Hydrocarbons, C10, aromatics, <1% naphthalene

Endpoint summary

Description of key information

There is no repeat dose toxicity data available for Hydrocarbons, C10, aromatics, <1% naphthalene. However, data available for structural analogues,Hydrocarbons, C10, aromatics, Hydrocarbons, C10, aromatics, and1,3,5-trimethylbenzene ispresented in the dossier. 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.

1,3,5 -trimethylbenzene

Repeated Dose Oral 90d NOAEL = 600 mg/Kg bw for rats (similar to OECD TG 408)

Hydrocarbons, C9 Aromatics

Repeated Dose Inhalation 12 month NOAEC = 900 mg/m³ for rats (similar to OECD TG 413)

Additionally, in order to comply with standard information requirements for Annex X substances, an OECD Guideline 90-day sub-chronic (OECD 408) toxicity test is proposed for a structural analogue Hydrocarbons, C11-C15, aromatics, <1% naphthalene (EC# 922-153-0). The testing proposal for the same has been presented in the lead registrant dossier for this substance already submitted to ECHA. This study will be conducted subsequent to ECHA's approval and this endpoint will be updated upon completion of the above study. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1995

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well-documented study report which meets basic scientific principles.

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 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

none

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

groups of 10 male and 10 female Sprague Dawley rats were administered via gavage 0, 50, 200, or 600 mg/kg 1,3,5-TMB in corn oil 5 days/week for 90 days. An additional group of rats (10/sex) were administered 600 mg/kg 1,3,5-TMB for 90 days and retained without treatment for 28 days.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

90 days and 90 days with 28 day recovery

Frequency of treatment:

once a day; 7 days a week

Remarks:

Doses / Concentrations:
0, 50, 200, or 600 mg/kg
Basis:
actual ingested

No. of animals per sex per dose:

10 males and 10 females per dose

Control animals:

yes, concurrent vehicle

Details on study design:

Groups of 10 male and 10 female Sprague Dawley rats were administered via gavage 0, 50, 200, or 600 mg/kg 1,3,5-TMB in corn oil 5 days/week for 90 days. An additional group of rats (10/sex) were administered 600 mg/kg 1,3,5-TMB for 90 days and retained without treatment for 28 days.

Positive control:

none

Observations and examinations performed and frequency:

Physical examinations, clinical observations, opthamological examinations, body weights, food consumption, hematological and clinical chemistry, organ weights, and gross and histopathology were assessed.

Clinical signs:

no effects observed

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:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
No Deaths were recorded. Abnormal clinical observations consisted of discolored and/or wet inguinal fur and salivation in the highest dose group of both sexes.

BODY WEIGHT AND WEIGHT GAIN
A non-significant decrease in cumulative body weight gain (11 percent lower than controls) was observed for the high dose males.

CLINICAL CHEMISTRY
Clinical chemistry parameters were ascertained at 30 days post-dosing and at the end of the 28-day recovery period. At the 30-day time point, statistically significantly affected parameters in treated animals versus controls consisted of increased albumin levels and albumin/globulin ratio, decreased globulin and cholesterol levels in high dose males; decreased cholesterol levels in mid dose males; and decreased blood urea nitrogen levels in high dose females. At the termination of dosing, significantly affected parameters occurred only in the high dose group. These consisted of increased alkaline phosphatase and phosphorus levels and decreased glucose levels in high dose males, and increased cholesterol and phosphorus levels and decreased sodium and chloride levels in high dose females. The 30-day differences were not considered treatment-related since they were not present post-dosing. The post-dosing differences, with the exception of increased serum phosphorus levels, were either within normal parameters or due to high values in two individual animals and were not statistically significant. The increased serum phosphorus levels were considered treatment-related but these effects were reversible with in the post-dosing recovery period.

GROSS PATHOLOGY
No abnormalities were noted to be treatment related

Key result

Dose descriptor:

NOAEL

Effect level:

600 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: Systemic Toxicity

Critical effects observed:

not specified

Conclusions:

Based on a lack of adverse effects at the highest dose level (reversible effects such as increased serum phosphorus levels and liver and kidney weights), the no-observed-adverse-effect level (NOAEL) for this study is therefore considered to be 600 mg/kg-day.

Executive summary:

In the subchronic study on the oral toxicity of 1,3,5-TMB, groups of 10 male and 10 female Sprague Dawley rats were administered via gavage 0, 50, 200, or 600 mg/kg 1,3,5-TMB in corn oil 5 days/week for 90 days. An additional group of rats (10/sex) were administered 600 mg/kg 1,3,5-TMB for 90 days and retained without treatment for 28 days. Based on a lack of adverse effects at the highest dose level (reversible effects such as increased serum phosphorus levels and liver and kidney weights), the no-observed-adverse-effect level (NOAEL) for this study is therefore considered to be 600 mg/kg-day.

Reference 2

Endpoint:

sub-chronic toxicity: oral

Data waiving:

other justification

Justification for data waiving:

other:

Justification for type of information:

The 'Justification for the read across' is provided in the 'Attached justification' section below.

Species:

rat

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

600 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Only key read across sub-chronic oral toxicity study available for assessment.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Source of data is from peer reviewed literature. Acceptable well-documented study report which meets basic scientific principles: non-GLP.

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 413 (Subchronic Inhalation Toxicity: 90-Day Study)

GLP compliance:

not specified

Species:

other: Rats and Dogs

Strain:

other: RATS: Harlan Wistar; DOGS: Beagles

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RATS: Harlan
-Number: RATS: 25 males; DOGS: 4 males

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

25 rats and four dogs per dose were used.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Gas chromatographic analyses of the nominal 0.25, 0.5, and 1.0 mg/liter vapor-air mixtures yielded mean measured concentrations of 0.10, 0.22, and 0.38 mg/liter or 17, 38, and 66 ppm.

Remarks:

Doses / Concentrations:
17, 38, and 66 ppm (0.10, 0.22, 0.38 mg/L)
Basis:
analytical conc.

No. of animals per sex per dose:

RATS: 6 males/dose (25 total); DOGS: 1 male/dose (4 total)

Details on study design:

Methods

Species and number. Twenty-five male rats and four dogs per level were used. Another 20 rats, from the same week of production, were maintained for use as challenge exposure controls (naive rats). The challenge exposures were run to determine whether the 6-hr daily inhalation of a non-lethal level of hydrocarbon, whether by acclimatization or induction of enzymes, would result in the rat becoming more or less resistant than non-exposed or naive controls from the same lot of animals.

Concentrations. A control group (exposed to dilution air) plus groups exposed to three graded levels of test material were utilized for each compound.

Duration. Exposures were 6 hr/day, 5 days/wk for 13 wk.

Observations. Once each week, body weights of both species and food consumption for dogs were determined. Overall appearance and behavior were checked daily.

Procedure. At 3, 8, and 13 wk of exposure three, three, and four rats, respectively, from each group, including controls, were sacrificed. After 13 wk of exposure 10 surviving rats from each group and 20 unexposed rats of the same age were used to detect any significant differences in time to death or in occurrence of signs of distress among the groups. The groups were “challenged” simultaneously by exposure to a vapor air concentration 1.25-2 times the 4-hr rat LC50 until 25 % of the group succumbed or for no more than a 6-hr period. The remaining rats, or those surviving the subacute exposure, exclusive of the ten per level reserved for the challenge exposure were sacrificed after 13 wk and tissues were taken for histopathological interpretation following gross autopsy. The assignment of rats to each of the above groups was made by random selection before the start of the study.

Clinical and hematological schemata. These tests were performed on all dogs initially and prior to sacrifice; and on rats, prior to sacrifice at 3, 8, and 13 wk of exposure. Minimum hematological evaluation for each animal included hematocrit, total erythrocyte count, reticulocyte count, and total and differential leucocyte counts. The biochemical survey included serum alkaline phosphatase, serum glutamic oxoacetic transaminase, serum glutamic pyruvic transaminase, and blood-urea-nitrogen on the rats, and these tests plus bilirubin and blood glucose on the dogs. Initial pre-terminal electrocardiograms were performed on all dogs. Urinalyses were conduct with both species.

Autopsy and pathology schemata. Gross examinations were made of all organ system Histopathological examination included brain (three sections), respiratory (three sections minimum, based on acute exposure data results), heart, thyroid, live kidney, adrenal, spleen, pancreas, stomach and intestines, skeletal muscle, bat marrow, and peripheral nerves. The reproductive organs and eyes were not scheduled for histopathological study unless abnormalities were discovered upon gross examination. Tissues were taken from all dogs and from rats sacrificed after 3, 8, and 13 wk of inhalation of the vapor.

Observations and examinations performed and frequency:

Observations. Once each week, body weights of both species and food consumption for dogs were determined. Overall appearance and behavior were checked daily.

Clinical and hematological schemata. These tests were performed on all dogs initially and prior to sacrifice; and on rats, prior to sacrifice at 3, 8, and 13 wk of exposure. Minimum hematological evaluation for each animal included hematocrit, total erythrocyte count, reticulocyte count, and total and differential leucocyte counts. The biochemical survey included serum alkaline phosphatase, serum glutamic oxoacetic transaminase, serum glutamic pyruvic transaminase, and blood-urea-nitrogen on the rats, and these tests plus bilirubin and blood glucose on the dogs. Initial pre-terminal electrocardiograms were performed on all dogs. Urinalyses were conduct with both species.

Sacrifice and pathology:

Autopsy and pathology schemata. Gross examinations were made of all organ system. Histopathological examination included brain (three sections), respiratory tract (three sections minimum, based on acute exposure data results), heart, thyroid, live kidney, adrenal, spleen, pancreas, stomach and intestines, skeletal muscle, bone marrow, and peripheral nerves. The reproductive organs and eyes were not scheduled for histopathological study unless abnormalities were discovered upon gross examination. Tissues were taken from all dogs and from rats sacrificed after 3, 8, and 13 wk of inhalation of the vapor.

Statistics:

Statistical analysis. Based on mortality during a 14-day observation period, the most probable LC50 with its fiducial range was calculated by the Thompson method of moving averages using tables by Weil (1952) and other unpublished tables. The results of the quantitative continuous variables, such as body weight changes, were intercompared for the dosage groups and the controls by the use of the following tests: Bartlett’s homogeneity of variance, analysis of variance, rank sum, and Duncan’s multiple range. The latter was used, if F for analysis of variance was significantly high, to delineate which groups differed from the controls. If Bartlett’s test indicated heterogeneous variances, the F test was used for each group versus the control. If these individual F tests were not significant, Student’s t test was used; if significant, the means were compared by the Cochran t test or the rank sum test. Frequency data, such as incidences of mortality or of micro-pathological conditions, were intercompared by the normal deviate of chi square calculated with Yates’ correction for continuity. In all cases the fiducial limit of 0.05 was employed to delineate the critical level of significance.
In general, only criteria that differed statistically significantly from the control group are discussed. Omission of comment is indicative that no valid differences were found. An attempt has been made to round off machine calculated data but if it is obvious that the data portend fictitious accuracy the implication should be ignored.

Clinical signs:

no effects observed

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:

no effects observed

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:

no effects observed

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Details on results:

RATS. One rat at the 0.10-mg/liter level died after 14 days. Death was attributed to a pneumonic infection as evidenced by extensive lung abscesses. None of the observations were dosage-related and are discounted for that reason.
Significant findings (Rats) - Concentration (mg/liter)
Specific gravity urine, 9 weeks, rats - 0.38 mg/liter - Not dosage-related;
Blood urea nitrogen, 3 weeks, rats 0.10 mg/liter - Not dosage related;
Red blood cell count, Packed cell volume, and Hemoglobin, 9 weeks, rats 0.38 mg/liter - Not dosage-related
Alkaline phosphatase, 9 weeks, rats 0.10 mg/liter - Not dosage-related;
Neutrophil differential, 13 weeks, rats 0.22 mg/liter - Not dosage-related;
Lymphocyte differential, 13 weeks, rats 0.22 mg/liter - Not dosage-related.

DOGS. Pre-exposure polymorphonuclear neutrophilic leucocytes for the 0.1 mg/liter dogs were slightly higher than the controls on an absolute basis, but on the basis of change from pre-exposure after 13 weeks of inhalation, there were no significant differences that were treatment related.

Key result

Dose descriptor:

NOAEC

Remarks:

Rat

Effect level:

> 0.38 mg/L air (analytical)

Sex:

male/female

Basis for effect level:

other: Systemic Toxicity

Key result

Dose descriptor:

NOAEC

Remarks:

Dog

Effect level:

> 0.38 mg/L air (analytical)

Sex:

male

Basis for effect level:

other: Systemic Toxicity

Critical effects observed:

not specified

Conclusions:

The test material’s NOAEC > 0.38 mg/liter (66 ppm), which was the highest achievable vapor concentration.

Executive summary:

Twenty-five male rats and four dogs per level were exposed for 6 hr/day, 5 days/wk for 13 wk. Another 20 rats, from the same week of production, were maintained for use as challenge exposure controls (naive rats). The challenge exposures were run to determine whether the 6-hr daily inhalation of a non-lethal level of hydrocarbon, would result in the rat becoming more or less resistant. One rat at the 0.10-mg/liter level died after 14 days. Death was attributed to a pneumonic infection as evidenced by extensive lung abscesses. None of the observations were dosage-related and are discounted for that reason. The test material’s NOAEC > 0.38 mg/liter (66 ppm), which was the highest achievable vapor concentration.

Reference 2

Endpoint:

chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1978/08/29-1980/01/25

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well-conducted study comparable to standard studies.

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 452 (Chronic Toxicity Studies)

GLP compliance:

no

Remarks:

prior to GLP

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Shell Toxicology Laboratory Breeding Unit
- Age at study initiation: 8-9 weeks
- Weight at study initiation: 150-300 g
- Housing: Hanging aluminum cages with stainless steel mesh bases. Paper lined catch trays were beneath each layer of cages and cleaned daily. Animals were identified using an ear punch/notch system.
- Diet (e.g. ad libitum): PRD Labsure food was available ad libitum
- Water (e.g. ad libitum): tap water ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): appox. 20
- Humidity (%): 50%
- Air changes (per hr): continuous airflow of 3-6 m³/min
- Photoperiod (hrs dark / hrs light): 12 hrs light/ 12 hrs dark

IN-LIFE DATES: 1978/08/29-1980/01/25

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: 8 m³stainless steel chamber.
- Method of holding animals in test chamber: cages
- Source and rate of air: air drawn from laboratory at 3-6m³/min
- Method of conditioning air: filters
- System of generating particulates/aerosols: Vapors were generated using quartz tubes with their surface temperature adjusted to 148°C, (high concentration), 130°C (medium concentration), 225°C (low concentration). The vapor entered the experiment chamber via micrometering pumps.
- Temperature, humidity, pressure in air chamber: 14-29.5°C, 35.5-73.5% humidity
- Air flow rate: 3-6m³/min
- Air change rate: continuous

TEST ATMOSPHERE
- Brief description of analytical method used: Test atmospheres were analyzed by a total hydrocarbon analyser for 10 min at intervals of 40 min during exposures. Test atmospheres were also analyzed continuously for 2 hrs during each exposure using gas chromatographs with a flame iionization detector.
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Control: Nominal 0 mg/m^3, measured 0 mg/m³
Low: Nominal 450 mg/m^3, measured 470 +/- 29 mg/m³
Medium: Nominal 900 mg/m^3, measured 970 +/- 70 mg/m³
High: Nominal 1800 mg/m^3, measured 1830 +/- 130 mg/m³

Duration of treatment / exposure:

12 months

Frequency of treatment:

6 hrs per day, 5 days per week except for 8 public holidays, 2 snowdays, and exposure limited on 2 other days for unknown reasons

Remarks:

Doses / Concentrations:
0, 470 mg/m³, 970 mg/m³, 1830 mg/m³
Basis:
analytical conc.

No. of animals per sex per dose:

50

Control animals:

yes, concurrent no treatment

Details on study design:

- Rationale for animal assignment (if not random): Randomized block design with each control and experimental group in one block from the same litter.
- Post-exposure recovery period in satellite groups: 4 months

Positive control:

None

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: before start of experiment, weekly for first 4 weeks, monthly thereafter

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 10 animals of each sex from the high exposure and control groups had blood drawn at weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 28, and 32 of exposure. Blood was also taken from 10 animals of each sex from each exposure level at the 26 and 52 week sacrfice, and from the 4 month recovery group.
- How many animals: 10 of each sex
- Parameters checked: Repeated sampling - erythrocyte count, mean cell volume, hemoglobin concentration, leucocyte count, mean corpuscular hemoglobin concentration, and hematocrit
Terminal sampling - erythrocyte count, mean cell volume, hemoglobin, leucocyte count, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, hematocrit, prothrombin time, kaolin-cephalin coagulation time, erythrocyte osmotic fragility. Reticulocytes were only counted in the high exposure and control groups at the 12 month sacrifice.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood taken from 10 animals of each sex from each exposure level at the 26 and 52 week sacrfice, and from the 4 month recovery group.
- Animals fasted: overnight
- How many animals: 10 of each sex
- Parameters checked: 12 month sacrifice - total protein, urea nitrogen, alkaline phosphatase, chloride ion, total bilirubin, total calcium, inorganic phosphate, uric acid, sodium, potassium, alanine amino transferase, aspartate amino transferase, glucose concentration, protein eleectrophoresis,
26 week sacrifice - protein, urea, alkaline phosphatase, alanine amino transferase, aspartate amino transferase, chloride, sodium, potassium, portein electrophoresis

URINALYSIS: Yes
- Time schedule for collection of urine: male and females from each exposure group at 0, 3, 6, 9, and 12 months exposure, and 3 months after exposure.
- Parameters checked: Glucose, protein, ketones, bilirubin, blood pigments, pH, nitrite, urobilinogen

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
Animals were sacrificed by injection of sodium pentobarbitone. All external surfaces, orifices, and the throacic and abdominal cavities were then examined. The following organs were then weighed: liver, kidneys, spleen, brain, heart, testes

HISTOPATHOLOGY: Yes
Histopathology was done on the following organs: salivary gland, stomach, heart, brain, spinal cord, pituitary gland, sciatic and posterier tibial nerves, lungs, prostate, seminal vesicles, testes, ovaries, uterus, skeletal muscle, adrenal glands, thyroids with esophagus and trachea, caecum, spleen, thymus, lymph node, mammary gland, small intestine, large intestine, pancreas, liver, kidneys, urinary bladder, eye and lachrymal glands, nasal cavity, spinal cord, tongue, knee joint and femur, any lesions

Statistics:

Body and organ weights were analyzed by covariance analysis. Hematological and clinical parameters were examined using analysis of variance. Significance of any difference between treated and control goup means was tested using the Williams t test. If a monotonic dose response could not be assumed, Dunnett's test was used instead.

Clinical signs:

no effects observed

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:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
No clinical signs attributable to exposure were observed. Five animals died during the study. 2 males and 1 female in the control group died during the exposure phase of the experiment, and 2 males in the medium exposure group died during the recovery phase. These deaths were not considered attributable to exposure to the test substance. 37 animals were removed from the study during both the exposure and recovery phase for various health reasons, most commonly sore hocks. The number of removals was similar for all exposure levels, including the control group and was not attributable to exposure to the test substance.


BODY WEIGHT AND WEIGHT GAIN
Body weight gain was decreased the first 4 weeks in high exposure males, and medium exposure females. High exposure females had decreased body weight gains for the first 12 weeks of exposure, but recovered after exposure was terminated.

HAEMATOLOGY
Though some statistically significant changes were observed, particularly in males, no biologically significant changes were observed.

CLINICAL CHEMISTRY
Minor clinical chemical changes were observed at both the 26 and 12 month sacrifice, but were within normal ranges.

URINALYSIS
No differences between exposure and control groups were observed.

ORGAN WEIGHTS
Liver and kidney weights in the high dose males were significantly increased, but there were no histopathological lesions, so this was considered a functional hypertrophy of the organs.

HISTOPATHOLOGY: NON-NEOPLASTIC
No histopathological changes that could be attributable to exposure to the test substance were detected.

Key result

Dose descriptor:

NOAEC

Effect level:

1 800 mg/m³ air (nominal)

Sex:

male

Basis for effect level:

other: Systemic Toxicity

Key result

Dose descriptor:

NOAEC

Effect level:

900 mg/m³ air (nominal)

Sex:

female

Basis for effect level:

other: body weight reduction

Critical effects observed:

not specified

Conclusions:

The NOAEC for male rats was determined to be 1800 mg/m3, the highest concentration tested. The NOAEC for female rats was determined to be 900 mg/m3, due to the reduced body weight noted.

Executive summary:

This study examined the effects of 12 months of inhalation exposure of rats to a commercial mixture of Hydrocarbons, C9 Aromatics. Male and female rats were exposed to concentrations of 450, 900, or 1800 mg/m³ 6 hrs/day, 5 days/week, for up to 12 months. Some of the rats were sacrificed at 26 weeks, others at 12 months, and others after a 4 month recovery period after the end of the 12 month exposure. Animals were examined for clinical signs and behaviour twice daily, and weighed weekly for the first 4 weeks, and monthly thereafter. After sacrifice, the animals were examined for clinical chemistry, hematology, urine analysis, gross pathology, histopathology, and organ weights. No deaths attributable to exposure to the test substance occurred. There was depressed weight during the first few months of the experiment in medium (900 mg/m³) and high dose males (1800 mg/m³). However, the animals quickly recovered and this effect is not considered biologically significant. High dose females (1800 mg/m³) had depressed weight gain for the first 3 months of exposure, but recovered in subsequent months and in the satellite recovery group. No other adverse effects attributable to exposure to the test substance were seen. Based on the reversibility of the reduced weight gain and the lack of any noted pathology, the NOAEC for male rats was 1800 mg/m³ and the NOAEC for female rats was 900 mg/m3.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

900 mg/m³

Study duration:

chronic

Species:

rat

Quality of whole database:

2 key (1 sub-chronic and 1 chronic) read across studies available for assessment.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

There is no repeat dose toxicity data available for Hydrocarbons, C10, aromatics, <1% naphthalene. However, data available for structural analogues,Hydrocarbons, C10, aromatics, Hydrocarbons, C10, aromatics, and1,3,5-trimethylbenzene ispresented in the dossier. 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.

Repeated Dose Oral Toxicity

1,3,5-trimethylbenzene

In the subchronic study on the oral toxicity of 1,3,5-trimethylbenzene (Koch Industries, 1995), groups of 10 male and 10 female Sprague Dawley rats were administered via gavage 0, 50, 200, or 600 mg/kg test material in corn oil 5 days/week for 90 days. An additional group of rats (10/sex) were administered 600 mg/Kg test material for 90 days and retained without treatment for 28 days. Based on a lack of adverse effects at the highest dose level (reversible effects such as increased serum phosphorus levels and liver and kidney weights), the no-observed-adverse-effect level (NOAEL) for this study is therefore considered to be 600 mg/Kg-day.

Additionally, in order to comply with standard information requirements for Annex X substances, an OECD Guideline 90-day sub-chronic (OECD 408) toxicity test is proposed for a structural analogue Hydrocarbons, C11-C15, aromatics, <1% naphthalene (EC# 922-153-0). The testing proposal for the same has been presented in the lead registrant dossier for this substance already submitted to ECHA. This study will be conducted subsequent to ECHA's approval and this endpoint will be updated upon completion of the above study. 

Inhalation

Hydrocarbons, C9, aromatics

A key study (Shell, 1981) examined the effects of 12 months of inhalation exposure of rats to a commercial mixture of Hydrocarbons, C9 Aromatics. Male and female rats were exposed to concentrations of 450, 900, or 1800 mg/m³ 6 hrs/day, 5 days/week, for up to 12 months. Some of the rats were sacrificed at 26 weeks, others at 12 months, and others after a 4 month recovery period after the end of the 12 month exposure. Animals were examined for clinical signs and behaviour twice daily, and weighed weekly for the first 4 weeks, and monthly thereafter. After sacrifice, the animals were examined for clinical chemistry, hematology, urine analysis, gross pathology, histopathology, and organ weights. No deaths attributable to exposure to the test substance occurred. There was depressed weight during the first few months of the experiment in medium (900 mg/m³) and high dose males (1800 mg/m³). However, the animals quickly recovered and this effect is not considered biologically significant. High dose females (1800 mg/m³) had depressed weight gain for the first 3 months of exposure, but recovered in subsequent months and in the satellite recovery group. No other adverse effects attributable to exposure to the test substance were seen. Based on the reversibility of the reduced weight gain and the lack of any noted pathology, the NOAEC for male rats was 1800 mg/m³ and the NOAEC for female rats was 900 mg/m3.

A supporting 90-day sub-chronic toxicity study examined the effects of 13 weeks of inhalation exposure of Hydrocarbons, C9, aromatics to rats (Shell, 1980). Male and female rats were exposed to 353, 706, and 1437 ppm of test substance 6 hrs/day, 5 days/week, for 13 weeks. Animals were observed daily for clinical signs, and body weights measured weekly. Blood samples were taken at the end of exposure and examined for hematological and clinical chemistry parameters. Animals were then sacrificed and histopathology, gross pathology, and organ weight parameters were examined. Body weight gains were significantly reduced in high exposure (1437 ppm) males and females, and medium exposure (706 ppm) females. Low grade anemia was present in females in all three exposure groups. The NOAEC for male rats is 706 ppm, and the LOAEC is 1437 ppm based on reduction in body weight gain. The LOAEC for female rats is 353 ppm based on low grade anemia.

Hydrocarbons, C10, aromatics

In a 90-day sub-chronic inhalation toxicity study (Carpenter et al., 1977), twenty-five male rats and four dogs per level were exposed for 6 hr/day, 5 days/wk for 13 weeks to Hydrocarbons, C10, aromatics. Another 20 rats, from the same week of production, were maintained for use as challenge exposure controls (naive rats). The challenge exposures were run to determine whether the 6-hr daily inhalation of a non-lethal level of hydrocarbon, would result in the rat becoming more or less resistant. One rat at the 0.10-mg/liter level died after 14 days. Death was attributed to a pneumonic infection as evidenced by extensive lung abscesses. None of the observations were dosage-related and are discounted for that reason. The test material’s NOAEC was determined to be >0.38 mg/L (66 ppm), which was the highest achievable vapor concentration.

Justification for classification or non-classification

Based on available read across data, Hydrocarbons, C10, aromatics, <1% naphthalene does not warrant classification as a repeated dose toxicant under Regulation (EC) 1272/2008 on classification, labelling and packaging of substances and mixtures (CLP).