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Acute Toxicity - Oral LD50 > 4150 mg/Kg in rats (OECD TG 401)


Acute Toxicity - Dermal LD50 > 1700 mg/Kg in rabbits (OECD TG 402)


Acute Toxicity - Inhalation LC50 > 5.28 mg/L (5280 mg/m3) (OECD TG 403)

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
Study period:
1985/07/11-1985/07/31
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: According to OECD 423 guideline. GLP
Justification for type of information:
The justification for read across is provided as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
only one dose tested
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Sex: Males (10); Females (10)
- Weight at study initiation: Males (130-135 g), Females (110-115 g)
- Housing: individual
- Acclimation period: 6d
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
A single dose of BP83HF (5 ml/kg; converted to 4.15 g/kg) was administered by oral gavage. An additional group of 5 males and 5 females were sham - dosed and acted as controls.
Doses:
5 ml/kg (converted to 4.15 g/kg)
No. of animals per sex per dose:
Male (10), Female (10); total animals (20)
Control animals:
yes
Details on study design:
The acute oral toxicity of BP83HF was investigated in a group of 5 male and 5 female CD rats of the Sprague - Dawley strain. Each animal received a single oral dose of 5 ml/kg (converted to 4.15 g/kg) administered by gavage. An additional group of 5 males and 5 females were 'sham - dosed and acted as controls. The condition of all animals was observed over a 14 day period following dosing.
Statistics:
Differences between treated and control group mean values for bodyweight gains were analyzed by Student t-test. When individual variance ratios were significant (P < 0.05), Cochran's approximation was applied (Snedecor and Cochran, 1973) .
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 4 150 mg/kg bw
Remarks on result:
other: (converted from 5 mL/kg bw) no mortality noted
Mortality:
No mortality was observed in any of the animals treated with 5 ml/kg (converted to 4.15 g/kg) of BP83HF.
Clinical signs:
Transient staining of the urogenital region with test material was observed in all test rats within 24 hours of dosing. Slight flaking of the skin on the feet of these, first noted on Day 7, resolved in most animals prior to termination. During days 0-2, a slight reduction of bodyweight gain was recorded for treated male rats when compared with controls, although subsequent weight gain was normal. Females were not similarly affected.
Body weight:
All surviving animals showed an increase in body weight over their initial values at the end of the observation period.
Gross pathology:
Macroscopic post mortem examination of all animals killed at termination (Day 14) revealed no findings considered to be related to treatment. Although a haemorrhagic focus was seen in the fore-stomach of a female dosed with the test material, this lesion was minimal and was considered to be incidental to treatment with the test material.
Interpretation of results:
other: Not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The LD50 for BP83HF following oral gavage was >5 ml/kg (converted to 4.15 g/kg). Classification as an oral toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.
Executive summary:

The acute toxicity of BP83HF was evaluated in rats via oral gavage at a dose of 5 ml/kg bw(converted to 4.15 g/kg). Observations were made as to the nature, onset, severity, and duration of toxicological signs once per day for a total of 14 days. All animals survived the entire observational period and displayed a low incidence of clinical symptoms.  The animals displayed little or no abnormalities. The LD50 for BP83HF following oral gavage was >5 ml/kg (converted to 4.15 g/kg). Classification as an oral toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
4 150 mg/kg bw
Quality of whole database:
One key read across study from structural analogues available for assessment.

Acute toxicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Equivalent or similar to OECD Guideline 403.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
yes
Test type:
acute toxic class method
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
no data
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
Exposure of the animals was conducted in a 250 liter stainless steel and glass chamber. The test material was introduced at a rate of 0.34 to 0.51 ml/minute into the top of a vertical counter current column that was packed with steel mesh and heated to approximately 50 °C. Pre-warmed nitrogen gas was introduced at the bottom of the column at a rate of 7 liters/minute. The nitrogen and test material vapors were then mixed with air and introduced into the exposure chamber. The test atmosphere was analyzed by IR every 15 minutes throughout the exposure. During each hour of the exposure, the test atmosphere was analyzed gravimetrically and visually (by flashlight) for aerosols of the test material. Test material consumption was determined by weighing the test material container before and after exposure. The quantity consumed was divided by the total airflow and this yielded the nominal exposure concentration. The mean exposure concentrations were: Nominal concentration 5.74 mg/l Analytical concentration 5.28 ±0.42 mg/l Gravimetric samples, collected on membrane filters, and aerosol checks with a flashlight showed some aerosol in the chamber. The nominal to analytical ratio and the gravimetric results both suggest the level of aerosol compared to level of vapor was insignificant in the exposure.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
5.28 +/- 0.42 mg/l
Duration of exposure:
4 h
Concentrations:
5.28 +/- 0.42 mg/l
No. of animals per sex per dose:
Five male and five female Sprague-Dawley rats were exposed to approximately 5 mg/l of test material as a single four-hour whole body exposure.
Details on study design:
Five male and five female Sprague-Dawley rats were exposed to approximately 5 mg/l of test material as a single four-hour whole body inhalation exposure. After the exposure the rats were kept for a 14 day observation period. Surviving animals at 14 days were sacrificed and subjected to a gross post-mortem examination. Records were made of any observed gross abnormalities. The lungs of all animals were preserved in formalin, sectioned and stained and then subjected to microscopic examination. No animals died following the exposure.
Preliminary study:
All except one animal had normal growth rates throughout the study. The one exception on day 8 had a body weight less than its starting body weight but by the end of the study normal growth had resumed. Decreased activity was exhibited by all animals during the exposure. Otherwise there were no treatment-related clinical signs of toxicity. No macroscopic lesions were observed in any animal at post-mortem and no microscopic changes were observed in any lung section examined.
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.28 mg/L air (analytical)
Exp. duration:
4 h
Mortality:
None
Clinical signs:
other: other:
Body weight:
All except one animal had normal growth rates throughout the study. The one exception on day 8 had a body weight less than its starting body weight but by the end of the study normal growth had resumed.
Gross pathology:
No macroscopic lesions were observed in any animal at post-mortem and no microscopic changes were observed in any lung section examined.
Interpretation of results:
other: Not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Classification as an inhalation toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.
Executive summary:

The LC50 was >5.28 mg/L. Classification as an inhalation toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1977
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given:comparable to guidelines/standards.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
GLP compliance:
not specified
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Ltd., Manston, Kent, UK
- Age at study initiation: 7-8 weeks
- Housing: tubular glass chamber, 2 of each sex
- Diet (e.g. ad libitum): ad libitum, except during 4 hr exposure period
- Water (e.g. ad libitum): ad libitum, except during 4 hr exposure period
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: tubular glass chamber
- System of generating particulates/aerosols: dynamically

TEST ATMOSPHERE
- Brief description of analytical method used: continuously by a high temperature total hydrocarbon analyser
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
13.1 mg/l (near saturation)
No. of animals per sex per dose:
2
Details on study design:
- Duration of observation period following administration: 14 days
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 13.1 mg/L air
Exp. duration:
4 h
Remarks on result:
other: near saturation level
Mortality:
None
Clinical signs:
other:
Interpretation of results:
study cannot be used for classification
Conclusions:
The LC50 for inhalation toxicity in rats is > 13.1 mg/l, which is near the maximum attainable vapor concentration. The LC50 for the test substance is greater than the saturation concentration.
Executive summary:

This study examined the inhalation toxicity of Dilutine M5 to rats. Two male and two female rats were exposed to test atmosphere containing near saturation concentration of the test substance vapors (13.1 mg/l air) for 4 hrs. After exposure, the rats were observed for the next 14 days for mortality. No rats died during the course of the study. Therefore, the LC50 for the test substance is > 13.1 mg/l air. Since this concentration is near the saturation concentration, the LC50 is greater than the saturation concentration. The test substance is not toxic via inhalation, and is not classified an inhalation toxin under OECD GHS or EU CLP guidelines.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
5 280 mg/m³
Quality of whole database:
Two key and one supporting read across study from structural analogues available for assessment.

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
Study period:
1985-07-11 to 1985-07-31
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable well-documented study report which meets basic scientific principles: GLP
Justification for type of information:
The justification for read across is provided as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
used occlusive wrap
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles Rivers UK Ltd
-Sex: Male (10); Female (10)
- Age at study initiation: 6 weeks
- Weight at study initiation: Male: 125-135g; Female: 110-115g
- Housing: individually housed
- Diet (e.g. ad libitum): No. 1, expanded pelleted maintenance diet for rats and mice from Special Diet Services Ltd., ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6-day acclimatisation


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-25
- Humidity (%): 58-90
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
On the day prior to application the trunk of each animal was clipped free of hair. For each treated animal, 2 mL/kg of BP83HF was applied to a patch of absorbent paper. The patch was applied to the trunk and held in place beneath a polythene sleeve under a Poroplast bandage. The whole patch assembly was held in place with tape. The patches were left in position for approximately 24 hours. Patches were similarly applied to control animals with the omission of test material. To prevent the animals from gaining access to the sites of application (and hence possibly ingesting traces of test material), collars were applied around the animals heads for a further 24 hours (control and test animals).
Duration of exposure:
24 hours
Doses:
Control: (5) males; (5) female
2 ml/kg (converted 1.7 g/kg): (5) males; (5) females
No. of animals per sex per dose:
Animals: (10) males; (10) female per dose for a total of 20 animals
Control animals:
yes
Details on study design:
SCORING SYSTEM: Draize scale
- Dermal response observations: daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
Differences between treated and control group mean values for bodyweight gain were analysed by Student's t-test. Where individual variance ratios were significant (P <0.05 or less), Cochran's approximation was applied (Snedecor and Cochran, Statistical Methods, 6th Ed. Iowa State. 1973). Where zero variance was found in one or more groups, intergroup comparison was performed by the Wilcoxon Rank Sum Test.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 1 700 mg/kg bw
Remarks on result:
other: (dose converted from >2 mL/kg bw)
Mortality:
There were no animal deaths prior to study termination.
Clinical signs:
Well-defined erythema was noted upon removal of the test patches in all animals exposed to BP83HF, generally persisting for a further 24 hours. Scab formation was subsequently observed on Day 5 and skin flaking was noted on Day 6 in all treated animals, persisting for a few days only in most animals. Plaster marks were noted on all test and control animals following patch removal; this is an artifact of the test procedure and is commonly seen in studies of this type. No other significant signs of ill health, behavioral change or reaction to treatment were noted.
Body weight:
The body weight gain of male rats was unaffected by treatment with the test material. A marginally larger overall weight gain was recorded for treated female rats when compared with the controls; this was considered to have arisen fortuitously and not related to treatment with BP83HF.
Gross pathology:
Post mortem examination of all animals killed at termination revealed an area of diffuse subcutaneous haemorrhage beneath the dorsal patch site in one male exposed to BP83HF. However, no other findings considered to be related to treatment were observed and no tissues were processed further for histopathological examination.
Other findings:
GROSS POSTMORTEM EXAMINATION

No alterations were noted.
Interpretation of results:
other: Not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The LD50 of BP83HF was > 2 ml/kg (converted 1.7 g/kg). Classification as an acute dermal toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.
Executive summary:

Five male and five female rabbits were exposed to BP83HF for 24h via an occluded patch.  Dermal evaluations occurred at 24 hours post patch removal and once daily until the study termination at day14. Exposure had no effect on viability; all animals survived the exposure.  The LD50 of BP83HF was > 2 ml/kg (converted 1.7 g/kg). Classification as an acute dermal toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
1 700 mg/kg bw
Quality of whole database:
One key and two supporting studies from structural analogues available for assessment.

Additional information

No acute oral, inhalation, or dermal toxicity data is available for Hydrocarbons, C14-C18, n-alkanes, isoalkanes, cyclics, aromatics (2 -30%). However, data is available for structural analogues, Hydrocarbons, C11-C20, n-alkanes, isoalkanes, cyclics, aromatics (2 -30%) and Kerosene. Petroleum substances of similar carbon number and aromatic content, principally kerosene and jet fuel, are typically in the range of C9-C16. These substances also contain similar types of molecules in similar proportions to those in C14-C20 aliphatic [2-30% Aromatics] Hydrocarbon solvents. In general, hydrocarbon solvents are more highly refined than petroleum substances. Accordingly, the petroleum substances typically represent a “worse case” with respect to hydrocarbon solvents and can be used for read across on that basis. This data is read across to based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

Acute Oral Toxicity

In a key study (DHC Solvent Chemie GmbH, 1985), the acute toxicity of the test material (Hydrocarbons, C11-C20, n-alkanes, isoalkanes, cyclics, aromatics (2-30%)) was evaluated in rats via oral gavage at a dose of 5 ml/kg bw (converted to 4.15 g/Kg). Observations were made as to the nature, onset, severity, and duration of toxicological signs once per day for a total of 14 days. All animals survived the entire observational period and displayed a low incidence of clinical symptoms. The animals displayed little or no abnormalities. The LD50for the test material following oral gavage was >5 ml/Kg (converted to 4.15 g/Kg). Classification as an oral toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Acute Inhalation Toxicity

A key acute toxicity study (Shell, 1977a) examined the inhalation toxicity of hydrocarbons, C9-C12, n-alkanes, isoalkanes, cyclics, 2-25% aromatics in rats. Two male and two female rats were exposed to test atmosphere containing near saturation concentration of the test substance vapors (13.1 mg/L air) for 4 hrs. After exposure, the rats were observed for the next 14 days for mortality. No rats died during the course of the study. Therefore, the LC50 for the test substance was determined to be > 13.1 mg/L air. Since this concentration is near the saturation concentration, the LC50 is greater than the saturation concentration. The test substance is not toxic via inhalation, and is not classified an inhalation toxin under OECD GHS or EU CLP guidelines.

In a key acute inhalation toxicity study (API, 1985a), five male and five female Sprague-Dawley rats were exposed to approximately 5 mg/L of the test material (Kerosine (petroleum)) as a single four-hour whole body inhalation exposure. After the exposure the rats were kept for a 14 day observation period. Surviving animals at 14 days were sacrificed and subjected to a gross post-mortem examination. Records were made of any observed gross abnormalities. The lungs of all animals were preserved in formalin, sectioned and stained and then subjected to microscopic examination. No animals died following the exposure.

All except one animal had normal growth rates throughout the study. The one exception on day 8 had a body weight less than its starting body weight but by the end of the study normal growth had resumed. Decreased activity was exhibited by all animals during the exposure. Otherwise there were no treatment-related clinical signs of toxicity. No macroscopic lesions were observed in any animal at post-mortem and no microscopic changes were observed in any lung section examined.

The LC50 was determined to be >5.28 mg/L. Classification as an inhalation toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Acute Dermal Toxicity

In a key study (DHC Solvent Chemie GmbH, 1985), five male and five female rabbits were exposed to test material (Hydrocarbons, C11-C20, n-alkanes, isoalkanes, cyclics, aromatics (2-30%)) for 24h via an occluded patch. Dermal evaluations occurred at 24 hours post patch removal and once daily until the study termination at day14. Exposure had no effect on viability; all animals survived the exposure. The LD50of the test material was > 2 ml/Kg (converted 1.7 g/Kg). Classification as an acute dermal toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

In a supporting acute dermal toxicity study (API, 1985b), undiluted test material (Kerosine (petroleum)) was applied to the shaved dorsal skin of each of two male and two female rabbits. One rabbit of each sex had abraded skin, the other had intact skin. The area of application was wrapped with gauze and over wrapped with an occlusive covering. 24 hours later, the covering was removed and the skin was wiped with wet disposable towels to remove any residual test material. The rabbits were observed for clinical signs and mortality for the first six hours of dosing, then daily for dermal irritation and twice daily for clinical signs of toxicity and mortality for 14 days. Body weights were recorded just prior to and again 7 days and 14 days after administration of test material. At study termination all animals were killed and subjected to a gross necropsy examination when any abnormalities were recorded.

No animals died during the study.Clinical signs observed during the study included hypoactivity and diarrhea. Dermal irritation ranged from slight to severe for erythema and edema; slight to marked for atonia, desquamation and fissuring; and slight to moderate for coriaceousness. Other dermal irritation observed included subcutaneous hemorrhage, blanching and scab formation. One of the rabbits (male abraded skin) weighed slightly less at the end of the study than at the beginning. All other rabbits had gained a small amount of body weight by the end of the study. The LD50 was determined to be >2000 mg/Kg and therefore, classification as a dermal toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Justification for classification or non-classification

Based on available substance and read across data, Hydrocarbons, C14-C18, n-alkanes, isoalkanes, cyclics, 2 -30% aromatics is minimally toxic via ingestion where the LD50 is >4150 mg/Kg, via dermal exposure where the LD50 is >1700 mg/Kg, and by inhalation where the LC50 is >5280 mg/m3. These findings do not warrant classification under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Hydrocarbons, C14-C18, n-alkanes, isoalkanes, cyclics, 2-30% aromatics is classified under EU CLP guidelines as a Category 1 aspiration hazard based on its physical and chemical properties (hydrocarbon fluid, viscosity ≤ 20.5 mm2/s).