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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

There is no substance specific reproductive data available for Octane. However, data is available for structural analogues commercial hexane and Decane and presented in the dossier. This data is read across to based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

Commercial hexane

Two-Generation Reproduction Toxicity Study (OECD TG 416)

Inhalation NOAEC (Reproductive toxicity) = 31680 mg/m3air

Decane

Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD TG 422)

Oral NOAEL (Reproductive toxicity) = 1000 mg/kg/day

 

An OECD 443 test is proposed for structural analogue, Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics. This endpoint will be updated subsequent to ECHA's approval of the testing proposal and availability of data upon completion of the study.

Link to relevant study records

Referenceopen allclose all

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:
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
F0 GENERATION

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.

Key result
Dose descriptor:
NOAEC
Effect level:
31 680 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
other: The value was re-calculated from the nominal dose of 9000 ppm.
Remarks on result:
other: Generation: reproductive toxicity
F1 GENERATION
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.
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
Key result
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 recalculated from the nominal dose of 9000 ppm
Remarks on result:
other: Generation F1, F2
Key result
Reproductive effects observed:
not specified

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)
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:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: According to or similar to guideline study OECD 422:GLP
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
not specified
Details on exposure:
Males were treated from day 14 prior to the mating phase until the end of the mating phase and then killed, Females were treated from day 14 prior to mating, through day 4 of lactation and then killed.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Males were dosed from the 14th day prior to mating, during mating until the end of the mating period. Females were dosed from the 14th day prior to the start of the mating phase to day 4 of lactation.
Frequency of treatment:
Single daily dose 7days/week
Remarks:
Doses / Concentrations:
0, 25, 150, or 1000 mg/kg/day (10 ml/kg dosing volume)
Basis:
other: gavage
No. of animals per sex per dose:
10 male, 10 female per group
Control group: 10 male, 10 female, 0.5% methylcellulose
Control animals:
yes
Parental animals: Observations and examinations:
Effects on general toxicity, neurobehavioral activity, clinical chemistry, and hematology were evaluated. Gross necropsies and histopathologic examination of tissues were conducted with emphasis on the male reproductive tract.
Reproductive assessment included mating, conception and fertility indices, reproductive organ weights and gross and histologic examination of the reproductive tract (special emphasis on stages of spermatogenesis in male gonads and interstitial testicular cell structure).
Sperm parameters (parental animals):
stages of spermatogenesis in male gonads and interstitial testicular cell structure
Litter observations:
Developmental toxicity assessment included, observations of external abnormalities, number of live and still births, mortality, sex determination and weights of pups.
Statistics:
Adult body weights and feed consumption, maternal body weight gains, gestation length and pup body weights were analyzed by ANOVA. Mean mating time was analyzed via the Kaplan Meier method. Pregnancy rates and mating, conception, viability index, post implantation losses, fertility and gestation indices were analyzed by the trend test, Chi-square 2XN and Fisher's exact test (all one tailed). The probability of survival per group was calculated by the product-limit procedure of Kaplan-Meier. Both a trend test and a log-rank test were used to analyze differences in survival among groups.
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
No deaths or clinical signs of toxicity or behavioral changes were noted. No significant differences in body weights or feed consumption were observed. Startle reflex, open field test, and forelimb grip reflex performance data also revealed no treatment-related findings in the parental animals. There were also no treatment-related changes in hematology or blood chemistry parameters, organ weights or gross pathology. An apparent treatment-related, slight to moderate hyperplasia of the non-glandular mucosa of the stomach, associated with degeneration, hyperkeratosis and submucosal subacute inflammation and, in a few cases, with erosion, was seen in animals of all treated groups. This effect was considered an artifact of the dosing method and not directly related to the toxicity of the test material. No other treatment related histological changes were observed.

There were no treatment-related effects at any dose level on any of the reproductive parameters evaluated in this study. These included measures of reproductive performance (mating, conception, gestation length, litter size), offspring survival (gestation and postnatal survival indices, percent pre- and post-implantation loss). The mean mating time of the 1000 mg/kg/day groups was slightly longer than of the control, however, the increase was not statistically significant and within the normal range of variability for this strain of rats. There was a, non dose-related, decrease in fertility (decreased fertility index) was observed in all treated groups (not statistically significant) compared to controls. However, this effect took place in the absence of any adverse effects on reproductive organs and may have resulted from changes in mating behavior due related to stomach irritation experienced by the treated animals.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: No effects noted at highest dose tested.
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not specified
There were no treatment-related effects at any dose level on any of the reproductive parameters evaluated in this study including offspring survival (gestation and postnatal survival indices, percent pre- and post-implantation loss), pup body weight and pup sex ratio. There were also no treatment-related effects on any of the developmental parameters evaluated including external abnormalities, number of live and still births, mortality, sex determination and weights of pups.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: No effects noted at highest dose tested.
Reproductive effects observed:
not specified
Conclusions:
Oral dosing of Linpar 10 to male and female Sprague Dawley rats at levels of 0, 25, 150, or 1000 mg/kg body weight /day produced no evidence of developmental toxicity or teratogenicity and no statistically significant treatment-related effects on any of the reproductive parameters evaluated in this study. Based on these data, the no-observable-adverse effect level (NOAEL) for developmental toxicity was 1000 mg/kg/day and the NOAEL for reproductive toxicity was 1000 mg/kg/day, the highest dose tested.
Executive summary:

Groups of 10 male and 10 female Sprague Dawley rats were dosed with Linpar 10 daily by gavage at exposure levels of 0, 25, 150, or 1000 mg/kg/day Males were dosed from the 14th day prior to mating, during mating until the end of the mating period. Females were dosed from the 14th day prior to the start of the mating phase to day 4 of lactation.  There were no treatment-related effects at any dose level on any of the reproductive parameters evaluated in this study.  These included measures of reproductive performance (mating, conception, gestation length, litter size), offspring survival (gestation and postnatal survival indices, percent pre- and post-implantation loss), pup body weight and pup sex ratio. There were no treatment-related effects at any dose level on any of the developmental paramters evaluated in this study including external abnormalities of pups, number of live and still births, mortality, sex determination, and weights of pups.  Based on these data, the no-observable-adverse-effect level (NOAEL) for developmental toxicity was 1000 mg/kg/day and the NOAEL for reproductive toxicity was 1000 mg/kg/day.

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
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
1 weight of evidence study from a structural analogue available for assessment.
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
31 680 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
1 key study 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 Octane, however; data is available for structural analogues, commercial hexane and Decane. This data is read across to based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

An OECD 443 test is proposed for structural analogue, Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics. This endpoint will be updated subsequent to ECHA's approval of the testing proposal and availability of data upon completion of the study.

Oral

Decane

In an OECD Guideline 422 study (Sasol, 1995), groups of 10 male and 10 female Sprague Dawley rats were dosed with decane daily by gavage at exposure levels of 0, 25, 150, or 1000 mg/kg/day. Males were dosed from the 14th day prior to mating, during mating until the end of the mating period. Females were dosed from the 14th day prior to the start of the mating phase to day 4 of lactation. There were no treatment-related effects at any dose level on any of the reproductive parameters evaluated in this study. These included measures of reproductive performance (mating, conception, gestation length, litter size), offspring survival (gestation and postnatal survival indices, percent pre- and post-implantation loss), pup body weight and pup sex ratio. There were no treatment-related effects at any dose level on any of the developmental parameters evaluated in this study including external abnormalities of pups, number of live and still births, mortality, sex determination, and weights of pups. Based on these data, the no-observable-adverse-effect level (NOAEL) for developmental toxicity was 1000 mg/kg/day and the NOAEL for reproductive toxicity was 1000 mg/kg/day.

Inhalation

 

Commercial hexane

In a reliable two generation reproduction study performed according to OECD 416 (Neeper-Bradley, 1991), CD (Sprague Dawley) rats were whole body exposed to vapour of commercial hexane. Exposure to commercial hexane (approx. 52% n-hexane) was at 0, 900, 3000 or 9000 ppm for 6 h/day, 5 days/week during a 70 day (10 weeks) pre-mating period and the 21 day (3 weeks) mating period. Females were further exposed during gestation (GD 1-19) and lactation (LD 5 to weaning). The F1 generation was treated similarly but the pre-mating exposure was 8 weeks (56 days). Animal observations included mortality, clinical signs, food consumption, and body weight. Offspring were examined for body weight, survival, and viability. Both parental animals and offspring were sacrificed and examined for gross abnormalities. Histopathological examinations were conducted on adult animals.

 

Exposure to commercial hexane did not induce adverse effects on fertility. Reproductive indices were similar in exposed and control groups. No macroscopic or microscopic alterations in male and female reproductive organs were observed. The only significant effect was reduced body weight in the F1 and F2 generations in both sexes in the 9000 ppm exposure group both in adults and offspring. The NOAEC for both male and female rats (adults and offspring) was 3000 ppm (corresponding to 10560 mg/m3). 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 which corresponds to 31680 mg/m3.

Effects on developmental toxicity

Description of key information

There is no data available for Octane. However, data is available for structural analogues, commercial hexane, Hydrocarbons, C7-C9, isoalkanes, <2% aromatics and Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics and presented in the dossier. This data is read across to based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

Commercial hexane

Prenatal Developmental Toxicity Study (OECD TG 414) (rat) - Inhalation Administration - developmental NOAEC = 9000 ppm (31680 mg/m3).

Prenatal Developmental Toxicity Study (OECD TG 414) (mouse) - Inhalation Administration - developmental NOAEC = 3000 ppm (10560 mg/m3).

 

Hydrocarbons, C7-C9, isoalkanes, <2% aromatics

Prenatal Developmental Toxicity Study (OECD TG 414) (rat) - Inhalation Administration - developmental NOAEC = 9000 ppm (31680 mg/m3).

 

Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics

Prenatal Developmental Toxicity Study (OECD TG 414) (rat) - Inhalation Administration - developmental NOAEC > 900 ppm (5220 mg/m3).

 

Additionally, OECD Guideline 414 (Prenatal Developmental Toxicity) rodent and non-rodent species tests are proposed for structural analogue, Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics. 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

Referenceopen allclose all

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
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
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)
Sex:
male/female
Basis for effect level:
other: developmental toxicity
Key result
Abnormalities:
not specified
Key result
Developmental effects observed:
not specified

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)
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
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
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)
Sex:
not specified
Basis for effect level:
other: developmental toxicity
Key result
Dose descriptor:
LOAEC
Effect level:
31 680 mg/m³ air (nominal)
Sex:
not specified
Basis for effect level:
other: developmental toxicity
Key result
Abnormalities:
not specified
Key result
Developmental effects observed:
not specified

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
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:
September 1978 - December 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:
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:
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
Remarks:
Not specified
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)
Remarks:
Doses / Concentrations:
400, 1200 ppm
Basis:
nominal conc.
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
Key result
Dose descriptor:
NOAEC
Effect level:
1 200 ppm (nominal)
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Key result
Dose descriptor:
NOAEC
Effect level:
1 200 ppm (nominal)
Basis for effect level:
other: teratogenicity
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no

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.

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
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable well-documented study report which meets basic scientific principles
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Conducted according to the Food and Drug Administration 1966 "Guidelines for Reproduction Studies for Safety Evaluation of Drugs for Human Use", Segment II (Teratological Study)
GLP compliance:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Bredding Laboratories
- Age at study initiation: females (58 days); males (sexually mature)

- Housing: individually except during mating
- Diet (e.g. ad libitum): ad libitum (food removed during exposure period)
- Water (e.g. ad libitum): ad libitum (water removed during exposure period)


Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Details on exposure:
Appropriate amounts of test material were transferred from a reservoir using a metering pump into a heated flask and flash evaporated. A stream of clean air was also passed through the flask and the vapor laden air transferred to a port in the chamber air inlet, where it was diluted with normal chamber intake air to give the desired concentration. Adjustments in the exposure air concentration were made by changing the rate of the flow of test material through the metering pump.

The stainless steel and glass exposure chambers and an effective exposure volume of 760 liters. They were operated dynamically at a flow rate of approximately 125 liters per minute. This provided one air change every 8 minutes and a 99% equilibrium time of 39 minutes.

Atmospheric sampling was performed using a Wilks Scientific Corp Miran IA Ambient Air Analyzer (long pathlength infrared). The infrared spectrum of the test material was measured and a strong band associated with the test material was observed at 3.4 microns. Calibration curves relating the absorption at this wavelength to the airborne concentration of the test materials were prepared. On each exposure day, three samples were drawn from each exposure chamber and the exposure concentration calculated by comparing the absorption of this sample to the standard curve.

Postive control animals were treated via gastric intubation on gestational days 6-15 with 400mg/kg/day of acetylsalicylic acid in 0.5% methocel.
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
All females selected for mating were places with male rats nightly in a 2:1 ratio. Vaginal smears were taken early in the morning and females were considered to have mated if sperm and/or a vaginal plug were observed. The day on which evidence of mating was first observed was established as Day 0 of gestation for that animal. Mated females were assigned to groups by daily body weight gain in an attempt to equalize Day 0 mean group body weights.
Duration of treatment / exposure:
Females were exposed on gestation days 6-15 by inhalation 6h/day
Frequency of treatment:
daily gestation days 6-15
Duration of test:
Day 6 of gestation ranged from 23 January-3 February 1978
Day 15 of gestation ranged for 1-12 February 1978
Remarks:
Doses / Concentrations:
300 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
900 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
Negative control (Chamber air)- 20 mated females
Postive control (acetylsalicylic acid)-20 mated females
300 ppm- 21 mated females
900ppm- 21 mated females

Control animals:
yes, sham-exposed
other: positive control treated with 400mg/kg/day acetylsalicylic acid
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: Days 0, 6-15, and 21 of gestation



POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Organs examined: uterus (number and location recorded for each horn of the following: live fetuses, dead fetuses, late resorptions, early resorptions, implantation sites); ovaries (number of corpora lutea per ovary)


Fetal examinations:
All fetuses were weighted, crown-rump distance measured, examined externally for malformations and sex determined externally (anogenital distance)
- External examinations: Yes: [all per litter ]
- Soft tissue examinations: Yes
- Skeletal examinations: Yes: [2/3 of litter ]
Fetuses designated for skeletal evaluation were eviscerated prior to initiation of the skeletal staining procedure. During the evisceration step the visceral contents of the thoracic and abdominal cavities were evaluated grossly in situ and sex was determined by internal inspection of gonads. Examination of skeleton for anomalies and ossification variations was performed after staining.
- Neural and Visceral defects: Yes: [1/3 of litter]
Statistics:
Comparisons between the negative control and treated groups and between the negative control and positive control groups were made where applicable by the chi-square method. Body weights, body weight gains, numbers of corpora lutea, implantations, resorptions, fetuses per dam, fetal and litter weights and crown-rump distances were compared to control by the F-test and Student’s t-test. When variances differed significantly, Student’s t-test was appropriately modified using Cochran’s approximation.
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
Animals treated with 900 ppm exhibited a slight increase in excessive lacrimation during the treatment and post-treatment periods. This same group also exhibited an increased incidence of brown flakes in the fur covering the head area during the treatment period. Premature delivery of the litter on Day 21 of gestation prior to maternal sacrifice was observed in one negative control female, and two test material treated females. There were no remarkable gross postmortem changes in the treated adult females. All other physical observations occurred with similar frequencies in all groups and were considered to represent common observations noted in rats in the laboratory environment.

Positive control animals demonstrated statistically significant decreased body weight gain. Females had in utero litters containing fewer live fetuses and more resorption sites than untreated control litters. The implantation efficiency value was significantly reduced and the incidence of dams with two or more resorptions was increased.
Key result
Dose descriptor:
NOAEC
Effect level:
>= 5 220 mg/m³ air (nominal)
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
All fetal survival, size and sex data for groups treated with test material were considered comparable to negative control data. Slight delays or variation in the normal ossification process were observed in treated animals. However such variation are common as the time of normal ossification can vary and were comparable to the variation observed in the control animals. The incidence of fetuses with external malformations and incidences of litters containing malformed fetuses in the groups treated with test material were considered comparable to the control data. No significant difference in the incidence of visceral malformations was observed in the treated groups. The incidence of fetuses with soft tissue malformation in groups treated with test material was comparable to the negative control.

In the positive control group, the percentage of live fetuses and mean fetal size data were significantly lower than the negative control and the percentage of resorbed fetuses was significantly higher than control. The incidence of fetuses with ossification variation was significantly higher than the control value. The incidence of fetuses with soft tissue malformations was significantly higher in the positive control treated group than the negative control.
Key result
Dose descriptor:
NOAEC
Effect level:
>= 5 220 mg/m³ air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Developmental Toxicity
Abnormalities:
not specified
Key result
Developmental effects observed:
no
Conclusions:
There was no evidence of maternal or fetal toxicity at either exposure level of MRD-77-44 tested. Based on these results, both the maternal and developmental NOAECs were greater than or equal to 900 ppm (>= 5220 mg/m^3).
Executive summary:

MRD-77-44 was administered to pregnant female rats by inhalation exposure to vapor concentrations of 300 or 900 ppm, 6 hours/day during gestation days 6 to 15 to assess developmental toxicity.  Included in this study was a negative control (chamber exposed) group and a positive control group that was treated via gastric intubation on gestational days 6-15 with 400mg/kg/day of acetylsalicylic acid.  All surviving females were sacrificed on Day 21 of testation and fetuses examined for external, soft tissue and skeletal malformations.  Pregnancy rate, mortality, body weight gain and gross postmortem observations were unaffected by treatment.  MRD-77-44 treatment at either dose level had no effect on reproductive endpoints, fetal size, sex distribution, ossification variation, or fetal examination endpoints.    Thus, there was no evidence of maternal or fetal toxicity at either exposure level of MRD-77-44 tested.  Based on these results, both the maternal and developmental NOAECs were greater than or equal to 900 ppm (5220 mg/m3).

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
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
10 560 mg/m³
Study duration:
subacute
Species:
mouse
Quality of whole database:
3 key studies and 1 weight of evidence study from structural analogues available for assessment.
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

There is no data available for Octane. However, data is available for structural analogues Commercial hexane, Hydrocarbons, C7-C9, isoalkanes, <2% aromatics and Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics. This data is read across to based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

Inhalation

 

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 (Neeper-Bradly, 1989). 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.

 

Hydrocarbons, C7-C9, isoalkanes, <2% aromatics

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.

 

Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics

In an OECD TG 414 study (ExxonMobil, 1978) the test material (Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics) was administered to pregnant female rats by inhalation exposure to vapor concentrations of 300 or 900 ppm, 6 hours/day during gestation days 6 to 15 to assess developmental toxicity.  Included in this study was a negative control (chamber exposed) group and a positive control group that was treated via gastric intubation on gestational days 6-15 with 400mg/kg/day of acetylsalicylic acid.  All surviving females were sacrificed on Day 21 of testing and fetuses examined for external, soft tissue and skeletal malformations.  Pregnancy rate, mortality, body weight gain and gross postmortem observations were unaffected by treatment.  Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics treatment at either dose level had no effect on reproductive endpoints, fetal size, sex distribution, ossification variation, or fetal examination endpoints. Thus, there was no evidence of maternal or fetal toxicity at either exposure level of Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics tested. Based on these results, both the maternal and developmental NOAECs were greater than or equal to 900 ppm (5220 mg/m3).

  

Additionally, OECD Guideline 414 (Prenatal Developmental Toxicity) rodent and non-rodent species tests are proposed for structural analogue, Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics. This endpoint will be updated subsequent to ECHA's approval of the testing proposals and availability of data upon completion of the studies.

Justification for classification or non-classification

Based on the available read across data from structural analogues Octane does not warrant classification as a reproductive or developmental toxicant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Additional tests (OECD 443 and OECD 414 (rodent and 2nd species)) are proposed and will be conducted on a structural analogue 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