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EC number: 202-436-9 | CAS number: 95-63-6
- 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
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- Nanomaterial surface chemistry
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- 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:
- multi-generation reproductive toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- migrated information: read-across based on grouping of substances (category approach)
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Near guideline study. Published in peer reviewed literature. Minor restrictions in design and/or reporting but otherwise adequate for assessment.
Data source
Reference
- Reference Type:
- publication
- Title:
- The reproductive and developmental toxicity of high flash aromatic naphtha
- Author:
- McKee RH, Wong ZA, Schmitt S, Beatty P, Swanson M, Schreiner CA and Schardein JL
- Year:
- 1 990
- Bibliographic source:
- Toxicology and Industrial Health Vol 6, No. 314, pp 441-460
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- Deviations:
- yes
- Remarks:
- Pre 2001 Guideline.
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Solvent naphtha (petroleum), light arom.
- EC Number:
- 265-199-0
- EC Name:
- Solvent naphtha (petroleum), light arom.
- Cas Number:
- 64742-95-6
- IUPAC Name:
- 64742-95-6
- Reference substance name:
- High Flash Aromatic naphtha
- IUPAC Name:
- High Flash Aromatic naphtha
- Details on test material:
- Test sample conformed to specifications for High-Flash Aromatic Naptha, Type 1 (as defined by ASTM method D-3734. Although commercially available, the test sample was specially prepared to meet the compositional requirements (i.e. at least 22% ethyltoluene isomers, at least 15% trimethylbenzene isomers and at least 75% total ethyltoluenes and trimethylbenzenes) specified in the test rule.
The sample was analysed for the weight percent reported as follows:
o-xylene: 3.20
cumene: 2.74
n-propylbenzene: 3.97
4-ethyltoluene: 7.05
3-ethyltoluene: 15.1
2-ethyltoluene: 5.44
1,3,5-trimethylbenzene: 8.37
1,2,4-trimethylbenzene: 40.5
1,2,3-trimethylbenzene: 6.18
>=C10's: 6.19
TOTAL: 98.74
Constituent 1
Constituent 2
Test animals
- Species:
- rat
- Strain:
- other: Charles River COBS CD
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Portage, MI, USA
- Age at study initiation: F0, 8-9 weeks old; F1, 5-7 weeks old; F2, 5-7 weeks old; F3, 22 days old
- Weight at study initiation: not reported
- Fasting period before study: none
- Housing: individually housed in wire mesh cages throughout the study, except during mating period when males and females co-habited (1:1).
- Housing during parturition: between gestational day (GD) 20 and lactational day (LD) 4, pregnant dams were individually housed in plastic cages with wood chips supplied for nesting materials.
- Diet: Purina Certified Rodent Chow No. 5002 ad libitum except during exposures
- Water : provided ad libitum - no other details
- Acclimation period: parents - 2-3 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): not reported
- Humidity (%): not reported
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): not reported
IN-LIFE DATES: not reported
Administration / exposure
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- other: air
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 16 cubic metre glass and stainless steel chambers
- Method of holding animals in test chamber: not specified
- Source and rate of air: chamber air supplied by HVAC system, separate from general laboratory air handling system
- Method of conditioning air: HVAC system, particulate-filtered and controlled for temperature and humidity.
- System of generating particulates/aerosols: test sample was vaporised with nitrogen through a heated glass column. Vapours diluted with chamber ventilation air to achieve desired exposure levels
- Temperature, humidity, pressure in air chamber: monitored every 30 minutes
- Air flow rate: not reported
- Air change rate: not reported
- Treatment of exhaust air: not reported
TEST ATMOSPHERE
- Brief description of analytical method used: gas-phase infrared spectrometer
- Samples taken from breathing zone: not specified - Details on mating procedure:
- 30 males and females per group were co-housed (1:1) for a 2 week mating period from each of the 3 generations.
F2 parents: due to toxicity, all surviving animals in the high dose group were mated, to produce the F3 generation. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Exposure levels were monitored with a gas-phase infrared spectrophotometer at hourly intervals throughout the study. The accuracy of this method was confirmed by the use of vapour standards. Additionally, the composition (on a weight percentage basis) of the test material within the exposure chamber was determined by gas chromatography during the first exposure week.
- Duration of treatment / exposure:
- 6 hours/day
- Frequency of treatment:
- F0 males: 6 hours per day, 5 days per week for 10 weeks before mating and 5 days/week during the 2 week mating period.
F0 females: 6 hours per day, 5 days per week for 10 weeks before mating, 5 days per week during mating, daily during pregnancy (gestational day 0 to 20) and daily from postnatal day 5 (LD5) until weaning (LD 21).
F1 males : no exposure after weaning until 5-7 weeks of age then 6 hours per day, 5 days per week for 10 weeks before mating and 5 days/week during the 2 week mating period.
F1 females: no exposure after weaning until 5-7 weeks of age then 6 hours per day, 5 days per week for 10 weeks before mating, 5 days/week during mating, daily during pregnancy (gestational day 0 to 20) and daily from postnatal day 5 (LD5) until weaning (LD 21).
F2 males : From postnatal day 22, 6 hours per day, 5 days per week for 10 weeks before mating and 5 days/week during the 2 week mating period.
F2 females: From postnatal day 22, 6 hours per day, 5 days per week for 10 weeks before mating, 5 days/week during mating, daily during pregnancy (gestational day 0 to 20) and daily from postnatal day 5 (LD5) until weaning (LD 21). - Details on study schedule:
- - Age at start of 10 week exposure period: F0, 8-9 weeks; F1, 5-7 weeks; F2, 22 days.
- Random selection of parents from F1 generation (30/sex/group) was done approximately 1 week after all had completed weaning on LD21.
The study was extended to a 3rd generation but exposure of the F2 animals used to produce the F3 generation began immediately after weaning (LD 22). Due to concerns about toxicity, 40 animals/sex/group were initially randomised and exposed. 30 animals/sex/group were then randomly selected for mating in the control, 100 and 500ppm groups. Due to the very high number of deaths in the first week at 1500ppm, all surviving animals were mated to produce the F3 pups.
- Age at mating of the mated animals in the study: F0, 18-19 weeks; F1, 15-17 weeks; F2, 14 weeks .
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
0, 100, 500 and 1500 ppm
Basis:
other: target concentrations
- Remarks:
- Doses / Concentrations:
0, 103 ± 2.1,495 ± 8.0, 1480 ± 20.5 ppm
Basis:
analytical conc.
- Remarks:
- Doses / Concentrations:
0, 107±2.4, 513±12.8 and 1483±33.0 ppm
Basis:
other: nominal concentration
- No. of animals per sex per dose:
- Exposure groups: 3 groups plus control group.
F0: 30 males caged with 30 females/group;
F1: 30 males caged with 30 females /group;
F2: 30 males caged with 30 females in control, low and mid dose groups, all survivors (4 males and 6 females) mated in high dose group. - Control animals:
- other: exposed to air only
- Details on study design:
- - Dose selection rationale: dose levels based on previous developmental and reproductive toxicity studies in rats of Aromatol, a branded product conforming to the specifications of High Flash Aromatic Naphtha.
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: recorded weekly until confirmation of mating
Females were also weighed on gestational days 0, 7, 14 and 21 and lactational days 0, 7, 14 and 21
FOOD CONSUMPTION: Yes
- Food consumption was measured weekly except during mating, gestation and lactation
- Oestrous cyclicity (parental animals):
- No information
- Sperm parameters (parental animals):
- No information
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter (4/sex/litter as nearly as possible); excess pups were killed and discarded.
PARAMETERS EXAMINED
The following parameters were examined in F1 / F2 / F3 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain.
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead. - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals at the end of the mating period.
- Maternal animals: All surviving animals after weaning.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS
The following organs were weighed: epididymides, lung, ovary, testis, prostate/seminal vesicle and uterus/vagina.
The following organs and tissues were submitted: epididymides, lung, ovary, pituitary, prostate, seminal vesicle, testis, uterus, vagina and regional lymph nodes and were examined microscopically in the control and high dose groups only. Any masses and gross lesions in any groups were examined. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 and F2 offspring not selected as parental animals were sacrificed at 4 days of age.
- These animals and any that died during the lactation period were necropsied and examined for anomalies.
GROSS NECROPSY
- Gross necropsy for anomalies - no further details
- Statistics:
- Fertility indices, sex ratio: Chi-square test criterion with Yates' correction for 2x2 contingency tables.
Parental body weights, maternal body weight changes, organ weights: analysis of variance (one-way), Bartlett's test for homogeneity of variance and appropriate t-test (for equal or unequal variance) using Dunnett's multiple comparison tables.
Mean no liveborn pups/litter, mean pup weight: analysis of variance and appropriate t-test. - Reproductive indices:
- Female mating index, female conception index, female gestation index, male fertility index, cohabitation time required for mating, litter size at birth.
- Offspring viability indices:
- Gestation survival index, postnatal survival index for days 4 and 21.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- effects observed, treatment-related
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- effects observed, treatment-related
Details on results (P0)
F0 females - at 1500 ppm, 7 females died or were killed - 3 prior to mating, 3 during gestation and 1 during lactation.
F1 males & females - at 1500 ppm ataxia was seen in 18 males and 23 females and reduced motor activity was seen in 11 males and 8 females.
F1 females - at 1500 ppm, 6 females died - 3 during exposure, 1 during gestation, 1 during delivery and 1 on day 2 of lactation. One female died in each of the other 3 groups.
F2 males & females - exposures were initiated on day 22 and most animals at 1500 ppm (36/40 males and 34/40 females) died within the first week.
BODY WEIGHT (PARENTAL ANIMALS)
F0 males - body weight gain was significantly reduced at 500 ppm (by (5-7%) and at 1500 ppm (by 14-16%).
F0 females- body weight gain was significantly reduced at 500 ppm (by (5-7%) and at 1500 ppm (by 5-7%).
F1 males & females - mean body weights were less than controls (by 17% and 12%, respectively) at the start of exposure. During exposure, bodyweight gain was reduced by 5-7% in males at 500 ppm, 21-25% in males at 1500 ppm and 9-14% in females at 1500 ppm.
F2 males & females - at 1500 ppm, body weights of survivors were 40% & 35% (males/females) below controls in week 4 and remained 31-38% / 21-30% (males/females) below controls for the remainder of the exposure period.
F2 males& females - at 500 and 100 ppm, body weights were initially lower than controls and remained at similar levels throughout the exposure period.
FOOD CONSUMPTION (PARENTAL ANIMALS)
There were no effects on food consumption at any exposure level in any of the generations.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Male fertility was statistically significantly lower (p< 0.05) at the 1500ppm group in the F1 generation only.
Effect levels (P0)
- Dose descriptor:
- NOAEC
- Effect level:
- 500 ppm (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: Based on severe systemic toxicity at higher dose level. No consistent evidence of reproductive toxicity in the presence of systemic toxicity
- Remarks on result:
- other: Generation: F0, F1, F2, F3 (migrated information)
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Sexual maturation:
- not specified
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Histopathological findings:
- not examined
Details on results (F1)
F2 - the mean number of live offspring/litter and number of live births/number delivered were reduced in the 1500 ppm group but this was associated with unconfirmed matings. Where mating was not confirmed, exposure of the dams continued until delivery.
The fraction of liveborn offspring was slightly but significantly reduced in the high dose group but survival throughout the weaning period was similar to controls.
F3 - there was little evidence of reproductive toxicity even at 1500 ppm, even though there were only 6 litters for evaluation.
CLINICAL SIGNS (OFFSPRING)
No effects.
BODY WEIGHT (OFFSPRING)
F2 - mean body weights were lower in 1500 ppm group from LD7 throughout the rest of the weaning period.
F3- mean bodyweights at 1500 ppm were significantly lower at birth but there were no significant differences at LD4. The reduced birth weight may have been a result of the small size of the dams.
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Exposure to analysed concentrations of 1500 ppm of High Flash Aromatic Naphtha caused toxicity but no consistent evidence of reproductive toxicity.
- Executive summary:
In the first generation parental body weights were significantly reduced at 1500 ppm but reproductive parameters were unaffected. There were no differences in litter size, mean birth weight, or postnatal survival. Once maternal exposures were reinitiated (at day 4L), offspring in the 1500 ppm group gained weight more slowly than controls.
In the second generation parental body weight gain was again reduced at 1500 ppm and, male fertility was lower. Litter size, birth weight, and postnatal survival appeared to be reduced in the 1500 ppm exposure group although this was affected by the inclusion of several litters exposed beyond GD20, until just prior to birth. In these litters, the frequency of live births and mean birth weight was reduced and survival early in lactation was poor. Litters from dams exposed to 1500 ppm to GD20 pup survival was 92.5% compared with 98.7% in controls.
For the third generation, exposure of each rat was continuous (i.e. there was no exposure-free period between weaning and commencement of exposure as in previous generations). In the 1500 ppm group, 88% of the rats died. There was no evidence of fertility or reproductive effects although only 6 litters were available for evaluation at 1500 ppm. Birth weights were lower in the 1500 ppm group although mean body weight at LD4 was not different from control. The toxicity of 1500 ppm in this generation precludes definitive evaluation of the potential for reproductive effects and clarification of the results obtained in the previous generation.
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