Registration Dossier

Administrative data

Description of key information

Oral:
Single doses of 5.0 g/kg of the test material diluted in peanut oil at a concentration of 714 mg/ml were administered intragastrically to five fasted male and female rats. No mortality was observed. No signs of toxicity were observed.
The gross pathological and histopathological changes observed were spontaneous and unrelated to treatment with the test material.
The LD50 was considered to be >5 g/kg (>5000 mg/kg) based on the results.
Dermal:
The test article, when administered dermally to 5 male and 5 female New Zealand white rabbits had an acute dermal LD50 of greater than 5 g/kg when administered as an 80% suspension of test material in mineral oil (>4 g/kg test material).

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:
10th to 24th June 1985
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was not conducted in accordance with a recognised guideline, however the study was conducted to GLP and is detailed with good scientific principles and is similar to OECD 401.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
not specified
GLP compliance:
yes
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: Charles River Breeding Laboratories, Inc., Wilmington, Massachusetts
- Age at study initiation: The males were 70 days of age and the females were 77 days of age at the time of dosing.
- Weight at study initiation: The males weighed 289-322 grams, and the females weighed 204-227 grams at the time of dosing.
- Fasting period before study: yes, overnight prior to dosing
- Housing: The animals were housed individually in wire-bottom cages in an air-conditioned room.
- Diet/water (e.g. ad libitum): The animals had free access to Purina Laboratory Rodent Chow #5001 and water except during the overnight period prior to dosing when only water was available.
- Acclimation period: the animals were allowed a conditioning period of 3 weeks prior to dosing in the laboratory.

ENVIRONMENTAL CONDITIONS
- Temperature (°C):22.2-22.8 °C
- Humidity (%): 57.3-65.7%
- Photoperiod (hrs dark / hrs light): The photoperiod consisted of a 12-hour light/dark cycle: lights on at 0630 and off at 1830.

Route of administration:
oral: gavage
Vehicle:
peanut oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: The test material was diluted in peanut oil at a concentration of 714 mg/ml.
- Lot/batch no. (if required): The peanut oil was a golden liquid, Lot/Batch No. A2B. It was received from Eastman Kodak Company, Rochester, New York and stored at room temperature.
- other: Five fasted animals of each sex were dosed with 7.0 ml/kg of peanut oil and served as the controls.

MAXIMUM DOSE VOLUME APPLIED:
limit dose of 5000 mg/kg b. wt.
Doses:
limit dose of 5000 mg/kg b. wt.
No. of animals per sex per dose:
5/sex/dose
Control animals:
yes
Details on study design:
- Duration of observation period following administration: The animals were dosed approximately four hours after the onset of the light cycle. They were observed frequently for any physiological or behavioral abnormalities on the day of dosing and at least once each weekday morning and late afternoon for 13 days after treatment; on weekends they were observed once daily. On Day 14, the animals were observed once prior to sacrifice.
- Frequency of observations and weighing: The animals were weighed immediately prior to dosing and at 2, 7, and 14 days after treatment. The mean body weights of the treated animals were compared to those of the respective controls using Student's t-test
- Necropsy of survivors performed: yes, all survivors were killed following the 14-day observation period were examined for gross pathological changes. The following organs and tissues were examined: skin, spleen, pancreas, esophagus, stomach, small and large intestine, liver, adrenals, kidneys, gonads, uterus or seminal vesicles, bladder, heart, thymus, salivary glands, lungs, trachea, thyroid, and fat. Abnormal tissues were preserved in 10% (v/v) neutral buffered formalin and submitted for histopathological examination.
- Other examinations performed: Tissues were submitted to Histopathology Reference Laboratory, Oakland, California, for tissue processing and preparation of routine five-micron H&E stained sections. The tissue sections were evaluated for microscopic abnormalities at Chevron Environmental Health Center, Inc.
Statistics:
no data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality was observed.
Clinical signs:
No signs of toxicity were observed.
Body weight:
There were no significant differences in mean body weights between treated and control animals.
Gross pathology:
Gross pathological changes observed at necropsy were limited to dilated renal pelves in two male and one female treated animals. Upon histopathological examination, hydronephrosis was observed in one male and one female treated animal. Renal lymphocytic infiltration was observed in one control male, These lesions were spontaneous and not related to treatment with the test material.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LD50 was considered to be >5 g/kg (>5000 mg/kg) based on the results.
Executive summary:

In a study conducted broadly in line with OECD guideline 401 and in accordance with GLP, single doses of 5.0 g/kg of the test material diluted in peanut oil at a concentration of 714 mg/ml were administered intragastrically to five fasted male and female rats. No mortality was observed. No signs of toxicity were observed.

The gross pathological and histopathological changes observed were spontaneous and unrelated to treatment with the test material.

The LD50 was considered to be >5 g/kg (>5000 mg/kg) based on the results.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw
Quality of whole database:
Klimisch code 1 (reliable without restriction)

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
Study period:
11th to 25th June 1985
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Comparable to guideline study with acceptable restrictions due to limited exposure concentration and duration. Exposure duration was not 4 hours. Can not be classified according to the EU as the animals were exposed for 1 hour and also the obtained results was a greater than value at a concentration of 1.67 mg/L (nominal) which would be in the range to be considered classifyable according to the DSD (67/548/EEC), however, since no mortality was observed it can not be classified either way.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
limited exposure concentration and duration
GLP compliance:
yes
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: Bantin and Kingman, Fremont, California
- Age at study initiation: The males were 118 days of age and the females were 118 days of age and at the time of exposure.
- Weight at study initiation: The males weighed 514-550 grams, and the females weighed 269-315 grams at the time of exposure.
- Fasting period before study: the animals had no access to food or water during exposure
- Housing: They were housed individually in wire-bottomed cages.
- Diet/water (e.g. ad libitum): They had free access to Purina Laboratory Rodent ChowR (#5001) and water except during exposure.
- Acclimation period: They were maintained for 77 days prior to exposure.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.6-22.9°C
- Humidity (%): 59.0-66.5%
- Photoperiod (hrs dark / hrs light): The animals were on a 12-hour light/dark cycle: on at 0630 and off at 1830.

Route of administration:
other: Vapor and condensed aerosol inhalation
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
Five rats of each sex were exposed for 60 minutes to vapors and condensation aerosols from heated test material. The generation system consisted of a vertical three-inch steel pipe, approximately 24 inches long with threaded steel caps at each end. The bottom cap was drilled with two 1/8-inch pipe holes and fitted with 1/4-inch copper compression fittings.

The supply air was delivered via two 1/4-inch copper tubes to these two holes. The top cap was drilled and tapped to receive a 1/4-inch pipe fitting. Air and vapors of test material exited the steel pipe at this point. Another hole in the side of the pipe, approximately five inches from the bottom, contained a copper fitting which held a thermister probe from a Cole-Parmer Versa-Therm (Model 60648) proportional temperature controller. This probe monitored the temperature of the test material in the pipe. The pipe contained 1527 grams of the test material and 1638 grams of 5 millimeter diameter glass beads. The combined materials filled the generator to about half its capacity. The glass beads served to disperse the air flowing through the test material and increased the surface area of test material in contact with the air. A tight mesh stainless steel screen was fitted in the bottom pipe cap to prevent the glass beads from plugging the supply air inlets at the bottom of the pipe. The bottom third of the pipe was wrapped with an electric heating tape which was powered by the proportional temperature controller and maintained the test material at a temperature of 170°C. Vapors were generated by passing laboratory compressed air up through the hot test material. The vapors and the condensation aerosol, which formed as the vapors cooled, passed out the top of the generator via 3/8-inch Teflon tubing and into one side of a 500 ml three-neck flask. The vapors and aerosol passed out the other side of the flask, horizontally via glass tubing to a 1-1/8 inch copper tube, then vertically to the inlet of the chamber. No dilution air was added.

Air flow through the generator was maintained at an average of 18.6 l/min during the exposure. Air was drawn out of the chamber through the exhaust manifold at an average flow of 14.5 L/min. The total concentration of aerosol and vapor was estimated by drawing chamber air from the end of the chamber through a cold trap consisting of three glass U-tubes (20.7 cm high, 1.7 cm i.d.) connected in series with flexible tubing and rubber stoppers. The tubes were approximately two-thirds submerged in a dry ice-acetone bath. The cold trap sampling train was operated continuously throughout the exposure at a rate of 5 L/min. Therefore, the total exhaust flow was approximately 19.5 L/min creating a negative pressure of 0.1 to 0.2 inches of water in the chamber. The cold trap tubes were weighed before and after the exposure to determine the amount of material collected.

Concentration of the aerosol in the chamber was determined gravimetrically by drawing chamber atmosphere through 25 mm glass fiber filters in in-line filter holders. Samples were taken from an unoccupied exposure port at 2 L/min for five minutes. The samples were taken approximately every 10 minutes during the exposure. The main exhaust from the chamber was decreased during sampling in order to maintain the total exhaust flow constant.

Aerodynamic size of the aerosol was determined by taking a cascade impactor sample (Lovelace Multijet Cascade Impactor, In-Tox Products, Albuquerque, New Mexico) before and after the exposure period. The samples were taken at 20 LPM for three minutes from the exposure port used for concentration sampling. During particle size sampling, the main exhaust was turned off. The amount of material collected on each substrate was determined gravimetrically.

The Mass Median Aerodynamic Diameter (MMAD) and Geometric Standard Deviation (GSD) were calculated using the cutoff diameters for each stage supplied by the manufacturer and assuming a lognormal size distribution. The cumulative fraction on each stage was converted to the number of standard deviations from the median (Z-value). The natural logarithm of the effective cutoff diameter (ECD) of each stage was fitted to the equation in ECD = aZ + b using linear regression. The MMAD was calculated from this relationship where Z = 0 or the median of the distribution, MMAD = eb. The GSD was calculated from the slope of the equation, GSD = ea.

The exposure chamber was a nose-only device purchased from In-Tox Products, Albuquerque, New Mexico. It was constructed from aluminum and steel with 24 exposure ports on each side. The animals were restrained in tubes constructed of clear plastic and metal (25 cm long by E.5 cm inside diameter). The nose piece of each tube was inserted into an exposure port and two O-rings maintained a tight seal. The rats were secured in the tubes with a plastic plug. The test material was introduced into the top of the chamber where it was distributed to each exposure port via internal baffling. The exhaust was drawn out through an internal exhaust manifold via four ports at the end of the chamber. Although animals were exposed on only one side of the chamber, the entire exhaust manifold was operated to ensure even internal distribution. The chamber exhaust passed through the sampling trains or through two parallel in-line filters (Mine Safety Appliances, Pittsburgh, Pennsylvania) with particulate and organic vapor elements in each. The exhaust flowed through a flowmeter and then to house vacuum. Five rats of each sex restrained in the same manner but exposed only to room air served as controls.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
Total weight of material collected in this cold trap was divided by total volume of atmosphere sampled to estimate total exposure (combined aerosol and vapor) concentration.
Duration of exposure:
60 min
Concentrations:
The average aerosol concentration was 0.87 mg/L. The concentration of vapors and aerosol combined (from the cold trap gravimetric analysis) was 1.67 mg/L.
No. of animals per sex per dose:
Five animals per sex per dose
Control animals:
yes
Details on study design:
- Duration of observation period following administration: All animals were weighed before the exposure and 2, 7, and 14 days following exposure. Mean body weights for control and exposed animals were compared using a Student's t-test. The animals were observed for adverse effects during the exposure and then twice daily following exposure, except on weekends when they were observed only once.
- Necropsy of survivors performed: Yes, the animals were killed with an intraperitoneal injection of Sleep-Away following the 14-day observation period and were examined for gross pathological changes. The following organs and tissues were examined: skin, spleen, pancreas, stomach, small and large intestine, liver, adrenals, kidneys, reproductive organs, bladder, heart, thymus, salivary glands, lungs, trachea, thyroid, and fat. Skulls, kidneys, and a portion of the liver were preserved in 10% neutral buffered formal in (NFB) for possible future histological examination. The lungs were infused in situ via the trachea and preserved with NBF.
- Other examinations performed: The lungs were submitted for histopathological evaluation. The tissues were trimmed into consecutively numbered cassettes, one number per animal. Histology numbers, cross referenced to study, and animal numbers were recorded. After trimming, cassettes immersed in NBF were submitted to Histopathology Reference Laboratory, Oakland, California, for tissue processing and slide preparation. Tissues were subjected to standard paraffin embedding and routine five-micron H&E stained sections were obtained. Slides and blocks were returned to Chevron Environmental Health Center, Inc. and verified against one another, as well as the histology record on each animal. After verification of the animal-tissue-block count and the quality of each slide, the tissues were evaluated for microscopic abnormalities.
Statistics:
No data
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 1.67 mg/L air
Based on:
test mat.
Exp. duration:
60 min
Remarks on result:
other: Actual test material concentration may have been underestimated.
Mortality:
No mortality after 1-hour exposure to combined aerosol and vapor concentration of 1.67 mg/L. All animals survived to termination of the
experiment.
Clinical signs:
other: No clinical signs of toxicity were observed during the exposure or observation periods.
Body weight:
Treatment did not affect effect mean body weight or body weight gain in either sex.
Gross pathology:
Microscopic examination of lung tissue detected no abnormalities in treated or control groups.

The animals were exposed to the vapors and condensation aerosol from heated test material for 60 minutes. The average aerosol concentration was 0.87 mg/L. The concentration of vapors and aerosol combined (from the cold trap gravimetric analysis) was 1.67 mg/L. The average MMAD and GSD of the condensation aerosol based on gravimetric analysis were 3.70 pm and 1.59, respectively. Approximately 99% of the aerosol was smaller than 10 µm. The heated air stream from the generator caused the air in the chamber to rise three degrees above the room temperature during the exposure.

No signs of toxicity were observed during the exposure or 14-day observation period. A Student's t-test showed that body weights of exposed animals were not significantly different from the control animals. At necropsy, no gross pathological changes were observed that could be attributed to the exposure. No microscopic changes were observed in the lungs of the exposed animals that could be attributed to the exposure.

Interpretation of results:
other: No data
Remarks:
Criteria used for interpretation of results: not specified
Conclusions:
1-hour LC50 > 1.67 mg/L (males and females)
Executive summary:

In a study conducted broadly in line with OECD Guideline 403 and in compliance with GLP, five rats of each sex were given a nose-only exposure for 60 minutes to the vapors and condensation aerosol from heated test material. The average total aerosol concentration was 0.87 mg/L. The average concentration of vapors plus aerosol was 1.7 mg/L. The average Mass Median Aerodynamic Diameter (MMAD) of the aerosol, based on gravimetric analysis, was 2.70 µm. Five rats of each sex were exposed to room air only and served as controls.

No signs of toxicity were observed in any exposed or control animals during the exposure or the 14-day observation period following the exposure. There were no statistical differences in mean body weights between exposed and control animals of either sex.

No gross pathologic changes that could be attributed to the exposure were observed at necropsy following a 14-day observation period. No exposure-related histologic changes were observed in the lungs.

The study cannot be used to assign classifiation to the substance according to the current EU criteria as the animals were exposed for only 1 hour as opposed to the 4 hour described in Directive 67/548/EEC. There were no signs of mortality during the study and consequently the LC50 was determined to be > 1.67 mg/L (males and females).

.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
1.67 mg/m³
Quality of whole database:
Klimisch code 2 (reliable with restrictions)

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:
11th to 25th June 1985
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was not conducted in accordance with a recognised guideline, however the study is detailed with good scientific principles and is similar to OECD 402. Only a single limit dose of 5g/kg was used.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
not specified
GLP compliance:
yes
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: L.I.T. Rabbitry, Whitehall, Montana
- Age at study initiation: The males/females were 18-20 weeks of age at the time of dosing.
- Weight at study initiation: The males weighed 3.11-3.64 kilograms, and the females weighed 2.91-3.58 kilograms at the time of dosing.
- Housing: The animals were housed individually in wire-bottom cages in an air-conditioned room.
- Diet (e.g. ad libitum): The animals were fed a daily ration of Purina Laboratory Rabbit Chow HF #5326.
- Water (e.g. ad libitum): Free access to water.
- Acclimation period: conditioning period of 10 weeks prior to dosing in the laboratory.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.5-22.8°C
- Humidity (%): 57.7-69.6%
- Photoperiod (hrs dark / hrs light): The photoperiod was a 12-hour light/dark cycle: lights on at 0630 and off at 1830.

Type of coverage:
occlusive
Vehicle:
other: Mineral oil (1.0 mL/kg)
Details on dermal exposure:
The fur on the trunks of five animals of each sex was clipped on the day prior to dosing. Five grams per kilogram of body weight of 80% of the test material w/w in mineral oil (4.0 g/kg test material) were applied to the trunk of each animal. This dose level was considered to be the highest dose level practical based on the dose volume that could be contained under the wrap. The material was held in contact with the animal's skin by a plastic sheet wrapped around the animal's trunk, and paper toweling was wrapped over the plastic sheet to prevent tearing. The mean volumes (+S.D.) of test material administered were 14.9 (0.7) ml for males and 14.9 (1.0) ml for females; the mean weights (+S.D.) of test material administered were 16.4 (0.9) g for males and 16.4 (1.1) g for females. Five clipped animals of each sex, treated with 1.0 ml/kg of mineral oil, were wrapped as described above and served as the controls. This volume was equal to the amount of mineral oil contained in the dosing mixture. All animals were collared during the exposure period to prevent damage to the wraps. The animals were dosed and wrapped approximately 4.5 hours after the onset of the light cycle.

After a 24-hour exposure period, the wrappings were removed from the animals. Any remaining test material was wiped off with a gauze pad and mineral oil. Collars remained on treated animals for 24 hours to prevent oral ingestion of residual test material and on controls for the same length of time.
Duration of exposure:
24 hours
Doses:
5g/kg of an 80% suspension of test material in mineral oil.
No. of animals per sex per dose:
5 per sex per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Duration of observation period following administration: The animals were observed frequently for any physiological or behavioral abnormalities on the day of dosing and at least once each weekday morning and late afternoon for 13 days after treatment; on weekends, they were observed once daily. On Day 14, the animals were observed once prior to sacrifice.

The skin at the application site was scored for irritation at 1, 7, and 14 days after treatment using the modified scoring system of Draize et al.

- Frequency of observations and weighing: The animals were weighed immediately prior to dosing and at 2, 7, and 14 days after treatment. The mean body weights of the treated animals were compared to those of the respective controls using Student's t-test.

- Necropsy of survivors performed: yes, all survivors killed following the 14-day observation period were examined for gross pathological changes. The following organs and tissues were examined: skin, spleen, pancreas, stomach, small and large intestine, liver, adrenals, kidneys, gonads, uterus or seminal vesicles, bladder, heart, thymus, salivary glands, lungs, trachea, thyroid, and fat. Sections of skin from each animal and any abnormal tissues were preserved in 10% (v/v) neutral buffered formalin and submitted for histopathological examination.

- Other examinations performed: Tissues were submitted to Histopathology Reference Laboratory, Oakland, California, for tissue processing and preparation of routine five-micron H&E stained sections. Tissue sections were evaluated for microscopic abnormalities at Chevron Environmental Health Center, Inc.
Statistics:
No data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 4 000 mg/kg bw
Based on:
other: 80% solution of the test material in mineral oil
Mortality:
No mortality.
Clinical signs:
Signs of toxicity observed during the study included dry and flaky skin and/or scabbed skin at the application site of all test material treated animals.Skin reactions at the site of application of the test material consisted of slight to moderate erythema with no to well defined edema in both sexes at
24 hours post dosing. On day 7 no to severe erythema with no to well defined edema was observed. Two males and four females exhibited eschar
formation. No irritation was evident in treated skin on day 14. Two vehicle control animals exhibited slight erythema or edema 24 hours after dosing. There were no findings in the vehicle controls on day 7 or 14.
Body weight:
Body weights were unremarkable.
Gross pathology:
The only compound related gross pathology changes observed at necropsy were dry and flaky skin in all treated animals. Histologically, minimal
acanthosis and/or hyperkeratosis were observed in all but one of the treated animals.
Other findings:
Other gross pathological signs observed at necropsy were scratch-like marks on both corneas, a single opaque and vascularized cornea, and white cheesy material at the site of the missing right salivary gland in one control animal. Histologically, chronic keratitis in one eye and abscess in the salivary gland were observed.

The test article, when administered dermally to 5 male and 5 female New Zealand white rabbits had an acute dermal LD50 of greater than 5 g/kg when administered as an 80% suspension of test material in mineral oil. 

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test article, when administered dermally to 5 male and 5 female New Zealand white rabbits had an acute dermal LD50 of greater than 5 g/kg when administered as an 80% suspension of test material in mineral oil.
Executive summary:

In a study conducted broadly in broadly in line with OECD 402 and under conditions of GLP, five adult rabbits of each sex were treated with a single dermal application of 5.0 g/kg of 80% of the test material weight/weight in mineral oil (4.0 g/kg test material). The test material was diluted due to its high viscosity. This dose level was considered to be the highest level practical based on the dose volume that could be contained under the wrap.

No mortality was observed. Signs of toxicity observed during the study were dry and flaky and/or scabbed skin at the application site and reduced food intake.

The only compound-related gross pathological change observed at necropsy was dry and flaky skin at the application site of all treated animals. Upon histological evaluation, minimal acanthosis and/or hyperkeratosis was observed in all but one of the treated animals.

The test article, when administered dermally to 5 male and 5 female New Zealand white rabbits had an acute dermal LD50 of greater than 5 g/kg when administered as an 80% suspension of test material in mineral oil.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
4 000 mg/kg bw
Quality of whole database:
Klimisch code 1 (reliable without restriction)

Additional information

Oral:

Value for CSA: >5000 mg/kg

In the key study for oral exposure (Brorby, 1986, Report number: SOCAL 2326) there was no mention of what guideline was followed, however the methodology suggests that it was conducted similarly to OECD 401. The study was conducted in line with GLP. A reliability rating of 1 according to the criteria of Klimisch, 1997. This was considered to be the most reliable study. Also of all the endpoints, this study gave the lowest LD50 (>5000 mg/kg) which is more appropriate for classification purposes.

There are also the following supporting studies for this endpoint:

- The Meyding et al study, 1962a (Hazleton report number: 20-0169-33) was not considered the key study as it was conducted less recently than the above key study and was not conducted according to a recognised guideline or GLP. Satisfactory methods and results are presented. The study was considered to have a reliability rating of 2, according to the criteria of Klimisch, 1997.

The acute oral LD50 of the test material for male albino rats is greater than 16.1 g/kg of body weight.

- The Meyding et al study, 1962b (Hazleton report number: 20-0169-33) was not considered the key study as it was conducted less recently than the above key study and was not conducted according to a recognised guideline or GLP. Satisfactory methods and results are presented. The study was considered to have a reliability rating of 2, according to the criteria of Klimisch, 1997.

The acute oral LD50 of the test material for male albino rats is greater than 19.3 g/kg of body weight.

- The Unpublished, 1975 study was not considered the key study as it was conducted less recently than the above key study and was obtained from the peer reviewed, 2006 OECD SIDS dossier due to the original report being unavailable. A reliability rating of 4 was assigned according to the criteria of Klimisch, 1997.

LD50 > 5000 mg/ kg b. wt. (males and females).

Dermal:

Value for CSA: >4000 mg/kg

In the key study for dermal exposure (Brorby, 1986; Report number: SOCAL 2327) there was no mention of what guideline was followed, however the methodology suggests that it was conducted similarly to OECD 402. The study was conducted in line with GLP. A reliability rating of 1 according to the criteria of Klimisch, 1997. This was considered the most reliable study.

The acute dermal LD50 of the test material was considered to be >5 g/kg when administered as an 80% suspension in mineral oil (>4 g/kg test material).

There are also the following supporting studies for this endpoint:

- The Meyers, 1986 study was not considered the key study as it was conducted less recently than the above key study, was conducted on abraded skin and the information was obtained from the peer reviewed, 2006 OECD SIDS dossier due to the original report being unavailable. A reliability rating of 4 was assigned according to the criteria of Klimisch, 1997.

In an acute dermal toxicity study with the test material a single limit dose of 2.0 g/kg was applied to the abraded skin of five male and five female rabbits for 24 hours. There were no deaths, and no signs of systemic toxicity were observed during the 14-day observation period. The acute dermal LD50 was > 2.0 g/kg.

- The Meyding et al study, 1962b (Hazleton report number: 20-0169-33) was not considered the key study as it was conducted less recently than the above key study and was not conducted according to a recognised guideline or GLP. Satisfactory methods and results are presented. The study was considered to have a reliability rating of 2, according to the criteria of Klimisch, 1997.

The acute dermal LD50 of the test material for rabbits is greater than 15 g/kg of body weight.

- The Meyding et al study, 1962a (Hazleton report number: 20-0169-33) was not considered the key study as it was conducted less recently than the above key study and was not conducted according to a recognised guideline or GLP. Satisfactory methods and results are presented. The study was considered to have a reliability rating of 2, according to the criteria of Klimisch, 1997.

The acute dermal LD50 of the test material for rabbits is greater than 15 g/kg of body weight.

Inhalation:

In a supporting study for inhalation exposure (Rittenhouse et al, 1985, Report number: SOCAL 2323) there was no mention of what guideline was followed, however the methodology suggests that it was conducted similarly to OECD Guideline 403 (Acute Inhalation Toxicity). The study was conducted in line with GLP. A reliability rating of 2 according to the criteria of Klimisch, 1997.

The study cannot be used to assign classification to the substance according to the current EU criteria as the animals were exposed for only 1 hour as opposed to the 4 hour described in Directive 67/548/EEC. There were no signs of mortality during the study and consequently the LC50 was determined to be > 1.67 mg/L (males and females).

In accordance with column 2 of REACH Annex VIII, section 8.5.2, it is considered justifiable to omit the acute toxicity: inhalation study. The substance only exists in liquid form and it will not be aerosolized in its normal use pattern and does not exist as small particles or droplets. As such testing via the inhalation route is not considered appropriate for this substance.


Justification for selection of acute toxicity – oral endpoint
Most reliable of 4 studies; all showing no adverse effect

Justification for selection of acute toxicity – inhalation endpoint
Only available study

Justification for selection of acute toxicity – dermal endpoint
Most reliable of 4 studies; all showing no adverse effect

Justification for classification or non-classification

Oral:

The key parameter chosen for acute toxicity for the oral route was greater than the criteria set out in Directive 67/548/EEC and also Regulation (EC) no 1272/2008, therefore classification for acute toxicity was not considered to be necessary.

Dermal:

The key parameter chosen for acute toxicity for the dermal route was greater than the criteria set out in Directive 67/548/EEC and also Regulation (EC) no 1272/2008, therefore classification for acute toxicity was not considered to be necessary.