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EC number: 270-658-3 | CAS number: 68475-70-7 A complex combination of hydrocarbons obtained by the fractionation pyrolysis at 816°C (1500°F) of naphtha and raffinate. It consists predominantly of aromatic hydrocarbons having carbon numbers predominantly in the range of C6 through C8, including benzene.
- 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
![](https://poisoncentres.echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Toxicity to reproduction
Administrative data
- Endpoint:
- two-generation reproductive toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP status unknown, non-guideline study, published in peer reviewed literature, no restrictions, fully adequate for assessment.
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- publication
- Title:
- Two generation reproduction study of ethylbenzene by inhalation in Crl-CD rats
- Author:
- Faber WD, Roberts LSG, Stump DG, Tardif R, Krishnan K, Tort M, Dimond S, Dutton D, Moran E and Lawrence W
- Year:
- 2 006
- Bibliographic source:
- Birth Defects Res (Part B) 77:10-21
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- EPA OPPTS 870.3800 (Reproduction and Fertility Effects)
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Ethylbenzene
- EC Number:
- 202-849-4
- EC Name:
- Ethylbenzene
- Cas Number:
- 100-41-4
- Molecular formula:
- C8H10
- IUPAC Name:
- ethylbenzene
- Details on test material:
- - CAS number: 100-41-4
- Source: The Dow Chemical (Midland, MI) via Ashland Chemical (Morrisville, PA, USA)
- Storage: under refrigeration
- Analytical purity: at least 99.9%
Constituent 1
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 (Raleigh, NC, USA) on 8 April 2003
- Age on arrival: approximately 38 days
- Randomisation: based on body weight
- Housing:
prior to pairing: individual housing in wire-mesh cages suspended above cage-board
cohabitation: home cage of the male
post mating: females transferred to plastic maternity cages with nesting material where housed until weaning of the litter
- Animal facility: AAALAC accredited
- Animal room environmentally controlled (no further details)
- Diet: PMI Nutrition International Inc. certified rodent LabDiet 5002, ad libitum
- Water: municipal water reverse-osmosis treated delivered by automatic system, ad libitum except during inhalation exposure
Administration / exposure
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- other: air
- Details on exposure:
- Exposure concentrations were based on death, clinical signs and reduced body weight gain of weanling rats exposed to 500 or 1000 ppm ethylbenzene in a preliminary study. Clinical signs included laboured respiration, unsteady gait and prostration.
- Details on mating procedure:
- 1 male:1 female for 14 days or until confirmation of mating observed. Sibling pairings were avoided.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- In exposure chambers, analysed by gas chromatography with flame ionization detection. Analysed concentrations were very close to nominal.
In dosing solutions, analysed by gas chromatography with mass spectroscopy. - Duration of treatment / exposure:
- Inhalation: 6 hours daily, 7 days per week. F0 and F1 animals exposed for at least 70 consecutive days prior to mating. Males continued on the same regime whilst on study. The females were similarly exposed throughout mating and gestation, through to day GD 20; exposure recommenced on day 5 of lactation (LD5) and continued through to weaning (LD21).
Oral gavage: females only days 1-4 of lactation. Ethylbenzene administered in corn oil at dose levels of 0, 26, 90, and 342 mg/kg/day (dose levels selected to result in similar internal maternal exposure based on PBPK modelling). Each dose was divided into 3 equal amounts and administered approximately two hours apart. - Frequency of treatment:
- daily
- Details on study schedule:
- After a pre-mating period of at least 70 days, each female was housed with a randomly selected male from the same exposure group, avoiding sibling matings. Each female was examined daily for the presence of sperm in a vaginal smear or the presence of a copulatory plug. The day of confirmation of mating was gestation day 0 (GD 0). Females failing to mate were given a second opportunity with another male. Females were allowed to litter naturally and rear their young to weaning (PND 21).
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 25, 100 and 500 ppm
Basis:
nominal conc.
- No. of animals per sex per dose:
- 30 F0, 25 F1
- Control animals:
- yes, concurrent vehicle
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily checks for mortality, clinical signs and changes in appearance and behaviour. Animals visible in inhalation chambers (50%) were observed for changes in appearance and behaviour at the mid point of exposure.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule: weekly and prior to necropsy. Females on GD 0, 4, 7, 11, 14, 20 and LD 1, 4, 5 (pre-exposure), 7, 14, and 21
FOOD CONSUMPTION:
- Time schedule: weekly except during the mating period. Females on GD 0, 4, 7, 11, 14, and 20 and LD 1, 4, 5, 7, 14, and 21
MATING:
- Pre-coital interval was calculated according to the number of 12-hr dark cycles before evidence of mating
BLOOD ANALYSIS:
- Blood samples from the tail vein were collected 1 hour after the third gavage dose from 4 F1 females per group on lactation day 4 and from the same females following the 6 hour period of inhalation exposure on day 22. The blood was analysed for ethylbenzene concentration.
- Oestrous cyclicity (parental animals):
- Daily vaginal smears to determine the stage of oestrus for 21 days before pairing and until evidence of mating observed or until the end of the mating period. The average cycle length was determined for complete oestrous cycles.
- Sperm parameters (parental animals):
- Sperm motility was assessed for all males using the Hamilton-Thorne HTM-IVOS Version 12 computer-assisted sperm analysis (CASA)
system. Sperm morphology was evaluated by light microscopy using a modified wet mount evaluation technique. Homogenization-resistant spermatid count and sperm production rate were determined using a DNA-specific fluorescent dye and the HTM-IVOS CASA system. - Litter observations:
- OBSERVATIONS:
- Each litter was examined twice daily for survival and signs of toxicity.
CULLING:
- To reduce variability, 10 F1 and F2 pups per litter were randomly selected on PND 4.
BLOOD SAMPLING:
- Pups from 4 F2 litters/group were used for analysis of ethylbenzene in blood on lactation day 4. Four male plus 4 female F2 pups were used to obtain blood samples 1 hr after completion of a single 6-hr inhalation exposure to ethylbenzene on PND 22.
SEX & BODY WEIGHTS
- Pups were sexed on PND 0, 4, 7, 14 and 21. F1 pups were individually weighed on PND 1, 4, 7, 14, and 21; F2 pups were individually weighed on PND 1, 4, 7, 11, 13, 17 and 21. Pups were weighed on the day of sexual maturation.
DEVELOPMENTAL LANDMARKS
- Assessed in F1 and F2 offspring: pinna detachment, hair growth, incisor eruption, eye opening, balanopreputial separation and vaginal patency. - Postmortem examinations (parental animals):
- SACRIFICE: All adult animals killed using isoflurane inhalation and exsanguination. Vaginal smears taken from all females on the day of euthanasia to determine stage of oestrus. Males were terminated after completion of parturition. All females that littered were terminated 6-10 days after weaning their litters. Females that mated but did not litter were terminated on presumed GD 25. Females that had total litter loss were terminated within 24 hr.
GROSS NECROPSY: yes, all animals
ORGAN WEIGHTS: brain, liver, kidneys, spleen, lungs, thyroids, prostate
HISTOPATHOLOGY: Selective histopathological examination was undertaken (no further details). Ovarian primordial follicle counts were recorded for all F1 females in the control and high dose group. - Postmortem examinations (offspring):
- SACRIFICE: Intact offspring dying PND 0-4 were necropsied. A detailed necropsy was carried out on any pup dying PND 4-21 and for all F1 pups dying PND 22-42. All F1 and F2 pups not selected were killed using CO2 inhalation on PND 21. All F2 pups not selected for neuropathological assessment were killed on PND 21. F2 pups selected for toxicokinetic evaluation were killed on PND 22.
GROSS NECROPSY: Yes all pups
ORGAN WEIGHTS: selected organs were weighed (no further details)
HISTOPATRHOLOGY: selective histopathological examination was undertaken (no further details) - Statistics:
- Test and control groups were compared by sex and the analyses used two-tailed tests for 5% significance. Chi squared test with Yates’ correction was used to analyse mating and fertility indices. Analysis for heterogeneity of variance and normality were applied to mean body weights, food consumption, food efficiency, organ weights, oestrous cycles, pre-coital intervals, gestation lengths, implantation sites, ovarian primordial follicle counts, pups born, live litter size, epididymal and testicular sperm numbers, sperm production rates, and days of developmental landmarks. A parametric one-way analysis of variance (ANOVA) was used to determine intergroup differences where data were homogeneous and normal. Dunnett’s test compared the control and test groups when ANOVA was significant (p<0.05). The non parametric ANOVA Kruskal-Wallis test was used where data were not homogeneous and normal to determine intergroup differences. The Mann-Whitney U-test was used where ANOVA showed statistical significance (p<0.05). Pup weights were analysed by sex using a nested analysis of covariance (ANCOVA) where the number of pups born was the covariate. ANCOVA made the following assumptions: homogeneity of regression slopes, linear relationship between pup weights and number of pups born, additive group and regression effects. A two-tailed Fisher ’s Exact test compared histopathological findings in test and control groups. Kruskal-Wallis non parametric ANOVA test to determine intergroup differences was used for mean litter proportions (%/litter) of pup survival, sex ratio at birth (% of males/ litter), percentage of motile and progressively motile sperm and percentage of sperm with normal morphology. Mann-Whitney U-test compared the test and control groups where ANOVA showed statistical significance (p<0.05).
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- effects observed, treatment-related
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
Details on results (P0)
Effect levels (P0)
- Dose descriptor:
- NOAEC
- Remarks:
- reproductive performance
- Effect level:
- >= 500 ppm
- Sex:
- male/female
- Basis for effect level:
- other: highest concentration tested
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
Effect levels (F1)
open allclose all
- Dose descriptor:
- NOAEC
- Remarks:
- reproductive performance
- Generation:
- F1
- Effect level:
- >= 500 ppm
- Sex:
- male/female
- Basis for effect level:
- other: highest concentration tested
- Dose descriptor:
- NOAEC
- Remarks:
- developmental toxicity
- Generation:
- F1
- Effect level:
- >= 500 ppm
- Sex:
- male/female
- Basis for effect level:
- other: no effect on number of pups born live, survival, clinical condition, body weight, acquisition of developmental landmarks
Results: F2 generation
Effect levels (F2)
- Dose descriptor:
- NOAEC
- Remarks:
- developmental toxicity
- Generation:
- F2
- Effect level:
- >= 500 ppm
- Sex:
- male/female
- Basis for effect level:
- other: no effect on number of pups born live, survival, clinical condition, body weight, acquisition of developmental landmarks
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- The NOEC and NOAECs of ethylbenzene for parental systemic toxicity were 100 and 500 ppm respectively and the NOAEC for reproductive and developmental toxicity was >500 ppm (equivalent to 2171 mg/m3).
- Executive summary:
Male and female Crl:CD(SD)IGS BR rats were exposed by inhalation to 0, 25, 100 or 500 ppm ethylbenzene for 6 hr/day throughout the 2-generation study except for females between lactation days 1 and 4 when the dose was administered in corn oil by oral gavage at dose levels of 26, 90 or 342 mg/kg/day (to provide similar maternal blood (AUC) as provided by inhalation).
At 500 ppm ethylbenzene, the males of both generations showed reduced body weight gain and increased liver and kidney weights whilst only liver weights were affected in females. As the reduced body weight gain in the 500 ppm males was transient and there were no histopathological changes associated with the increased organ weights in the 500 ppm males and females, these changes were considered not to be adverse. Therefore, for parental systemic toxicity the NOEC was considered to be 100 ppm and the NOAEC 500 ppm. There were no adverse effects of ethylbenzene on reproductive performance in either generation. Neither were there any effects of treatment on spermatogenic endpoints, ovarian follicle counts, reproductive organ weights or macroscopic pathology. The NOAEC for reproductive toxicity and offspring development was 500 ppm ethylbenzene.
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