Heptane

Endpoint summary

Description of key information

Repeated Dose Inhalation – NOAEC (systemic) ≥ 12470 mg/m³ for rats

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: oral

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

a short-term toxicity study does not need to be conducted because a reliable sub-chronic (90 days) or chronic toxicity study is available, conducted with an appropriate species, dosage, solvent and route of administration

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 study available

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: Study meets generally accepted scientific principles, acceptable for assessment. Only one dose employed; statistical methods not identified.

Principles of method if other than guideline:

Single concentration repeated dose study for peripheral nerve toxicity.

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: not specified
- Weight at study initiation: 308 ± 18 g

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: room air

Remarks on MMAD:

MMAD / GSD: not applicable, vapour

Details on inhalation exposure:

TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatography and Kitagawa gas detection

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Animals were actually exposed to 2960 ± 200 ppm of Normal-Heptane.

Duration of treatment / exposure:

16 weeks

Frequency of treatment:

12 hours/day, 7 days/week

Remarks:

Doses / Concentrations:
12.47 mg/L (re-calculated; corresponding to 3000 ppm)
Basis:
nominal conc.

No. of animals per sex per dose:

7 males

Control animals:

yes, sham-exposed

Details on study design:

- Post-exposure recovery period: none

Positive control:

none

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: no data
- Cage side observations included: behaviour


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: before and after 4, 5, 12, 16 weeks of exposure


BODY WEIGHT: Yes
- Time schedule for examinations: not further specified, very likely weekly


OTHER:
Neurophysiology: motor nerve conductivity velocity (MCV), distal latency (DL), mixed nerve conduction velocity (MNCV)
- Time schedule: before and at 4, 5, 12, 16 weeks of exposure

Sacrifice and pathology:

GROSS PATHOLOGY: No data
HISTOPATHOLOGY: Yes (one rat): gastrocnemeius and soleus muscles, the dorsal trunk of the tail nerve and the tibial nerve were examined by light and electron microscopy

Statistics:

Employed but not identified by test name.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Details on results:

CLINICAL SIGNS AND MORTALITY
No abnormal behavioural changes were observed.

BODY WEIGHT AND WEIGHT GAIN
Body weight gain was statistically significantly depressed (p<0.01) after 8 weeks of exposure compared to controls but gradually increased throughout the experiment, albeit to body weight levels below control values, but not statistically significantly lower.


HISTOPATHOLOGY: NON-NEOPLASTIC
Peripheral nerves, muscles and neuromass junctions, examined microscopically, were normal.

OTHER FINDINGS
Neurophysiology: There were no statistically significant differences in motor nerve conduction velocity, distal latency or mixed nerve conduction velocity in any region of the tail.

Key result

Dose descriptor:

NOAEC

Remarks:

neurotoxicity

Effect level:

12 470 mg/m³ air (nominal)

Sex:

male

Basis for effect level:

other: no effects except reversible body weight changes

Key result

Dose descriptor:

NOAEC

Remarks:

systemic

Effect level:

12 470 mg/m³ air (nominal)

Sex:

male

Basis for effect level:

other: no effects except reversible body weight changes

Key result

Critical effects observed:

not specified

Normal-Heptane is not a neurotoxicant in this assay system.

Conclusions:

Normal-heptane is not a neurotoxicant in this assay system.

Executive summary:

Normal-heptane is not a neurotoxicant in this assay system.

Reference 2

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Study period:

17 April 1978 - 30 March 1979

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions. Limited documentation on animal housing, only 2 concentrations tested, exposure duration 84 days, no ophthalmological examination.

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:

no

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, Mass. 01887
- Age at study initiation: males 6 wks, females 7 wks
- Weight at study initiation: males 185 g mean (range 165-217 g); females 162 g mean (range 138-189)
- Fasting period before study: no
- Housing: paired in chamber, individual out of chamber
- Diet (e.g. ad libitum): Standard laboratory pellet diet (Purina Laboratory Chow) ad libitum (out of chamber only)
- Water (e.g. ad libitum): ad libitum (out of chamber only)
- Acclimation period: 13 days

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Remarks on MMAD:

MMAD / GSD: not applicable, vapour

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: stainless steel and glass chambers with 1 cubic meter total volume (760 L effective volume)
- Source and rate of air:
- Method of conditioning air:
- System of generating particulates/aerosols:
- Temperature, humidity, pressure in air chamber:
- Air flow rate: 134 L/min
- Air change rate: 8 per hour
- Method of particle size determination: not applicable, vapour


TEST ATMOSPHERE
- Brief description of analytical method used: Atmospheric sampling was performed using a Wilks Scientific Corp., Miran 1A Ambient Air Analyzer (long pathlength infrared). A calibration curve relating the absorption to the airborne concentration of the test material was prepared. On each exposure day, three samples were drawn from each exposure chamber (at about 1, 3, and 5 hours) and the exposure concentration calculated by comparing the absorption of this sample to the standard curve.
In addition, the composition of the test atmosphere was analyzed for homogeneity by gas chromatographic analysis of several charcoal-trapped vapour samples collected from each chamber during the 12-wk exposure period

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The test atmosphere was analysed for concentration and homogeneity by measurement of the infrared spectrum and by gas chromatographic analysis, respectively. Based on the infrared analysis the animals were exposed to cumulative mean concentrations of 385 and 1200 ppm, respectively. Gas chromatographic analysis of the chamber atmosphere demonstrated that the test material composition was representative of the initial sample.

Duration of treatment / exposure:

12 weeks

Frequency of treatment:

6 hours/day, 5 days/week

Remarks:

Doses / Concentrations:
400, 1200 ppm
Basis:
nominal conc.

No. of animals per sex per dose:

35

Control animals:

yes, sham-exposed

Details on study design:

- Rationale for animal assignment (if not random): assigned to group by weight

Positive control:

none

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations included: incidence of abnormal signs


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly (full recorded physical assessment)


BODY WEIGHT: Yes
- Time schedule for examinations: weekly, from 5 days prior to exposure through termination


WATER CONSUMPTION: No


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes (retro-orbital sinus)
- Time schedule for collection of blood: 4, 8, 12 weeks
- Anaesthetic used for blood collection: Yes (exsanguination under ether anesthesia)
- Animals fasted: Yes (fasted overnight prior to bleeding)
- How many animals: 10/sex/group (4 and 8 weeks), 15/sex/group (12 weeks, all survivors)
- Parameters examined: hemoblobin, hematocrit, erythrocyte count, clotting time, total and differential leukocytes


CLINICAL CHEMISTRY: Yes (retro-orbital sinus)
- Time schedule for collection of blood: 4, 8, 12 weeks
- Animals fasted: Yes (exsanguination under ether anesthesia)
- How many animals: 10/sex/group (4 and 8 weeks), 15/sex/group (12 weeks, all survivors)
- Parameters examined: blood urea nitrogen, serum glutamic pyruvic transaminase (SGPT), glucose, alkaline phosphatase


OTHER:
Organ weights and organ/body weight ratios determined in animals sacrificed at 4, 8 and 12 weeks (adrenals, brain (sans pituitary), gonads, kidneys, liver, lungs)

Sacrifice and pathology:

GROSS PATHOLOGY: Yes: adrenals, brain (without pituitary), gonads, kidneys, liver, lungs
HISTOPATHOLOGY: Yes (control and 1200 ppm group): adrenals (2), bone marrow (sternal), brain (2 sections), eye, gonad, heart (with coronary vessels) intestine, colon, duodenum, ileum, kidneys (2), liver (2 sections), lung (2 sections), lymph node (mesenteric), mammary gland, pancreas, pituitary, salivary gland, skeletal muscle, skin, spinal cord (cervical), spleen, stomach, thyroid, trachea, urinary bladder, uterus/prostate, gross lesions, tissue masses

Statistics:

Body weight, hematology and clinical chemistry parameters, organ weights and organ/body weight ratios were statistically evaluated. Mean values for all treatment groups were compared to the control group at each time interval (4, 8, and 12 weeks). Hematology and clinical chemistry parameters were compared by the F-test and Student's t-test. When variances differed significantly (F-test), Student's t-test was appropriately modified using Cochran's approximation (t'). Body weight, organ weight and organ/body weight ratios were compared to control according to Dunnett.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

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:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
No treatment-related mortality occured (1 male of the 1200 ppm group was accidentally killed).
Several animals in all groups exhibited dry rales and red and mucoid nasal discharge (more numerous in the treated groups, but not clearly treatment-related), moist rales, excessive lacrimation, hair loss and chromodacryorrhea were found in a limited number of animals in all groups (not treatment-related)
1200 ppm: singular occurrences of excessive salivation, laboured, irregular breathing; yellow staining of the anogenital fur in 6 males and 35 females from wk 3 through 12
400 ppm: yellow staining of the anogenital fur in 2 females
Control: singular occurrences of excessive salivation and bleeding inside the ear; a limited number of animals with brown staining of the ano-genital region and soft stool; three observations (in one animal) of an abnormally dark red or red and yellow eye

BODY WEIGHT AND WEIGHT GAIN
1200 ppm: mean body weights in males significantly higher at wk 2 and significantly lower (p?0.05) from wk 8 through 11 than in controls
400 ppm: mean body weight and weight gains in males similar to control throughout the study, except wk 2 (significantly higher, p?0.01), in females mean body weights significantly depressed (p?0.01 and p?0.05) at wk 5 through 8.

HAEMATOLOGY
Several statistically significant (p < 0.05 and p < 0.01) decreases in mean hematocrit values of males and females of both treated groups at wk 4 and 8, statistically significant decreases (p?0.05) in mean hemoglobin values at wk 8 in the males of both treated groups and the females of the 400 ppm group at wk 4. Mean red blood cell values were significantly decreased in 1200 ppm males at wk 8 and 400 ppm females at wk 12. Since all values were within normal biological limits, these findings were not considered to be treatment-related.

CLINICAL CHEMISTRY
Mean SGPT levels were significantly (p?0.01) depressed in 1200 ppm males at wk 4, 400 and 1200 ppm males at wk 8, and in 1200 ppm females at wk 12. Mean blood urea nitrogen levels were significantly increased in the males of both treated groups at wk 8. Mean glucose levels were significantly (p?0.01 or p?0.05) increased in 400 ppm males at wk 8, decreased in 1200 ppm males at wk 12, and decreased in 1200 ppm females at wk 4 and 12. The observed effects were not considered to be treatment-related.

ORGAN WEIGHTS
Mean kidney weights and kidney/body weight ratios were significantly (p?0.05) higher in the 1200 ppm males at wk 8. In the 400 ppm males these values were also elevated, but not statistically significant. At wk 12, mean kidney weights and kidney/body weight ratios for 400 and 1200 ppm males were significantly (p?0.01) elevated, indicating a treatment-related response. The only other statistically significant (p?0.05) findings were elevated mean adrenal/body weight ratios for the 1200 ppm males at wk 4 and the 400 ppm females at wk 12.

GROSS PATHOLOGY
Microscopic evaluation of organs and tissues from the control and high level exposure groups revealed a mild tubular injury in the kidneys of some exposed male rats sacrificed after exposure for 8 and 12 wk. Other changes were unrelated to group or sex and were considered to be spontaneous.

HISTOPATHOLOGY: NON-NEOPLASTIC
See Gross Pathology

Key result

Dose descriptor:

NOAEC

Effect level:

1 200 ppm (nominal)

Sex:

male

Basis for effect level:

other: overall effects

Critical effects observed:

not specified

Significantly increased mean kidney weights and kidney/body weight ratios were observed in males at 400 ppm, which were considered to be treatment-related by the authors of the study.

The kidney was confirmed as potential target organ for the test material-induced toxicity by the observation of mild tubular injury found in the histopathological examination of high dose males.

The fact, that these effects were strictly limited to male rats and that the test substance belongs to a category of substances which are known for their ability to induce nephropathy in male rats due to their exclusive expression of alpha-2u-globulin, the protein known to play the crucial role in the onset of this disease, the observed effects in the kidney have to be regarded as species-specific and therefore not relevant for risk assessment in humans. Therefore, these effects were not considered for the determination of the NOAEC.

Conclusions:

In a 12 -week inhalation study with rats the test substance hydrocarbons, C7 -C9, isoalkanes was tested. Significantly increased mean kidney weights and kidney/body weight ratios were observed in males at 400 ppm, which were considered to be treatment-related by the authors of the study.

The kidney was confirmed as potential target organ for the test material-induced toxicity by the observation of mild tubular injury found in the histopathological examination of high dose males.

The fact, that these effects were strictly limited to male rats and that the test substance belongs to a category of substances which are known for their ability to induce nephropathy in male rats due to their exclusive expression of alpha-2u-globulin, the protein known to play the crucial role in the onset of this disease, the observed effects in the kidney have to be regarded as species-specific and therefore not relevant for risk assessment in humans. Therefore, these effects were not considered for the determination of the NOAEC.

Renal effects were strictly limited to males, therefore the authors concluded an alpha-2u-globulin-related mechanism for the observed nephropathy. The observation was not considered for determination of the NOAEC.

Executive summary:

In a 12 -week inhalation study with rats the test substance hydrocarbons, C7 -C9, isoalkanes was tested. Significantly increased mean kidney weights and kidney/body weight ratios were observed in males at 400 ppm, which were considered to be treatment-related by the authors of the study. The kidney was confirmed as potential target organ for the test material-induced toxicity by the observation of mild tubular injury found in the histopathological examination of high dose males. The fact, that these effects were strictly limited to male rats and that the test substance belongs to a category of substances which are known for their ability to induce nephropathy in male rats due to their exclusive expression of alpha-2u-globulin, the protein known to play the crucial role in the onset of this disease, the observed effects in the kidney have to be regarded as species-specific and therefore not relevant for risk assessment in humans. Therefore, these effects were not considered for the determination of the NOAEC. Renal effects were strictly limited to males, therefore the authors concluded an alpha-2u-globulin-related mechanism for the observed nephropathy. The observation was not considered for determination of the NOAEC.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

12 470 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

Short-term, sub-chronic and chronic substance specific data available and a sub-chronic read across study from a structural analogue available for assessment

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

a short-term toxicity study does not need to be conducted because a reliable sub-chronic (90 days) or chronic toxicity study is available, conducted with an appropriate species, dosage, solvent and route of administration

Critical effects observed:

not specified

Reference 2

Endpoint:

sub-chronic toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Inhalation data is available for Heptane and structural analogue, Hydrocarbons, C7-C9, isoalkanes. Additionally, an intraperitoneal injection study is available for Heptane. 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.

Oral:

 

An OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents) test is proposed for structural analogue, Hydrocarbons, C7-C9, isoalkanes. 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. This endpoint will be updated subsequent to ECHA's approval of the testing proposal and availability of data upon completion of the study.

 

Inhalation:

 

Heptane

In a comparative study designed to evaluate peripheral nerve toxicity of pentane, hexane and heptane (Ono et al., 1979 and Takeuchi et al., 1980, 1981), male rats were exposed to 0 or 3000 ppm 12 hours/day, 7 days/week, for 16 weeks. The conduction velocity of tail nerves was measured to determine the functional status of the peripheral nerves. For animals exposed to Normal-Heptane, the body weight gain was statistically significantly depressed (p<0.01) after 8 weeks of exposure compared to control animals but gradually increased throughout the experiment to body weight levels below control values but not statistically significantly lower. No abnormal behavioral changes were observed. There were no statistically significant differences in motor nerve conduction velocity, distal latency or mixed nerve conduction velocity in any region of the tail for Normal-Heptane exposed rats. Peripheral nerves, muscles and neuromass junctions, examined microscopically were normal. The NOAEC was determined to be > 3000 ppm corresponding to 12470 mg/m³.

 

Rats were exposed to heptane via whole body inhalation at 0, 398 and 2970 ppm for 26 weeks with a subsequent 2-week recovery period conducted similar to OECD 413 (Shell, 1980). There were no treatment-related deaths during the study. The only treatment-related observations were labored breathing or rapid breathing and slight prostration during the first week of exposure and anogenital fur and dry rales during weekly observations. The in chamber signs were generally more numerous and severe at the higher concentration and appeared to abate by the second week of the study. No treatment-related effects were observed for body weight, hematology or urinalysis. Serum alkaline phosphatase was significantly elevated in high-concentration females and slightly elevated in low-concentration females. All other clinical chemistry values appeared normal with the exception of one high-concentration male whose serum glutamic pyruvic transaminase and serum alkaline phosphatase levels were markedly elevated when compared to all other exposed male rats. Proteinuria, elevated specific gravity and ketones were observed but were not considered related to treatment. Clinical pathology results had no correlate in histopathology. The NOAEC was 2970 ppm corresponding to 12200 mg/m³.

In a chronic study designed to evaluate polyneuropathy and urinary metabolites of solvents used in shoe factories (Frontali et al., 1981), rats were exposed to 0 or 1500 ppm heptane, 9 hours/day, 5 days/week, for 7, 14, or 30 weeks. No overt signs of systemic or neurotoxicity were observed and body weights were similar between treated and control groups. No differences between mean values for hindlimb spread were observed and no histological signs of giant axonal degeneration were reported. Therefore, the NOAEC was determined to be > 1500 ppm corresponding to 6150 mg/m³.

In a short-term auditory sensitivity study (Simonsen and Lund, 1995), Normal-Heptane induced a loss of auditory sensitivity equal to 10 dB in male rats (NOAEC = 3.3 mg/L air (analytical)).

 

In a short-term neurochemical study (Savolainen and Pfäffli, 1980), levels of Normal-Heptane increased in brain and perirenal fat during 2 weeks of exposure. None of the rats showed clinical signs of neurotoxicity. Neurochemical changes seen at week 2, including increased proteolysis and higher RNA brain content were at control levels after 2 weeks recovery.

 

Hydrocarbons, C7-C9, isoalkanes

Systemic toxicity of hydrocarbons, C7-C9, iso-alkanes was assessed in a 12-week inhalation toxicity study in rats (ExxonMobil Chemical,1979). In this study, repeated exposure to 400 or 1200 ppm of the test substance for 6 hours/day, 5 days/week, for 12 weeks resulted in male rat kidney effects consistent with the alpha-2µ-globulin-induced nephropathy in male rats. There was no treatment-related mortality and clinical findings were unremarkable. Under the test conditions, the NOAEC (excluding male rat nephropathy) was determined to be >1200ppm.

 

The fact that alpha-2µ-globulin-induced nephropathy was strictly limited to male rats and that the test substance belongs to a category of substances which are known for their ability to induce nephropathy in male rats due to their exclusive expression of alpha-2µ -globulin, the protein known to play the crucial role in the onset of this disease, the observed effects in the kidney have to be regarded as species-specific and are not relevant for risk assessment in humans.

 

Other routes:

Heptane 

Biochemical changes and potential for hepatotoxicity were investigated in rats (6 females per exposure period) treated with ca. 684 mg/kg bw of heptane or normal saline daily for 1, 2, 7 days or twice a week for 45 days by a single intraperitoneal injection (Goel et al., 1988). At the specified time points, animals were sacrificed and the livers were removed and homogenised. The activities of microsomal drug-metabolizing enzymes (aniline hydroxylase, benz(a)pyrene hydroxylase, aminopyrine demethylase), and glucose-6-phosphatase were assayed in the postmitochondrial supernatant. Sulfhydryl content (free and total) and protein content were estimated. In addition, the effect on pentabarbitone (50mg/kg)-induced sleeping time (time elapsed between loss and regaining of righting reflex) was measured in rats treated with heptane for 2 or 7 days.

Animals did not show any overt signs of toxicity. Rats administered heptane had decreased hepatic protein content compared to controls. Decreased total sulfhydryl content was noted in animals treated for 7 and 45 days. Glucose-6-phosphatase activity was also decreased from 2 days of treatment onward. Lipid peroxidation activity increased significantly after 24 and 48 h treatment. Marked inhibition of biotransforming activity was demonstrated by prolonged elapsed sleeping time (100% longer than controls) after 2 and 7 days. Markedly decreased activity of marker metabolizing enzymes were seen at 7 and 45 days of treatment. The peroxidative decomposition of lipids demonstrated in this study stimulates a series of reactions that can disrupt the equilibrium between synthesis and degradation of hepatic protein. These results correlate with excessive levels of alkaline phosphatase in the liver reported by Goel et al., 1982 and the depressed biotransforming activity of the liver and consequent increase in pentabarbitone induced sleeping time. Mechanisms of cytotoxicity may be attributed to reactive aldehydes produced by peroxidation of membrane lipids in the liver endoplasmic reticulum. Similar biochemical changes have been reported for n-octane and n-nonane by the same authors.

Justification for classification or non-classification

Based on available substance specific and read across data, Heptane does not meet the criteria for classification for repeated dose toxicity (STOT-RE) under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).