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Description of key information

No specific acute toxicity data are available on any of the streams within this category (CAS Numbers; 102110-14-5, 64741-84-0, 64742-49-0, 68476-55-1, 92128-65-9). However there are data on constituents present in some streams which indicate that acute toxicity is expected to be low and that Aliphatics and Cyclics C5 and Higher streams do not pose an acute hazard following ingestion (oral LD50 > 2000 mg/kg), skin contact (dermal LD50 > 5000 mg/kg) or acute inhalation (4 hour LC50 > 20 mg/L) exposures. Following acute exposures to toluene in humans a number of subjective sensations such as headache, dizziness, feeling of intoxication, irritation and sleepiness and decreases in acute neurobehavioural performance are seen. The NOAEC for acute neurobehavioural effects in humans is 50 ppm (188 mg/m3).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study from the literature, (pre-GLP), in which the test parameters documented do not totally comply with the specific testing guideline, but are sufficient to accept the data and well documented and scientifically acceptable
Reason / purpose for cross-reference:
data waiving: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
Pre-guideline. Used one sex for some age groups
GLP compliance:
not specified
Test type:
other:
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight: young adult rats (80-160 g); older adult rats (300-470 g).
- Not fasted prior to dosing
- Dosed by gavage

ENVIRONMENTAL CONDITIONS
- no data

IN-LIFE DATES: no data
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Doses:
No details of actual doses reported
No. of animals per sex per dose:
Groups of 6 males were used for studies in the young and older adult rats.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 7days
- Frequency of observations and weighing: not reported
- Necropsy of survivors performed: no
- Other examinations performed: none reported
Statistics:
LD50 and associated confidence limits were calculated both by the method of Litchfield and Wilcoxon and by a probit analysis statistical program. Parallel probit analyses were carried out on the LD50 values to compare the potencies within the age groups.
Sex:
male
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Remarks on result:
other: young and older adults had LD50 of 3.8 (2.9-4.8) and 5.6 (4.0-7.8) mL/kg respectively

Acute oral LD50 in mL/kg (95% CL)

Young adults:  3.8 (2.9 -4.8)

Older adults : 5.6 (4.0 -7.8)

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Acute oral LD50 for adult rats >2000mg/kg
Executive summary:

Acute oral toxicity was determined in groups of at least 6 rats per age and dose level. Benzene was demonstrated to be of low acute oral toxicity (LD50 >2000 mg/kg) and does not warrant classification under Dir 67/548/EEC or GHS

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Studies in rats demonstrate that the oral LD50 for benzene exceeds 2000 mg/kg bw.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non GLP near guideline study available as unpublished report (in German) but otherwise fully adequate for assessment.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: air
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
Nominal: 7, 31.6, 52.2, 78.3, 104.4 mg/L
Analysed: 6.08, 20.00, 23.98, 38.87, 61.80 mg/L
No. of animals per sex per dose:
10
Control animals:
no
Statistics:
Probit analysis based on Finney (1971)
Sex:
male/female
Dose descriptor:
LC50
Effect level:
28.1 mg/L air (analytical)
Exp. duration:
4 h
Remarks on result:
other: 5/20 mortalities at 23.98 and 18/20 mortalities at 38.87 mg/L
Sex:
male
Dose descriptor:
LC50
Effect level:
25.7 mg/L air (analytical)
Exp. duration:
4 h
Remarks on result:
other: 3/10 mortalities at 23.98 and 10/10 at 38.87 mg/L
Sex:
female
Dose descriptor:
LC50
Effect level:
30 mg/L air (analytical)
95% CL:
>= 25.5 - <= 36.8
Exp. duration:
4 h
Remarks on result:
other: 2/10 mortalities at 23.98 and 8/10 mortalities at 38.87 mg/L
Mortality:
Mortality at 6.08, 20.00, 23.98, 38.87, 61.80 mg/L
Males: 0/10, 1/10, 3/10, 10/10, 10/10
Females: 0/10, 1/10, 2/10, 8/10, 10/10
Clinical signs:
other: Animals showed watery discharge from eyes and nose, unrest, increased respiration, rocking gait, narcosis, startling movements and hyperaemia of the ears and extremities. In the highest exposure group, salivation was observed. In the group exposed to 6.08
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Acute inhalation LC50 > 20 mg/L
Executive summary:

Acute inhalation toxicity of toluene was investigated in 5 groups of 10 male and female rats exposed for 4 hours at concentrations of 6.08, 20.00, 23.98, 38.87 or 61.80 mg/L.

Adverse clinical signs and mortality were seen at concentrations of 20 mg/L and above. All surviving animals were normal by day 3. The LC50 exceeded 20 mg/L (25.7 mg/L in males, 30 mg/L in females).

Toluene does not warrant classification under Dir 67/548/EEC or GHS.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
25 700 mg/m³ air
Quality of whole database:
Adequate information is available on the constituents to characterise the short-term hazards of these streams.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-guideline, non-GLP, animal experimental study, published in peer-reviewed literature. Pre-dates implementation of GLP and guideline but otherwise acceptable for assessment
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
according to guideline
Guideline:
other: 21 CFR 191.10
Deviations:
yes
Remarks:
rabbit skin abraded, animals not immobilised for 24 hours, 4 rabbits/group, no mortality or clinical observations/ bodyweight or gross necropsy results reported. Guinea pigs also tested.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
other: guinea pig and rabbit
Strain:
other: Hartley-derived guinea pigs, white rabbits
Sex:
male/female
Details on test animals or test system and environmental conditions:
Guinea pigs: male Hartley-derived, 400-900 g
Rabbits: male or female (not specified) white, 1-4 kg
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Duration of exposure:
24 hours
Doses:
A minimum of 3 doses used - details not reported
No. of animals per sex per dose:
4 animals/dose (sex not specified)
Control animals:
not required
Details on study design:
No other data available
Statistics:
LD50 was calculated by the method of Finney
Sex:
not specified
Dose descriptor:
LD50
Effect level:
> 9.4 mL/kg bw
Remarks on result:
other: rabbit abraded skin
Sex:
male
Dose descriptor:
LD50
Effect level:
> 9.4 mL/kg bw
Remarks on result:
other: guinea pig intact skin
Sex:
male
Dose descriptor:
LD50
Effect level:
> 9.4 mL/kg bw
Remarks on result:
other: guinea pig abraded skin
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute dermal LD50 for benzene in the rabbit (applied to abraded skin) and the guinea pig (applied to intact abdominal or abraded back skin) was determined to be >9.4 mL/kg (8260 mg/kg) bodyweight.
Executive summary:

The acute dermal LD50 for benzene was determined in groups of 4 rabbits (abraded skin) or guinea pigs (abraded back skin or non-abraded abdominal skin) using occlusive dressings. 

The acute dermal LD50 was >9.4 mL/kg (8260 mg/kg) in each case.

In conclusion, benzene is of low acute dermal toxicity and does not warrant classification under Dir 67/548/EEC or GHS.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
8 260 mg/kg bw
Quality of whole database:
Adequate information is available on the constituents to characterise the short-term hazards of these streams.

Additional information

Non-human information

Acute toxicity of streams in this category is expected to be low. There are no specific studies on the streams (CAS Numbers; 102110-14-5, 64741-84-0, 64742-49-0, 68476-55-1, 68956-55-8, 92128-65-9). Acute oral toxicity data on the specific constituents benzene (Kimura et al, 1971), toluene (Withey and Hall, 1975), n-hexane, cyclohexane and xylenes indicate oral LD50 values in rats of > 2000 mg/kg. Acute inhalation toxicity on the specific constituents benzene (Drew and Fouts, 1974), toluene (BASF, 1980), n-hexane, cyclohexane and xylenes indicate acute inhalation LC50 values in rats of > 20 mg/L. Acute dermal toxicity on the specific constituents benzene (Roudabush et al, 1969), toluene (Smyth et al, 1969) indicate acute dermal LD50 values in rats of > 5000 mg/kg.

Human information

There are no specific studies on the oral, inhalation or dermal toxicity in humans for streams in this category. Human data on oral toxicity indicate that ingestion of 15 mL (176 mg/kg bw) benzene can cause death after collapse, bronchitis and pneumonia (EU RAR, 2003). Similar effects are expected with other constituents of the streams and the viscosity and surface tension are likely to be sufficiently low that streams in this category should be considered as aspiration hazards.

Data from occupational exposure and/or volunteer studies that provide information on acute exposures that are of value to the risk assessment process are available for benzene and toluene:

Benzene (Classification: Category 1, H304): Human data on oral toxicity indicate that ingestion of 15 mL (176 mg/kg bw) benzene can cause death after collapse, bronchitis and pneumonia (EU RAR, 2008). Exposure for 5-10 minutes to benzene vapours of 65-61 mg/L is fatal and exposure to 25 mg/L for 30 minutes is dangerous to life, while a one-hour exposure to 1.6 mg/L causes only some symptoms of illness.

Toluene (Classification: Category 1, H304, Cat 3 H336): The acute effects of toluene inhalation exposure include headache, dizziness, feeling of intoxication, irritation and sleepiness and decreases in acute neurobehavioural performance at concentrations ≥ 75 ppm (EU RAR, 2003). A NOAEC of 50 ppm (188 mg/m3) can be determined for acute neurobehavioural effects in humans (Muttray et al, 2005).

Cyclohexane (Classification: Category 1, H304, Cat 3 H336):

Cyclohexane is of low acute toxicity by the oral (LC50 >5,000 mg/kg), inhalation (4 h LC50 >32,880 mg/m3) or dermal (LD50 >2,000 mg/kg) routes. Cyclohexane is classified in Annex VI of the CLP regulation as having a potential for aspiration if swallowed and CNS depression if inhaled.

Heptane (Classification: Category 1, H304, Cat 3 H336): Heptane is classified in Annex VI of the CLP regulation as having a potential for aspiration if swallowed and CNS depression if inhaled.

Isoprene: The oral LD50 of isoprene is reported as 2125 mg/kg (range of 2,043 to 2,210 mg/kg) and the 4-hour inhalation LC50 in rat is 180,000 mg/m3and 2-hour LC50 in the mouse is 157,000 mg/m3. The dermal LD50 of isoprene is >679 mg/kg (> 1mL/kg). Considering read-across from 2 -methyl-2 -butene (structurally similar to isoprene), it is considered that weight of evidence suggest an LD50 in excess of 2000 mg/kg.

References:

EU RAR (2003). European Union Risk Assessment Report for Toluene. EC Joint Research Centre http: //ecb. jrc. ec. europa. eu/DOCUMENTS/Existing- Chemicals/RISK_ASSESSMENT/REPORT/toluenereport032. pdf

EU RAR (2008). European Union Risk Assessment Report for Benzene. EC Joint Research Centre. http: //ecb. jrc. ec. europa. eu/documents/Existing-chemicals/RISK_ASSESSMENT/REPORT/benzenereport063. pdf.


Justification for selection of acute toxicity – oral endpoint
Acute oral toxicity data on the marker substances present indicate LD50 values greater than 2000 mg/kg. Results obtained for the key constituent benzene (LD50 = 3.8 ml/kg bw, equivalent to 3310 mg/kg bw based on density = 0.87) are considered indicative of the overall short term effects of these streams following ingestion. The EU RAR concluded "depending on the dose the main clinical signs are sedation and hind-limb paralysis".


Justification for selection of acute toxicity – inhalation endpoint
Acute inhalation toxicity data for the marker substances present indicate LC50 values greater than 20 mg/l. Results obtained for the key constituent toluene (LC50 25700 mg/m3) are considered indicative of the overall short term effects of these streams after inhalation.

Justification for selection of acute toxicity – dermal endpoint
Acute dermal toxicity data on the marker substances present indicate LD50 values greater than 5000 mg/kg. Results obtained for the key constituent benzene (LD50 = 9.4 ml/kg bw, equivalent to 8180 mg/kg bw based on density = 0.87) are considered indicative of the overall short term effects of these streams after skin contact.

Justification for classification or non-classification

Although there are no studies on the streams identified for this category, data from experimental exposure of human volunteers with a number of constituents show that dizziness and sleepiness are experienced at air levels < 20 mg/L which justifies classification Category 3 H336 under Reg (EC) 1272/2008.

The viscosity and surface tension of Aliphatics and Cyclics C5 and Higher streams justifies classification as harmful and should be labelled under Reg (EC) 1272/2008 "Aspiration toxicity Category 1, H304".

Data from experimental exposure of human volunteers with a number of constituents show that dizziness and sleepiness are experienced at air levels < 20 mg/L which justifies classification Category 3 H336 under Reg (EC) 1272/2008.