[No public or meaningful name is available]

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

August 21, 1990 - September 18, 1990

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

This study is classified as reliable with restriction because it was conducted to read-across substance. However, the study was conducted according to OECD TG 410 guideline and in accordance with GLP.

Justification for type of information:

Read-across justification: Based on the chemical composition, the renewable hydrocarbons produced from raw materials such as fatty acid rich oil like Crude Tall Oil (CTO) or triglyserides, using a hydrotreatment process have similar hydrocarbon fractions and they contain the same critical constituents than fossil diesel fuels. According to the identified hydrocarbon blocks, the typical carbon number ranges and the physicochemical properties, the renewable hydrocarbons with diesel type fractions can be considered as having structural similarities and similar behaviour in contact with water and in the physiological processes than the analogue source substances (fossil diesel fuels). Their irritation properties, skin sensitisation property as well as acute and long-term adverse effects to human health is similar. Therefore, and in order to avoid the unnecessary animal testing, the read-across data from the analogue fossil diesel fuels is used to evaluate skin and eye irritation, the genetic toxicity, carcinogenicity, developmental toxicity and short term and/or long-term toxicological effects of the target substance

Cross-reference

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

August 21, 1990 - September 18, 1990

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

This study is classified as reliable with restriction because it was conducted to read-across substance. However, the study was conducted according to OECD TG 410 guideline and in accordance with GLP.

Justification for type of information:

Read-across justification: Based on the chemical composition, the renewable hydrocarbons produced from raw materials such as fatty acid rich oil like Crude Tall Oil (CTO) or triglyserides, using a hydrotreatment process have similar hydrocarbon fractions and they contain the same critical constituents than fossil diesel fuels. According to the identified hydrocarbon blocks, the typical carbon number ranges and the physicochemical properties, the renewable hydrocarbons with diesel type fractions can be considered as having structural similarities and similar behaviour in contact with water and in the physiological processes than the analogue source substances (fossil diesel fuels). Their irritation properties, skin sensitisation property as well as acute and long-term adverse effects to human health is similar. Therefore, and in order to avoid the unnecessary animal testing, the read-across data from the analogue fossil diesel fuels is used to evaluate skin and eye irritation, the genetic toxicity, carcinogenicity, developmental toxicity and short term and/or long-term toxicological effects of the target substance

Qualifier:

according to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Sasco, Inc., Omaha, Nebraska
- Age at study initiation: Young adult
- Weight at study initiation: Males: 200 to 300 grams; Females: 125 to 200 grams
- Housing: Individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
-Acclimation period: 19 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 26
- Humidity (%): 40 to 70%
- Air changes (per hr): 10 per hour or more
- Photoperiod (hrs dark / hrs light): 12 hour dark/ 12 hour light

IN-LIFE DATES: From:1990-08-20 To: 1990-09-18

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on exposure:

TEST SITE
- Area of exposure: Back
- % coverage: 10% of the body surface area
- Type of wrap if used: Latex dental damsecured in place with surgical adhesive tape
- Time intervals for shavings or clippings: As needed during the study

REMOVAL OF TEST SUBSTANCE
- Washing (if done): residual test article was wiped from the application site
- Time after start of exposure: 6h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.01, 0.05, or 0.5 ml/kg/day adjusted in accordance with the most recent body weight
- Constant volume or concentration used: no

USE OF RESTRAINERS FOR PREVENTING INGESTION: no

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

4 weeks

Frequency of treatment:

6 hours a day, 5 days a week

Remarks:

Doses / Concentrations:
0.01, 0.05, or 0.50 mL/kg/day
Basis:
nominal per unit body weight

No. of animals per sex per dose:

10

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: Doses were selected based on a range-finding study.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice a day
- Cage side observations checked for mortality and viability.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once a week

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: Five days a week just prior to application of the test article, 24 hours after the fifth application, and just prior to necropsy

BODY WEIGHT: Yes
- Time schedule for examinations: Prior to study initiation, three days a week (Monday, Wednesday, and Friday) throughout the dosing period, and at study termination

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At study termination
- Anaesthetic used for blood collection: Yes (halothane)
- Animals fasted: Yes
- How many animals: All surviving animals
- Parameters checked in table 1 were examined

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At terminal sacrifice
- Animals fasted: Yes
- How many animals: All surviving animals
- Parameters checked in table 1 were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: Organ weight: Yes. Listed in table 1

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (see table 2)

Statistics:

Clinical pathology data, terminal organ weights, and organ to body weight ratios were statistically analyzed. Statistical evaluation of equality of means was done by an appropriate one way analysis of variance and a test for ordered response in the dose groups.
For the parametric procedures, a standard one way ANOVA using the F distribution to assess significance was used.
For the nonparametric procedures, the test of equality of means was performed using Kruskal-Wallis test.
Mean Draize irritation scores were plotted by group and time.

Clinical signs:

no effects observed

Dermal irritation:

effects observed, treatment-related

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY: There were no treatment-related effects on clinical signs (except dermal irritation) or mortality.

BODY WEIGHT AND WEIGHT GAIN: There were no treatment-related effects on body weight.

HAEMATOLOGY: There were no treatment-related effects on haematology.

CLINICAL CHEMISTRY: There were no treatment-related effects on clinical chemistry.

ORGAN WEIGHTS: There were no treatment-related effects on organ weights.

GROSS PATHOLOGY: At necropsy, the only findings occurred at the treatment site and included dry skin, oedema, and eschar.

HISTOPATHOLOGY: NON-NEOPLASTIC: At the dermal application sites (A and B) there were increased incidences of acanthosis, epidermal crusting, erosion, fibrosis, chronic inflammation, and hyperkeratosis.

OTHER FINDINGS: Dermal irritation occurred in treated animals.
0.01 mL/kg/day: Very slight erythema, slight eschar, and slight dried skin.
0.05 mL/kg/day: Very slight to moderate erythema, slight to moderate eschar, sporadic very slight to slight oedema, and slight to moderately dried skin.
0.50 mL/kg/day: Skin irritation was great enough that the application site changed. For the original site (site A), moderate to severe dermal irritation (erythema, eschar, oedema, dried skin, fissuring, and ulcerations) occurred with a maximum mean daily score of 8.2 in males and 8.1 in females out of a total of 17. These effects decreased after the test site was moved. Similar effects were noted at site B, but the maximum mean daily score was 5.2 in males and 5.4 in females.

Dose descriptor:

NOEL

Remarks:

local

Effect level:

< 0.01 other: ml/kg

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: dermal irritation

Dose descriptor:

NOEL

Remarks:

systemic

Effect level:

0.5 other: ml/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No systemic effects were noted at highest dose level studied.

Critical effects observed:

not specified

Conclusions:

Thermocracked kerosine was applied dermally at doses 0, 0.01, 0.05 and 0.50 mL/kg bw / day to rats for 28 days. The following NOELS were established: systemic NOEL of 0.50 mL/kg/day ( no effects observed at highest dose tested) and local NOEL of < 0.01 mL/kg/day (dermal irritation at application site).

Executive summary:

This study was conducted for the read-across substance, thermocracked kerosine. In a 28-day dermal toxicity study, the test substance was applied to the shaved skin of 10 Sprague-Dawley rats/sex/dose at dose levels of 0, 0.01, 0.05, or 0.5 mL/kg bw/day, 6 hours/day for 5 days/week during a 28-day period. The test compound irritated the skin in a dose-dependent manner. In the high-dose group, the irritation became severe so the application site was moved to a cephalad location at the beginning of the fourth week. There were no compound related effects in mortality, clinical signs, body weight, haematology, clinical chemistry, organ weights, or gross and histologic pathology (except the skin). The LOAEL for dermal irritation is 0.01 mL/kg/day, based on slight to severe dermal irritation occurring at all doses tested. No dermal irritation NOAEL was established. There was no systemic LOAEL, based on the lack of systemic effects. The systemic NOAEL is greater than or equal to 0.5 mL/kg/day.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1992

Report date:

1992

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

F-133 (thermocracked kerosene)

IUPAC Name:

F-133 (thermocracked kerosene)

Constituent 2

Reference substance name:

Naphtha (petroleum), heavy coker

EC Number:

269-778-9

EC Name:

Naphtha (petroleum), heavy coker

Cas Number:

68333-23-3

IUPAC Name:

Naphtha (petroleum), heavy coker

Details on test material:

- Name of test material (as cited in study report): F-133 (thermocracked kerosene), CAS No. 68333-23-3
- Substance type:kerosine
- Physical state: liquid
- Analytical purity: 100 %
- Storage condition of test material: < 80 deg. F.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Sasco, Inc., Omaha, Nebraska
- Age at study initiation: Young adult
- Weight at study initiation: Males: 200 to 300 grams; Females: 125 to 200 grams
- Housing: Individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
-Acclimation period: 19 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 26
- Humidity (%): 40 to 70%
- Air changes (per hr): 10 per hour or more
- Photoperiod (hrs dark / hrs light): 12 hour dark/ 12 hour light

IN-LIFE DATES: From:1990-08-20 To: 1990-09-18

Administration / exposure

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on exposure:

TEST SITE
- Area of exposure: Back
- % coverage: 10% of the body surface area
- Type of wrap if used: Latex dental damsecured in place with surgical adhesive tape
- Time intervals for shavings or clippings: As needed during the study

REMOVAL OF TEST SUBSTANCE
- Washing (if done): residual test article was wiped from the application site
- Time after start of exposure: 6h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.01, 0.05, or 0.5 ml/kg/day adjusted in accordance with the most recent body weight
- Constant volume or concentration used: no

USE OF RESTRAINERS FOR PREVENTING INGESTION: no

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

4 weeks

Frequency of treatment:

6 hours a day, 5 days a week

Doses / concentrations

Remarks:

Doses / Concentrations:
0.01, 0.05, or 0.50 mL/kg/day
Basis:
nominal per unit body weight

No. of animals per sex per dose:

10

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: Doses were selected based on a range-finding study.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice a day
- Cage side observations checked for mortality and viability.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once a week

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: Five days a week just prior to application of the test article, 24 hours after the fifth application, and just prior to necropsy

BODY WEIGHT: Yes
- Time schedule for examinations: Prior to study initiation, three days a week (Monday, Wednesday, and Friday) throughout the dosing period, and at study termination

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At study termination
- Anaesthetic used for blood collection: Yes (halothane)
- Animals fasted: Yes
- How many animals: All surviving animals
- Parameters checked in table 1 were examined

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At terminal sacrifice
- Animals fasted: Yes
- How many animals: All surviving animals
- Parameters checked in table 1 were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: Organ weight: Yes. Listed in table 1

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (see table 2)

Statistics:

Clinical pathology data, terminal organ weights, and organ to body weight ratios were statistically analyzed. Statistical evaluation of equality of means was done by an appropriate one way analysis of variance and a test for ordered response in the dose groups.
For the parametric procedures, a standard one way ANOVA using the F distribution to assess significance was used.
For the nonparametric procedures, the test of equality of means was performed using Kruskal-Wallis test.
Mean Draize irritation scores were plotted by group and time.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Dermal irritation:

effects observed, treatment-related

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY: There were no treatment-related effects on clinical signs (except dermal irritation) or mortality.

BODY WEIGHT AND WEIGHT GAIN: There were no treatment-related effects on body weight.

HAEMATOLOGY: There were no treatment-related effects on haematology.

CLINICAL CHEMISTRY: There were no treatment-related effects on clinical chemistry.

ORGAN WEIGHTS: There were no treatment-related effects on organ weights.

GROSS PATHOLOGY: At necropsy, the only findings occurred at the treatment site and included dry skin, oedema, and eschar.

HISTOPATHOLOGY: NON-NEOPLASTIC: At the dermal application sites (A and B) there were increased incidences of acanthosis, epidermal crusting, erosion, fibrosis, chronic inflammation, and hyperkeratosis.

OTHER FINDINGS: Dermal irritation occurred in treated animals.
0.01 mL/kg/day: Very slight erythema, slight eschar, and slight dried skin.
0.05 mL/kg/day: Very slight to moderate erythema, slight to moderate eschar, sporadic very slight to slight oedema, and slight to moderately dried skin.
0.50 mL/kg/day: Skin irritation was great enough that the application site changed. For the original site (site A), moderate to severe dermal irritation (erythema, eschar, oedema, dried skin, fissuring, and ulcerations) occurred with a maximum mean daily score of 8.2 in males and 8.1 in females out of a total of 17. These effects decreased after the test site was moved. Similar effects were noted at site B, but the maximum mean daily score was 5.2 in males and 5.4 in females.

Effect levels

1

Dose descriptor:

NOEL

Remarks:

local

Effect level:

< 0.01 other: ml/kg

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: dermal irritation

2

Dose descriptor:

NOEL

Remarks:

systemic

Effect level:

0.5 other: ml/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No systemic effects were noted at highest dose level studied.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Thermocracked kerosine was applied dermally at doses 0, 0.01, 0.05 and 0.50 mL/kg bw / day to rats for 28 days. The following NOELS were established: systemic NOEL of 0.50 mL/kg/day ( no effects observed at highest dose tested) and local NOEL of < 0.01 mL/kg/day (dermal irritation at application site).

Executive summary:

This study was conducted for the read-across substance, thermocracked kerosine. In a 28-day dermal toxicity study, the test substance was applied to the shaved skin of 10 Sprague-Dawley rats/sex/dose at dose levels of 0, 0.01, 0.05, or 0.5 mL/kg bw/day, 6 hours/day for 5 days/week during a 28-day period. The test compound irritated the skin in a dose-dependent manner. In the high-dose group, the irritation became severe so the application site was moved to a cephalad location at the beginning of the fourth week. There were no compound related effects in mortality, clinical signs, body weight, haematology, clinical chemistry, organ weights, or gross and histologic pathology (except the skin). The LOAEL for dermal irritation is 0.01 mL/kg/day, based on slight to severe dermal irritation occurring at all doses tested. No dermal irritation NOAEL was established. There was no systemic LOAEL, based on the lack of systemic effects. The systemic NOAEL is greater than or equal to 0.5 mL/kg/day.