umol/l range) were approx. 9-fold higher in rats, and approx. 4-fold higher in mice, than in the volunteer with the greatest EO burden (quantified in the nmol/l range).
At higher exposures of 50 ppm ET, EO formation in blood was approx. 6-fold higher in rats, and approx. 3-fold greater in mice, than in humans.
Measured and calculated adduct levels were higher in rats than in mice. The difference was more apparent in the calculated values, which varied by 2-5 orders of magnitude. The measured values were 1-2 times higher in rats for HB adducts and 1-3 times for DNA adducts. Comparison of rodent and human adducts is not possible due to the significant differences in ET exposure levels.
Applicant's summary and conclusion
- Conclusions:
- At ET concentrations up to 30 ppm, formation of EO was approx. 9-fold higher in rats, and approx. 4-fold higher in mice, than in human volunteers. At exposures of 50 ppm ET and above, EO formation was approx. 6-fold higher in rats, and approx. 3-fold greater in mice, compared to humans. Overall, formation of EO from ET followed the relationship rat>mouse>human.
- Executive summary:
Formation of ethylene oxide (EO) from ethylene (ET) was quantified in blood and exhaled air from groups of mice, rats and human volunteers exposed to defined concentrations of ET (1 – 10000 ppm). EO formation was measured using GC-FID and/or GC-MSD. At ET concentrations up to 30 ppm, formation of EO was approx. 9-fold higher in rats, and approx. 4-fold higher in mice, than in human volunteers. At exposures of 50 ppm ET, EO formation was approx. 6-fold higher in rats, and approx. 3-fold greater in mice, compared to humans. Measured levels of EO in blood were also used to calculate formation of the adducts N-(2-hydroxyethyl)valine in haemoglobin and N7-(2-hydroxyethyl)guanine in DNA; this predicted higher levels of adduct formation in rats compared to mice, but there were inconsistencies between the predictions and measured values obtained by others. Overall the results demonstrate clear species differences, with humans being less efficient than rodents in converting ET to EO in vivo. They also suggest that ethylene oxide formed in vivo during the metabolism of ethylene has some capacity to bind to cellular macromolecules such as haemoglobin and DNA.
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.