2,3-dimethylbutane

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Study period:

1989-04-10 to 1989-07-12

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: This study is classified as reliable without restrictions because it is well documented and follows OECD Guideline 413.

Justification for type of information:

A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.

Cross-reference

Reason / purpose for cross-reference:

read-across: supporting information

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Study period:

1989-04-10 to 1989-07-12

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: This study is classified as reliable without restrictions because it is well documented and follows OECD Guideline 413.

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 source

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):

no effects observed

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
No rats died during the study. Transient excess lacrimation was observed in the female rats. No other effects attibutable to exposure were noted.

BODY WEIGHT AND WEIGHT GAIN
Females in the high exposure group had sporadic reduced weight gain. As there was no consistant overall effect, this was not considered treatment related.

FOOD CONSUMPTION
There was no effect on food consumption.


OPHTHALMOSCOPIC EXAMINATION
Two males in the high exposure group showed corneal dystrophy. As this is not uncommon in males of this strain of rat, it is not considered treatment related.

HAEMATOLOGY
There were increased platelets in high exposure males. High and medium exposure males also had increased mean corpuscular volume. The significance of these changes are uncertain.

CLINICAL CHEMISTRY
High exposure males had increased creatinine, total protein, and albumin. They had decreased serum chloride. The significance of these changes are also uncertain.

ORGAN WEIGHTS
High exposure males had increased organ/body and organ/brain weight ratios. High exposure males and females had increased relative spleen weights. Liver weights were also increased in high exposure males. The liver effects appeared to be treatment related.

GROSS PATHOLOGY
No treatment related effects were noted.

HISTOPATHOLOGY: NON-NEOPLASTIC
There was hemorrhage and inflammation in male rat livers at the high dose level. There was also inflammation in the kidneys of males in the high and middle exposure groups. The significance of these effects are uncertain.

Key result

Dose descriptor:

NOAEC

Effect level:

2 984 ppm

Sex:

male

Basis for effect level:

other: 10504 mg/m3

Key result

Dose descriptor:

LOAEC

Effect level:

8 992 ppm

Sex:

male

Basis for effect level:

other: 31652 mg/m3; liver and kidney effects

Key result

Dose descriptor:

NOAEC

Effect level:

8 992 ppm

Sex:

female

Basis for effect level:

other: 31652 mg/m3

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

8 992 ppm

System:

other: Hepatobiliary and urinary

Organ:

kidney

liver

Treatment related:

yes

Dose response relationship:

not specified

Relevant for humans:

not specified

Conclusions:

The NOAEC for male rats exposed via inhalation was 2984 ppm based on liver and kidney effects. The LOAEC for male rats was 8992 ppm. The NOAEC for female rats was 8992 ppm.

Executive summary:

This data is being read across from the source study that tested commercial hexane based on analogue read across.

The purpose of this study was to determine the sub-chronic toxicity of commercial hexane via inhalation. Groups of 10 male and 10 female rats were exposed to concentrations of 0, 904, 2,984, and 8,992 ppm of test substance for 6 hrs/day, 5 days/week, for 13 weeks. During the exposure period, animals were examined for mortality, body weight, clinical signs, opthamological effects, and food consumption. At the end of the exposure period, the animals were sacrificed and examined for hematological parameters, clinical chemistry, gross pathology, organ weights, and histopathology.

There was no mortality among the exposed groups, and no treatment related effects to body weight gain. At sacrifice, the only possible treatment related effects were hemorrhage and inflammation in high dose male livers. The significance of this effect is uncertain. The NOAEC for male rats in 2984 ppm (10504 mg/m³), and the LOAEC is 8992 ppm (31652 mg/m³). The NOAEC for female rats in 8992 ppm (31652 mg/m³).

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

GLP compliance:

yes

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

commercial hexane

IUPAC Name:

commercial hexane

Details on test material:

- Name of test material (as cited in study report): commercial hexane
- Physical state: clear, water white liquid
- Analytical purity: 100% active ingredient
- Composition of test material, percentage of components: 40-55% n-hexane, >10% methylcyclopentane
- Lot/batch No.: H01-26-89

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Raleigh, NC
- Age at study initiation: 8 weeks
- Weight at study initiation: approx. 181 g male, approx. 123 g female
- Housing: individually in stainless steel wire mesh cages, identified by tail tattoo
- Diet (e.g. ad libitum): Purina Rodent Chow Brand Animal Diet#5002, ad libitum
- Water (e.g. ad libitum): ad libitum, Elizabethtown Water Company
- Acclimation period: 20 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 68-75 degree F
- Humidity (%): 40-60
- Photoperiod (hrs dark / hrs light): 12 hrs light/12 hrs dark


IN-LIFE DATES: From: April 10, 1989 To: July 12, 1989

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Remarks on MMAD:

MMAD / GSD: Particle size measurements showed that there was no measurable amount of test substance present as aerosol.

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1000 l glass and stainless steel exposure chamber
- Method of holding animals in test chamber: individual cages
- Source and rate of air: chamber supplied air, 200-216 lpm
- Method of conditioning air: Test substance in a 5-gallon drum passed through a fluid metering pump into teflon tubing to a coiled glass rod in the volatilization chamber. Nitrogen was also fed into the volitization chamber. A heating element was positioned in the center of the glass coil to aid volatilization. The nitrogen and test substance mixture, then entered the exposure chamber.
- Air flow rate: 200-216 lpm
- Air change rate: 4.6-5.0 min.

TEST ATMOSPHERE
- Brief description of analytical method used: GC
- Samples taken from breathing zone: yes, once per week

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Air samples were drawn from the chamber via teflon tubing into charcoal tubes.

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

6 hrs/day, 5 days/week

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 900, 3,000, 9000 ppm
Basis:
nominal conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0, 904, 2,984, 8,992 ppm (0, 3182, 10504, 31652 mg/m3)
Basis:
analytical conc.

No. of animals per sex per dose:

10 animals of each sex per dose

Control animals:

yes, sham-exposed

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations: mortality, toxicological and pharmacological effects


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to test and week during the test


BODY WEIGHT: Yes
- Time schedule for examinations: twice prior to test, weekly during test and at termination


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Weekly beginning one week prior to test

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to test and prior to sacrifice


HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to test on 10 animals per sex, and at sacrifice
- Animals fasted: Yes
- Anaesthetic used for blood collection: Yes, ether
- Parameters checked: erythrocyte count, hemoglobin count, hematocrit, total and differential leucocyte count, platelet count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to test on 10 animals per sex, and at sacrifice
- Animals fasted: Yes
- Parameters checked: glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, creatinine, blood urea nitrogen, fasting glucose, total protein, alkaline phosphatase, albumin, potassium, sodium, calcium, chloride, inorganic phophorus, gamma glutamyl transpeptidase, total bilirubin, creatine phosphokinase, lactic acid dehydrogenase

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
all orifices, cranial cavity, brain, spinal cord, nasal cavity, thoracic, abdominal, and pelvic cavities

ORGAN WEIGHTS: Yes
adrenals, ovaries, testes with epididymides, kidneys, liver, brain, lungs, heart, spleen


HISTOPATHOLOGY: Yes
abdominal aorta, adrenals, bone, bone marrow, brain, esophagus, eyes, optic nerve, larynx, ovaries, testes with epididymus, heart, kidneys, liver, intestine, gall bladder, lungs, lymph nodes, nerve, skeletal muscle, trachea, nasopharyngeal tissues, pancreas, pituitary, prostate, salivary gland, thymus, spinal cord, seminal vesicles, spleen, skin, stomach, thyroid, urinary bladder, uterus, exorbital lacrimal glands, Zymbal gland

Statistics:

Statistical analysis was done on body weight, body weight gain, change in body weight, food consumption, change in food consumption, hematology, clinical chemistry, organ weights, organ/body and organ/brain weight ratios.

Results and discussion

Results of examinations

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):

no effects observed

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
No rats died during the study. Transient excess lacrimation was observed in the female rats. No other effects attibutable to exposure were noted.

BODY WEIGHT AND WEIGHT GAIN
Females in the high exposure group had sporadic reduced weight gain. As there was no consistant overall effect, this was not considered treatment related.

FOOD CONSUMPTION
There was no effect on food consumption.


OPHTHALMOSCOPIC EXAMINATION
Two males in the high exposure group showed corneal dystrophy. As this is not uncommon in males of this strain of rat, it is not considered treatment related.

HAEMATOLOGY
There were increased platelets in high exposure males. High and medium exposure males also had increased mean corpuscular volume. The significance of these changes are uncertain.

CLINICAL CHEMISTRY
High exposure males had increased creatinine, total protein, and albumin. They had decreased serum chloride. The significance of these changes are also uncertain.

ORGAN WEIGHTS
High exposure males had increased organ/body and organ/brain weight ratios. High exposure males and females had increased relative spleen weights. Liver weights were also increased in high exposure males. The liver effects appeared to be treatment related.

GROSS PATHOLOGY
No treatment related effects were noted.

HISTOPATHOLOGY: NON-NEOPLASTIC
There was hemorrhage and inflammation in male rat livers at the high dose level. There was also inflammation in the kidneys of males in the high and middle exposure groups. The significance of these effects are uncertain.

Effect levels

1

Key result

Dose descriptor:

NOAEC

Effect level:

2 984 ppm

Sex:

male

Basis for effect level:

other: 10504 mg/m3

2

Key result

Dose descriptor:

LOAEC

Effect level:

8 992 ppm

Sex:

male

Basis for effect level:

other: 31652 mg/m3; liver and kidney effects

3

Key result

Dose descriptor:

NOAEC

Effect level:

8 992 ppm

Sex:

female

Basis for effect level:

other: 31652 mg/m3

Target system / organ toxicity

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

8 992 ppm

System:

other: Hepatobiliary and urinary

Organ:

kidney

liver

Treatment related:

yes

Dose response relationship:

not specified

Relevant for humans:

not specified

Applicant's summary and conclusion

Conclusions:

The NOAEC for male rats exposed via inhalation was 2984 ppm based on liver and kidney effects. The LOAEC for male rats was 8992 ppm. The NOAEC for female rats was 8992 ppm.

Executive summary:

The purpose of this study was to determine the sub-chronic toxicity of commercial hexane via inhalation. Groups of 10 male and 10 female rats were exposed to concentrations of 0, 904, 2,984, and 8,992 ppm of test substance for 6 hrs/day, 5 days/week, for 13 weeks. During the exposure period, animals were examined for mortality, body weight, clinical signs, opthamological effects, and food consumption. At the end of the exposure period, the animals were sacrificed and examined for hematological parameters, clinical chemistry, gross pathology, organ weights, and histopathology.

There was no mortality among the exposed groups, and no treatment related effects to body weight gain. At sacrifice, the only possible treatment related effects were hemorrhage and inflammation in high dose male livers. The significance of this effect is uncertain. The NOAEC for male rats in 2984 ppm (10504 mg/m³), and the LOAEC is 8992 ppm (31652 mg/m³). The NOAEC for female rats in 8992 ppm (31652 mg/m³).