Registration Dossier

Administrative data

Description of key information

Available data for one stream within this category (CAS 68516-20-1) and data on specific components (benzene, buta-1,3 -diene, toluene, n-hexane, naphthalene, isoprene and cyclohexane) that are present in some streams indicate that acute toxicity is expected to be low. CAS 68516-20-1 did not pose an acute hazard following oral or dermal (LD50 > 5000 mg/kg) or acute inhalation (4 hour LC50 > 20 mg/L) exposures. Xylenes are considered to be hazardous following inhalation and dermal exposure. Dicyclopentadiene is considered to be hazardous following oral and inhalation exposure. 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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant, guideline study, available as unpublished report, minor restrictions in design and/or reporting but otherwise adequate for assessment
Qualifier:
according to
Guideline:
EPA OTS 798.1175 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Sasco, Inc., Omaha, Nebraska, USA
- Sex: 5 males and 5 females
- Age at study initiation: Young adults (less than 12 weeks of age)
- Weight at study initiation: 190-350 g at pre-fast. Weights were within 20% of the group mean
- Housing: Individually in stainless steel, wire mesh bottom cages
- Diet: Agway Rodent Feed ad libitum, except overnight prior to dosing
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature: 64-79°F
- Humidity: 40-70%
- Air changes: At least 10/hr
- Photoperiod: 12hrs dark / 12hrs light

IN-LIFE DATES: From: 23 February 1990 To: 26 February 1990
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
- Undiluted test article was administered by oral gavage.
- Individual dosing volumes were adjusted based on the density of the test article and the animal's fasted bodyweight.
Doses:
5000 mg/kg to each animal
No. of animals per sex per dose:
5 per sex
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 4 days
- Frequency of observations and weighing: Observations were made hourly for the first 4 hours immediately after dosing and twice daily (a.m. and p.m.) for the next 4 days - a total of 5 days of observation.
- Necropsy of survivors performed: yes. Animals dying on test also underwent a post mortem examination.
- Other examinations performed: Animal body weights were recorded on arrival, the day before dosing (pre-fast), the day of dosing (fasted) and at animal death.

Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Remarks on result:
other: 1/10 mortalities at 5000 mg/kg
Mortality:
0/5 males, 1/5 females (day 3)
Clinical signs:
All of the animals on study exhibited one or more of following: oral / nasal / ocular discharge, tremors, ataxia, abnormal stools, lethargy, moribund, stained coat, alopecia, hunched posture.
Body weight:
No effects.
Gross pathology:
One animal had alopecia in abdominal area, one had staining in the nasal and perineal regions
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral LD50 for E000144700 is greater than 5000 mg/kg.
Executive summary:

The acute oral toxicity of E000144700 (CAS 68516 -20 -1) was determined in a group of 5 male and 5 female rats administered a single dose of undiluted test substance at a dose of 5000 mg/kg. One of the animals died and adverse clinical signs including oral / nasal / ocular discharge, tremors, ataxia, abnormal stools, lethargy, moribund, stained coat, alopecia, hunched posture were observed.

The acute oral LD50 is greater than 5000 mg/kg and no classification is warranted under GHS/CLP.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw
Quality of whole database:
Adequate information is available to characterise the short-term hazards of these streams.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
20 000 mg/m³
Quality of whole database:
Adequate information is available 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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant, guideline study, available as unpublished report, minor restrictions in reporting but otherwise adequate for assessment
Qualifier:
according to
Guideline:
EPA OTS 798.1100 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
occlusive dressing used
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Camm Research, Wayne, New Jersey, USA
- Sex: 5 males and 5 females
- Age at study initiation: Young adult
- Weight at study initiation: Approximately 2.0-3.0 kg.
- Housing: Individually in stainless steel, wire mesh bottom cages
- Diet: Agway rabbit food ad libitum
- Water: ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature: 61-70°F
- Humidity: 40-60%
- Air changes: At least 10/hour
- Photoperiod: 12 hrs dark / 12 hrs light
IN-LIFE DATES: From: 6 March 1990 To: 20 March 1990
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: dorsal (size of application area not reported)
- Type of wrap if used: Occlusive (no further details reported)

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg
- Constant volume or concentration used: yes (Individual dose volumes were adjusted based on the density (0.9145 g/mL) and the animal's bodyweight).
Duration of exposure:
24 h
Doses:
2000 mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of weighing: On arrival, the day of dosing, week 1 and at termination
- Clinical observations made hourly for first 4 hours after dosing, and twice (a.m. and p.m.) for the following 13 days.
- Necropsy of survivors performed: yes
Statistics:
Not required
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Remarks on result:
other: no mortality or evidence of systemic toxicity at only dose tested
Mortality:
No mortalities.
Clinical signs:
All animals on study exhibited one or more of following: oedema, erythema, eschar and dried skin at test site, abnormal stools.
Body weight:
All animals gained weight during the study.
Gross pathology:
All animals exhibited one or more of following: oedema, erythema, eschar and dried skin at test site.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute dermal LD50 for E000144700 is greater than 2000 mg/kg.
Executive summary:

The acute dermal toxicity of E000144700 (CAS 68516-20-1) was assessed in a group of 5 male and 5 female albino rabbits. The test substance was applied at 2000 mg/kg under an occlusive dressing for 24 hours. None of the animals died and there were no significant signs of systemic toxicity.

The acute dermal LD50 for E000144700 (CAS 68516-20-1) is greater than 2000 mg/kg and no classification is warranted under GHS/CLP.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Adequate information is available to characterise the short-term hazards of these streams.

Additional information

Human information

Non-human information

Acute oral, dermal and inhalation toxicity data are available on the stream CAS 68516-20-1. These data indicate low toxicity with LD50 values in rats > 2000 mg/kg and no acute inhalation toxicity at the highest achievable concentrations. Data on the components benzene, toluene, n-hexane, 1,3-butadiene, naphthalene, isoprene and cyclohexane, indicate that no classification is warranted on the basis of acute lethality following exposure via oral, dermal or inhalation routes. However, toluene produces unsteady gait and other indications of neurobehavioural activity at concentrations < 20 mg/L justifying H336. n-Hexane is also classified as H336. Mixed xylenes are considered to be harmful following acute dermal and inhalation exposures and are classified as H312 and H332. Dicyclopentadiene is harmful by the oral route with an LD50 value of 590 mg/kg which justifies classification Category 4 (H302) under CLP (Harmonised classification). The calculated dicyclopentadiene 4 hr LC50 of 1972 mg/m3 justifies classification as Category 2 classification under CLP H330 (Fatal if inhaled).Dicyclopentadiene is of low toxicity with an LD50 greater than 2000 mg/kg and therefore does not warrant classification under CLP.

Human information

There are no specific studies on the oral, inhalation or dermal toxicity in humans for streams in this category.

Data from human exposures that provide information on acute exposures that are of value to the risk assessment process are available for benzene, styrene, DCPD, hexane, toluene, and naphthalene:

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, 2008b). 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.

Styrene (Classification: Category 4, H332): Styrene is classified in Annex VI of the CLP regulation as being harmful if inhaled.

Dicyclopentadiene (Classification: Category 4, H302; Category 2, H330). Dicyclopentadiene is classified in Annex VI of the CLP regulation as being harmful if swallowed or inhaled. The available animal data indicate that the substance is fatal inf inhaled.

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

Toluene (Classification: Category 1, H304; Category 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).

Naphthalene (Classification: Category 4, H302) The EU RAR (2003b) concluded “Naphthalene is of low toxicity in rats, with mice being more sensitive. It appears that rodents are not suitable animal models for the acutely toxic human health effects of naphthalene in relation to haemolytic anaemia. Thus, while the LD50 results from the rat suggest relatively low acute toxicity in this species, the available information in humans indicates significant toxicity. Very severe haemolytic anaemia occurred in one case report (of a 16 year old female) at an estimated single oral dose of approximately 6 g. It is possible that this represents a lethal dose given that a number of blood transfusions were required.”

 

Justification for selection of acute toxicity – oral endpoint Acute oral toxicity data on category stream and the marker substances present indicate LD50 values greater than 2000 mg/kg. Results obtained for the key component 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 category stream and most marker substances present indicate LC50 values greater than 20 mg/l. Results obtained for the key component 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 stream and marker substances present indicate LD50 values greater than 2000 mg/kg. Results obtained for the key component 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

There are sufficient data on tested streams to indicate that High Benzene Naphtha streams are of low acute toxicity by the oral, inhalation, and dermal routes and do not warrant classification for these end-points under the CLP Regulation. However, some of the consituents in the streams are classified under GHS/CLP, therefore classifications will apply as described below:

High Benzene Naphtha streams that contain ≥25% naphthalene and/ or DCPD will justify the following classification: acute oral toxicity Category 4 H302 under Reg (EC) 1272/2008. Streams that contain ≥25% DCPD will justify classification: acute inhalation toxicity Category 2 H330. Streams that contain ≥25% Xylene and/or Ethylbenzene and/ or Styrene will justify a classification: acute inhalation toxicity Category 4 H332.Streams that contain ≥25% Xylene will justify a classification: acute dermal toxicity Category 4 H312.

It is assumed that High Benzene Naphtha streams will meet the low kinematic viscosity requirements or contain ≥10% of constituents that are classified as H304. Therefore, it is proposed that all streams are classified as Aspiration toxicity Category 1, H304 under Reg (EC) 1272/2008.

High Benzene Naphtha streams that contain ≥20 % of constituent(s) classified as H336 will justify classification as STOT SE Category 3 H336 (may cause drowsiness or dizziness), under Reg (EC) 1272/2008.