Registration Dossier
Registration Dossier
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EC number: - | CAS number: -
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
There is no reproductive toxicity data available for Hydrocarbons, C6-C10 (even numbered), n-alkanes, isoalkanes, >5% n-hexane. However, data is available for a structural analogue, hexane and presented in the dossier. This data is read across to Hydrocarbons, C6-C10 (even numbered), n-alkanes, isoalkanes, >5% n-hexane based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.
Commercial hexane
Two-Generation Reproduction Toxicity Study (OECD TG 416)
Inhalation NOAEC (Reproductive toxicity) = 31680 mg/m3air
An OECD Guideline 422 screening reproductive/developmental toxicity study (oral route) in rodents is planned with Hydrocarbons, C6-C10 (even numbered), n-alkanes, isoalkanes, <2% aromatics (EC# 701-352-4).Additionally, an OECD 443 test is proposed for Hydrocarbons, C7-C9, isoalkanes. This endpoint will be updated subsequent to ECHA's approval of the testing proposal already submitted to ECHA and availability of data upon completion of the above studies.
Link to relevant study records
- Endpoint:
- two-generation reproductive toxicity
- Remarks:
- based on test type
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 1989-09-18 to 1990-06-16
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: This study is classified as reliable without restriction because it followed a protocol comparable to OECD Guideline 416.
- 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
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- yes
- 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, Portage, MI
- Age at study initiation: (P) 28 days; (F1) 29-31 days
- Weight at study initiation: (P) Males: 75-100 g; Females: 65-80 g
- Housing: individually except during mating and lactation in stainless steel wire mesh cages, females were housed in plastic cages from gestational day (GD 20) through weaning; animals were identified by ear notches or toe clips
- Diet (e.g. ad libitum): Certified Ground Rodent Diet RMH 3200, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: two weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 68-73 degree F
- Humidity (%): 40-63
- Photoperiod (hrs dark / hrs light): 12 hrs light/12 hrs dark
IN-LIFE DATES: From: Sept. 18, 1989 To: June 16, 1990 - Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- not specified
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 900 l glass and stainless steel chambers.
- Method of holding animals in test chamber: cages
- Source and rate of air: 200 l/min
- Method of conditioning air: Test substance was metered from a piston pump into a heated glass evaporator with a temperature of 36-61 degree C. Conditioned air was passed through the evaporator, where it carried the vapor into the exposure chamber.
- Temperature, humidity: monitored every 30 minutes
- Air flow rate: 200 l/min
- Air change rate: 20 min
- Treatment of exhaust air: filtration
TEST ATMOSPHERE
- Brief description of analytical method used: GC with flame ionization detection
- Samples taken from breathing zone: yes, six times per exposure - Details on mating procedure:
- - M/F ratio per cage: 1/1 - If mating failed, females were switched to the male of an unmated pair in the same dose group after 7 days. If mating failed again, they were switched after another 7 days.
- Length of cohabitation: 3 weeks, including during exposure
- Proof of pregnancy: vaginal plug, day 0 - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples were taken six times per exposure period and analyzed with GC-FID. Distribution of test substance was evaluated by sampling nine different areas of the exposure chamber.
- Duration of treatment / exposure:
- 10 weeks pre-breeding, 3 weeks during breeding
Females continued to be exposed through GD 19. Exposure was resumed on postnatal day 5, and continued through weaning.
The F1 generation was treated similarly, but pre-breeding exposure was 8 weeks. - Frequency of treatment:
- 6 hrs/day, 5 days/week
- Details on study schedule:
- - F1 parental animals not mated until 9 weeks after selected from the F1 litters.
- Selection of parents from F1 generation when pups were 28 days of age.
- Age at mating of the mated animals in the study: 13-16 weeks - Remarks:
- Doses / Concentrations:
0, 900, 3000, 9000 ppm
Basis:
nominal conc. - Remarks:
- Doses / Concentrations:
892, 2995, 9019 ppm
Basis:
analytical conc. - No. of animals per sex per dose:
- 25 per sex per dose
- Control animals:
- yes, sham-exposed
- Details on study design:
- none provided
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations: mortality, toxicity, littering, mating
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION:
- Food consumption: Yes, food consumption of pregnant females was measured in 3-4 day intervals, and through postnatal day 28. - Litter observations:
- STANDARDISATION OF LITTERS
Parents of the F2 generation were selected on day 28 postpartum, at least one pup per litter was selected, with a second pup selected only if all litters were already represented. The F2 generation was standardized on day 4 postpartum.
PARAMETERS EXAMINED
The following parameters were examined in F1 and F2 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical abnormalities
GROSS EXAMINATION OF DEAD PUPS:
yes, for external abnormalities - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals after parturition of the first litter
- Maternal animals: All surviving animals day after weaning.
GROSS NECROPSY
- Gross necropsy consisted of external surfaces, orifices, cranial cavity, carcass, brain, spinal cord, thoracic cavity, abdominal cavity, pelvic cavity, cervical tissues and organs
HISTOPATHOLOGY / ORGAN WEIGHTS
Tissues from 25 male and females from the high dose and control groups were examined including testes of males failing to mate. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 28 days of age.
- These animals were subjected to postmortem examinations as follows: stillborn and pups dying during lactation, culled pups
GROSS NECROPSY
- Gross necropsy consisted of external examinations. - Statistics:
- Quantitative continuous variables were compared by use of Levene's test for equal variance, analysis of variance, and t-tests. Significance for t-tests were corrected by the Bonferroni method. Nonparametric data was evaluated using the Kruskal-Wallis test, followed by the Mann-Whitney test. Indices were compared using Fisher's exact test. 0.05 was used as the criteria for statistical significance.
- Reproductive indices:
- mating index, fertility index, gestational index, live birth index,
- Offspring viability indices:
- 4-day survival index, 7-day survival index, 14-day survival index, 21-day survival index, lactation index
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Other effects:
- not examined
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- effects observed, treatment-related
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 3 000 ppm (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: reduced body weight
- Remarks on result:
- other: Generation: F1, F2
- Dose descriptor:
- LOAEC
- Effect level:
- 9 000 ppm
- Sex:
- male/female
- Basis for effect level:
- other: reduced body weight
- Remarks on result:
- other: Generation: F1, F2
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 9 000 ppm
- Sex:
- male/female
- Remarks on result:
- other: Generation: reproductive toxicity
- Clinical signs:
- not examined
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Histopathological findings:
- not examined
- Key result
- Dose descriptor:
- NOAEC
- Generation:
- F1
- Effect level:
- 3 000 ppm (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: reduced body weight
- Remarks on result:
- other: Generation: F1, F2
- Dose descriptor:
- LOAEC
- Generation:
- F1
- Effect level:
- 9 000 ppm (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: reduced body weight
- Remarks on result:
- other: Generation: F1, F2
- Reproductive effects observed:
- not specified
- Conclusions:
- The NOAEC for both male and female rats (adults and offspring) was 3000 ppm (10560 mg/m3). The LOAEC for these groups was 9000 ppm based on reduced body weight. There were no adverse effects to reproduction, therefore the NOAEC for reproduction is 9000 ppm (31680 mg/m3).
- Executive summary:
The purpose of this study was to determine the effect of commerical hexane on reproduction in rats. Groups of 25 male and 25 female rats were exposed to nominal concentrations of 0, 900, 3000, or 9000 ppm of test substance for 10 weeks pre-breeding, 3 weeks during breeding, and postnatal days 4 -28. After weaning, pups were selected to be parents for the F2 generations, and treated similarly to their parents, except their pre-breeding exposure was 8 weeks. During exposure, animals were monitored for mortality, clinical signs, food consumption, and body weight. Offspring were examined for body weight, survival, and viability. Both parents and offspring were sacrificed and examined for gross abnormalities, and in the case of adults histopathology. Reproductive parameters were similar in exposure groups and control groups. There was reduced body weight in the F1 and F2 generation in both sexes in the 9000 ppm exposure group in both adults and offspring. The NOAEC is therefore 3000 ppm (10560 mg/m3), and the LOAEC is 9000 ppm (31680 mg/m3). Since there were no adverse effects in offspring without adverse maternal effects, the NOAEC for reproduction is 9000 ppm (31680 mg/m3).
- Endpoint:
- two-generation reproductive toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 18 Sept 1989 - 16 June 1990
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Comparable to guideline study.
- 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 416 (Two-Generation Reproduction Toxicity Study)
- GLP compliance:
- yes (incl. QA statement)
- 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, Portage, MI
- Age at study initiation: (P) 28 days; (F1) 29-31 days
- Weight at study initiation: (P) Males: 75-100 g; Females: 65-80 g
- Housing: individually except during mating and lactation in stainless steel wire mesh cages, females were housed in plastic cages from gestational day (GD 20) through weaning; animals were identified by ear notches or toe clips
- Diet (e.g. ad libitum): Certified Ground Rodent Diet RMH 3200, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: two weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 68-73 degree F
- Humidity (%): 40-63
- Photoperiod (hrs dark / hrs light): 12 hrs light/12 hrs dark
IN-LIFE DATES: From: Sept. 18, 1989 To: June 16, 1990 - Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 900 l glass and stainless steel chambers.
- Method of holding animals in test chamber: cages
- Source and rate of air: 200 l/min
- Method of conditioning air: Test substance was metered from a piston pump into a heated glass evaporator with a temperature of 36-61 degree C. Conditioned air was passed through the evaporator, where it carried the vapor into the exposure chamber.
- Temperature, humidity: monitored every 30 minutes
- Air flow rate: 200 l/min
- Air change rate: 20 min
- Treatment of exhaust air: filtration
TEST ATMOSPHERE
- Brief description of analytical method used: GC with flame ionization detection
- Samples taken from breathing zone: yes, six times per exposure - Details on mating procedure:
- - M/F ratio per cage: 1/1 - If mating failed, females were switched to the male of an unmated pair in the same dose group after 7 days. If mating failed again, they were switched after another 7 days.
- Length of cohabitation: 3 weeks, including during exposure
- Proof of pregnancy: vaginal plug, day 0 - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples were taken six times per exposure period and analyzed with GC-FID. Distribution of test substance was evaluated by sampling nine different areas of the exposure chamber.
- Duration of treatment / exposure:
- 10 weeks pre-breeding, 3 weeks during breeding
Females continued to be exposed through GD 19. Exposure was resumed on postnatal day 5, and continued through weaning.
The F1 generation was treated similarly, but pre-breeding exposure was 8 weeks. - Frequency of treatment:
- 6 hrs/day, 5 days/week
- Details on study schedule:
- - F1 parental animals not mated until 9 weeks after selected from the F1 litters.
- Selection of parents from F1 generation when pups were 28 days of age.
- Age at mating of the mated animals in the study: 13-16 weeks - Remarks:
- Doses / Concentrations:
0, 900, 3000, 9000 ppm
Basis:
nominal conc. - Remarks:
- Doses / Concentrations:
892, 2995, 9019 ppm
Basis:
analytical conc. - No. of animals per sex per dose:
- 25 per sex per dose
- Control animals:
- yes, sham-exposed
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations: mortality, toxicity, littering, mating
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION:
- Food consumption: Yes, food consumption of pregnant females was measured in 3-4 day intervals, and through postnatal day 28. - Litter observations:
- STANDARDISATION OF LITTERS
Parents of the F2 generation were selected on day 28 postpartum, at least one pup per litter was selected, with a second pup selected only if all litters were already represented. The F2 generation was standardized on day 4 postpartum.
PARAMETERS EXAMINED
The following parameters were examined in F1 and F2 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical abnormalities
GROSS EXAMINATION OF DEAD PUPS:
yes, for external abnormalities - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals after parturition of the first litter
- Maternal animals: All surviving animals day after weaning.
GROSS NECROPSY
- Gross necropsy consisted of external surfaces, orifices, cranial cavity, carcass, brain, spinal cord, thoracic cavity, abdominal cavity, pelvic cavity, cervical tissues and organs
HISTOPATHOLOGY / ORGAN WEIGHTS
Tissues from 25 male and females from the high dose and control groups were examined including testes of males failing to mate. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 28 days of age.
- These animals were subjected to postmortem examinations as follows: stillborn and pups dying during lactation, culled pups
GROSS NECROPSY
- Gross necropsy consisted of external examinations. - Statistics:
- Quantitative continuous variables were compared by use of Levene's test for equal variance, analysis of variance, and t-tests. Significance for t-tests were corrected by the Bonferroni method. Nonparametric data was evaluated using the Kruskal-Wallis test, followed by the Mann-Whitney test. Indices were compared using Fisher's exact test. 0.05 was used as the criteria for statistical significance.
- Reproductive indices:
- mating index, fertility index, gestational index, live birth index,
- Offspring viability indices:
- 4-day survival index, 7-day survival index, 14-day survival index, 21-day survival index, lactation index
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 31 680 mg/m³ air (nominal)
- Basis for effect level:
- other: The value was re-calculated from the nominal dose of 9000 ppm.
- Remarks on result:
- other: Generation: reproductive toxicity (migrated information)
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 10 560 mg/m³ air (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: reduced body weight The value was re-calculated from the nominal dose of 3000 ppm.
- Remarks on result:
- other: Generation: F1, F2 (migrated information)
- Dose descriptor:
- LOAEC
- Effect level:
- 31 680 mg/m³ air (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: reduced body weight The value was re-calculated from the nominal dose of 9000 ppm.
- Remarks on result:
- other: Generation: F1, F2 (migrated information)
- Key result
- Dose descriptor:
- NOAEC
- Generation:
- F1
- Effect level:
- 10 560 mg/m³ air (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: reduced body weight The value was re-calculated from the nominal dose of 3000 ppm.
- Key result
- Dose descriptor:
- LOAEC
- Generation:
- F1
- Effect level:
- 31 680 mg/m³ air (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: reduced body weight The value was re-calculated from the nominal dose of 9000 ppm.
- Key result
- Dose descriptor:
- NOAEC
- Generation:
- F2
- Effect level:
- 10 560 mg/m³ air (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: reduced body weight The value was re-calculated from the nominal dose of 3000 ppm.
- Key result
- Dose descriptor:
- LOAEC
- Generation:
- F2
- Effect level:
- 31 680 mg/m³ air (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: reduced body weight The value was re-calculated from the nominal dose of 9000 ppm.
- Reproductive effects observed:
- not specified
- Conclusions:
- The NOAEC for both male and female rats (adults and offspring) was 3000 ppm. The LOAEC for these groups was 9000 ppm based on reduced body weight. There were no adverse effects on reproduction, therefore the NOAEC for reproduction is 9000 ppm.
- Executive summary:
The purpose of this study was to determine the effect of commercial hexane on reproduction in rats. Groups of 25 male and 25 female rats were exposed to nominal concentrations of 0, 900, 3000, or 9000 ppm of test substance for 10 weeks pre-breeding, 3 weeks during breeding, and postnatal days 4 -28. After weaning, pups were selected to be parents for the F2 generations, and treated similarly to their parents, except their pre-breeding exposure was 8 weeks. During exposure, animals were monitored for mortality, clinical signs, food consumption, and body weight. Offspring were examined for body weight, survival, and viability. Both parents and offspring were sacrificed and examined for gross abnormalities, and in the case of adults histopathology. Reproductive parameters were similar in exposure groups and control groups. There was reduced body weight in the F1 and F2 generation in both sexes in the 9000 ppm exposure group in both adults and offspring. The NOAEC is therefore 3000 ppm, and the LOAEC is 9000 ppm. Since there were no adverse effects in offspring without adverse maternal effects, the NOAEC for reproduction is 9000 ppm.
- Endpoint:
- reproductive toxicity, other
- Remarks:
- other: acute inhalation toxicity study
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 1987
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: This study is classified as reliable with restrictions because there was no GLP statement provided, and limited data on methods were reported, but the study seemed to be well-conducted.
- 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:
- no guideline required
- Guideline:
- other: OECD Guideline 403 (Acute Inhalation Toxicity)
- GLP compliance:
- no
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, Italy
- Weight at study initiation: 180-220 g
- Housing: steel wire cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum - Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: airtight Lucite boxes
- Method of holding animals in test chamber: cages
- Source and rate of air: 3 l/min
- Method of conditioning air: Air from a compressed air bottle and regulated by a flowmeter conveyed n-hexane vapor from a bubbler immersed in a 23.5 degree C water bath. This air mixed with air from a pump in a glass chamber before entering the control chamber.
TEST ATMOSPHERE
- Brief description of analytical method used: A total hydrocarbon analyzer was connected to the exhaust from exposure group chambers. - Details on mating procedure:
- Not applicable
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- (1) a single 24-hour exposure, (2) repeated 16-hour/day exposures for up to 8 days, or (3) repeated 16-hour/day exposures, 6 hours/day for up to 6 weeks.
- Remarks:
- Doses / Concentrations:
5000 ppm
Basis: - No. of animals per sex per dose:
- 12-39 per group
- Control animals:
- other: pair fed
- Details on study design:
- - Dose selection rationale: not provided
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily
BODY WEIGHT: Yes
- Time schedule for examinations: weekly - Oestrous cyclicity (parental animals):
- Not applicable
- Sperm parameters (parental animals):
- Parameters examined in males: epididymyal tubules, testicular lesions
- Litter observations:
- Not applicable
- Postmortem examinations (parental animals):
- Not provided
- Postmortem examinations (offspring):
- not applicable
- Statistics:
- Body weight data was analyzed using the Student t-test.
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- not examined
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- not examined
- Dose descriptor:
- other: LC50
- Effect level:
- > 5 000 ppm
- Based on:
- test mat.
- Sex:
- male
- Remarks on result:
- other: Generation: not applicable
- Key result
- Dose descriptor:
- LOAEC
- Remarks:
- 24 hour
- Effect level:
- > 5 000 ppm
- Sex:
- male
- Remarks on result:
- other: Generation: not applicable
- Clinical signs:
- not examined
- Mortality / viability:
- not examined
- Body weight and weight changes:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Histopathological findings:
- not examined
- Remarks on result:
- other: Generation not applicable
- Reproductive effects observed:
- not specified
- Conclusions:
- There was no mortality of animals due to a single 24-hr exposure to 5000 ppm test substance. Rats receiving a single 24-hour exposure to n-hexane also showed a measure of recovery after 2–4 weeks following the termination of exposure. By contrast, rats exposed repeatedly to 5000 ppm n-hexane over a 6-week period showed complete atrophy of the seminiferous tubules. The animals exposed for up to 6 weeks displayed a reduction in food consumption and body weight gain; these effects were accompanied by signs of incipient neuropathy. There was also a wide range of testicular lesions that did not completely resolve during the recovery period even though body weights and clinical symptoms improved. The LC50 is > 5000 ppm for male rats.
- Executive summary:
In an acute inhalation toxicity study researchers exposed male Sprague-Dawley rats (12–39/group) to 5000 ppm n-hexane (99% pure) in either (1) a single 24-hour exposure, (2) repeated 16-hour/day exposures for up to 8 days, or (3) repeated 16-hour/day exposures, 6 hours/day for up to 6 weeks. Two control groups were employed, one of which was pair-fed. Treated animals were allowed to recover for different lengths of time after the end of treatment (from 2 days to 29 weeks, depending on the original exposure duration).
Rats exposed to 5000 ppm n-hexane displayed some evidence of neuropathy such as paralysis, and extreme cases were sacrificed moribund and necropsied rather than being allowed to die and undergo partial autolysis. Focal degeneration of spermatocytes and exfoliation of elongated spermatids was observed in rats treated with n-hexane. Early meiotic prophase spermatocytes (leptotene and zygotene) and transitional spermatocytes as well as those undergoing meiotic metaphase appeared to be more susceptible to the action of n-hexane than pachytene spermatocytes.
After the 24-hr treatment was suspended, damage to the seminiferous epithelium increased for the first 7 days, while the epididymis also exhibited focal infiltration by inflammatory cells; recovery was completed from Days 14 to 30. Animals exposed for 16 hr/day, 6 days/week at the same concentration of 5000 ppm for up to 6 weeks induced progressive increases in testicular and epididymal lesions, which, after 5 weeks (when most animals began to show clinical symptoms of polyneuropathy), reached aplasia of the germinal epithelium involving also the spermatogonia. A fter interruption of the treatment, the testicular lesions became increasingly severe, up to complete atrophy of the seminiferous tubules, which suggests irreversible sterility.
- Endpoint:
- extended one-generation reproductive toxicity - with developmental neurotoxicity (Cohorts 1A, 1B without extension, 2A and 2B)
- 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
Referenceopen allclose all
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No treatment related effects observed.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
There were no treatment related effects to food consumption. Males in the 9000 ppm group had reduced body weight during week 13. Body weight gains in this group were reduced during weeks 7, 11-12, and 12-13. Males in the 3000 ppm group had reduced body weight gain in weeks 4-5, and reduced weight in weeks 9-10. Females weight gains were reduced in the 9000 ppm group in weeks 5-6.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Lactational food consumption was significantly reduced during days 7-11, and days 19-21 in the 9000 ppm group. No other reproductive parameters differed significantly from controls.
GROSS PATHOLOGY (PARENTAL ANIMALS)
No treatment related abnormalities were seen.
HISTOPATHOLOGY (PARENTAL ANIMALS)
Hyaline droplet nephropathy and tubular basophilia were seen in the 9000 ppm males.
F1 GENERATION
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No treatment related effects were observed. One female in the 900 ppm group died on day 83 due to prolonged delivery.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Body weights of 9000 ppm males were significantly reduced throughout the exposure period. Weight gain was reduced in this group during the weeks 9-10, and 10-11. Females in the 9000 ppm group had reduced body weight during the first 3 weeks of pre-breeding exposure.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
In the 9000 ppm group, food consumption was reduced on gestational days 0-4, and 4-7, and gestational intervals 0-7, and 7-14. This group also had reduced food consumption during lactational days 21-24, 26-27, 21, and 28. In the 3000 ppm group, food consumption was reduced during lactational days 22-23, and in the 900 ppm group during days lactational days 21-22.
GROSS PATHOLOGY (PARENTAL ANIMALS)
No treatment related abnormalities were seen.
HISTOPATHOLOGY (PARENTAL ANIMALS)
Hyaline droplet nephropathy and tubular basophilia were seen in the 9000 ppm males.
VIABILITY (OFFSPRING)
The number of dead pups was increased in the 900 ppm exposure group, however, as this was not seen at higher doses, it was not considered treatment related.
BODY WEIGHT (OFFSPRING)
The body weight of pups in the 9000 ppm group were reduced beginning on lactational day 14. Body weight gains in this group were reduced during lactational days 14-21 for females, and lactational days 7-14 for all pups.
GROSS PATHOLOGY (OFFSPRING)
No treatment related effects were noted.
F2 GENERATION
VIABILITY (OFFSPRING)
Viability was unaffected by exposure.
BODY WEIGHT (OFFSPRING)
The body weight of pups in the 9000 ppm group were from lactational day 7-28. Body weight gains in this group were reduced during lactational days 14-21 for females, and lactational days 7-14 for all pups. There were significantly reduced body weight gains in pups in the 9000 ppm group during lactational days 4-7, and 7-14, and slightly reduced weight gains on lactational days 14-21.
GROSS PATHOLOGY (OFFSPRING)
No treatment related effects were noted.
Significant Results of Reproductive Toxicity Study on Rats
Concentration (ppm) |
0 |
900 |
3000 |
9000 |
Body weight of F0 adult males - week 13 (g) |
463.7 (48.93) |
455.2 (34.22) |
455.2 (40.25) |
436.1 (24.83) |
Body weight gain of F0 adult males - week 4-5 (g) |
32.6 (8.98) |
28.9 (8.56) |
24.2 (7.89) |
28.9 (3.78) |
Body weight gain of F0 adult males - week 6 -7 (g) |
25.4 (6.17) |
25.4 (6.28) |
23.7 (4.94) |
21.2 (4.31) |
Body weight gain of F0 adult males - week 9-10 (g) |
24.2 (6.00) |
21.6 (6.07) |
18.6 (6.82) |
19.9 (6.17) |
Body weight gain of F0 adult males - week 11-12 (g) |
11.9 (5.40) |
10.7 (6.51) |
12.7 (4.83) |
3.3 (5.70) |
Body weight gain of F0 adult males - week 12-13 (g) |
11.8 (6.26) |
7.4 (6.34) |
8.7 (7.28) |
6.4 (6.09) |
Body weight gain of F0 adult females - week 0-1 (g) |
0.3 (3.08) |
3.4 (3.25) |
1.9 (2.74) |
0.8 (3.67) |
Body weight gain of F0 adult females - week 5-6 (g) |
11.8 (4.01) |
11.0 (4.40) |
12.3 (3.57) |
9.0 (3.20) |
Lactational food consumption F0 - day 7-11 (g/animal/day) |
44.63 (3.859) |
42.93 () |
43.54 (3.796) |
41.45 (3.244) |
Lactational food consumption F0 - day 19-21 (g/animal/day) |
64.41 (5.833) |
64.87 (5.439) |
62.32 (6.595) |
59.81 (8.212) |
No. dead F1 pups - lactational day 4 |
5 |
26 |
12 |
7 |
F1 pup body weight - lactational day 21 (g) |
41.93 (3.950) |
42.50 (4.125) |
39.97 (3.292) |
38.92 (3.996) |
F1 female pup body weight - lactational day 21 (g) |
41.48 (4.151) |
41.75 (4.168) |
39.52 (3.430) |
38.10 (4.063) |
Body weight changes in F1 pups - lactational day 7-14 (g) |
11.91 (1.617) |
12.11 (1.328) |
11.48 (1.381) |
10.56 (1.780) |
Body weight changes in F1 male pups - lactational day 7-14 (g) |
12.00 (1.628) |
12.24 (1.306) |
11.41 (1.708) |
10.71 (1.847) |
Body weight changes in F1 female pups - lactational day 7-14 (g) |
11.81 (1.677) |
12.00 (1.420) |
11.51 (1.536) |
10.35 (1.789) |
Body weight changes in F1 female pups - lactational day 14-21 (g) |
15.86 (1.933) |
15.47 (2.162) |
14.39 (1.744) |
14.24 (2.343) |
Food consumption in F1 females - week 0-1 (g/animal/day) |
20.9 (1.87) |
20.9 (2.00) |
20.7 (2.68) |
19.0 (1.62) |
Food consumption in F1 females - week 1-2 (g/animal/day) |
21.5 (1.45) |
21.2 (2.29) |
21.2 (2.80) |
19.1 (1.90) |
Food consumption in F1 females - week 3-4 (g/animal/day) |
22.0 (2.40) |
21.8 (2.74) |
21.5 (2.98) |
19.6 (1.99) |
Food consumption in F1 females - week 5-6 (g/animal/day) |
20.8 (2.02) |
21.2 (2.60) |
20.6 (2.87) |
19.1 (2.00) |
Food consumption in F1 females - week 7-8 (g/animal/day) |
20.3 (1.84) |
20.3 (2.24) |
20.0 (2.37) |
18.4 (1.99) |
F1 Gestational food consumption - day 0-4 (g/animal/day) |
22.87 (3.172) |
21.93 (2.407) |
21.93 (3.237) |
19.67 (1.703) |
F1 Gestational food consumption - day 4-7 (g/animal/day) |
24.31 (3.047) |
23.63 (3.228) |
23.42 (3.077) |
21.81 (2.072) |
F1 Gestational food consumption - day 0-7 (g/animal/day) |
23.48 (2.972) |
22.44 (2.503) |
22.57 (2.905) |
20.56 (1.760) |
F1 Gestational food consumption - day 7-14 (g/animal/day) |
26.28 (3.268) |
25.25 (3.108) |
24.52 (3.055) |
23.70 (2.565) |
F1 lactational food consumption - day 21-22 (g/animal/day) |
87.77 (15.326) |
79.55 (8.381) |
80.31 (8.272) |
74.01 (9.711) |
F1 lactational food consumption - day 22-23 (g/animal/day) |
91.26 (10.218) |
87.42 (9.649) |
83.36 (8.764) |
81.23 (10.532) |
F1 lactational food consumption - day 23-24 (g/animal/day) |
97.23 (11.339) |
94.59 (9.185) |
90.30 (6.703) |
85.17 (13.188) |
F1 lactational food consumption - day 26-27 (g/animal/day) |
115.86 (11.445) |
114.19 (16.261) |
109.85 (11.689) |
105.38 (15.023) |
F1 lactational food consumption - day 21-28 (g/animal/day) |
102.87 (7.787) |
100.49 (8.471) |
97.47 (6.852) |
94.04 (10.541) |
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No treatment related effects observed.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
There were no treatment related effects on food consumption. Males in the 9000 ppm group had reduced body weight during week 13. Body weight gains in this group were reduced during weeks 7, 11-12, and 12-13. Males in the 3000 ppm group had reduced body weight gain in weeks 4-5, and reduced weight in weeks 9-10. Females weight gains were reduced in the 9000 ppm group in weeks 5-6.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Lactational food consumption was significantly reduced during days 7-11, and days 19-21 in the 9000 ppm group. No other reproductive parameters differed significantly from controls.
GROSS PATHOLOGY (PARENTAL ANIMALS)
No treatment related abnormalities were seen.
HISTOPATHOLOGY (PARENTAL ANIMALS)
Hyaline droplet nephropathy and tubular basophilia were seen in the 9000 ppm males.
F1 GENERATION
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No treatment related effects were observed. One female in the 900 ppm group died on day 83 due to prolonged delivery.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Body weights of 9000 ppm males were significantly reduced throughout the exposure period. Weight gain was reduced in this group during the weeks 9-10, and 10-11. Females in the 9000 ppm group had reduced body weight during the first 3 weeks of pre-breeding exposure.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
In the 9000 ppm group, food consumption was reduced on gestational days 0-4, and 4-7, and gestational intervals 0-7, and 7-14. This group also had reduced food consumption during lactational days 21-24, 26-27, 21, and 28. In the 3000 ppm group, food consumption was reduced during lactational days 22-23, and in the 900 ppm group during days lactational days 21-22.
GROSS PATHOLOGY (PARENTAL ANIMALS)
No treatment related abnormalities were seen.
HISTOPATHOLOGY (PARENTAL ANIMALS)
Hyaline droplet nephropathy and tubular basophilia were seen in the 9000 ppm males.
VIABILITY (OFFSPRING)
The number of dead pups was increased in the 900 ppm exposure group, however, as this was not seen at higher doses, it was not considered treatment related.
BODY WEIGHT (OFFSPRING)
The body weight of pups in the 9000 ppm group were reduced beginning on lactational day 14. Body weight gains in this group were reduced during lactational days 14-21 for females, and lactational days 7-14 for all pups.
GROSS PATHOLOGY (OFFSPRING)
No treatment related effects were noted.
F2 GENERATION
VIABILITY (OFFSPRING)
Viability was unaffected by exposure.
BODY WEIGHT (OFFSPRING)
The body weight of pups in the 9000 ppm group were reduced from lactational day 7-28. Body weight gains in this group were reduced during lactational days 14-21 for females, and lactational days 7-14 for all pups. There were significantly reduced body weight gains in pups in the 9000 ppm group during lactational days 4-7, and 7-14, and slightly reduced weight gains on lactational days 14-21.
GROSS PATHOLOGY (OFFSPRING)
No treatment related effects were noted.
Significant Results of Reproductive Toxicity Study on Rats
Concentration (ppm) |
0 |
900 |
3000 |
9000 |
Body weight of F0 adult males – week 13 (g) |
463.7 (48.93) |
455.2 (34.22) |
455.2 (40.25) |
436.1 (24.83) |
Body weight gain of F0 adult males – week 4-5 (g) |
32.6 (8.98) |
28.9 (8.56) |
24.2 (7.89) |
28.9 (3.78) |
Body weight gain of F0 adult males – week 6-7 (g) |
25.4 (6.17) |
25.4 (6.28) |
23.7 (4.94) |
21.2 (4.31) |
Body weight gain of F0 adult males – week 9-10 (g) |
24.2 (6.00) |
21.6 (6.07) |
18.6 (6.82) |
19.9 (6.17) |
Body weight gain of F0 adult males – week 11-12 (g) |
11.9 (5.40) |
10.7 (6.51) |
12.7 (4.83) |
3.3 (5.70) |
Body weight gain of F0 adult males – week 12-13 (g) |
11.8 (6.26) |
7.4 (6.34) |
8.7 (7.28) |
6.4 (6.09) |
Body weight gain of F0 adult females – week 0-1 (g) |
0.3 (3.08) |
3.4 (3.25) |
1.9 (2.74) |
0.8 (3.67) |
Body weight gain of F0 adult females – week 5-6 (g) |
11.8 (4.01) |
11.0 (4.40) |
12.3 (3.57) |
9.0 (3.20) |
Lactational food consumption F0 – day 7-11 (g/animal/day) |
44.63 (3.859) |
42.93 () |
43.54 (3.796) |
41.45 (3.244) |
Lactational food consumption F0 – day 19-21 (g/animal/day) |
64.41 (5.833) |
64.87 (5.439) |
62.32 (6.595) |
59.81 (8.212) |
No. dead F1 pups - lactational day 4 |
5 |
26 |
12 |
7 |
F1 pup body weight – lactational day 21 (g) |
41.93 (3.950) |
42.50 (4.125) |
39.97 (3.292) |
38.92 (3.996) |
F1 female pup body weight – lactational day 21 (g) |
41.48 (4.151) |
41.75 (4.168) |
39.52 (3.430) |
38.10 (4.063) |
Body weight changes in F1 pups – lactational day 7-14 (g) |
11.91 (1.617) |
12.11 (1.328) |
11.48 (1.381) |
10.56 (1.780) |
Body weight changes in F1 male pups – lactational day 7-14 (g) |
12.00 (1.628) |
12.24 (1.306) |
11.41 (1.708) |
10.71 (1.847) |
Body weight changes in F1 female pups – lactational day 7-14 (g) |
11.81 (1.677) |
12.00 (1.420) |
11.51 (1.536) |
10.35 (1.789) |
Body weight changes in F1 female pups – lactational day 14-21 (g) |
15.86 (1.933) |
15.47 (2.162) |
14.39 (1.744) |
14.24 (2.343) |
Food consumption in F1 females – week 0-1 (g/animal/day) |
20.9 (1.87) |
20.9 (2.00) |
20.7 (2.68) |
19.0 (1.62) |
Food consumption in F1 females – week 1-2 (g/animal/day) |
21.5 (1.45) |
21.2 (2.29) |
21.2 (2.80) |
19.1 (1.90) |
Food consumption in F1 females – week 3-4 (g/animal/day) |
22.0 (2.40) |
21.8 (2.74) |
21.5 (2.98) |
19.6 (1.99) |
Food consumption in F1 females – week 5-6 (g/animal/day) |
20.8 (2.02) |
21.2 (2.60) |
20.6 (2.87) |
19.1 (2.00) |
Food consumption in F1 females – week 7-8 (g/animal/day) |
20.3 (1.84) |
20.3 (2.24) |
20.0 (2.37) |
18.4 (1.99) |
F1 Gestational food consumption – day 0-4 (g/animal/day) |
22.87 (3.172) |
21.93 (2.407) |
21.93 (3.237) |
19.67 (1.703) |
F1 Gestational food consumption – day 4-7 (g/animal/day) |
24.31 (3.047) |
23.63 (3.228) |
23.42 (3.077) |
21.81 (2.072) |
F1 Gestational food consumption – day 0-7 (g/animal/day) |
23.48 (2.972) |
22.44 (2.503) |
22.57 (2.905) |
20.56 (1.760) |
F1 Gestational food consumption – day 7-14 (g/animal/day) |
26.28 (3.268) |
25.25 (3.108) |
24.52 (3.055) |
23.70 (2.565) |
F1 lactational food consumption – day 21-22 (g/animal/day) |
87.77 (15.326) |
79.55 (8.381) |
80.31 (8.272) |
74.01 (9.711) |
F1 lactational food consumption – day 22-23 (g/animal/day) |
91.26 (10.218) |
87.42 (9.649) |
83.36 (8.764) |
81.23 (10.532) |
F1 lactational food consumption – day 23-24 (g/animal/day) |
97.23 (11.339) |
94.59 (9.185) |
90.30 (6.703) |
85.17 (13.188) |
F1 lactational food consumption – day 26-27 (g/animal/day) |
115.86 (11.445) |
114.19 (16.261) |
109.85 (11.689) |
105.38 (15.023) |
F1 lactational food consumption – day 21-28 (g/animal/day) |
102.87 (7.787) |
100.49 (8.471) |
97.47 (6.852) |
94.04 (10.541) |
Effect on fertility: via oral route
- Endpoint conclusion:
- no study available
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEC
- 31 680 mg/m³
- Study duration:
- subchronic
- Experimental exposure time per week (hours/week):
- 30
- Species:
- rat
- Quality of whole database:
- 3 key studies from a structural analogue available for assessment.
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
There is no reproductive toxicity data available for Hydrocarbons, C6 -C10 (even numbered), n-alkanes, isoalkanes, cyclics, >5% n-hexane. However, data is available for a structural analogues, hexane and presented in the dossier. This data is read across to Hydrocarbons, C6-C10 (even numbered), n-alkanes, isoalkanes, cyclics, >5% n-hexane based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.
Commercial Hexane
In a key study (API, 1991a), the effect of commercial hexane on reproduction in rats was determined. Groups of 25 male and 25 female rats were exposed to nominal concentrations of 0, 900, 3000, or 9000 ppm of test substance for 10 weeks pre-breeding, 3 weeks during breeding, and postnatal days 4 -28. After weaning, pups were selected to be parents for the F2 generations, and treated similarly to their parents, except their pre-breeding exposure was 8 weeks. During exposure, animals were monitored for mortality, clinical signs, food consumption, and body weight. Offspring were examined for body weight, survival, and viability. Both parents and offspring were sacrificed and examined for gross abnormalities, and in the case of adults histopathology. Reproductive parameters were similar in exposure groups and control groups. There was reduced body weight in the F1 and F2 generation in both sexes in the 9000 ppm exposure group in both adults and offspring. The NOAEC is therefore 3000 ppm, and the LOAEC is 9000 ppm. Since there were no adverse effects in offspring without adverse maternal effects, the NOAEC for reproduction is 9000 ppm.
In another key study (Daughtrey et al., 1994), the effect of commerical hexane on reproduction in rats was determined. Groups of 25 male and 25 female rats were exposed to nominal concentrations of 0, 900, 3000, or 9000 ppm of test substance for 10 weeks pre-breeding, 3 weeks during breeding, and postnatal days 4 -28. After weaning, pups were selected to be parents for the F2 generations, and treated similarly to their parents, except their pre-breeding exposure was 8 weeks. During exposure, animals were monitored for mortality, clinical signs, food consumption, and body weight. Offspring were examined for body weight, survival, and viability. Both parents and offspring were sacrificed and examined for gross abnormalities, and in the case of adults histopathology. Reproductive parameters were similar in exposure groups and control groups. There was reduced body weight in the F1 and F2 generation in both sexes in the 9000 ppm exposure group in both adults and offspring. The NOAEC is therefore 3000 ppm (10560 mg/m3), and the LOAEC is 9000 ppm (31680 mg/m3). Since there were no adverse effects in offspring without adverse maternal effects, the NOAEC for reproduction is 9000 ppm (31680 mg/m3).
n-hexane
In an acute inhalation toxicity study (De Martino et al. 1987) researchers exposed male Sprague-Dawley rats (12–39/group) to 5000 ppm n-hexane (99% pure) in either (1) a single 24-hour exposure, (2) repeated 16-hour/day exposures for up to 8 days, or (3) repeated 16-hour/day exposures, 6 hours/day for up to 6 weeks. Two control groups were employed, one of which was pair-fed. Treated animals were allowed to recover for different lengths of time after the end of treatment (from 2 days to 29 weeks, depending on the original exposure duration).
Rats exposed to 5000 ppm n-hexane displayed some evidence of neuropathy such as paralysis, and extreme cases were sacrificed moribund and necropsied rather than being allowed to die and undergo partial autolysis. Focal degeneration of spermatocytes and exfoliation of elongated spermatids was observed in rats treated with n-hexane. Early meiotic prophase spermatocytes (leptotene and zygotene) and transitional spermatocytes as well as those undergoing meiotic metaphase appeared to be more susceptible to the action of n-hexane than pachytene spermatocytes.
After the 24-hr treatment was suspended, damage to the seminiferous epithelium increased for the first 7 days, while the epididymis also exhibited focal infiltration by inflammatory cells; recovery was completed from Days 14 to 30. Animals exposed for 16 hr/day, 6 days/week at the same concentration of 5000 ppm for up to 6 weeks induced progressive increases in testicular and epididymal lesions, which, after 5 weeks (when most animals began to show clinical symptoms of polyneuropathy), reached aplasia of the germinal epithelium involving also the spermatogonia. A fter interruption of the treatment, the testicular lesions became increasingly severe, up to complete atrophy of the seminiferous tubules, which suggests irreversible sterility.
In addition, an OECD 443 test is proposed for a structural analogue, Hydrocarbons, C7-C9, isoalkanes. Also, an OECD Guideline 422 screening reproductive/developmental toxicity study (oral route) in rodents is planned with Hydrocarbons, C6 -C10 (even numbered), n-alkanes, isoalkanes, >5% n-hexane (EC# 701-352-4). This endpoint will be updated subsequent to ECHA's approval of the testing proposal and availability of data upon completion of the above studies.
Effects on developmental toxicity
Description of key information
There is no developmental toxicity data available for Hydrocarbons, C6 -C10 (even numbered), n-alkanes, isoalkanes, >5% n-hexane. However, data is available for structural analogues, Hydrocarbons, C7-C9, isoalkanes and hexane and presented in the dossier. This data is read across to Hydrocarbons, C6-C10 (even numbered), n-alkanes, isoalkanes, >5% n-hexane based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.
Commercial hexane
Prenatal Developmental Toxicity Study (OECD TG 414, rats) - Inhalation Administration
Developmental NOAEC = 9000 ppm (31680 mg/m3).
Prenatal Developmental Toxicity Study (OECD TG 414, mouse) - Inhalation Administration
Developmental LOAEC = 3000 ppm (10560 mg/m3).
n-hexane
Developmental Toxicity Study (mouse) - Inhalation Administration
Developmental LOAEC = 200 ppm (704 mg/m3).
Additionally, OECD Guideline 414 (Prenatal Developmental Toxicity) rodent and non-rodent species tests are proposed for structural analogue, Hydrocarbons, C7-C9, isoalkanes. This endpoint will be updated subsequent to ECHA's approval of the testing proposals and availability of data upon completion of the studies.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 24 Mar - 27 Apr 1989
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Comparable to guideline study.
- 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 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, NY
- Age at study initiation: 63 days males, 56 days females at arrival
- Weight at study initiation: 250-300 g male, 175-200 g females
- Housing: individually in stainless steel wire mesh cages, identified with ear tags
- Diet (e.g. ad libitum): Prolab Certified Rodent Food, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 63-74 degree F
- Humidity (%): 40-71
- Photoperiod (hrs dark / hrs light): 12 hrs light/12 hrs dark
IN-LIFE DATES: From: April 9, 1989 To: April 21, 1989 - Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 4320 l glass and stainless steel chambers.
- Method of holding animals in test chamber: cages
- Source and rate of air: 1000 l/min
- Method of conditioning air: Test substance was metered from a piston pump into one or two heated glass evaporators with a temperature of 27-70 degree C. Conditioned air was passed through the evaporators, where it carried the vapor into the exposure chamber.
- Temperature, humidity: monitored every 30 minutes
- Air flow rate: 1000 l/min
- Air change rate: 20 min, 14 air changes per hour
- Treatment of exhaust air: filtration
TEST ATMOSPHERE
- Brief description of analytical method used: GC with flame ionization detection
- Samples taken from breathing zone: yes, 7 times per exposure - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples were taken seven times per exposure period and analyzed with GC-FID. Distribution of test substance was evaluated by sampling five different areas of the exposure chamber.
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: April 2, 1989-April 6, 1989
- Proof of pregnancy: vaginal plug referred to as day 0 - Duration of treatment / exposure:
- gestation day (GD) 6-15
- Frequency of treatment:
- 6 hrs/day
- Duration of test:
- GD 21
- Remarks:
- Doses / Concentrations:
0, 900, 3000, 9000 ppm
Basis:
nominal conc. - Remarks:
- Doses / Concentrations:
914, 3026, 9107 ppm
Basis:
analytical conc. - No. of animals per sex per dose:
- 25 pregnant females per exposure group
- Control animals:
- yes
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: mortality, clinical signs
BODY WEIGHT: Yes
- Time schedule for examinations: GD 0, 6, 9, 12, 15, 18, 21
FOOD CONSUMPTION: Yes
WATER CONSUMPTION: Yes
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Organs examined: gravid uterus, ovaries, cervix, vagina, abdominal cavities, thoracic cavities, liver, kidneys
- Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: live and dead fetuses - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter were examined for thoracic and abdominal visceral abnormalities
- Skeletal examinations: Yes: half per litter - Statistics:
- Quantitative continuous variables were compared by use of Levene's test for equal variance, analysis of variance, and t-tests with Bonferroni probabilities. Nonparametric data was evaluated using the Kruskal-Wallis test, followed by the Mann-Whitney U test. Indices were compared using Fisher's exact test. 0.05 was used as the criteria for statistical significance.
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
There were no treatment related effects to mortality or pregnancy rates. In the 9000 ppm exposure group, there was a significant reduction in weight gain on GD 6-9, and GD 6-15, and slightly reduced on GD 9-12. In the 3000 ppm group, there was a significant reduction in weight gain on GD 9-12, but significantly increased on GD 18-21. Food consumption was significantly reduced in the 9000 ppm group on days 6-9, 9-12, 12-15, and 6-15. There were color changes in the lungs of females in the 9000 ppm group. These changes were also seen in one female each in the 0, 900 and 3000 ppm groups. The color changes in the 900 and 3000 ppm groups were not considered treatment related. There were no treatment related effects to gestational parameters. - Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 10 560 mg/m³ air (nominal)
- Basis for effect level:
- other: maternal toxicity
- Key result
- Dose descriptor:
- LOAEC
- Effect level:
- 31 680 mg/m³ air (nominal)
- Basis for effect level:
- other: maternal toxicity
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 31 680 mg/m³ air (nominal)
- Basis for effect level:
- other: developmental toxicity
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
There were no treatment related effects to the development of fetuses. - Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 31 680 mg/m³ air (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Developmental Toxicity
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- In rats, the maternal NOAEC was 3000 ppm, and the maternal LOAEC was 9000 ppm based on color changes in the lungs, reduced body weight gain, and reduced food consumption. The developmental NOAEC 9000 ppm in rats.
- Executive summary:
The purpose of this study was to examine the developmental toxicity of commercial hexane in rats. Groups of 25 pregnant female rats were exposed to concentrations of 0, 900, 3000, or 9000 ppm for 6 hrs/day during gestational days 6 -15. The animals were then sacrificed on GD 21. During the study, the animals were examined for clinical signs, mortality, food and water consumption, and body weights taken. After sacrifice, the internal organs were examined, and the uterus was examined for viable fetuses, number of resorptions, and number of corpora lutea. Fetuses were examined for malformations. Necropsy revealed color changes in the lungs of females in the 9000 ppm groups along with reduced body weight gain, and reduced food consumption. No treatment related abnormalities was seen in the fetuses. The maternal NOAEC in rats was 3000 ppm, and the LOAEC 9000 ppm based on lung color changes, reduced body weight gain, and reduced food consumption. The developmental NOAEC in rats was 9000 ppm.
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 27 Mar - 20 Apr 1989
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Comparable to guideline study.
- 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 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- mouse
- Strain:
- CD-1
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, NY
- Age at study initiation: 42 days at arrival
- Weight at study initiation: 30 g male, 24 g females
- Housing: individually in stainless steel wire mesh cages, identified with toe clips and ear notches
- Diet (e.g. ad libitum): Prolab Certified Rodent Food, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 66-72 degree F
- Humidity (%): 50-71
- Photoperiod (hrs dark / hrs light): 12 hrs light/12 hrs dark
IN-LIFE DATES: From: April 5, 1989 To: April 18, 1989 - Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 4320 l glass and stainless steel chambers.
- Method of holding animals in test chamber: cages
- Source and rate of air: 1000 l/min
- Method of conditioning air: Test substance was metered from a piston pump into one or two heated glass evaporator with a temperature of 27-70 degree C. Conditioned air was passed through the evaporator, where it carried the vapor into the exposure chamber.
- Temperature, humidity: monitored every 30 minutes
- Air flow rate: 1000 l/min
- Air change rate: 20 min, 14 air changes per hour
- Treatment of exhaust air: filtration
TEST ATMOSPHERE
- Brief description of analytical method used: GC with flame ionization detection
- Samples taken from breathing zone: yes, 7 times per exposure - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples were taken seven times per exposure period and analyzed with GC-FID. Distribution of test substance was evaluated by sampling five different areas of the exposure chamber.
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: March 27, 1989-April 2, 1989
- Proof of pregnancy: vaginal plug referred to as day 0 - Duration of treatment / exposure:
- gestation day (GD) 6-15
- Frequency of treatment:
- 6 hrs/day
- Duration of test:
- GD 18
- Remarks:
- Doses / Concentrations:
0, 900, 3000, 9000 ppm
Basis:
nominal conc. - Remarks:
- Doses / Concentrations:
914, 3026, 9107 ppm
Basis:
analytical conc. - No. of animals per sex per dose:
- 30 pregnant females per exposure group
- Control animals:
- yes
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: mortality, clinical signs
BODY WEIGHT: Yes
- Time schedule for examinations: GD 0, 6, 9, 12, 15
FOOD CONSUMPTION: Yes
WATER CONSUMPTION: Yes
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 18
- Organs examined: gravid uterus, ovaries, cervix, vagina, abdominal cavities, thoracic cavities, liver, kidneys
- Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: live and dead fetuses - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter were examined for thoracic and abdominal visceral abnormalities
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: [all per litter / half per litter / #? per litter ] / No / No data - Statistics:
- Quantitative continuous variables were compared by use of Levene's test for equal variance, analysis of variance, and t-tests with Bonferroni probabilities. Nonparametric data was evaluated using the Kruskal-Wallis test, followed by the Mann-Whitney U test. Indices were compared using Fisher's exact test. 0.05 was used as the criteria for statistical significance.
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
There were no significant treatment related effects to body weight, clinical signs, food consumption, weight changes, or organ weights. There was increased water consumption on GD 6-9, 9-12, 6-15, and 15-18 in the 3000 ppm group. There was also increased water consumption in the 900 ppm group on GD 3-6 and 6-9. There was a statistically significant increase in lung color changes in the 9000 ppm group. Four dams also had brown foci. Two dams in the 3000 ppm group had lung color changes as well, and three had dark brown foci. - Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 3 168 mg/m³ air (nominal)
- Basis for effect level:
- other: maternal toxicity
- Key result
- Dose descriptor:
- LOAEC
- Effect level:
- 10 560 mg/m³ air (nominal)
- Basis for effect level:
- other: maternal toxicity
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 10 560 mg/m³ air (nominal)
- Basis for effect level:
- other: developmental toxicity
- Key result
- Dose descriptor:
- LOAEC
- Effect level:
- 31 680 mg/m³ air (nominal)
- Basis for effect level:
- other: developmental toxicity
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
Gestational parameters were similar between exposure and control groups. There was a statistically significant increase in two skeletal malformations in the 9000 ppm group, bilateral bone island at the first lumbar arch, all intermediate phalanges of the hindlimb unossified. No other dose related abnormalities were noted. - Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 10 560 mg/m³ air (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Developmental Toxicity
- Key result
- Dose descriptor:
- LOAEC
- Effect level:
- 31 680 mg/m³ air (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Developmental Toxicity
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- In mice, the maternal NOAEC was 900 ppm, and the maternal LOAEC was 3000 ppm based on color changes in the lungs. The developmental NOAEC was 3000 ppm and the LOAEC was 9000 ppm in mice.
- Executive summary:
The purpose of this study was to examine the developmental toxicity of commercial hexane in mice. Groups of 30 pregnant female mice were exposed to concentrations of 0, 900, 3000, or 9000 ppm for 6 hrs/day during gestational days 6 -15. The animals were then sacrificed on GD 18. During the study, the animals were examined for clinical signs, mortality, food and water consumption, and body weights taken. After sacrifice, the internal organs were examined, and the uterus was examined for viable fetuses, number of resorptions, and number of corpora lutea. Fetuses were examined for malformations. Necropsy revealed color changes in the lungs of females in the 3000 and 9000 ppm groups. Fetuses in from dams in the 9000 ppm group had a statistically significant increase in some skeletal abnormalities. The maternal NOAEC in mice was 900 ppm, and the LOAEC 3000 ppm based on lung color changes. The developmental NOAEC in mice was 3000 ppm and the LOAEC 9000 ppm based on skeletal abnormalities.
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 1988
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: This study is classified as reliable with restrictions because there was no GLP statement provided, and limited data on methods were reported, but the study seemed to be well-conducted.
- 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:
- no guideline followed
- Principles of method if other than guideline:
- This study examined the effect of inhalation of n-hexane vapors to fetal development. Groups of 35 pregnant and 10 virgin female mice were exposed to concentrations of 0, 200, 1000, or 5000 ppm of test substance vapors for 20 hrs/day, daily, during gestational days 6 -17. During exposure, females were weighed regularly. At the end of the exposure period, the females were sacrificed, and the uterine contents were examined for parameters including number of live fetuses, number of implantations, and number of resorptions. Fetuses were also examined for malformations.
- GLP compliance:
- no
- Limit test:
- yes
- Species:
- mouse
- Strain:
- CD-1
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, Raleigh NC
- Weight at study initiation: 28.7-31.5 g
- Housing: cages
- Diet (e.g. ad libitum): NIH-07 diet, ad libitum
- Water (e.g. ad libitum): ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 73 +/- 3 degrees F
- Humidity (%): 50 +/- 15 %
- Air changes (per hr): approx. 15
- Photoperiod (hrs dark / hrs light): 12 hrs light/12 hrs dark - Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Battelle-designed chambers, 2.3 m3 stainless steel chambers
- Method of holding animals in test chamber: cages
- Method of conditioning air: Hexane in a 19 l stainless steel reservoir is pumped into delivery tubes to vaporizers at the fresh air inlet to the exposure chambers. The vaporizers are heated to aid in evaporation. Micrometering pumps are used to adjust the concentration.
- System of generating particulates/aerosols:
- Temperature, humidity in air chamber: 73 +/- 3 degree F, 50 +/- 15%
- Air change rate: approx. 15 changes per hour
- Treatment of exhaust air: building exhaust
TEST ATMOSPHERE
- Brief description of analytical method used: Atmosphere was tested using a on-line GC with automatic 8-port sampling valve.
- Samples taken from breathing zone: yes - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Atmosphere was tested using a on-line GC with automatic 8-port sampling valve.
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1 male to 1-2 females
- Length of cohabitation: up to five nights
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy - Duration of treatment / exposure:
- 20 hrs/day
- Frequency of treatment:
- daily
- Duration of test:
- gestation days 6-17
- Remarks:
- Doses / Concentrations:
0, 200, 1000, 5000 ppm
Basis:
nominal conc. - No. of animals per sex per dose:
- 35 pregnant females, 10 virgins per dose
- Control animals:
- yes, sham-exposed
- Maternal examinations:
- BODY WEIGHT: Yes
- Time schedule for examinations: plug positive females - days 0, 6, 9, 12, and 18
virgin females - 12 day prior to exosure, days 1, 4 and 7, before sacrifice
POST-MORTEM EXAMINATIONS: Yes / No / No data
- Sacrifice on gestation day 20
- Organs examined: nongravid uteri - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter - Statistics:
- SAS statistical software, Duncan's multiple range test
Mean body weigths: SAS General Linear Models Procedure with analysis of variance
Dose response: orthogonal trend test - Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
Mean weight gain for pregnant females in the 5000 ppm group was significantly reduced compared to controls. There was also a significant reduction in gravid uterine weight in the 200 and 5000 ppm groups. A significant reduction in uterine weight to extra-gestational weight gain was seen in the 5000 ppm group as well. Number of implantations per litter was also reduced in the 5000 ppm group, and also the number of live implants per litter. An increase in intrauterine death was significantly greater only in the 200 ppm group. The incidence of late resorptions was significantly increased in the 5000 ppm group. - Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 1 000 ppm
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- LOAEC
- Effect level:
- 5 000 ppm
- Basis for effect level:
- other: maternal toxicity
- Key result
- Dose descriptor:
- LOAEC
- Effect level:
- 200 ppm
- Basis for effect level:
- other: developmental toxicity
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
Fetal weights of females in the 5000 ppm group were significantly reduced. The only significant increase in malformations as compared to controls, was an exencephalic fetus in the 5000 ppm group, however, as this was only seen in one fetus, and this malformation was also present in the control group, it is not considered treatment related. Rather it is an anomalous result due to the low background incidence of this malformation. - Key result
- Dose descriptor:
- LOAEC
- Effect level:
- 200 ppm
- Basis for effect level:
- other: developmental toxicity
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- The maternal NOAEC was 1000 ppm, and the maternal LOAEC was 5000 ppm based on reduced body weight. The developmental LOAEC was 200 ppm (704 mg/m3) based on increased resorptions and reduced uterine weight. There was no NOAEC for developmental toxicity.
- Executive summary:
This study examined the effect of inhalation of n-hexane vapors to fetal development. Groups of 35 pregnant and 10 virgin female mice were exposed to concentrations of 0, 200, 1000, or 5000 ppm of test substance vapors for 20 hrs/day, daily, during gestational days 6 -17. During exposure, females were weighed regularly. At the end of the exposure period, the females were sacrificed, and the uterine contents were examined for parameters including number of live fetuses, number of implantations, and number of resorptions. Fetuses were also examined for malformations. Body weight was significantly reduced in 5000 ppm exposure females. There was significant reduction in gravid uterine weight in the 200 ppm group, there was also an increase in intrauterine death in this group. Fetal weights were also reduced in the 5000 ppm group. No biologically significant increase in malformations was found. The NOAEC for maternal toxicity is 1000 ppm, and the LOAEC is 5000 ppm based on reduced body weight. There was no NOAEC found for developmental toxicity, and the LOAEC is 200 ppm (704 mg/m3) based on reduced fetal weight gain.
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 1987
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: This study is classified as reliable with restrictions because there was no GLP statement provided, and limited data on methods were reported, but the study seemed to be well-conducted.
- 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:
- no guideline followed
- Principles of method if other than guideline:
- Groups of 30 pregnant and 10 virgin female rats were exposed to concentrations of 0, 200, 1000, or 5000 ppm of test substance vapors for 20 hrs/day, daily, during gestational days 6 -20. During exposure, females were weighed regularly. At the end of the exposure period, the females were sacrificed, and the uterine contents were examined for parameters including number of live fetuses, number of implantations, and number of resorptions. Fetuses were also examined for malformations.
- GLP compliance:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, Raleigh, NC
- Weight at study initiation: 232.4-323.8 g
- Housing: 5 same sex animals per cage
- Diet (e.g. ad libitum): NIH-07 diet, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 20 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 73 +/- 3 degree F
- Humidity (%): 50 +/- 15%
- Air changes (per hr): 14.3-15.3 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hrs light/12 hrs dark - Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Battelle-designed chambers, 2.3 m3 stainless steel chambers
- Method of holding animals in test chamber: cages
- Method of conditioning air: Hexane in a 19 l stainless steel reservoir is pumped into delivery tubes to vaporizers at the fresh air inlet to the exposure chambers. The vaporizers are heated to aid in evaporation. Micrometering pumps are used to adjust the concentration.
- System of generating particulates/aerosols:
- Temperature, humidity in air chamber: 73 +/- 3 degree F, 50 +/- 15%
- Air change rate: approx. 15 changes per hour
- Treatment of exhaust air: building exhaust
TEST ATMOSPHERE
- Brief description of analytical method used: Atmosphere was tested using a on-line GC with automatic 8-port sampling valve.
- Samples taken from breathing zone: yes - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Atmosphere was tested using a on-line GC with automatic 8-port sampling valve.
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 2 females/1 male
- Length of cohabitation: up to 4 nights
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- 20 hrs
- Frequency of treatment:
- daily
- Duration of test:
- Gestation days 6-20
- Remarks:
- Doses / Concentrations:
0, 200, 1000, 5000 ppm
Basis:
nominal conc. - No. of animals per sex per dose:
- 30 pregnant dams, 10 virgin females
- Control animals:
- yes, sham-exposed
- Maternal examinations:
- BODY WEIGHT: Yes
- Time schedule for examinations: sperm-positive females - days 0, 6, 13, and 20
virgin females - 14 day prior to exposure, days 1 and 8, before sacrifice
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: nongravid uteri - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter - Statistics:
- SAS statistical software, Duncan's multiple range test
Mean body weigths: SAS General Linear Models Procedure with analysis of variance
Dose response: orthogonal trend test - Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
2 pregnant dams in the 2000 ppm group, one non-pregnant dam in the 200 ppm group, and one virgin in the 5000 ppm group showed ulceration at the time of sacrifice. Virgin females in the 5000 ppm group had significantly reduced body weight for 14 consecutive days. A significant reduction in body weight was seen in 5000 ppm pregnant females as well. Body weight gain was reduced significantly for pregnant females in the 1000 ppm group on day 20, and 5000 ppm group at days 13 and 20. A significant reduction in gravid uterine weight was seen in females in the 5000 ppm group. Extra-gestational weight gain was reduced for females in the 5000 ppm group significantly. - Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 200 ppm
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- LOAEC
- Effect level:
- 1 000 ppm
- Basis for effect level:
- other: maternal toxicity
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 200 ppm
- Basis for effect level:
- other: developmental toxicity
- Dose descriptor:
- LOAEC
- Effect level:
- 1 000 ppm
- Basis for effect level:
- other: developmental toxicity
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
There was a significant reduction in fetal body weights in the 1000 and 5000 ppm groups. Male fetal body weights were significantly reduced at 1000 and 5000 ppm, female fetal weights were only significantly reduced at 5000 ppm. There was a statistically significant increase in per litter incidence of reduced ossification of sternebrae 1-4 in the 5000 ppm group. However, this increase was likely related to the fetal growth retardation at this exposure. - Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 200 ppm
- Basis for effect level:
- other: developmental toxicity
- Dose descriptor:
- LOAEC
- Effect level:
- 1 000 ppm
- Basis for effect level:
- other: developmental toxicity
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- The LOAEC for maternal toxicity was 1000 ppm based on reduced body weight gain. The NOAEC was 200 ppm for maternal toxicity. The NOAEC for developmental toxicity was 200 ppm (704 mg/m3), and the LOAEC was 1000 ppm (3520 mg/m3) based on reduced fetal weight gain.
- Executive summary:
This study examined the effect of inhalation of n-hexane vapors to fetal development. Groups of 30 pregnant and 10 virgin female rats were exposed to concentrations of 0, 200, 1000, or 5000 ppm of test substance vapors for 20 hrs/day, daily, during gestational days 6 -20. During exposure, females were weighed regularly. At the end of the exposure period, the females were sacrificed, and the uterine contents were examined for parameters including number of live fetuses, number of implantations, and number of resorptions. Fetuses were also examined for malformations. Body weight gain was significantly reduced in 1000 ppm exposure females, and body weight was reduced in 5000 ppm exposure females. Fetal weights were also reduced in the 1000 and 5000 ppm exposure groups. A significant increase in reduced ossification of sternebrae 1 -4 in the 5000 ppm fetuses, but this was likely due to the fetal growth retardation. The NOAEC for maternal toxicity is 200 ppm, and the LOAEC is 1000 ppm based on reduced body weight gain. The NOAEC for developmental toxicity is 200 ppm (704 mg/m3), and the LOAEC is 1000 ppm (3520 mg/m3) based on reduced fetal weight gain.
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- September 1978 - Dezember 1979
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study meets generally accepted scientific principles, acceptable for assessment, limited documentation.
- Justification for type of information:
- The justification for read across is provided as an attachment in IUCLID Section 13.
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- according to guideline
- Guideline:
- other: Food and Drug Administration 1966 "Guidelines for Reproduction Studies for Safety Evaluation of Drugs for Human Use", Segment II (Teratology Study).
- Deviations:
- yes
- Remarks:
- Administration via inhalation route
- GLP compliance:
- no
- Limit test:
- no
- Species:
- rat
- Strain:
- other: CD (SD)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Labs, Inc., Wilmington, Mass. 01887
- Age at study initiation: 9 wks
- Fasting period before study: no
- Housing: individually (except during mating)
- Diet (e.g. ad libitum): Standard Laboratory diet (Purina Lab Chow), fresh food presented as needed, except during each 6-hour exposure.
- Water (e.g. ad libitum): Automated water system (Elizabethtown Water Company), except during each 6-hour exposure.
- Acclimation period: 18 days
ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- not specified
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1 cubic meter exposure chamber
- Method of holding animals in test chamber: no data
- Method of conditioning air:
- Temperature, humidity, pressure in air chamber: room temprature, dried air
- Method of particle size determination: not applicable - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- No details given.
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: overnight
- Verification of same strain and source of both sexes: no, males from in-house colony
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- GD6 - 15
- Frequency of treatment:
- 6 hours/day
- Duration of test:
- until GD21 (all surviving dams), until day 21 postmating (all surviving non-pregnant females)
- No. of animals per sex per dose:
- 20 females
- Control animals:
- yes, sham-exposed
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations included: mortality, gross signs of toxicologic or pharmacologic effects
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: GD 0, 6-15, and 21
BODY WEIGHT: Yes (including calculation of Body Weight Change)
- Time schedule for examinations: GD 0, 6-15, and 21
POST-MORTEM EXAMINATIONS: Yes, all females
- Sacrifice on gestation day # 21
- Organs examined: appendix containing the data was missing
OTHER:
Dams showing signs of abortion or premature delivery were sacrificed and fetuses obtained 19 days or later were processed and examined for skeletal anomalies. Only grossly abnormal fetuses obtained earlier than GD19 weresaved for possible future examination. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes (evidence of implantation, but no recognizable fetus)
- Number of late resorptions: Yes (recognizable dead fetus undergoing degeneration)
- Dead fetuses: Yes (dead fetus with no visible degeneration)
- Live fetuses - Fetal examinations:
- - External examinations: Yes: all fetuses (weight, crown-rump distance from the parietal-interparietal suture to the base of the tail, malformations, sex based upon anogenital distance)
- Soft tissue examinations: Yes: two-thirds of fetuses (gross dissection and examination of viscera including internal sex determination)
- Skeletal examinations: Yes: two-thirds of fetuses (malformations and ossification variations)
- Head examinations: No data - Statistics:
- Comparisons between negative and positive control and between negative control and each test substance-treated group were made where applicable (incidence data) by the chi-square method or by the F-test and Student's t-test (absolute data). When variances differed significantly, Student's t-test was appropriately modified using Cochran's approximation (t'). Mean number of live fetuses, resorptions, implantations and corpora lutea were compared to control by the one-tailed t-test.
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 1 200 ppm (nominal)
- Basis for effect level:
- other: maternal toxicity
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 1 200 ppm (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: teratogenicity
- Abnormalities:
- no effects observed
- Developmental effects observed:
- no
- Conclusions:
- Under the design of the study the test substance, hydrocarbons, C7-C9, isoalkanes, produced no negative effects.
- Executive summary:
Under the design of the study the test substance, hydrocarbons, C7-C9, isoalkanes, produced no negative effects.
- Endpoint:
- developmental toxicity
- 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:
- developmental toxicity
- 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:
- rabbit
Referenceopen allclose all
Gestational Body Weight Changes (g)
0.0 ppm |
900.0 ppm |
3000.0 ppm |
9000.0 ppm |
|
Day 0-6 |
28.21 (11.819) |
31.55 (6.463) |
31.19 (9.344) |
29.36 (8.245) |
Day 6-9 |
11.55 (8.103) |
9.12 (6.009) |
11.18 (4.539) |
4.34 (6.029) |
Day 9-12 |
16.02 (5.296) |
16.31 (5.531) |
11.33 (8.446) |
12.65 (4.974) |
Day 12-15 |
17.03 (6.807) |
19.04 (4.473) |
21.84 (9.577) |
19.03 (6.453) |
Day 15-18 |
43.52 (9.483) |
41.27 (5.755) |
37.83 (16.192) |
44.11 (9.902) |
Day 18-21 |
51.61 (15.190) |
57.79 (8.681) |
63.34 (11.295) |
57.30 (12.247) |
Day 6-15 |
44.59 (12.727) |
44.47 (9.565) |
44.35 (9.870) |
36.02 (7.850) |
Results of Developmental Toxicity Study on Mice
0.0 ppm |
900.0 ppm |
3000.0 ppm |
9000.0 ppm |
|
No. of dams with lung color change |
0 |
0 |
2 |
12 |
All inter. Phalanges (hindlimb) unossified (litters, %) |
76.9 |
72.0 |
84.0 |
100.0 |
Bone island – first lumbar arch – bilateral (litters, %) |
0.0 |
0.0 |
8.0 |
23.1 |
Significant results of mouse developmental toxicity study
Concentration |
0 ppm |
200 ppm |
1000 ppm |
5000 ppm |
Mean body weight – gestational day 18 (g) |
57.0 ± 5.0 |
54.8 ± 4.0 |
55.7 ± 4.9 |
53.7 ± 4.6 |
Uterine mean weight (g) |
21.4 ± 3.8 |
19.2 ± 3.4 |
20.2 ± 3.5 |
17.8 ± 3.9 |
Live fetuses/litter |
12.0 ± 2.6 |
10.6 ± 2.2 |
11.4 ± 2.4 |
10.2 ± 2.7 |
Resorptions/litter |
0.6 ± 0.7 |
1.6 ± 1.7 |
0.8 ± 0.9 |
1.1 ± 1.2 |
Late resorptions/litter |
0.0 ± 0.2 |
0.4 ± 0.9 |
0.4 ± 0.6 |
0.5 ± 0.8 |
% live fetuses/litter |
95.5 ± 5.6 |
87.2 ± 12.2 |
93.5 ± 7.2 |
89.7 ± 12.4 |
% resorptions/litter |
4.5 ± 5.6 |
12.8 ± 12.2 |
6.5 ± 7.2 |
10.3 ± 12.4 |
% late resorptions/litter |
0.3 ± 1.3 |
3.4 ± 6.6 |
2.9 ± 4.6 |
4.5 ± 6.5 |
Female fetal weight (g) |
1.39 ± 0.10 |
1.37 ± 0.10 |
1.35 ± 0.10 |
1.31 ± 0.11 |
% exencephaly/litter affected |
0 ± 0 |
0 ± 0 |
0 ± 0 |
0.5 ± 2.5 |
Significant results of rat developmental toxicity study
Concentration |
0 ppm |
200 ppm |
1000 ppm |
5000 ppm |
Mean body weight virgins - day of sacrifice (g) |
287.6 ± 23.2 |
290.9 ± 29.0 |
282.4 ± 29.6 |
252.7 ± 33.7 |
Mean body weight dams - gestation day 13 (g) |
331.2 ± 20.6 |
326.4 ± 25.6 |
325.1 ± 24.1 |
310.2 ± 33.1 |
Mean body weight dams - gestation day 20 (g) |
408.1 ± 29.2 |
394.8 ± 34.8 |
385.2 ± 28.4 |
366.9 ± 45.0 |
Mean uterine weight (g) |
79.2 ± 14.6 |
78.2 ± 13.7 |
73.3 ± 16.5 |
69.5 ± 13.9 |
Extra-gestational gain (g) |
51.0 ± 13.4 |
40.8 ± 20.8 |
39.2 ± 19.8 |
28.5 ± 17.5 |
Average fetal weight (g) |
3.48 ± 0.37 |
3.54 ± 0.36 |
3.27 ± 0.32 |
2.97 ± 0.38 |
Average placental weight (g) |
0.44 ± 0.05 |
0.42 ± 0.05 |
0.41 ± 0.06 |
0.38 ± 0.05 |
Average male fetal weight (g) |
3.60 ± 0.39 |
3.66 ± 0.39 |
3.33 ± 0.33 |
3.05 ± 0.41 |
Average female fetal weight (g) |
3.33 ± 0.37 |
3.43 ± 0.37 |
3.23 ± 0.32 |
2.86 ± 0.36 |
Average male placental weight (g) |
0.45 ± 0.05 |
0.43 ± 0.05 |
0.41 ± 0.05 |
0.37 ± 0.05 |
Average female placental weight (g) |
0.43 ± 0.05 |
0.42 ± 0.05 |
0.41 ± 0.07 |
0.37 ± 0.05 |
Reduced ossificantion of sternebrae 1-4 (%) |
13.8 ± 21.6 |
16.3 ± 16.5 |
29.0 ± 28.6 |
38.7 ± 23.7 |
A) Maternal data:
Pregnancy rates were comparable between the negative control and the treated groups. No mortality occurred in the negative control and the treated groups. Mean body weight gain during the pre-dosing and the dosing intervals were comparable between negative control and treated groups, during the post-dosing interval mean weight gain was statistical significant higher in the treated groups.
Physical observations:
No indication of a treatment effect. Likewise, the data were generally comparable between the negative and the positive control groups.
Reproduction data:
Mean number of corpora lutea, implantation sites, live fetuses, resorption sites, and the incidence of dams with one or more resorption sites were comparable between the negative control and the treated groups.
Implantation efficiency values were slightly higher in the treated groups than in the negative control, in some instances differences were statistically significant, however, this was not considered indicative of an adverse effect.
In contrast, in the positive control group the mean number of live fetuses was significantly decreased and the mean number of resorption sites significantly increased compared to the negative control. Likewise, the incidence of dams with two or more resorptions was also significantly higher than in the negative control group. The mean number of corpora lutea, implantations, and the implantation efficiency value were comparable between the positive and negative control groups.
Gross postmortem examinations:
Few gross lesions were observed at necropsy of treated females (not further specified), no treatment-related effect was indicated.
B) Fetal data:
Mean fetal weights and mean crown-rump distances of both sexes were comparable for negative control and treated groups, while in the positive control group they were significantly lower. Mean numbers of male and female fetuses were comparable between negative control and treated groups. Likewise, sex ratio data was comparable for these groups. In contrast, the mean numbers of male and female fetuses in the positive control group were significantly lower compared to the negative control, due to lower numbers of fetuses in this group.
Variations in degree of ossification:
These variations may represent delays in the ossification process or slight ossification irregularities. The incidences of fetuses with ossification variations was comparable between negative control and the 400 ppm-treated group. In the 1200 ppm-treated group the incidence of fetuses with at least one ossification variation was significantly higher compared to the negative control. The incidence of litters containing fetuses with ossification variations was comparable between negative and treated groups. Likewise, the types and incidences of ossification variations were generally similar between the negative control and the treated groups.
In contrast, in the positive control group the incidence of fetuses with at least one variation was significantly higher, ossification was retarded.
Teratology data:
No treatment-related external, gross evisceration, soft tissue and skeletal malformations were observed in the fetuses of the treated and the negative control group. One late resorption from one female of the 400 ppm group showed extreme edema, however, no other unusual observations were noted in the other late resorptions of treated and negative control groups. In contrast, in the positive control group, external malformations were noted in 14.4 % of the fetuses, the most common symptom was craniorachischisis with protruding tongue and clubbed forelimbs. The incidences of soft tissue malformations were comparable between the negative control and the treated groups, no treatment-related effect was indicated. In the positive control group, these incidences were significantly higher than in the negative control.
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 2 830 mg/kg bw/day
- Study duration:
- subacute
- Species:
- mouse
- Quality of whole database:
- 1 supporting read across study from a structural analogue available for assessment.
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEC
- 10 560 mg/m³
- Study duration:
- subacute
- Experimental exposure time per week (hours/week):
- 30
- Species:
- mouse
- Quality of whole database:
- 5 key and 2 supporting read across studies from structral analogues available for assessment.
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
There is no developmental toxicity data available for Hydrocarbons, C6-C10 (even numbered), n-alkanes, isoalkanes, >5% n-hexane. However, data is available for structural analogues, Hydrocarbons, C7-C9, isoalkanes, and hexane and presented in the dossier. This data is read across to Hydrocarbons, C6-C10 (even numbered), n-alkanes, isoalkanes, >5% n-hexane based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.
Hydrocarbons, C7-C9, isoalkanes
A Segment II teratology study on hydrocarbons, C7-C9, isoalkanes, showed no evidence of embryonic or teratogenic effects in rats (ExxonMobil Chemical,1979). In this study, pregnant rats were exposed to 0, 400, or 1200 ppm for 6 h/day during gestational days 6 to 15. There was no mortality and no treatment-related effects to the dams. No treatment-related effects were observed in the number of live foetuses, foetal size, sex distribution, and external soft-tissue or skeletal examinations. Under the conditions of the study, there was no evidence of embryotoxicity or teratogenicity. The NOAEC for developmental toxicity was 1200 ppm, the highest dose tested.
Commercial Hexane
The potential developmental toxicity of commercial hexane was examined in two reliable studies performed according to OECD 414 with mice and rats, respectively (API, 1989a,b). Groups of pregnant female animals (30 CD-1 mice, 25 Sprague-Dawley rats) were whole body exposed to vapour of commercial hexane (approx. 52% n-hexane) at 0, 900, 3000, or 9000 ppm for 6 h/day during gestational days (GD) 6-15. Following exposure, animals were sacrificed on GD 18 (mice) or 21 (rats). During the study, animals were examined for clinical signs, mortality, food and water consumption, and body weight gain. After sacrifice, the internal organs were examined, and the uterus was examined for viable foetuses, number of resorptions, and number of corpora lutea. Foetuses were examined for malformations.Necropsy of mice revealed colour changes in the lungs of females in the 3000 and 9000 ppm groups. Foetuses from dams in the 9000 ppm group had a statistically significant increase in the incidence of some skeletal abnormalities. Rats showed colour changes in the lungs of females in the 9000 ppm groups along with reduced body weight gain, and reduced food consumption. No treatment-related abnormalities were seen in the foetuses.
The maternal NOAEC in mice was 900 ppm (3168 mg/m3), and the LOAEC 3000 ppm (10560 mg/m3) based on lung colour changes. The developmental NOAEC in mice was 3000 ppm (10560 mg/m3) and the LOAEC 9000 ppm (31680 mg/m3) based on skeletal abnormalities.
In rats, the maternal NOAEC was 3000 ppm (10560 mg/m3), and the LOAEC 9000 ppm (31680 mg/m3) based on lung colour changes, reduced body weight gain, and reduced food consumption. The developmental NOAEC in rats was 9000 ppm, corresponding to 31680 mg/m3.
n-hexane
In a key developmental toxicity study the effect of inhalation of n-hexane vapors to fetal development was examined (Mast, 1987). Groups of 30 pregnant and 10 virgin female rats were exposed to concentrations of 0, 200, 1000, or 5000 ppm of test substance vapors for 20 hrs/day, daily, during gestational days 6 -20. The LOAEC for maternal toxicity was 1000 ppm based on reduced body weight gain. The NOAEC was 200 ppm for maternal toxicity. The NOAEC for developmental toxicity was 200 ppm (704 mg/m3), and the LOAEC was 1000 ppm (3520 mg/m3) based on reduced fetal weight gain.
In another key development toxicity study the effect of inhalation of n-hexane vapors to fetal development was determined (Mast, 1988). Groups of 35 pregnant and 10 virgin female mice were exposed to concentrations of 0, 200, 1000, or 5000 ppm of test substance vapors for 20 hrs/day, daily, during gestational days 6 -17. The maternal NOAEC was 1000 ppm, and the maternal LOAEC was 5000 ppm based on reduced body weight. The developmental LOAEC was 200 ppm (704 mg/m3) based on increased resorptions and reduced uterine weight. There was no NOAEC for developmental toxicity.
A supporting study (Bus et al., 1979) was conducted to determine the inhalation developmental toxicity of n-hexane. Groups of pregnant female rats were exposed 1000 ppm of n-hexane vapours for 6 hrs days during gestational days 8-12, days 12-16, or days 8-16. Animals were sacrificed on gestational day 22 and the contents of the uterus examined, and the foetuses examined for abnormalities. One group of animals was allowed to deliver and the growth of the pups examined for the next 7 weeks. There were no abnormalities in the foetuses, therefore the test substance is not teratogenic. There was reduced body weight in pups during the first 7 weeks of life, therefore the LOAEL for developmental toxicity is 1000 ppm (3250 mg/m3)
Another supporting study (Marks et al., 1980) examined the effects of oral exposure of pregnant female mice to the test substance n-hexane. Groups of 6 -34 pregnant female mice were exposed by oral gavage to doses of 0.26, 0.66, 1.32, or 2.20 g/kg once daily, and other groups were exposed three times daily for total doses of 2.17, 2.83, 7.92, or 9.90 g/kg. Dams were exposed during days 6 -15 of gestation and sacrificed on gestation day 18. After sacrifice, the contents of the uterus were examined for number of implants, resorptions, and live and dead fetuses. Fetuses were examined for weight, sex, and malformations. Mortality and reduced weight gain were seen in dams at the 2.20 g/kg dose level and above. Reduced weight gain was seen in fetuses at the 7.92 g/kg dose level and above. No increase in fetal malformations was seen at any dose level. The NOAEL for maternal toxicity was 2170 mg/kg, and the LOAEL was 2200 mg/kg. The NOAEL for developmental toxicity was 2830 mg/kg, and the LOAEL was 7920 mg/kg. The test substance was not teratogenic.
Additionally, OECD Guideline 414 (Prenatal Developmental Toxicity) rodent and non-rodent species tests are proposed for Hydrocarbons, C7-C9, isoalkanes. This endpoint will be updated subsequent to ECHA's approval of the testing proposals and availability of data upon completion of the above studies.
Justification for classification or non-classification
Based on the available read across data from structural analogues, Hydrocarbons, C6-C10 (even numbered), n-alkanes, isoalkanes, >5% n-hexane meets the criteria for classification as a Category 2 (H361: Suspected of damaging fertility or the unborn child) reprodutive toxicant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).
An OECD Guideline 422 screening reproductive/developmental toxicity study (oral route) in rodents is planned with Hydrocarbons, C6-C10 (even numbered), n-alkanes, isoalkanes, <2% aromatics (EC# 701-352-4). Additionally, OECD 414 (rodents and non-rodents) and OECD 443 tests are proposed for a structural analogue Hydrocarbons, C7-C9, isoalkanes and will be conducted subsequent to ECHA's approval of the same. This endpoint will be updated upon completion of the above studies subject to ECHA's approval.
Additional information
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