Registration Dossier

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

There is no reproductive toxicity data available for Hydrocarbons, C10 -C13, n-alkanes, however; data is available from structural analogues Decane and Undecane.

Decane

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

NOAEL (developmental toxicity) = 1000 mg/kg/day

NOAEL (reproductive toxicity) = 1000 mg/kg/day

Undecane

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

NOAEL (developmental toxicity) = 1000 mg/kg/day

NOAEL (reproductive toxicity) = 1000 mg/kg/day

Additionally, an OECD 443 (extended one-generation reproductive toxicity - with developmental neurotoxicity (Cohorts 1A, 1B without extension, 2A and 2B)) test is proposed for structural analogues, Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics and Hydrocarbons, C14-C19, 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. 

This endpoint will be updated subsequent to ECHA's approval of the testing proposal and availability of data upon completion of the study. Additionally, OECD Guideline 422 screening reproductive/developmental toxicity studies (oral route) in rodents are planned with structural analogues, Hydrocarbons, C9-C11, n-alkanes, isoalkanes, cyclics, <2% aromatics (EC# 919-857-5) and Hydrocarbons, C11-C14, n-alkanes, isoalkanes, cyclics, <2% aromatics (EC# 926-141-6).

Link to relevant study records

Referenceopen allclose all

Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1996
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
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
Number of Animals: Males, 48; females, 48 (total)
Crj:CD (SD strain) SPF male and female rats 8 weeks old were purchased from Nippon Charles River Co., Ltd., and quarantined for 14 days. The administration was started when the animals were 10 weeks old, and the mean body weight (body weight range) of males at the start of administration was 400.3 g (374-431 g), and that of females was 226.5 g (192-255 g).

The animals were individually placed in metal bracket cages with a metal mesh floor before mating, one male and one female per cage during mating, one mother animal per cage during gestation, and a mother and her newborns after birth.

Animals were maintained in a barrier-isolated room with a temperature of 23 +/- 3°C, humidity of 55 +/- 10%, ventilation changes of 10-15 times per hour, and an illumination of 12 hr/day. After the 17th day of gestation, the metal mesh floor was changed to a stainless steel pan spread with a floor-covering material for experimental animals. Solid feed (CRF-1, manufactured by Oriental Yeast Industry Co., Ltd.), and tap water (tap water of the City of Sapporo) were given freely.
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on exposure:
The administration of the test substance was carried out by oral gavage. The volume administered was 5 mL per kg of body weight, and it was calculated based on the results of body weight measured on the day closest to the day of administration. The administration period was 46 days, which including 14 days before mating and during the mating period for males. The administration period for the female rats began 14 days before mating and continued until after the first 3 days of nursing. The administration was started when the animals were 10 weeks old, and the mean body weight (body weight range) of males at the start of administration was 400.3 g (374-431 g), and that of females was 226.5 g (192-255 g).
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
The administration period was 46 days, which including 14 days before mating and during the mating period for males. The administration period for the female rats began 14 days before mating and continued until after the first 3 days of nursing.
Frequency of treatment:
once per day
Remarks:
Doses / Concentrations:
0 (vehicle), 100, 300, 1000 mg/kg/day
Basis:
actual ingested
oral gavage
No. of animals per sex per dose:
Males, 12 ; females, 12 per dose
Control animals:
yes, concurrent vehicle
Parental animals: Observations and examinations:
General conditions, body weight and feed intake:
For all cases, the general conditions were observed once a day throughout the study term. The body weight measurements were carried out on the 1st (before administration), 2nd, 5th, 7th, 10th and 14th day after administration and subsequently, every 7 days (including the last day of administration) as well as 0th, 1st, 3rd, 5th, 7th, 10th, 14th, 17th and 20th day of gestation and the 0th, 1st and 4th day of nursing for females. In addition, the body weight gain and rate were calculated from the 1st day of administration to the 46th day for males and for females, from the 1st day to the 14th day, 0th day to the 20th day of gestation and 0th day to the 4th day of nursing. The amount of feed intake was measured on the same days as those of body weight measurements except mating period and dissection day for males and 0th day of gestation and 0th day of nursing for females. Incidentally, with respect to the number of day of pregnancy, the successful copulation day was set as the 0th day of gestation, and in the case of lactation, the day of delivery completion was set as the 0th day of nursing.

Urinary tests:
In the final week (43rd-44th day of administration) during the administration term, 6 male cases of each group were placed in metabolism-measurement cages, and their urine samples were collected under non-starvation conditions. For urine samples, collected in about 3 hr, pH, protein, glucose, ketone, urobilinogen, bilirubin, occult blood reaction, and sedimentation (microscopic observation) were tested, and for urine samples collected for 21 hr, volume, and specific gravity were measured. In addition, the amount of drinking water (weight) in urine samples was also measured.

Hematological tests:
Before dissection, all male animals were starved for about 16 hr, blood samples were collected from the femoral vein under ether anesthesia, and EDTA•2K-treated blood samples were used to measure the erythrocyte count, mean erythrocyte volume, platelet count, leucocyte count, hemoglobin content (cyanmethemoglobin method), hematocrit (calculated from erythrocyte count and mean erythrocyte volume), mean erythrocyte hemoglobin content (calculated from erythrocyte count and hemoglobin content), mean erythrocyte hemoglobin concentration (calculated from hematocrit and hemoglobin content), reticulocyte proportion (Brecher method) and leucocyte fraction (microscopic observation). In addition, untreated blood samples were used to measure coagulation time (fluid viscosity change air pressure measurement, Gryner Microcogulometer). Furthermore, plasma samples, which were prepared by collecting blood samples from the abdominal aorta, treating with sodium citrate and subsequently carrying out centrifugation at 3,000 rpm for 10 min, were used to measure prothrombin time (thromboplastin method) and activated partial thromboplastin time (ellagic acid method).

Hematobiochemical test:
After the hematological tests, serum samples of all male cases, which were prepared by collecting from the abdominal aorta, were used to measure GOT, GPT (IFCC method), GPT (glutamyl-p-nitroanilide substrate clathrate method), choline esterase (butyrylthiocholine iodide substrate method), blood glucose (hexokinase method), total cholesterol and phospholipids (enzymatic method), triglyceride (free glycerol deduction method), total bilirubin (azobilirubin method), urea nitrogen (urease-indophenol method), creatinine (Yaffe method), calcium (OCPC method), inorganic phosphorus (Fiske-Subbarow method), total protein (Biuret method) and albumin (BCG method) (Hitachi automated analyzer, Model 7150); sodium and potassium (flame photometry: Corning flame photometer, Model 480); chlorine (coulometric titration method: Hiranuma chloride counter, Model CL-6M); A/G ratio (calculated from total protein and albumin); and protein fraction (cellulose acetate electrophoresis).
Litter observations:
The viability of the newborns was confirmed once a day from delivery completion to the 4th day of nursing. The viability of newborns for 4 days [(No. of live pups on the 4th day/No. of pups born) x 100] was calculated. In addition, the general condition and appearance of the pups was observed. The body weight was measured on the 0th, 1st and 4th day of nursing, and the body weight gain and the rate of body weight gain were calculated. Dead pups were dissected immediately after discovery. All pups were sacrificed and dissected on the 4th day of nursing.
Postmortem examinations (parental animals):
Dissection and organ weight measurement:
After the 46th day of administration, all males were sacrified ex sanguine under ether anesthesia after blood sampling and dissected. Any newborns that died were dissected immediately after discovery. Females that successfully copulated were sacrificed on the 4th day of nursing. Female rats who did not successfully copulate on the 25th day of gestation (infertile cases) on the 26th day of gestation were sacrified. The implantation sites in the uterus and corpus luteum of pregnancy in the ovaries were counted. In addition, the weight measurements were carried out for the liver, kidney, thymus gland, adrenal gland, testes, epididymis and ovary, and the ratio to body weight was calculated.

Histopathological observation:
The following tissues were embedded in paraffin and stained with hematoxylin-eosin or with oil red O staining/ luxol fast blue-Bodian double stain to conduct a histopathological examination: the liver, kidney, spleen, heart, lung, brain (cerebrum and cerebellum), hypophysis, thymus gland, adrenal gland, thyroid gland, stomach (anterior stomach and glandular stomach), duodenum, jejunum, ileum, cecum, colon, rectum, testes, epididymis, prostate gland, ovary and abnormal sites.
Statistics:
Fisher’s accuracy probability test was carried out to compare the control and undecane-administered groups for the sexual cycle, copulation index, fertility index, gestation index and nursing index. Other test parameters were analyzed by using Bartlett’s homogeneity of variance and subsequently single dimensional configuration variance analysis or Kruskal-Walls method. If the results were found to be significant, the Dunnett ‘s method or Mann-Whitney U-test method was used to compare the undecane-administered groups from the control group. However, those qualitative items in urinary tests were analyzed by using the Kruskal-Walls method and Mann-Whitney U-test method. The viability of newborns on the 4th day and body weight were analyzed using the litter as a unit and the results were compared with the control group. A significance level of less than 5% was considered to be statistically significant.
Reproductive indices:
Reproductive ability test:
For female rats, vaginal smear specimens were prepared every day starting from 10 days before administration. Specimens were prepared until successful copulation was confirmed in order to evaluate any abnormalities in the sexual cycle.

On the 14th day of administration, males and females rats (1 to 1 pairs; same dose) were allowed to cohabit for a maximum of 14 days. Successful copulation was confirmed when spermatozoa were detected in the vaginal smear of the female. Gestation was confirmed through the detection of implantation sites in the uterus. In addition, the copulation index [(No. of pairs with successful copulation/No. of pairs mated) x 100] and fertility index [(No. of pregnant animals/No. of pairs with successful copulation) x 100] were calculated.
Offspring viability indices:
The viability of the newborns was confirmed once a day from the delivery completion day to the 4th day of nursing. The viability of newborns for 4 days [(No. of live pups on the 4th day/No. of pups born) x 100] was calculated. In addition, the general condition and appearance of the pups was observed. The body weight was measured on the 0th, 1st and 4th day of nursing, and the body weight gain and the rate of body weight gain were calculated. Dead pups were dissected immediately after discovery. All pups were sacrificed and dissected on the 4th day of nursing.
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 examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
In the repeat dose toxicity test, salivation was observed in males and females given 300 and 1000 mg/kg. Body weight gain was suppressed in males given 1000 mg/kg, and body weights were increased in females given 1000 mg/kg during the lactation period. Food consumption was decreased in males given 300 and 1000 mg/kg in the first half of the administration period, increased in males given 1000 mg/kg in the second half of the administration period, and increased in females given 1000 mg/kg in the second half of pregnancy and during the lactation period. Hematological and blood chemical examinations revealed a decrease in hemoglobin concentration, an increase in the white blood cell count, a decrease in albumin, and increases in a2-globulin, GPT, cholinesterase and total cholesterol in males given 1000 mg/kg. Relative liver weights and absolute and relative thymus weights were increased in males given 1000 mg/kg, and absolute and relative liver weights were elevated in females given 1000 mg/kg. No effects were detected in the autopsy or histopathology findings. Due to the lack of effects in both sexes and the lack of corresponding histopathology, these effects are determined not to be toxicologically relevant. The NOAEL for repeat dose toxicity is considered to be 1000 mg/kg/day for both sexes.

Reproductive and developmental toxicity
No effects of undecane administration were observed on the sex cycle of females and copulation and conception of males and females. In addition, no effects of undecane administration were observed on the weights of reproductive organs (testis, epididymis and ovary) and there were no abnormalities noted in the dissection and histopathological examination. Incidentally, the reproductive organs of infertile cases showed no histopathological findings suggesting the causes. Abnormal cases observed in this study were confirmed to be spontaneous when compared to historical controls. Those cases observed in the present study were considered to be unrelated to undecane.

The number of live or dead pups delivered per each dam in the undecane-administered group showed no apparent difference from that in the control group if those dead and unknown pups in those cases of abnormal delivery or death of all of the litter during nursing were excluded. The body weight gain rates of both males and females in the 1,000 mg/kg group were observed to be reduced, but no effects of undecane were observed as a result of general condition observation or dissection. The NOAEL for reproductive performance is considered to be 1000 mg/kg/day.
Dose descriptor:
NOAEL
Remarks:
reproductive performance
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: No effects noted at highest dose tested.
Dose descriptor:
NOAEL
Remarks:
repeat dose
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
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:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
No effects were detected with regard to reproductive ability, reproductive organ weights, or autopsy or histopathology findings in either sex, and there was no apparent influence on delivery or maternal behavior of dams. Body weight gain was decreased in male and female offspring of the 1000 mg/kg group. This was not considered a toxicological effect. No effects were noted in terms of viability, general condition or autopsy findings of offspring.
Dose descriptor:
NOAEL
Remarks:
developmental
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: No effects noted at highest dose tested.
Reproductive effects observed:
not specified
Conclusions:
The NOAEL for repeat dose toxicity is considered to be >=1000 mg/kg/day for both sexes. The NOAELs for reproductive performance is considered to be >=1000 mg/kg/day.
Executive summary:

In the repeat dose toxicity test, males and female rats were given 0, 100, 300 and 1000 mg/kg. Male rats were dosed for 46 days (14 days prior to mating and then during the mating period) and female rat from 14 days before mating to day 3 of lactation. The NOAEL for repeat dose toxicity is considered to be >=1000 mg/kg/day for both sexes. The NOAEL for reproductive performance is considered to be >=1000 mg/kg/day.

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
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.
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.
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.

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:
2 weight of evidence studies from structural analogues are available.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

There is no reproductive toxicity data available for Hydrocarbons, C10 -C13, n-alkanes, <2% aromatics, however; OECD Guideline 422 studies are available from structural analogues, Decane and Undecane. Additionally, an OECD 443 (extended one-generation reproductive toxicity - with developmental neurotoxicity (Cohorts 1A, 1B without extension, 2A and 2B)) test is proposed for structural analogues, Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics and Hydrocarbons, C14-C19, 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. 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.

Undecane

In the OECD Guideline 422 repeat dose toxicity test (MHW, 1996), males and female rats were given 0, 100, 300 and 1000 mg/kg. Male rats were dosed for 46 days (14 days prior to mating and then during the mating period) and female rat from 14 days before mating to day 3 of lactation. The NOAEL for repeat dose toxicity is considered to be >=1000 mg/kg/day for both sexes. The NOAEL for reproductive performance is considered to be >=1000 mg/kg/day.

Effects on developmental toxicity

Description of key information

There is no data available for Hydrocarbons, C10 -C13, n-alkanes, <2% aromatics. However, data is available for structural analogue 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. Additionally, OECD Guideline 414 (Prenatal Developmental Toxicity) rodent and non-rodent species tests are proposed for structural analogues, Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics and Hydrocarbons, C14-C19, 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.

Prenatal Developmental Toxicity Study (OECD TG 414) - Inhalation Administration - The maternal and developmental NOAECs were greater than 900 ppm (5220 mg/m3).

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
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
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.
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.
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
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 NOAELs 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 NOAELs were greater than or equal to 900 ppm (5220 mg/m3).

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
5 220 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
1 weight of evidence study available from a structural analogue.
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

There is no data available for Hydrocarbons, C10 -C13, n-alkanes, <2% aromatics. However, data is available for structural analogue 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

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 analogues, Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics and Hydrocarbons, C14-C19, 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, Hydrocarbons, C10 -C13, n-alkanes, <2% aromatics 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).

However, OECD 422 tests will be conducted on structural analogues Hydrocarbons, C9-C11, n-alkanes, isoalkanes, cyclics, <2% aromatics (EC# 919-857-5) and Hydrocarbons, C11-C14, n-alkanes, isoalkanes, cyclics, <2% aromatics (EC# 926-141-6). Additional tests (OECD 443 and OECD 414 (rodent and 2nd species)) are proposed 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