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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1986-11-11 to 1987-03-06
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restrictions because it was conducted according to or similar to guideline study OECD TG 411.
Justification for type of information:
Concawe believes that dermal is the most relevant exposure route, and is sufficiently robust, to identify any potential hazards from repeated exposures to petroleum products to be able to adequately manage the potentially associated risks. However, the primary objective of the testing required for REACH is the identification of hazard, for which the default exposure route under the regulation is oral as this is considered to maximise systemic exposure. To address the regulatory exposure route issue, Concawe will review the current data base for evidence of systemic toxicity after dermal exposure and will also conduct a number of oral OECD 422 studies on prioritized substances in each relevant petroleum category. The document attached provides a concise overview of the information to further support the dermal route of exposure and proposed additional work, as part of a larger testing strategy (the strategy document can be found in Annex 13).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
Animals were smaller than recommended.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
64742-04-7
Cas Number:
64742-04-7
IUPAC Name:
64742-04-7
Constituent 2
Reference substance name:
Distillate aromatic extract
IUPAC Name:
Distillate aromatic extract
Test material form:
other: viscous oily liquid
Details on test material:
This substance can be considered “worst case” by comparison to unrefined / acid treated oils, in that the extract contains higher concentrations of biologically active components than the unrefined / acid treated oils.

- Name of test material (as cited in study report): 318 Isthmus Furfural Extract

- CAS number: 64742-04-7

Read across from untreated distillate aromatic extracts

- Substance type:heavy paraffinic distillate solvent extract (petroleum)
- Physical state: liquid
- Analytical purity: not provided
- Impurities (identity and concentrations): not provided
- Composition of test material, percentage of components (wt. %):
total non-aromatics 22.3
total aromatics 77.7
less than 3 ring polynuclear aromatic hydrocarbons 37.2
3 to 5 ring polynuclear aromatic hydrocarbons 23.0
N-polynuclear aromatic hydrocarbons- 2.3% (non-basic = 1.6; basic 0.7)
S-polynuclear aromatic hydrocarbons- 12.8%
- Isomers composition: not provided
- Purity test date: not provided
- Lot/batch No.: CRU no. 86187
- Expiration date of the lot/batch: April 30, 1991
- Stability under test conditions: 5 years

Test animals

Species:
rat
Strain:
other: Tac:N(SD)fBR
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Taconic, Germantown, New York
- Age at study initiation: 49 days
- Weight at study initiation: Males were approximately 180 grams and females were approximately 140 grams
- Housing: Individually in suspended stainless steel cages
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 22
- Humidity (%): 40 to 60%
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12 hour dark/12 hour light

IN-LIFE DATES: From: 1986-12-02 To: 1987-03-05

Administration / exposure

Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: Dorsal trunk
- % coverage: Not reported
- Type of wrap if used: None
- Time intervals for shavings or clippings: As needed, but at least once a week

REMOVAL OF TEST SUBSTANCE
- Washing (if done): None reported

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): Varied depending on body weight
- Constant volume or concentration used: No

USE OF RESTRAINERS FOR PREVENTING INGESTION: Yes
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data reported.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
5 days a week
Doses / concentrations
Remarks:
Doses / Concentrations:
30, 125, 500, or 1250 mg/kg/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
Ten animals per sex per dose
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: Not reported
- Rationale for animal assignment (if not random): Randomly based on body weights

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Once daily
- Cage side observations included appearance, behaviour, excretory function and discharges.

DETAILED CLINICAL OBSERVATIONS: No data

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Prior to study initiation and weekly

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

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 data

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At 5 and 13 weeks
- Anaesthetic used for blood collection: Yes (diethyl ether)
- 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 5 and 13 weeks
- Animals fasted: Yes
- How many animals: All surviving animals
- Parameters checked in table 2 were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: At 5 and 13 weeks
- Metabolism cages used for collection of urine: No
- Animals fasted: No data
- Parameters checked in table 3 were examined.

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:
GROSS PATHOLOGY: Yes, but details were not provided.
HISTOPATHOLOGY: Yes (see table 4)
Other examinations:
Organ weights double XX in table 4 were weighed. Sperm morphology was examined in the 125 mg/kg/day group.
Statistics:
An analysis of variance with associated F-test followed by Student-Newman-Keuls test were used when appropriate.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
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 clinical signs of toxicity in the 500- and 1250-mg/kg/day groups. The signs included pallor and skin cool to the touch (indicating reduced body temperature). All the animals in the 1250-mg/kg/day group were dead or sacrificed prior to study termination. In the 500-mg/kg/day group, all the males and three of the females were dead or sacrificed moribund. Minimal skin irritation occurred in the treated groups, but data were not provided in the study report (stated to be in Appendix 6.1, which was not provided).

BODY WEIGHT AND WEIGHT GAIN: Male rats in the two highest dose groups and all female treatment groups had a significantly reduced body weight by study termination (Table 5).

HAEMATOLOGY: There were several significant changes in haematology parameters (Table 6). Haematology effects were noted at both the 5 and 13 week time points and were generally dose-dependent at doses greater than or equal to 125 mg/kg/day.

CLINICAL CHEMISTRY: There were also numerous effects noted in clinical chemistry, some beginning as early as 5 weeks (Table 7). Some of the significant changes were not related to treatment or were transient in nature. In the males, there were fewer significant changes after 13 weeks because the animals in the two highest groups, which had the majority of the changes at 5 weeks, died before the 13 week measurement. Table 2 provides only the toxicologically significant changes.

URINALYSIS: There were no treatment-related effects on urinalysis.

ORGAN WEIGHTS: There were several changes in relative organ weights in females; however, these were due to the significantly reduced body weights at sacrifice and were not directly attributed to treatment. Organ weight changes related to treatment included increased liver weights and decreased thymus weights (Table 8). The results were dose-dependent in both males and females with significant changes occurring in relative weights even at the lowest dose tested.

GROSS PATHOLOGY: Gross pathological changes were noted in the skin of all treatment groups (red foci, areas of discoloration, streaks, scabs, and sores or raised areas). In the highest two groups, focal areas of red discoloration occurred in the brain, spinal cord, stomach, and testes. The thymus was noticeably small as is indicated by decreased organ weights. The male sex organs (epididymides, prostate, seminal vesicles and testes) were stated to be small in the two high dose groups. These groups did not have organs weighed due to mortality.

HISTOPATHOLOGY: Treatment-related histopathology was generally dose-dependent and occurred in the following tissues: adrenals, bone marrow, kidneys, liver, lymph nodes, treated skin, stomach and thymus (Table 5). Atrophy occurred in the male sex organs (testes, seminal vesicle, and prostate).

OTHER FINDINGS: There was a significant increase in abnormal sperm heads in the 500 mg/kg/day group.

Effect levels

Dose descriptor:
LOAEL
Effect level:
30 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: Body weight; clinical chemistry; gross pathology; organ weights; histopathology

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

 Table 5

 Body weight and body weight gain after dermal exposure to 318 Isthmus Furfural Extract for 13 weeks

 

Study initiation

Week 7

Week 14

Body weight gain

% of control

Males

 

 

 

 

 

Control

183.3

405.4

461.5

278.2

100

30 mg/kg/day

179.7

393.3

465.8

286.1

103

125 mg/kg/day

181.4

389.2

456.6

275.2

99

500 mg/kg/day

180.8

355.9 *

Dead

--

--

1250 mg/kg/day

182.1

295.0 *

Dead

--

--

 

 

 

 

 

 

Females

 

 

 

 

 

Control

142.4

263.3

301.0

158.6

100

30 mg/kg/day

141.0

249.7

278.0 *

137.0

86

125 mg/kg/day

142.6

241.8

275.4 *

132.8

84

500 mg/kg/day

147.4

229.2 *

248.7 *

101.3

64

1250 mg/kg/day

145.4

218.5 *

dead

--

--

* Statistically significantly different from the control; p<0.05

Table 6

Treatment-related changes in haematology after dermal exposure to 318 Isthmus Furfural Extract for 13 weeks

 

Control

30 mg/kg/day

125 mg/kg/day

500 mg/kg/day

1250 mg/kg/day

Week 5

Males

n=10

n=10

n=10

n=10

n=10

Red blood cells (millions/cubic mm)

9.17

8.99

8.82

8.48 *

8.06 *

Platelets (thousands/cubic mm)

1152

1163

1159

618 *

357 *

Haemoglobin (g/dl)

17.1

16.7

15.9 *

15.1 *

14.2 *

Haematocrit (%)

53.7

52.6

50.4 *

48.2 *

45.7 *

Mean corpuscular haemoglobin (picograms)

18.7

18.6

18.1

17.8 *

17.5 *

Mean corpuscular haemoglobin concentration (%)

31.9

31.7

31.6

31.3

31.0 *

 

 

 

 

 

 

Females

n=10

n=10

n=10

n=10

n=10

Red blood cells (millions/cubic mm)

8.79

9.20

8.82

7.99 *

8.17 *

Platelets (thousands/cubic mm)

1217

1153

1076

668 *

516 *

Haemoglobin (g/dl)

17.1

16.7

16.3

13.9 *

14.6 *

Haematocrit (%)

52.6

53.1

51.5

46.1 *

45.7 *

 

 

 

 

 

 

Week 13

Males

n=10

n=10

n=10

dead

dead

Red blood cells (millions/cubic mm)

9.59

9.32

8.55 *

--

--

Platelets (thousands/cubic mm)

1064

1090

591 *

--

--

Haemoglobin (g/dl)

16.7

16

14.6 *

--

--

Haematocrit (%)

55.1

53

48.6 *

--

--

 

 

 

 

 

 

Females

n=10

n=10

n=9

n=7

dead

Red blood cells (millions/cubic mm)

9.08

9.11

8.50 *

6.64 *

--

Platelets (thousands/cubic mm)

1069

1007

843 *

258 *

--

Haemoglobin (g/dl)

16.9

16.5

15.5 *

11.9 *

--

Haematocrit (%)

55.2

54

51.5 *

40.8 *

--

Mean corpuscular haemoglobin concentration (%)

30.6

30.5

30.1 *

29.3 *

--

* Statistically significantly different from the control; p<0.05

  Table 7

Treatment-related changes in clinical chemistry after dermal exposure to 318 Isthmus Furfural Extract for 13 weeks

 

Control

30 mg/kg/day

125 mg/kg/day

500 mg/kg/day

1250 mg/kg/day

Week 5

Males

n=10

n=10

n=10

n=10

n=10

Uric acid

1.2±0.6

1.1±0.4

1.1±0.4

0.7±0.4

0.6±0.2 *

glucose

134.5±9.0

127.1±6.6

121.4±11.0 *

124.0±11.9

106.7±11.1 *

Urea nitrogen

16.8±4.1

17.6±3.0

15.2±2.1

20.4±2.4 *

23.4±2.7 *

Asparate aminotransferase

96±24

88±11

91±22

100±13

120±26 *

Inorganic phosphorus

8.2±0.5

8.4±0.5

8.2±0.6

7.8±0.4

7.1±0.6 *

Sorbitol dehydrogenase

5±2

5±1

9±4

16±3 *

21±8 *

 

 

 

 

 

 

Week 13

Males

n=10

n=10

n=10

dead

dead

Uric acid

1.0±0.4

0.9±0.3

0.3±0.3 *

--

--

cholesterol

99.7±14.1

101.2±12.2

132.0±33.5 *

--

--

Total bilirubin

0.30±0.07

0.19±0.06 *

0.17±0.03 *

--

--

Sorbitol dehydrogenase

5±2

10±5 *

11±3 *

--

--

 

 

 

 

 

 

Week 5

Females

n=10

n=10

n=10

n=10

n=10

Uric acid

1.4±0.2

1.4±0.3

1.4±0.4

0.7±0.4 *

0.4±0.2 *

Urea nitrogen

16.8±2.8

18.4±1.5

20.0±3.1 *

20.2±2.0 *

21.0±3.1 *

Cholesterol

110.5±20.5

114.1±23.5

157.4±24.3 *

242.9±28.7 *

169.7±37.1 *

Sorbitol dehydrogenase

10±3

19±13

15±5

15±4

40±26 *

 

 

 

 

 

 

Week 13

Females

n=10

n=10

n=9

n=7

dead

Uric acid

0.7±0.2

0.8±0.2

0.6±0.3

0.4±0.2 *

--

Urea nitrogen

16.5±3.7

18.9±2.7

18.6±2.0

20.3±1.7 *

--

Cholesterol

96.2±18.4

118.0±15.6

176.2±37.6 *

220.9±33.3 *

--

Triglycerides

22.0±3.2

34.1±9.4 *

38.1±9.1 *

41.3±12.3 *

--

Inorganic phosphorus

6.4±0.5

6.7±0.5

6.0±0.5 *

5.4±0.3 *

--

* Statistically significantly different from the control; p<0.05

Table 8

Treatment-related changes in organ weight after dermal exposure to 318 Isthmus Furfural Extract for 13 weeks

 

Control

30 mg/kg/day

125 mg/kg/day

500 mg/kg/day

1250 mg/kg/day

Males

n=10

n=10

n=10

dead

dead

Final body weight

435.1±36.7

434.0±19.2

424.7±32.6

--

--

Liver (absolute)

13.225±1.760

14.773±1.459

18.871±1.371 *

--

--

Liver (relative)

3.034±0.239

3.404±0.291 *

4.449±0.198 *

--

--

Thymus (absolute)

0.404±0.120

0.329±0.049

0.227±0.067 *

--

--

Thymus (relative)

0.093±0.029

0.076±0.011 *

0.054±0.017 *

--

--

 

 

 

 

 

 

Females

n=10

n=10

n=10

n=7

dead

Final body weight

277.2±23.7

256.3±25.0 *

250.1±18.4 *

224.8±10.0 *

--

Liver (absolute)

8.045±0.735

8.679±0.914

10.407±0.914 *

12.594±1.004 *

--

Liver (relative)

2.910±0.234

3.395±0.293 *

4.162± 0.214 *

5.598±0.262 *

--

Thymus (absolute)

0.338 ±0.068

0.268±0.057 *

0.163±0.059 *

0.065±0.010 *

--

Thymus (relative)

0.122±0.032

0.105±0.022

0.065±0.021 *

0.029±0.004 *

--

* Statistically significantly different from the control; p<0.05

Applicant's summary and conclusion

Conclusions:
The LOAEL for 318 Isthmus Furfural Extracts via dermal application is 30 mg/kg/day based on decreased body weights, increased sorbitol dehydrogenase, increased triglycerides, increased absolute and relative liver weight, decreased absolute and relative thymus weight, gross pathology, and/or changes in histopathology in male and female rats. There is no NOAEL due to effects noted at the lowest dose tested.
Executive summary:

Justification for Read Across

A DAE is produced as a by product in the refining of lubricating oil base stocks and waxes. Straight run vacuum distillates are extracted with solvents such as furfural, phenol, or N-methyl-2-pyrrolidone to selectively remove the undesirable polycyclic aromatic compounds, (especially 3-7 fused ring structures). A DAE can be considered “worst case” by comparison to unrefined / acid treated oils, in that the extract contains higher concentrations of biologically active components than the unrefined / acid treated oils.

In a 90-day dermal toxicity study, 318 Isthmus Furfural Extract was applied to the shaved skin of 10 Tac:N(SD)fBR rats/sex/dose at dose levels of 0, 30, 125, 500 or 1250 mg/kg bw/day, 5 days a week for 13 weeks (total of 65 applications). Rats were fit with Elizabethan collars to deter ingestion as the test article.

 

There were clinical signs of toxicity in the 500- and 1250-mg/kg/day groups. The signs included pallor and skin cool to the touch (indicating reduced body temperature). All the animals in the 1250-mg/kg/day group were dead or sacrificed prior to study termination. In the 500-mg/kg/day group, all the males and three of the females were dead or sacrificed moribund. Minimal skin irritation occurred in the treated groups, but data were not provided in the study report (stated to be in Appendix 6.1, which was not provided). Male rats in the two highest dose groups and all female treatment groups had a significantly reduced body weight by study termination. There were several significant changes in haematology parameters including decreased red blood cell count, haematocrit, haemoglobin, and platelets at doses greater than or equal to 125 mg/kg/day. Haematology effects were noted at both the 5 and 13 week time points and were generally dose-dependent. There were also numerous effects noted in clinical chemistry, some beginning as early at 5 weeks including changes in uric acid, urea nitrogen, cholesterol, triglycerides, and sorbitol dehydrogenase. There were no treatment-related effects on urinalysis. Organ weight changes related to treatment included dose-dependent increases in liver weights and decreases in thymus weights. Gross pathological changes were noted in the skin of all treatment groups (red foci, areas of discoloration, streaks, scabs, and sores or raised areas). In the highest two groups, focal areas of red discoloration occurred in the brain, spinal cord, stomach, and testes. The thymus was noticeably small as is indicated by decreased organ weights. The male sex organs (epididymides, prostate, seminal vesicles and testes) were stated to be small in the two high dose groups. These groups did not have organs weighed due to mortality. Treatment-related histopathology was generally dose-dependent and occurred in the following tissues: adrenals, bone marrow, kidneys, liver, lymph nodes, treated skin, stomach and thymus. Atrophy occurred in the male sex organs (testes, seminal vesicle, and prostate). There was a significant increase in abnormal sperm heads in the 500 mg/kg/day group. The LOAEL is 30 mg/kg/day, based on body weight, clinical chemistry, organ weights, gross pathology, and histopathology. No NOAEL is identified.

 

This study received a Klimisch score of 1 and is classified as reliable without restrictions because it was conducted according to or similar to guideline study OECD TG 411.