Registration Dossier

Administrative data

Description of key information

Based on assessment of the available data for 2-methylbut-2-ene (2M2B), the oral LD50 is in the range of 1000 to 1700 mg/kg.  The dermal LD50 is >2000 mg/kg.  The 4-hour LC50 is >175,000 mg/m3.  Inhalation of 2M2B can produce central nervous system depression, anaesthesia and/or asphyxiation that are reversible following cessation of exposures. 

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other: Non-GLP, available as unpublished report, near guideline study, minor restrictions in design and/or reporting but otherwise adequate for assessment
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Shell Toxicology Laboratory, Breeding Unit, Tunstall, UK
- Age at study initiation: 10-11 weeks
- Weight at study initiation: 260-366 g males, 177-248 g females
- Fasting period before study: 18 hours
- Housing: 3-4/cage in hanging polypropylene cages with stainless steel wire mesh floors and tops (33 x 21 x 17 cm)
- Diet: PRD (Labsure Animal Foods Ltd) ad libitum (except for pre-dose fast)
- Water: Filtered public supply ad libitum
- Acclimation period: 4 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: 19-25 °C
- Humidity: 50-60%
- Air changes (per hr): Not reported
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 7 May 1980 To: 18 July 1980
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Doses:
1.0, 1.6, 2.5, 4.0, 6.3 and 10.0 mL/kg
No. of animals per sex per dose:
6
Control animals:
no
Details on study design:
- Dose levels selected following a range-finding test in which 2 rats/sex/group were given a single oral dose at 0.5, 1.0, 5.0 or 10.0 mL/kg.
- Due to volatility of 2-methyl-2-butene, it was stored on ice, temperature of substance at dosing was approximately 5°C.
- Duration of observation period following administration: 14 days.
- Frequency of observations and weighing: Observations daily, weighed on days 7 and 14.
- Necropsy of survivors performed: no
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 - 4 mL/kg bw
Remarks on result:
other: equivalent to 700 - 2600 mg/kg. Further examination of data (SIDS, 2005) places in the range of 1000 - 1700 mg/kg
Mortality:
Cumulative mortality (over 14 days) was 0, 6, 4, 9, 9 and 12 (6 male and 6 females/group) for the 1.0, 1.6, 2.5, 4.0, 6.3 and 10.0 mL/kg dose levels respectively.
Clinical signs:
Virtually all animals, even at the lowest doses, had diarrhoea, bleeding from the anus and piloerection on the day of dosing. Most animals were also lethargic. Most deaths occurred within 3 days and most surviving animals had recovered by day 3. However, there were a few animals in which signs of intoxication persisted for up to a week after dosing.
Body weight:
All but one of the survivors had gained weight at the conclusion of the 14 day observation period.
Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Acute oral LD50 of 2-methyl-2-butene to male and female rats was approximately 1-4 mL/kg (700 - 2600 mg/kg)
Executive summary:

Acute oral LD50 of 2-methyl-2-butene to male and female rats was approximately 1-4 mL/kg (700 - 2600 mg/kg). Further assessment of the data allows refinement to a range of 1000 - 1700 mg/kg (OECD SIDS, 2005).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
1 000 mg/kg bw
Quality of whole database:
Adequate information is available to characterise the short-term hazards of this substance after ingestion

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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant, guideline study, available as unpublished report, no restrictions, fully adequate for assessment
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
EPA OPP 81-3 (Acute inhalation toxicity)
Deviations:
not specified
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Shell Toxicology Laboratory, Tunstall Unit
- Age at study initiation: Approximately 9 weeks
- Weight at study initiation: 302 - 318g (males) and 221 - 239 g (females)
- Fasting period before study: none
- Housing: Individually in hanging stainless steel cages with wire mesh floor and top
- Diet: PRD, Labsure Animal Foods Ltd ad libitum except during exposure
- Water: ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature: Approximately 20°C
- Humidity: Approximately 55%
- Air changes (per hr): no data
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 25 November 1980 to 9 December 1980
Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The test atmospheres were generated by means of a wick-type saturator maintained at 0°C in an ice/water bath, and were supplied to two identical, glass inhalation chambers
- Exposure chamber volume: 7 litres
- Method of holding animals in test chamber: The animals were housed in two 7 litre tubular glass chambers fitted with stainless steel mesh carriers to accommodate five animals each.
- The test atmosphere was supplied to the chambers at a rate in the range 5.0 to 13.5 litres per minute.
- The chambers were located in a fume cupboard together with the atmosphere generator.
- The air flow rate through each chamber was approximately 6 litres min-1.

TEST ATMOSPHERE
- Brief description of analytical method used: The atmospheric concentration of the 2-methyl-2-butene was measured continuously throughout the exposure by means of a MIRAN infra red analyser. The instrument was calibrated by injecting known volumes of test substance into a closed loop recycle system of known volume, which included the 5.6 litre analyser gas cell.
- Samples taken from breathing zone: yes
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
6.1% (v/v) (range 3.3-9.4%) (nominal 61,000 ppm equivalent to 175,000 mg/m3)
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observed for toxic signs continuously for the first 30 min and thereafter at 15 min intervals throughout the exposure. Immediately following exposure, they were observed for 3 hrs at 15 minute intervals. Over the following 14 days, the animals were observed twice daily.
- Initial, 7 day and 14 day body weights were recorded.
- Necropsy of survivors performed: yes
- The current recommendation for the minimum concentration of oxygen in test atmospheres for use in inhalation toxicity testing is 19% (v/v). Whilst larger concentrations of the test substance in air can be generated, a concentration of 9.5% (v/v) test substance would reduce the oxygen content to 19% (v/v).

Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 6.1 other: %
Remarks on result:
other: >175000 mg/m3
Mortality:
None.
Clinical signs:
During the exposure period both male and female rats first became ataxic, this condition also being associated with body tremors. After approximately 40 min of exposure both male and female animals became narcotized whilst exhibiting intermittent movements of front and hind limbs. The animals remained narcotized for the remainder of the exposure period. On removal from the exposure chambers, all the animals regained consciousness within 90 sec although symptoms of ataxia persisted for a further 10 to 15 min. Within 30 min, all the animals had fully recovered and no further signs of toxicity were observed throughout the 14 day observation period.
Body weight:
No effects on body weight.
Gross pathology:
No compound related effects.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute 4 hour inhalation LC50 of 2-methyl-2-butene in rats is greater than 6.1% (v/v) equivalent to 175,000 mg/m3.
Executive summary:

A group of 5 male and 5 female rats was exposed for 4 hours to a test atmosphere containing 6.1% (v/v) 2-methyl-2-butene. During the exposure the animals became narcotized, but revived within 30 min of cessation of exposure. There were no deaths. Macroscopic and microscopic examination of animals killed 14 days after exposure revealed no compound related effects. The acute 4 hour inhalation LC50 of 2-methyl-2-butene in rats is greater than 6.1% (v/v) (175,000 mg/m3).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
175 000 mg/m³
Quality of whole database:
Adequate information is available to characterise the short-term hazards of this substance after inhalation

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-GLP, available as unpublished report, near guideline study, minor restrictions in design and/or reporting but otherwise adequate for assessment
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Shell Toxicology Laboratory, Breeding Unit, Tunstall, UK
- Age at study initiation: 10-11 weeks
- Weight at study initiation: 260-366 g males, 177-248 g females
- Fasting period before study: 18 hours
- Housing: Individually for the duration of the dermal application, 3 per cage thereafter in hanging polypropylene cages with stainless steel wire mesh floors and tops (33 x 21 x 17 cm)
- Diet: PRD (Labsure Animal Foods Ltd) ad libitum (except for the duration of the dermal application)
- Water: Filtered public supply ad libitum
- Acclimation period: 4 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: 19-25 °C
- Humidity: 50-60%
- Air changes (per hr): Not reported
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 7 May 1980 To: 18 July 1980
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: Approximately 60% of the dorsal area.
- Preparation of skin site: 24 hours prior to application site closely shorn with electric clippers.
- Type of wrap if used: Aluminium foil held in place by a double overwrap of waterproof adhesive tape.

DOSING:
- Dose levels selected following a range-finding test in which 2 rats/sex/group were given a single dermal dose at 0.5, 1.0 or 2.0 mL/kg.
- Due to volatility of 2-methyl-2-butene, it was stored on ice, temperature of substance at dosing was approximately 5°C.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Warm dilute detergent.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 3.03 mL/kg bw.
Duration of exposure:
24 hours
Doses:
3.03 mL/kg
No. of animals per sex per dose:
6
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations daily, bodyweights initial, days 7 and 14
- Necropsy of survivors performed: no
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 3.03 mL/kg bw
Remarks on result:
other: >2000 mg/kg
Mortality:
No mortalities
Clinical signs:
Some animals bled from the nose on day 1 and many of the animals had sores and scabs on their backs
Body weight:
All animals gained weight within one week of dosing
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute dermal LD50 of 2-methyl-2-butene to male and female rats was >2000 mg/kg.
Executive summary:

The acute dermal LD50 of 2 -methyl-2 -butene to male and female rats was >3.03 mL/kg (>2000 mg/kg).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
Adequate information is available to characterise the short-term hazards of this substance after skin contact

Additional information

2 -methylbut-2-ene (2M2B) has a low order of acute toxicity in animals by the dermal and inhalation routes of exposure.  It is classifiable as harmful by the oral route of exposure.

Non-human data

Oral

In order to determine the acute oral LD50 of 2M2B a range-finding and definitive study have been performed in albino Wistar rats.

In the definitive study, groups of six males and six females were dosed with 1.0, 1.6, 2.5, 4.0, 6.3 and 10 ml/kg. The majority of deaths occurred within the first 3 days following dosing and most survivors had recovered from signs of intoxication by the third day. The author estimated the oral LD50 to be in the range of 1 to 4 ml/kg (i.e., 700 to 2600 mg/kg) (SRC, 1980).  Further inspection of the data (OECD SIDS, 2005) allows this to be refined to a range of 1.6 to 2.5 mL/kg (1000 to 1700 mg/kg).

Dermal

In order to determine the acute dermal LD50 of 2M2B range-finding and definitive studies have been performed in albino Wistar rats.  The acute dermal LD50 value of 2M2B is >2000 mg/kg (SRC, 1980).

Inhalation

In a limit test, groups of 5 male and 5 female albino Wistar rats were exposed for 4 hours to a test atmosphere containing 61000 ppm (175,000 mg/m3) of 2M2B.  Inhalation of 2M2B can produce symptoms of central nervous system depression, anaesthesia and/or asphyxiation that are reversible following cessation (within 3 minutes) of exposures. There were no deaths and macroscopic and microscopic examination at necropsy of animals killed 14 days post-exposure revealed no compound related effects.  The acute 4 hours inhalation LC50 of 2M2B in rats is >175,000 mg/m3 (SRC, 1982).

Studies in Humans

No human information available

 


Justification for selection of acute toxicity – oral endpoint
Available information indicates that the acute oral LD50 of this substance is in a range 1000 - 1700 mg/kg bw

Justification for selection of acute toxicity – inhalation endpoint
Available information indicates that the acute inhalation LC50 of this substance exceeds 175,000 mg/m3

Justification for selection of acute toxicity – dermal endpoint
Available information indicates that the acute dermal LD50 of this substance exceeds 2000 mg/kg bw

Justification for classification or non-classification

The acute oral LD50 has been concluded to be in the range of 1000 – 1700 mg/kg and therefore 2 -methylbut-2 -ene (2M2B) should be classified as Category 4,H302: Harmful if swallowed under CLP.

 

Based on assessment of the available data, 2M2B does not warrant classification under CLP for acute dermal and inhalation toxicity. In relation to classification under CLP, a Category 3 STOT SE applies: H336: May cause drowsiness and dizziness (relating to the acute inhalation data).

 

Aspiration is a known hazard of hydrocarbons and, although there is no evidence of aspiration hazard from the animal studies considered, classification is based on the physical characteristics of 2M2B which has a kinematic viscosity below the cut off values for CLP of 20.5 mm2/s for hydrocarbons and therefore classification is warranted. Classification as Cat1 (H304: May be fatal if swallowed and enters airways) is warranted.