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EC number: 271-802-8 | CAS number: 68608-82-2 A complex combination of hydrocarbons obtained by the alkylation of benzene with ethene. It consists primarily of ethylbiphenyls, diethylbenzenes with lesser amounts of butylbenzenes and polyethylbenzenes.
- 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
- Study period:
- Not applicable
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Well conducted and reported study conducted according to a relevant guideline and under GLP.
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 987
- Report date:
- 1987
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Details on test material:
- Identification: Flux Oil (MCS 2170/Therminol@ 59 heat transfer fluid)
Chemical Name: Mixture of alkyl substituted aromatics
Lot Number: NBP 2933500 t
EHL Code Number: T850028
Appearance: Light yellow liquid
Source: Monsanto Chemical Company.
Stated Stability: No special precautions
Stated Purity: Distilled
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- Species and- Strain: Sprague-Dawley rat (Crl : CD@ (SD) BR)
Source: Charles River Breeding Laboratories, Inc.,
Kingston, NY
Approximate Age and Weight at Initiation of Mating:
Females - 12 weeks, > 210 g
Males - 11 weeks, > 299 g
Number on Study : Twenty-f ive mated females /group.
Identification: Animals were individually identified using metal ear tags containing an animal quarantine number. An animal study number was assigned to each mated female when selected for study.
Housing: Animals were individually housed in susp,ended wire-bottom, stainless steel cages. All wire-inhalation cages were used during exposure. Environmental conditions were maintained at approximately 72 +/-2 deg. F and 40-60% relative humidity, with 12 hours of artificial illumination daily.
Food and Water: Purina Certified Rodent Chow@ 5002 and tap water were available ad libitum, except during exposure.
Pretest examination and Acclimation: Upon receipt, animals were retained in quarantine for 10 days in order to determine their health status. Inspections were performed daily in an effort to identify unhealthy or diseased animals. Only healthy animals were released for use on Study.
Administration / exposure
- Route of administration:
- inhalation: aerosol
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- Exposure System: The exposure system consisted of 10 m3 glass and stainless steel New York University-style inhalation chambers and an atmospheric generation system. Test material atmospheres were generated as aerosols by metering test material through Laskin-style nebulizers. A particle-size separator was employed to prevent most of the large, non-respirable aerosol particles from entering the exposure chambers. Airflow in the
chambers was nominally maintained at 1700 liters per minute.
Unifomrmity of distribution of the test material in the exposure chambers was determined once for each expostire level either during the study period or just prior to the study period. Particle-size analysis was performed gravimetrically using an Andersen Cascade impactor for the mid and high exposure levels. These analyses were performed four times during the first exposure week and weekly therafter .The mass median aerodynamic
diameter and geometric standard deviation and'percentage of particles less than 10 microns were calculated for each analysis. Chamber airflow, temperature, and humidity were monitored continuously, with specific values recorded every 30 minutes per chamber per day. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis of Test Atmospheres: Exposure chamber environment was monitored (for test'material concentrations at least three times per day in all chambers except the control. The control chamber was checked for the presence of test material twice during the study. Samples of test atmosphere for analysis were drawn through and collected in impingers containing, iso-octane. The amount of test material in each sample was analytically determined using gas chromatography. Because the test material was a mixture of components the most prominent peak in the chromatogram (m-ethyl-diphenylethage) was used to quantitate the overall relative amount of test material. Nominal concentration measurements were performed daily for each exposure level.
- Details on mating procedure:
- Unfit animals were eliminated prior to cohabitation. Selected females and males were cohoused 1:1 for mating. The occurrence of copulation was determined by inspection for copulatory plugs each day following cohabitation. The day of which a plug was detected was designated gestation day 0.
- Duration of treatment / exposure:
- The test material was administered by inhalation, six hours per day on days 6-15 of gestation.
- Frequency of treatment:
- daily from GD6 - 15
- Duration of test:
- Mating, then Exposure from GD6 through to 21
- No. of animals per sex per dose:
- 25 females per dose group
- Control animals:
- yes, sham-exposed
- Details on study design:
- Test Groups and Dose Levels: Three treatment groups, each consisting of 25 mated females, were exposed to target flux oil concentrations omf 20, 100 and 400 mg/m3. These exposure levels are also expressed in this report as 0.02, 0.1 and 0.4 mg/l. A concurrent control group of equal size received house-conditioned air only.
Dose levels were se1ected from results of a prior 30 day inhalation study (EHL 84105).
Dosing Regimen: The test material was administered by inhalation, six hours per day on days 6-15 of gestation.
Assignment to Test Groups: Mated females were xandomly assigned to treatment and control groups using a block design based on equivalent gestation day 0 body weights.
Examinations
- Maternal examinations:
- Mated females underwent a detailed physical 'examination on gestation day 0 and daily on days 6-21. Examinations were performed after exposure on treatment days. In addition, observations were made during exposure for treatment-related signs of toxicity. Only those animals in view in the chambers underwent exposure observations. Clinical signs were not recorded during exposure on exposure days 14 and 18-20.
Body Weight: Individual female body weights were recorded on gestation days 0, 6, 10,'13, 16, and 21. Individual body weight change was determined for the corresponding intervals.
Sacrifice: Surviving dams were sacrificed on, gestation day 21 by C02 inhalation.
Dams underwent a gross necropsy and abnormal maternal findings were recorded.
Early Deliveties: Dams which were observed to deliver prior to the nominal gestation day 21 were sacrificed as soon as possible and underwent a gross necropsy. Abnormal maternal findings and the number of ilmplantations i n each uterine horn were recorded. - Ovaries and uterine content:
- Immediately following' sacrifice the uterus was opened and the fetuses removed. The number and relative placement of live fetuses, dead fetuses, early resorptions, and late resorptions were recorded. The number of corpora lutea per ovary was also determined.
- Fetal examinations:
- All live fetuses from dams which survived to 'scheduled sacrifice were subjected to a gross external examination, sexed, weighed, and tagged for identification. Approximately one-half of each litter was placed in Bouin's fixative for subsequent serial sectioning and visceral examination. The remaining fetuses were eviscerated and fixed in alcohol for subsequent staining with Alizarin Red and skeletal examination.
Abnormal findings were classified as malformations or variations. Fetuses from Dams which delivered were subjected to a gross external examination if there was little or no evidence of fetal autolysis or cannibalism. These fetuses were then processed and examined for visceral or. skeletal malformations. - Statistics:
- Data. were analyzed statistically to aid in interpretation of results. Differences between the treatment groups and the control group were analyzed using one-gided comparisons and a critical level of 0.05, except two-sided comparisons were used for comparison of fetal sex distribution.
Maternal body weight, maternal body weight change, and fetal body weight were compared using Dunnett's test.
Pre- and postimplantation loss and the number of liv;e fetuses, dead fetuses, early resorptions, late resorptions, implantations, corpora lutea and fetal sex distribution were compared using the Mann-Whitney U test.
Pregnancy rate and the number of litters with malformed fetuses or variatons were compared using Fisher's Exact test
Bonferroni's inequality was used to assess the significance of comparing multiple treatment groups with a control group when the Mann-Whitney U test or Fisher's exact test indicated apparent statistical significance.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No females died spontaneously in any of the exposure groups or the control group. Most pregnant females in the high exposure group exhibited wet fur and staining/encrustation (principally of the head, neck and forelimbs), urineary staining and piloerection. A few pregnant females in the high exposure group also exhibited hunched posture/head tilt and single pregant female incidencess of ptosis and red vaginal discharge were observed. Fur staining/encrustation was also observed in the mid and low exposure groups, but the incidence was much lower than in the high exposure group. One pregnant female exhibited piloerection in the mid exposrue group. Alopecia was observed at a low incidence in all of the exposure groups and in the control group. No remarkable clinical signs were recorded during exposure. Most females did not exhibit any remarkable postmortem findings and there did not appear to be any treatment related findings with the possible exception of reduced body fat recorded for two females in the high exposure group.
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- no mortality observed
- Description (incidence):
- No females died spontaneously in any of the exposure groups or the control group.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The only statistically significant effects on mean body weight were observed in the high exposure groups on gestation days 10, 13, and 16. Mean body weight of high exposure females was a little over 8% lower than control group mena body weight on gestation day 16. Statistically significant differences from mean control group values in body weight change were observed for both the mid and high exposure groups. In the high exposure group body weight loss was observed for gestation day 6-10 and reduced body weight gain was observed for gestation days 10-13 and for the overall period of gestation days 6-21. Reduced body weight gain was observed for mid exposure group females for gestation days 6-10 and 10-13.
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
Maternal developmental toxicity
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- No statistically significant differences between the control group values and any of the exposure groups were observed for reproductive parameters including numbers of live fetuses, dead fetuses, early or late resorptions, preimplantation loss and post implantation loss. The data indicate that there were no treatment related effects on reproductive parameters.
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- No statistically significant differences between the control group values and any of the exposure groups were observed for reproductive parameters including numbers of live fetuses, dead fetuses, early or late resorptions, preimplantation loss and post implantation loss. The data indicate that there were no treatment related effects on reproductive parameters.
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- No statistically significant differences between the control group values and any of the exposure groups were observed for reproductive parameters including numbers of live fetuses, dead fetuses, early or late resorptions, preimplantation loss and post implantation loss. The data indicate that there were no treatment related effects on reproductive parameters.
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified - Changes in number of pregnant:
- no effects observed
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
Clinical signs of wet, matted or stained- fur, piloerection and urinary staining were observed in most females of the high exposure group and hunched posture/head tilt was observed in several females. High exposure level females also exhibited lower mean body weights on gestation days 10, 13 and 16 and body weight loss (gestation days 6-10) and reduced weight gain (gestation days 10-13) compared to control values. Some toxicity was also observed at the mid exposure level. A few females exhibited fur staining or encrustation and piloerection was observed in one female. Reduced body weight gain was observed for mid exposure females for gestation days 6-10 and 10-13. The body weight effects were most severe during the initial exposure period (gestation days 6-10) and weight gains after completion of exposures (gestation days 16-21) were comparable to control values. No treatment related toxic effects were observed in low dose level females. Most females did not exhibit remarkable postmortem findings and, except for reduced abdominal fat observed in two high exposure level females, there were no findings judged to be treatment related.
Effect levels (maternal animals)
open allclose all
- Dose descriptor:
- NOAEC
- Effect level:
- 20 mg/m³ air (nominal)
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEC
- Effect level:
- 100 mg/m³ air
- Basis for effect level:
- other: developmental toxicity
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- There were no statistically significant differences between any of the exposure groups and control group values for fetal body weights or fetal sex distribution. Although high exposure group male and female mean fetal weights were lower than corresponding values for the control group and the other exposure groups, the lack of statistical significance indicates that this should not be ascribed as a treatment related effect.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed - Reduction in number of live offspring:
- not specified
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- There were no statistically significant differences between any of the exposure groups and control group values for fetal body weights or fetal sex distribution. Although high exposure group male and female mean fetal weights were lower than corresponding values for the control group and the other exposure groups, the lack of statistical significance indicates that this should not be ascribed as a treatment related effect.
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- not examined
- External malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- An increase in the total number of litters with malformations was observed for the high exposure group compared to the control group. The increase was not statistically significant at the 5% level after application of the Bonferroni inequality for comparison of multiple treatment with controls. Most of this was due to a number of litters with fetuses exhibiting bent ribs. Other malformations in the high exposure group were restricted in distribution to single fetuses with four of the eleven malformation findings occuring in a single fetus and two other malformation findings (sternoschesis and anus absent/tail short) each occurring in a single fetus. The only malformation observed in the mid exposure group was a single fetus with microphthalmia and the only malformations observed in the low dose group were two fetuses in two litters with bent ribs.
- Skeletal malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- A variation finding of reduced ossification of inner ear bones was elevated on a fetal basis in all exposure groups compared to the control group incidence. However, the elevations in incidence were not statistically significant at the 5% level with the Bonferroni inequality correction and were not significant in terms of nmbers of litters affected for any of the exposure groups. Although there were elevations in some types of other variation findings in the high exposure group liters (reduced skull ossification, sternebrae #5 and /or 6 unossified, cervical #7 rib, and 13 full pairs of rudimentary ribs), none of these findings were statistically significant compared to the control group on either a litter or fetal incidence basis.
- Visceral malformations:
- not specified
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
An increase above control in the number of bent ribs observed inhigh dose fetuses. (7 fetuses in 5 litters, compared to 1 fetus in the control.). Although the increased incidence of bent ribs in the high,exposure group may have been treatment related, the incidence of this finding alone was not statistically significant when compared to the control group incidence. Other malformation findings in the high exposure level group were restricted to single incidences in three fetuses (one with multiple head malformations). Because of the restricted distribution of these findings they are not '
considered to be definitely treatment related. One malformation (microphthalmia) was observed in one fetus in-the mid exposure group and two fetuses with bent ribs were observed in the low exposure group.
Effect levels (fetuses)
- Remarks on result:
- not determinable due to adverse toxic effects at highest dose / concentration tested
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- This study identified an increased maternal toxicity in the mid and high dose groups and some evidence of malformations but only in conjunction of maternal toxicity. It is therefore possible that these effects may be as a result of the general toxicity observed in the Das rather than specific teratogneicity or developmental toxicity. With the exception of some small changes in malformation incidence, there was no evidence of embryotoxicity or fetotoxicity, that would lead to a conclusion that this substance is developmentally toxic.
- Executive summary:
Mated female Sprague-Dawley rats, in groups of 25, were exposed by inhalalation to target flux oil concentrations of 20, 100 and 400 mg/m3 for six hours per day on gestation days 6-15. A concurrent control group was exposed to house-conditioned air only. Dams were sacrificed on gestation day 21, implantations were described, and fetuses were removed from the uterus. Fetuses were weighed, underwent a gross external examination and were processed for subsequent visceral or skeletal examination. Abnormal fetal findings were classified as malformations or variations.
Study mean exposure concentrations and standard deviations determined by analytical methods were 19 ± 2, 110 ± 30 and 410 ± 54 mg/m3 for the target levels of 20, 100 and 400mg/m3, respectively. Distribution of test material within the exposure chambers was found to be reasonably uniform and most (>80%) of the aerosol particles in the mid and high exposure level groups were less than 10 urn in size. No significant decomposition of the test material was observed during the study.
There were no spontaneous deaths in any of the exposure groups or -the control group. Maternal toxicity was observed in the high exposure group. Clinical signs of wet, matted or stained- fur, epiloerection and urinary staining were observed in most females of the high exposure group and hunched posture/head tilt was observed in several females. High exposure level females also exhibited lower mean body weights on gestation days 10, 13 and 16 and body weight loss (gestation days 6-10) and reduced weight gain (gestation days 10-13) compared to control values. Some toxicity was also observed at the mid exposure level. A few females exhibited fur staining or encrustation and piloerection was observed in one female. Reduced body weight gain was observed for mid exposure females for gestation days 6-10 and 10-13. The body weight effects were most severe during the initial exposure period (gestation days 6-10) and weight gains after completion of exposures (gestation days 16-21) were comparable to control values. No treatment related toxic effects were observed in low dose level females. Most females did not exhibit remarkable postmortem findings and, except for reduced abdominal fat observed in two high exposure level females, there were no findings judged to be treatment related.
The total number of litters with malformations was elevated in the high exposure level group. The difference in total litters formations was significant at the 5% level without, but not with, the Bonferroni inequality correction for comparison of multiple treatment groups with a control group. The increase was primarily because of findings of bent ribs in 7 fetuses in 5 litters in the high exposure group. This finding was also observed in one fetus in the control group. Although the increased incidence of bent ribs in the high,exposure group may have been treatment related, the incidence of this finding alone was not statistically significant when compared to the control group incidence. Other malformation findings in the high exposure level group were restricted to single incidences in three fetuses (one with multiple head malformations). Because of the restricted distribution of these findings they are not considered to be definitely treatment related. One malformation (microphthalmia) was observed in one fetus in the mid exposure group and two fetuses with bent ribs were observed in the low exposure group.
There were no clear, treatment-related effects on reported variations in any of the exposure level groups. Although increases were observed in the fetal incidence of reduced inner ear ossification of all exposure groups compared to the control group the increases were not judged to be treatment related because of lack of a dose response pattern, lack of significant effects on litter incidence, lack of fetal weight effects, and lack of statistical significance with the Bonferroni inequality correction. Although increases in certain other variation findings were observed in the high exposure group, none of these increases was statistically different from control values on either a litter or fetal "incidence" basis. These increases in, variation findings in the high exposure group are not judged to be clear indications of treatment related effects. The incidences of variation findings other than reduced ear ossification in the -low and mid exposure level groups were comparable to control incidence levels and did not indicate treatment related effects.
In, conclusion, maternal toxicity was observed at exposure levels of 400 and 100 mg/m3 but not at 20 mg/m3. No treatment related embryotoxicity or fetotoxicity was observed at any of the exposure levels. An increase in litters with malformations and litters with bent ribs was observed at the 400 mg/rn3 level; These observations are considered t o be possible indications of a treatment related effect , although it is also possible that the effects are not treatment related. Moreover, significant maternal toxicity was evident in the high exposure level females and the effects observed may have been secondary to maternal toxicity. No treatment related effects on malformations or variations were observed at the 100 or 20 mg/m3 exposure levels. Therefore, these effects may be as a result of the general toxicity observed in the Dams rather than specific teratogenicity or developmental toxicity. With the exception of some small changes in malformation incidence, there was no evidence of embryotoxicity or fetotoxicity, that would lead to a conclusion that this substance is developmentally toxic.
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