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EC number: 265-099-7 | CAS number: 64741-98-6 A complex combination of hydrocarbons obtained as the extract from a solvent extraction process. It consists predominantly of aromatic hydrocarbons having carbon numbers predominantly in the range of C7 through C12 and boiling in the range of approximately 90°C to 220°C (194°F to 428°F).
- 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
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: GLP compliant, guideline animal experimental study, published in peer reviewed literature, no restrictions, fully adequate for assessment.
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 2 007
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- EPA OTS 798.4350 (Inhalation Developmental Toxicity Screen)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Toluene
- EC Number:
- 203-625-9
- EC Name:
- Toluene
- Cas Number:
- 108-88-3
- Molecular formula:
- C7H8
- IUPAC Name:
- toluene
- Details on test material:
- - Source: BDH Ltd, Poole, Dorset, UK
- Purity: 99.9%
- Physical state: clear colourless liquid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl: CD (SD) BR VAF/Plus
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: 9-10 wk
- Weight at study initiation: 170-229 g
- Diet: ad libitum except during exposure
- Water: ad libitum except during exposure
ENVIRONMENTAL CONDITIONS
- Temperature: 20±2°C
- Humidity: 60 ± 20%
- Air changes (per hr): not reported
- Photoperiod: 12hrs dark / 12hrs light
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
Toluene vapour generated by metering toluene from a central pressurised reservoir onto a sintered glass disc contained within a glass vessel through which dried, filtered air was flowed. The resulting vapour was introduced into the inlet duct of the exposure chamber.
At the end of 6 h exposure, chambers were cleared with clean air for 20 min, after which test animals were removed to their holding cages. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- TEST ATMOSPHERE
Chamber atmospheres analysed approximately hourly during exposure and analysed by GC-FID. Nominal concentration calculated daily, by dividing weight of test material used by total airflow in chambers during exposure.
Target and achieved chamber concentrations were similar throughout the exposure period; analysed concentrations were within 1-4% of nominal.
Homogeneity of chamber atmospheres was verified during pre-exposure trials by sampling from seven different locations within each chamber. - Details on mating procedure:
- - Mating: time mated to males (14-15 wk old) of the same strain
- Proof of pregnancy: sperm in vaginal smear or presence of a vaginal plug - Duration of treatment / exposure:
- 6 h/day
- Frequency of treatment:
- gestation day 6-15 (GD 6-15) where day of positive smear/vaginal plug was taken as day gestation day 0 (GD0)
- Duration of test:
- 20 days
- No. of animals per sex per dose:
- 25 females per group
- Control animals:
- yes, sham-exposed
- Details on study design:
- RATIONALE FOR DOSE SELECTION
12 presumed-pregnant females/group exposed (whole body) to 0, 500, 1000, 2000, 3500 or 5000 ppm toluene for 6 h/day on GD 6-15 as part of a range-finding study. Dose-related maternal and developmental toxicity at exposures of ≥2000 ppm, including decreased maternal and foetal body weight and post-implantation loss.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS:
Dams observed twice daily before and after exposure for clinical signs, changes in general appearance and mortality.
During exposure, 8 different animals were observed each day at half-hour intervals in the inhalation chamber. Cage positions were rotated daily to assure uniform exposure of all rats. Any altered behavioural signs and response to tapping on the chamber wall (to monitor alertness) were recorded.
BODY WEIGHT:
Presumed pregnant rats were weighed on GD0, 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20. Final GD20 bodyweights were corrected for gravid uterine weight.
FOOD CONSUMPTION:
Food consumption was measured from weigh day to weigh day, beginning on GD0.
WATER CONSUMPTION:
Water consumption was monitored daily.
POST-MORTEM EXAMINATIONS:
Killed on GD20 - gross abnormalities assessed. - Ovaries and uterine content:
- Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Uteri from females that appeared non-gravid and individual uterine horns without visible implantations were opened and placed in 10% ammonium sulphide solution for visualisation of implantation sites. - Fetal examinations:
- - External examinations: all per litter
- Soft tissue examinations: half per litter
- Skeletal examinations: half per litter - Statistics:
- Statistical methods included: ANOVA followed by intergroup comparisons using Williams' or Shirley’s tests - body weight, adjusted maternal body weight, maternal body weight changes, water and food consumption; Kruskal-Wallis test with Shirley's test or t-tests - mean number of corpora lutea, implantations, pre- and post-implantation loss, early and total foetal death, live foetuses, litter weight, mean foetal weight, gravid uterus weight, sex ratio, and most sternebral variants; mixed model ANOVA using litter as the basis for analysis- foetal body weights.
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
3000 ppm: Ataxia, hunched posture, uncoordinated gait, limb tremor, closed eyelids, hyper-responsivity, increased water intake, decreased food consumption and reduced maternal body weight gain from initiation of exposure to GD20.
1500 ppm: Ataxia, hunched posture, uncoordinated gait, closed eyelids, hyper-responsivity and reduced maternal body w eight gain during the exposure period only (GD6-15).
Effect levels (maternal animals)
open allclose all
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 750 ppm (nominal)
- Basis for effect level:
- other: maternal toxicity
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 2 812 mg/m³ air (nominal)
- Basis for effect level:
- other: maternal toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
Gravid uterus weight, mean litter weight and mean foetal body weights were statistically significantly lower than controls at 3000 ppm and there was a higher incidence of unossified or reduced sternebra. Mean foetal bodyweights were statistically significantly decreased at 1500 ppm and a slightly increased incidence of sternebral variants (unossified, reduced).
No malformations occurred in the control or 750 ppm group animals, however, the incidence of total events in the 250, 1500 and 3000 ppm groups was increased significantly. Soft tissue anomalies occurred most frequently in controls. Skeletal anomalies occurred at similar incidences in all groups other than 750 ppm. The most frequent observation involved reduced and/or no ossification of sternebrae (primarily 5 and 6) in foetuses from groups 250, 1500 and 3000 ppm (statistically significant, for 1500 and 3000 ppm groups).
Effect levels (fetuses)
open allclose all
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 750 ppm (nominal)
- Basis for effect level:
- other: Developmental Toxicity
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 2 812 mg/m³ air (nominal)
- Basis for effect level:
- other: Developmental Toxicity
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
Adjusted maternal bodyweight (ie excluding uterine contents) on GD20:
(Table based on Roberts LG et al, 2007, Reproductive Toxicology 23, 521-531,Table 3)
0 (control) (n=24) |
250 ppm (n=22) |
750 ppm (n=20) |
1500 ppm (n=19) |
3000 ppm (n=22) |
|
Mean adjusted maternal bodyweight (g) |
270 |
273 |
271 |
274 |
249** |
Mean maternal body weight change (g):
(Table based on Roberts LG et al, 2007, Reproductive Toxicology 23, 521-531,Table 3)
Gestation day |
0 (control) (n=24) |
250 ppm (n=22) |
750 ppm (n=20) |
1500 ppm (n=19) |
3000 ppm (n=22) |
0 - 6 |
31.3 |
31.8 |
33.8 |
36.1 |
34.1 |
6 - 10 |
18.8 |
19.9 |
16.5 |
12.3** |
- 4.5** |
6 - 16 |
55.1 |
56.9 |
52.0 |
47.4* |
20.6** |
16 - 20 |
50.4 |
50.9 |
49.4 |
53.6 |
53.9 |
6 - 20 |
105.5 |
107.8 |
100.4 |
101.3 |
74.4** |
* P 0.05; ** P0.01
Incidence of malformations and anomalies
There were no increases in the incidence of specific or total malformations with increased exposure and low incidences (<2.5%) of malformations in toluene exposed groups were considered to be incidental to treatment.
Summary of reproduction and mean foetal weight data:
There were no adverse effects on implantations, number and viability of foetuses or foetal sex distribution.
Table based on Roberts LG et al, 2007, Reproductive Toxicology 23, 521-531,Table 4
0 (control) |
250 ppm |
750 ppm |
1500 ppm |
3000 ppm |
|
No. females mated |
25 |
25 |
25 |
25 |
25 |
No. pregnant (%) |
24 (96) |
22 (88) |
20 (80) |
19 (76) |
23 (92) |
No. with viable foetuses |
24 |
22 |
20 |
19 |
22 |
Corpora lutea |
14.0 |
14.4 |
14.6 |
14.9 |
14.8 |
Implantation sites |
12.0 |
13.3 |
12.2 |
13.4 |
13.6 |
Gravid uterus weight (g) |
66.7 |
64.7 |
61.5 |
62.5 |
58.6 |
Pre-implantation loss index % (mean) |
8.3 |
7.5 |
16.6 |
9.5 |
8.1 |
No. viable foetuses |
293 |
272 |
233 |
236 |
277 |
Foetal deaths (mean) |
0.6 |
0.9 |
0.5 |
1.0 |
1.0 |
Post-implantation loss % (mean) |
5.3 |
7.0 |
4.7 |
7.6 |
7.2 |
Mean litter size |
12.2 |
12.4 |
11.7 |
12.4 |
12.6 |
No. litters with resorptions % |
9 |
11 |
7 |
10 |
13 |
Sex distribution (% males) |
47.6 |
50.5 |
45.2 |
45.3 |
48.4 |
Mean litter weight (g) |
41.4 |
41.0 |
39.8 |
39.7 |
37.9* |
Mean body weight of viable foetuses |
3.47 |
3.32* |
3.44 |
3.20** |
3.02** |
male |
3.59 |
3.41* |
3.50 |
3.29** |
3.10** |
female |
3.39 |
3.23 |
3.38 |
3.13** |
2.93** |
Pre-implantation loss = (corpora lutea - implants) / (corpora lutea) Post-implantation lost = (implants - live foetuses) / (implants) * P 0.05; ** P0.01 |
Foetal sternebral variants
There were slightly increased incidences of unossified sternebra at 3000 and 1500ppm.
Table based on Roberts LG et al, 2007, Reproductive Toxicology 23, 521-531,Table 7
Toluene concentration (ppm) |
|||||
|
0 |
250 |
750 |
1500 |
3000 |
No. of litters |
24 |
22 |
20 |
19 |
22 |
Foetuses examined |
146 |
131 |
116 |
116 |
138 |
Sternebral variants - Unossified (No./Mean %) |
55/37 |
57/44 |
48/37 |
65/53 |
83/60* |
Sternebral variants - Reduced (No./Mean %) |
37/29 |
60/45 |
36/31 |
49/44 |
61/45* |
Sternebral variants - Total with variants (No./Mean %) |
77/55 |
94/72 |
69/57 |
89/75* |
106/77 |
* P 0.05
Applicant's summary and conclusion
- Conclusions:
- The maternal NOAEC for toluene in pregnant Sprague Dawley rats, exposed whole-body during gestational days 6-15 (inclusive), 6h/day, was 750 ppm (2812 mg/m3). The foetal NOAEC was 750 ppm (2812 mg/m3).
- Executive summary:
The developmental toxicity of toluene was evaluated following whole body inhalation (6 h/day) in pregnant Sprague Dawley rats exposed to toluene (99.9% pure) at concentrations of 0, 250, 750, 1500 or 3000 ppm from GD6-15. Doses were selected based on a preliminary study performed over a range of concentrations from 0 to 5000 ppm in which maternal and foetal toxicity was observed at 2000 ppm and above.
Toluene induced clinical signs in pregnant dams included ataxia, hyper-responsivity, increased water intake, decreased food consumption and lower body weight gain at 3000 ppm. At 1500 ppm ataxia, hyper-responsivity and reduced body weight gain during the exposure period were seen. There were no adverse effects on implantation number, foetal viability or foetal sex distribution at caesarean section on GD20. Litter weight and mean foetal weight was reduced at 3000 ppm and mean foetal weight was lower at 1500 ppm. Instances of reduced or unossified skeletal elements occurred at the same dose levels. Low incidences (2.5%) of various malformations occurred in the 250, 1500 and 3000 ppm groups, however, there was no exposure-related increase in the incidence of specific or total malformations and thus these findings were not attributed to toluene.
Based on these observations the NOAEC for maternal toxicity and for foetal toxicity was 750 ppm (2812 mg/m3).
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