Registration Dossier
Registration Dossier
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EC number: 919-006-8 | CAS number: -
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
No reproductive toxicity/fertility data is available for Hydrocarbons, C16-C20, n-alkanes, isoalkanes, cyclics, aromatics (2-30%). However, data is available for structural analogues, Hydrocarbons, C9-C12, n-alkanes, isoalkanes, cyclics, aromatics (2-25%), JP-8 and Kerosene. Petroleum substances of similar carbon number and aromatic content, principally kerosene and jet fuel, are typically in the range of C9-C16. These substances also contain similar types of molecules in similar proportions to those in C14-C20 aliphatic [2-30% Aromatics] Hydrocarbon solvents. In general, hydrocarbon solvents are more highly refined than petroleum substances. Accordingly, the petroleum substances typically represent a “worse case” with respect to hydrocarbon solvents and can be used for read across on that basis. 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.
Hydrocarbons, C9-C12, n-alkanes, isoalkanes, cyclics, aromatics (2-25%):
NOAEC for reproductive toxicity in rats ≥ 300 ppm (1720 mg/m3)
JP-8:
NOAEL for reproductive toxicity in male rats ≥3000 mg/kg/day
NOAEL for reproductive toxicity in female rats ≥1500 mg/kg/day
Kerosene:
NOAEL for reproductive toxicity in female rats > 494 mg/kg/day
Additionally, an OECD 443 test is proposed for Hydrocarbons, C16-C20, n-alkanes, isoalkanes, cyclics, aromatics (2-30%). 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
- Endpoint:
- one-generation reproductive toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Study period:
- 1991
- 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:
- The justification for read across is provided 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 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
- Principles of method if other than guideline:
- Male rats were given 0, 750, 1500 or 3000 mg/kg neat JP-8 daily by gavage for 70 days prior to mating with naive females to assess fertility and sperm parameters.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Labs, Kingston, NY
- Weight at study initiation: (P) Males: 180 to 220 g
- Diet (e.g. ad libitum): Formula 5008, Ralston Purina, St. Louis, MO, ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-25
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- JP-8 was administered by gavage without a vehicle (neat). Control animals were dosed with 1.0 mL distilled water under the same conditions as test groups. Volumes to be administered each day were calculated from the individual daily body weights and the density of the test material (0.81 g/mL).
- Details on mating procedure:
- In order to stagger delivery dates, male rats were paired with more than one female rat between 70 and 90 days of dosing with JP-8. Male rats were gavaged during cohabitation and returned to individual cages after successful mating. Exposure was continued until the rats were euthanized by carbon dioxide overdose at 90 days
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- daily; 7 days/ week
- Details on study schedule:
- The rats were given 0 (control), 750, 1500 or 3000 mg/kg JP-8 daily by gavage for 70 days prior to mating with naive females. Male rats were cohabitated with one female at a time. In order to stagger delivery dates, male rats were paired with more than one female rat between 70 and 90 days of dosing with JP-8. Male rats were gavaged during cohabitation and returned to individual cages after successful mating.
- Remarks:
- Doses / Concentrations:
0 (control), 750, 1500 or 3000 mg/kg
Basis:
actual ingested - No. of animals per sex per dose:
- 20 males
- Control animals:
- yes, sham-exposed
- Positive control:
- none
- Parental animals: Observations and examinations:
- body weight and mortality
- Oestrous cyclicity (parental animals):
- not examined
- Sperm parameters (parental animals):
- The epididymides were collected from each male rat at necropsy. The epididymides were then minced in phosphate buffered saline with bovine serum albumin; the resulting sperm suspension was videotaped in a Petroff Hauserr chamber. Determinations were made from the videotape using the CellSoft Automated Semen Analyzer (CRYO Resources, Ltd., New York, NY). Motility parameters measured by the CellSoft Analyzer were: sperm concentration, motile sperm concentration, percent motility, velocity, linearity, maximum amplitude of lateral head displacement (ALH), mean ALH and beat/cross frequency. The CellSoft Analyzer also measured the following parameters: mean radius, number of circular cells, percent circular cells/motile cells and percent circular cells/all cells.
- Litter observations:
- not examined
- Postmortem examinations (parental animals):
- not examined
- Postmortem examinations (offspring):
- not examined
- Statistics:
- Statistical Analyses for General Toxicity Data
Adult body weights, organ weights and urine metabolites were analyzed by an ANOVA with multiple comparisons. Clinical chemistry results, hematology values, urinalysis data and severity of pathological changes were compared using an ANOVA. The level of significance was accepted at p<0.05 unless stated otherwise.
Statistical Analyses for Reproductive Measures
A one-factor (dose) or two-factor (dose and pup sex) analysis of variance (ANOVA) was performed for continuous variables. Error terms used were either dam(dose) or pup sex and dam(dose). One-way ANOVA was used with gestation lengths, sperm parameters and litter sizes while two-way was used for pup weights. Post-hoc paired comparisons of dose used two-tailed t-tests with pooled error.
For categorical variables, a Chi-square test of proportions was used to determine differences among the doses. Chi-square tests were used for pregnancy rates and percent viability. Posthoc paired comparison for the viability parameter was performed with Fisher's Exact test. The level of significance was accepted at p<0.05 unless stated otherwise. - Reproductive indices:
- Unexposed females mated with dosed males were allowed to give birth in order to determine gestation length. Successful mating (gestation day 0) was determined by presence of copulatory plug or sperm in a vaginal contents smear. Pregnancy rate (%) and gestation duration (days) were recorded for all dams. All rats were euthanized by carbon dioxide overdose.
- Offspring viability indices:
- not examined
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Other effects:
- not examined
- Reproductive function: oestrous cycle:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- fertility
- Effect level:
- >= 3 000 mg/kg bw/day (actual dose received)
- Sex:
- male
- Basis for effect level:
- other: Lack of adverse treatment-related effects observed at the highest dose tested.
- Clinical signs:
- not examined
- Mortality / viability:
- not examined
- Body weight and weight changes:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Histopathological findings:
- not examined
- Remarks on result:
- not measured/tested
- Remarks:
- F1 parameters were not examined in the study
- Reproductive effects observed:
- not specified
- Conclusions:
- The NOAEL ≥3000 mg/kg/day for male rat fertility.
- Executive summary:
Male rats were given 0, 750, 1500 or 3000 mg/kg neat JP-8 daily by gavage for 70 days prior to mating with naive females to assess fertility and sperm parameters. Males were allowed to mate while continuing to receive treatment. Aside from a decrement in male body weight, no clinical signs were observed. There were no statistical differences noted in any reproductive parameter measured. The reproductive NOAEL ≥3000 mg/kg/day for male rats.
- Endpoint:
- one-generation reproductive toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Study period:
- 1991
- 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:
- The justification for read across is provided 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 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
- Principles of method if other than guideline:
- Female rats were dosed with neat JP-8 (0, 325, 750, 1500 mg/kg) daily by gavage for a total of 21 weeks (90-day plus mating with naive males, gestation and lactation) in an effort to assess general toxicity, fertility and reproductive endpoints.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Labs, Kingston, NY
- Weight at study initiation: (P) Females: 180 to 200 g
- Diet (e.g. ad libitum): Formula 5008, Ralston Purina, St. Louis, MO, ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-25
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- JP-8 was administered by gavage without a vehicle (neat). Control animals were dosed with 1.0 mL distilled water under the same conditions as test groups. Volumes to be administered each day were calculated from the individual daily body weights and the density of the test material (0.81 g/mL).
- Details on mating procedure:
- The rats were given 0 (control), 325, 750 or 1500 mg/kg JP-8 daily by gavage for 21 weeks (90-days followed by cohabitation, gestation, delivery and lactation). The male rats, not exposed to JP-8, were housed 1:1 with treated female rats. Dams were euthanized one day after weaning (Day 22 of lactation); male rats were euthanized after pregnancy was confirmed. Litters were standardized to four male pups and four female pups on postnatal day (PND) 5. All rats were euthanized by carbon dioxide overdose.
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 90 days followed by cohabitation, gestation, delivery and lactation
- Frequency of treatment:
- daily; 7 days/ week
- Details on study schedule:
- Young female Sprague-Dawley rats weighing 180-200 g were randomly assigned to 4 exposure groups. Groups contained a minimum of 35 female rats. The rats were given 0 (control), 325, 750 or 1500 mg/kg JP-8 daily by gavage for 21 weeks (90-days followed by cohabitation, gestation, delivery and lactation). The male rats, not exposed to JP-8, were housed 1:1 with treated female rats. Dams were euthanized one day after weaning (Day 22 of lactation); male rats were euthanized after pregnancy was confirmed. Litters were standardized to four male pups and four female pups on postnatal day (PND) 5. All rats were euthanized by carbon dioxide overdose.
- Remarks:
- Doses / Concentrations:
0 (control), 325, 750 or 1500 mg/kg
Basis:
actual ingested - No. of animals per sex per dose:
- 35 females
- Control animals:
- yes, sham-exposed
- Positive control:
- none
- Parental animals: Observations and examinations:
- A subset of dams from each treatment group (maximum n of 10) was selected for hematology, clinical chemistry and urine analyses. The same subsets were also used for organ weights and histopathology. Whole blood was collected from the dam's inferior vena cava at necropsy. The following hematology parameters were measured: red blood cell count, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, red cell distribution width, mean corpuscular hemoglobin concentration, hematocrit, platelet count and differential leukocyte count. Determinations were made using an automated counter (H-1 System, Technicon Instruments, Corporation, Tarrytown, NY).
The following clinical chemistry parameters were measured in serum from dams: sodium,
glucose, magnesium, carbon dioxide, potassium, albumin, chloride, total protein, calcium, blood urea nitrogen, total bilirubin, uric acid, inorganic phosphate, creatinine, triglycerides, cholesterol, AST, ALT, alkaline phosphatase, lactate dehydrogenase, creatine kinase and gamma-glutamyl transferase. Assays were performed with the Ektachem 700XR chemistry analyzer (Eastman Kodak, Rochester, NY).
The dams were transferred to metabolism cages upon weaning and urine was collected for 24- hours prior to sacrifice. The total volume of urine was noted and the urine was assayed for pH, specific gravity, total protein and creatinine. Specific gravity was measured with a refractometer (American Optical Corp., Southbridge, MA) and pH was measured with an electronic meter (Model 601A, Orion Research Inc., Cambridge, MA). Urine protein assays were performed on an automated chemistry analyzer (Model ACA IV, DuPont, Wilmington, DE). Urine creatinine determinations were made using the Ektachem 700XR analyzer. - Oestrous cyclicity (parental animals):
- not examined
- Sperm parameters (parental animals):
- not examined
- Litter observations:
- not examined
- Postmortem examinations (parental animals):
- A gross pathologic examination was performed on a subset of dams from each treatment group following euthanasia. A maximum of 10 rats per group was designated for clinical pathology and histopathology. Tissues were collected and prepared for histopathologic examination and included: gross lesions, thymus, brain, kidneys, lungs, adrenals, trachea, pancreas, heart, ovaries, uterus, liver, nasal turbinates, spleen, esophagus, duodenum, stomach, jejunum, colon, ileum, rectum, urinary bladder, sternum, mandibular lymph nodes, sciatic nerve, mesenteric lymph nodes, skeletal muscle. Brain, kidneys, liver, spleen and ovaries were weighed during necropsy.
- Postmortem examinations (offspring):
- not examined
- Statistics:
- Statistical Analyses for General Toxicity Data
Adult body weights, organ weights and urine metabolites were analyzed by an ANOVA with multiple comparisons. Clinical chemistry results, hematology values, urinalysis data and severity of pathological changes were compared using an ANOVA. The level of significance was accepted at p<0.05 unless stated otherwise.
Statistical Analyses for Reproductive Measures
A one-factor (dose) or two-factor (dose and pup sex) analysis of variance (ANOVA) was performed for continuous variables. Error terms used were either dam(dose) or pup sex and dam(dose). One-way ANOVA was used with gestation lengths, sperm parameters and litter sizes while two-way was used for pup weights. Post-hoc paired comparisons of dose used two-tailed t-tests with pooled error.
For categorical variables, a Chi-square test of proportions was used to determine differences among the doses. Chi-square tests were used for pregnancy rates and percent viability. Posthoc paired comparison for the viability parameter was performed with Fisher's Exact test. The level of significance was accepted at p<0.05 unless stated otherwise. - Reproductive indices:
- Gestation day 0 was determined by presence of copulatory plug or sperm in a vaginal contents smear. Pregnancy rate (%) and gestation duration (days) were recorded for all dams. Size of the entire litter and the number born dead were noted on PND 1; the resulting numbers were compared between treatment groups.
- Offspring viability indices:
- Size of the entire litter and the number born dead were noted on PND 1; the resulting numbers were compared between treatment groups. Pups were weighed on PND 1, 4, 7, 14, 21 and 90; male and female pup weights were compared between treatment groups and between sexes.
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Other effects:
- not examined
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- fertility
- Effect level:
- >= 1 500 mg/kg bw/day (actual dose received)
- Sex:
- female
- Basis for effect level:
- other: highest dose tested
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Histopathological findings:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 750 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- other: based on decreased pup weight
- Reproductive effects observed:
- not specified
- Conclusions:
- The NOAEL ≥1500 mg/kg/day for female fertility.
- Executive summary:
Female rats were dosed with neat JP-8 (0, 325, 750, 1500 mg/kg) daily by gavage for a total of 21 weeks (90-day plus mating with naive males, gestation and lactation) in an effort to assess general toxicity, fertility and reproductive endpoints. The NOAEL ≥1500 mg/kg/day for female fertility. The NOAEL ≥1500 mg/kg/day for female fertility. The NOAEL for the pup was 750 mg/kg/day based on a decrement in body weight which correlated with a decrease in maternal body weight at 1500 mg/kg/day.
- 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:
- 1980
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Comparable to guideline study.
- Justification for type of information:
- The justification for read across is provided as an attachment in IUCLID Section 13.
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- no
- Limit test:
- yes
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, MA
- Age at study initiation: males - 10 weeks, females - 9 weeks at initiation of pre-treatment mating period, 8 weeks at initiation of post-treatment mating period
- Weight at study initiation: 281-289 g
- Housing: stainless steel wire mesh cages, animals were housed individually during exposure and at a 2:1 female/male ratio during mating
- Diet (e.g. ad libitum): Purina Laboratory Chow, ad libitum
- Water (e.g. ad libitum): ad libitum
IN-LIFE DATES: From: August 21, 1978 To Oct. 13, 1978 - Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: one cubic meter stainless steel and glass chamber
- Method of conditioning air: The MRD-78-25 (300 ppm) was transferred from a 500 ml Erlenmeyer flask using a metering pump, or a 50 cc Tomac glass syringe into a heated flask (100 ppm) and flash evaporated. Clean air was also passed through the flask to pick up vapor. The vapor air mixture was then fed into the chamber inlets and diluted to the desired concentration. The MRD-78-26 was put in fritted bottom gas-washing bottles (400 and 1200 ppm). Air was passed through the bottles, and the vapor air mixture was then fed into the chamber inlets and diluted to the desired concentration.
- Air flow rate: 132 l/min
- Air change rate: complete air change every 7.6 min, with a 99% equilibration time of 35 min. - Details on mating procedure:
- Each male cohabitated for two weeks with two females. Females were sacrificed 18 days after beginning cohabitation. Males were then exposed to the test substance for 8 weeks. Two hours after the last exposure, two untreated virgin females were placed in the males cages. These females cohabitated for seven days and replaced with two new females.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- - Brief description of analytical method used: IR spectrum taken with a Miran IA Ambient Air Analyzer (Wilks Scientific Corp.), analyzed at 3.4 microns.
- Samples taken from breathing zone: yes, at 1, 3, and 5 hrs after exposure began each day - Duration of treatment / exposure:
- 6 hours/day
- Frequency of treatment:
- 5 days/week for 8 weeks
- Remarks:
- Doses / Concentrations:
100 ppm
Basis:
nominal conc. - Remarks:
- Doses / Concentrations:
300 ppm
Basis:
nominal conc. - No. of animals per sex per dose:
- 10 males, 40 females
- Control animals:
- yes, concurrent no treatment
- Positive control:
- triethylenemelamine
- Justification for choice of positive control(s): Triethylenemelamine has been shown to induce dominant-lethal mutations
- Route of administration: intraperitoneally
- Doses / concentrations: 0.5 mg/kg - Parental animals: Observations and examinations:
- Animals were examined for mortality, pharmacological observations, toxicological observations (twice daily), physical observations, body weight (weekly), gross necropsy, and histopathology (seminal vesicles, epididymis, testes, prostate).
- Postmortem examinations (parental animals):
- The following organs were examined in males: seminal vesicles, epididymis, testes, prostate.
- Statistics:
- Comparisons between controls and treatment groups were made using the Chi-square method. Data was compared using the F-test and student's t-test, with the student's t-test modified using Cochran's approximation.
- Reproductive indices:
- Males were considered fertile if at least one female became pregnant.
- Offspring viability indices:
- implantation sites, early resorption sites, late resorption sites, viable fetal swellings
- 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
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- >= 300 ppm
- Sex:
- male/female
- Basis for effect level:
- other: 1720 mg/m3
- 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:
- no effects observed
- Histopathological findings:
- not examined
- Key result
- Dose descriptor:
- NOAEC
- Generation:
- F1
- Effect level:
- >= 300 ppm
- Sex:
- male/female
- Basis for effect level:
- other: 1720 mg/m3
- Reproductive effects observed:
- not specified
- Conclusions:
- The NOAEC for reproductive and developmental screening is 300 ppm in rats via inhalation.
- Executive summary:
This study was conducted to assess the reproductive and developmental toxicity potential of MRD-78-25 when administered to male rats. Male rats were cohabitated for two weeks with two female rats. Males were exposed for 6 hrs/day, 5 days/week, for 8 weeks. At the end of the 8 week exposure period, the male rats the cohabitated for 7 days with two virgin female rats. After this cohabitation, the males were again cohabitated with two new virgin females for another 7 days. 18 days after the beginning of cohabitation, the females were sacrificed. There were also a negative control group, and a positive control group exposed to triethylenemelamine prior to mating. Animals were examined for mortality, pharmacological observations, toxicological observations, physical observations, body weight, gross necropsy, and histopathology. Males proven fertile were then exposed to 100 or 300 ppm of test substance vapors via inhalation (10 males per concentration). The number of implantation sites, early resorption sites, late resorption sites, and viable fetal swellings were also examined. Pregnancy rates, implantation rate, and implantation efficiency were comparable between exposure groups and negative controls. The NOAEC for reproductive screening is 300 ppm for rats via inhalation.
- Endpoint:
- fertility, other
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Study period:
- 1997
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: According to or similar to guideline study OECD 421: GLP.
- Justification for type of information:
- The justification for read across is provided as an attachment in IUCLID Section 13.
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- female
- Route of administration:
- dermal
- Vehicle:
- other: mineral oil
- Details on exposure:
- The study was performed in accordance with OECD guideline 421 with the addition that males were treated for 8 weeks to improve observation of effects on the reproductive system. Also females were weighed 7 times during gestation rather than 4, and at necropsy, 7 organs in addition to the reproductive organs were weighed. Ten male Sprague Dawley rats (aged approximately eight week old, weighing 275-285g) and 10 females (same age and weighing 183-187g) were treated dermally with kerosene at concentrations of 0 (sham-treated and vehicle control groups), 20, 40 or 60% (v/v) in mineral oil in a dosing volume of 1 ml/kg. Dosage equivalents were 0, 165, 330 and 494 mg/kg. These doses were selected on the basis of the results of a preliminary 2- week range finding study. Test material was applied daily to the shorn skin of the animals 7 days/week from 14 days premating, during 14 days mating and through 20 days of gestation. Collars were fitted to the animals during the dosing period to prevent ingestion of applied materials. After the final dose, the collars were removed and residual test material was wiped from the skin. Males continued treatment through gestation until final female sacrifice on days 4-6 of lactation. There were two control groups: the vehicle control was given mineral oil only and in the sham-treated group the animals had been fitted with collars and were stroked with the tip of a syringe, but no material was applied. During the mating period the test material remained on the animal's backs for 6 hours. Prior to pairing, the test material was removed by wiping. Rats were mated overnight on a 1:1 ratio and were separated the following morning. Collars were then applied prior to the next dose being applied. Females were monitored for evidence that mating had taken place.
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- Dosage equivalents were 0, 165, 330 and 494 mg/kg. Test material was applied daily to the shorn skin of the animals 7 days/week from 14 days premating, during 14 days mating and through 20 days of gestation. Collars were fitted to the animals during the dosing period to prevent ingestion of applied materials. After the final dose, the collars were removed and residual test material was wiped from the skin. Males continued treatment through gestation until final female sacrifice on days 4-6 of lactation. There were two control groups: the vehicle control was given mineral oil only and in the sham-treated group the animals had been fitted with collars and were stroked with the tip of a syringe, but no material was applied.
- Frequency of treatment:
- Dosage equivalents were 0, 165, 330 and 494 mg/kg. Test material was applied daily to the shorn skin of the animals 7 days/week from 14 days premating, during 14 days mating and through 20 days of gestation. Collars were fitted to the animals during the dosing period to prevent ingestion of applied materials. After the final dose, the collars were removed and residual test material was wiped from the skin. Males continued treatment through gestation until final female sacrifice on days 4-6 of lactation. There were two control groups: the vehicle control was given mineral oil only and in the sham-treated group the animals had been fitted with collars and were stroked with the tip of a syringe, but no material was applied.
- Remarks:
- Doses / Concentrations:
0, 165, 330 and 494 mg/kg
Basis:
nominal conc. - No. of animals per sex per dose:
- Ten male Sprague Dawley rats (aged approximately eight week old, weighing 275-285g) and 10 females (same age and weighing 183-187g) were treated dermally with kerosene at concentrations of 0 (sham-treated and vehicle control groups), 20, 40 or 60% (v/v) in mineral oil in a dosing volume of 1 ml/kg. Dosage equivalents were 0, 165, 330 and 494 mg/kg. These doses were selected on the basis of the results of a preliminary 2- week range finding study.
- Control animals:
- yes, sham-exposed
- Details on study design:
- Dosage equivalents were 0, 165, 330 and 494 mg/kg. Test material was applied daily to the shorn skin of the animals 7 days/week from 14 days premating, during 14 days mating and through 20 days of gestation. Collars were fitted to the animals during the dosing period to prevent ingestion of applied materials. After the final dose, the collars were removed and residual test material was wiped from the skin. Males continued treatment through gestation until final female sacrifice on days 4-6 of lactation. There were two control groups: the vehicle control was given mineral oil only and in the sham-treated group the animals had been fitted with collars and were stroked with the tip of a syringe, but no material was applied.
During the mating period the test material remained on the animal's backs for 6 hours. Prior to pairing, the test material was removed by wiping. Rats were mated overnight on a 1:1 ratio and were separated the following morning. Collars were then applied prior to the next dose being applied. Females were monitored for evidence that mating had taken place.
Pregnancy was determined by the presence of a vaginal plug or sperm in a vaginal lavage sample. If observed, the female was considered to be at day 0 of gestation. Any female that did not show evidence of mating was placed with the same male the following evening. Any female that did not show evidence of mating at the end of a 2 week mating period was presumed pregnant (gestation day 0 = last day of cohabitation).
Animals were checked twice daily for morbidity and mortality during weekdays but only once daily at weekends. Animals were also observed immediately prior to dosing and after the last animal had been dosed for appearance, behavior and motor activity, respiratory function, central nervous system function, excretory function and biological discharges. Effects of test material on the skin were assessed and scored weekly, using Draize scales for erythema and edema and for chronic deterioration. Males were weighed on the first day of dosing, then weekly and on the day of sacrifice. Females were also weighed on the first day of dosing, then weekly until mating was confirmed and thereafter on gestation days 0, 3, 6, 10, 13, 16 and 20 and on post partum days 0 and 4. Food consumption was also monitored on a similar schedule except through the mating period. Each presumed-pregnant female was observed daily from gestation day 20 for parturition; evidence of dystocia was noted. The day of delivery was designated postpartum day 0. Maternal behavior and appearance were monitored daily until sacrifice. Each litter was examined as soon as possible after birth to establish the number and sex of pups, stillbirths, live births and the presence of gross abnormalities. Pups were examined daily for presence of milk in their stomachs. Any pup found dead was examined externally and unusual findings were recorded. The body weight of each viable offspring was individually measured and recorded on post partum days 1 and 4. Adult females that did not deliver were sacrificed on day 25 of gestation. Dams that delivered and maintained their litters until post partum day 4 were sacrificed with their offspring on post partum days 4-6. All males were sacrificed after the females had been killed. All animals were examined macroscopically for structural anomalies and pathological changes, with emphasis on the reproductive organs. The numbers of implantation sites and corpora lutea of each adult female was recorded. No tissues from offspring were retained. The liver, kidneys, adrenals, thymus, spleen, brain and heart of all parental animals were weighed. In addition the testes and epidiymides of parental males were weighed. Skin from treated sites, ovaries and testes and epididymides were prepared for histological examination. Pathological evaluation was performed on reproductive organs from all males and pregnant females in both control groups and the high dose group and on treated skin from all groups. - Parental animals: Observations and examinations:
- Animals were checked twice daily for morbidity and mortality during weekdays but only once daily at weekends. Animals were also observed immediately prior to dosing and after the last animal had been dosed for appearance, behavior and motor activity, respiratory function, central nervous system function, excretory function and biological discharges. Effects of test material on the skin were assessed and scored weekly, using Draize scales for erythema and edema and for chronic deterioration. Males were weighed on the first day of dosing, then weekly and on the day of sacrifice. Females were also weighed on the first day of dosing, then weekly until mating was confirmed and thereafter on gestation days 0, 3, 6, 10, 13, 16 and 20 and on post partum days 0 and 4. Food consumption was also monitored on a similar schedule except through the mating period. Each presumed-pregnant female was observed daily from gestation day 20 for parturition; evidence of dystocia was noted. The day of delivery was designated postpartum day 0. Maternal behavior and appearance were monitored daily until sacrifice.
- Litter observations:
- Each litter was examined as soon as possible after birth to establish the number and sex of pups, stillbirths, live births and the presence of gross abnormalities. Pups were examined daily for presence of milk in their stomachs. Any pup found dead was examined externally and unusual findings were recorded. The body weight of each viable offspring was individually measured and recorded on post partum days 1 and 4. Adult females that did not deliver were sacrificed on day 25 of gestation. Dams that delivered and maintained their litters until post partum day 4 were sacrificed with their offspring on post partum days 4-6.
- Postmortem examinations (parental animals):
- All males were sacrificed after the females had been killed. All animals were examined macroscopically for structural anomalies and pathological changes, with emphasis on the reproductive organs. The numbers of implantation sites and corpora lutea of each adult female was recorded. No tissues from offspring were retained. The liver, kidneys, adrenals, thymus, spleen, brain and heart of all parental animals were weighed. In addition the testes and epidiymides of parental males were weighed. Skin from treated sites, ovaries and testes and epididymides were prepared for histological examination. Pathological evaluation was performed on reproductive organs from all males and pregnant females in both control groups and the high dose group and on treated skin from all groups.
- Statistics:
- Quantitative data (body weight and food consumption) were analyzed by parametric methods: analysis of variance (ANOVA) and associated F-test, followed by Dunnet's test for multiple comparisons, provided there was statistical significance in the ANOVA. Maternal reproductive data were evaluated by ANOVA followed by group comparisons using Fisher's exact test. Differences between control and treatment groups were considered statistically significant only if the probability of the differences being due to chance was less than 5% (P< 0.05).
- 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
- Dose descriptor:
- NOAEL
- Remarks:
- reproductive
- Effect level:
- > 494 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: No systemic or reproductive effects were noted
- 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
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- > 494 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: No effects were noted on pup survival or weight.
- Reproductive effects observed:
- not specified
- Conclusions:
- The reproductive NOAEL > 494 mg/kg. The pup NOAEL >494 mg/kg based on survival and weight. Classification is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP) or under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.
- Executive summary:
The reproductive NOAEL > 494 mg/kg. The pup NOAEL >494 mg/kg based on survival and weight. Classification is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP) or under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.
- Endpoint:
- extended one-generation reproductive toxicity - with developmental neurotoxicity (Cohorts 1A, 1B without extension, 2A and 2B)
- Type of information:
- experimental study planned
- Study period:
- Will be completed in the timescale as indicated in the ECHA decision letter.
- Justification for type of information:
- This testing proposal has been presented in the lead registrant dossier for this substance submitted to ECHA in 2019. This is a source dossier where the overall approach should be seen in the context of a category of 108 different substances, where the substances are hydrocarbon solvents covering a carbon number range of C5-C20, based on alkane constituents and a range from approximately C8-C18 for aromatic constituents. The basis for this test proposal is set out in detail in the document ‘Hydrocarbon Solvents Test Proposals, Test Plans and Read-Across Strategy for Human Health Endpoints’, which is attached to this endpoint study record and in Section 13.2 of the IUCLID dossier.
TESTING PROPOSAL ON VERTEBRATE ANIMALS
NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out : Hydrocarbons, C16-C20, n-alkanes, isoalkanes, cyclics, aromatics (2-30%) (EC# 919-006-8)
- Name of the substance for which the testing proposal will be used [if different from tested substance] : Not different
CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION [please address all points below]:
- Available GLP studies : There are no OECD Guideline 443 studies available on this substance to evaluate the reproductive toxicity endpoint.
- Available non-GLP studies : There are no ‘non-GLP’ studies available for this substance to evaluate the reproductive toxicity endpoint.
- Historical human data: No human data exist for this substance to evaluate reproductive toxicity hazard.
- (Q)SAR : There are no recognised (Q)SAR methods available for reliable prediction of reproductive toxicity.
- In vitro methods : There are no in vitro methods currently accepted by Regulatory Authorities for the reliable prediction of reproductive toxicity.
- Weight of evidence : Currently there are insufficient data available to develop a robust weight of evidence approach for reproductive toxicity.
- Grouping and read-across : This test proposal maybe used to help develop a category approach for a wider range of hydrocarbons.
- Substance-tailored exposure driven testing [if applicable] : Insufficient data available
- Approaches in addition to above [if applicable]: None applicable
- Other reasons [if applicable] : None identified
CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- There are no specific adaptions for this endpoint
FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Details on study design / methodology proposed: See 'any other information on materials and methods incl. tables' for further information. - Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)
- GLP compliance:
- yes (incl. QA statement)
- Justification for study design:
- SPECIFICATION OF STUDY DESIGN FOR EXTENDED ONE-GENERATION REPRODUCTION TOXICITY STUDY WITH JUSTIFICATIONS:
See 'any other information on materials and methods incl. tables' for further information. - Species:
- rat
- Sex:
- male/female
- Route of administration:
- oral: feed
Referenceopen allclose all
Gestation parameters for unexposed females mated with treated males are shown below (Table 1). Pregnancy rates and gestation lengths were not adversely affected by paternal gavage exposure to JP-8. These parameters were not significantly different between dose groups. As a whole, these dams had low pregnancy rates, including the controls.
Epididymal sperm samples from males exposed by gavage to 0, 750, 1500 and 3000 mg/kg/day JP-8 for 90 days were evaluated using the CellSoft Automated Semen Analyzer. Table 2 contains sperm values for each dose group. The number of male rats per group ranged from 20 to 23. Outliers were removed after rigorous statistical analysis and were not related to dose. Significant differences were not found under any condition of analysis.
TABLE 1. GESTATION PARAMETERS OF UNEXPOSED DAMS MATED TO MALE RATS
| Dose Group | Number of Dams | Pregnancy Rate | Gestation Length |
| mg/kg/day | (n) | (%) | mean (+/- SE) |
| 0 | 36 | 47 | 21.24 (0.26) |
| 750 | 38 | 39 | 21.07 (0.18) |
| 1500 | 42 | 57 | 21.08 (0.15) |
| 3000 | 32 | 53 | 21.41 (0.12) |
TABLE 2. SPERM PARAMETERS (MEAN ± SE) IN MALE RATS EXPOSED
| Parameter | 0 mg/kg/day | 750 mg/kg/day | 1500 mg/kg/day | 3000 mg/kg/day |
| (n=21) | (n=21) | (n=23) | (n=20) | |
| Percent Motile | 25.06 +/- 2.07 | 29.60 +/- 2.26 | 25.10 +/- 1.59 | 24.60 +/- 2.01 |
| Conc. Motile (million/mL) | 0.21 +/- 0.02 | 0.19+/- 0.02 | 0.20 +/- 0.02 | 0.16 +/- 0.02 |
| Mean Velocity (um/s) | 112.21 +/- 4.14 | 122.59 +/- 5.64 | 117.85 +/- 5.09 | 117.04 +/- 4.84 |
| Mean Linearity | 3.74 +/- 0.14 | 3.70 +/- 0.21 | 4.27 +/- 0.16 | 4.04 +/- 0.21 |
| Max ALH (um) | 4.04 +/- 0.19 | 4.28 +/- 0.24 | 4.06 +/- 0.15 | 4.00 +/- 0.19 |
| Mean ALH (um) | 3.44 +/- 0.15 | 3.64 +/- 0.18 | 3.47+ 0.1 | 3.41 +/- 0.14 |
| Beat/Cross Frequency Hz (1/s) | 10.42 +/- 0.28 | 10.34 +/- 0.23 | 10.86 +/- 0.19 | 10.70 +/- 0.27 |
| Avg Radius (um) | 16.04 +/- 1.19 | 15.67 +/- 0.92 | 15.93 +/- 1.22 | 13.79 +/- 0.93 |
| Circular % of Motile | 14.18 +/- 1.43 | 13.96 +/- 1.72 | 17.26 +/- 1.86 | 16.38 +/- 2.3 |
| Circular % of All Cells | 3.87 +/- 0.63 | 4.33 +/- 0.71 | 4.23 +/- 0.5 | 4.30 +/- 0.72 |
Pregnancy rates and litter sizes for treated animals were not significantly different from controls. Gestation length was calculated from dams that became pregnant within one estrous cycle. Of the 87 dams that became pregnant, 77 took 1 to 4 days of cohabitation to become pregnant. The remaining 13 dams had reported times to impregnation ranging from 5 to 11 days. Most of these dams had gestation lengths as short as 14 days due to misidentification of the first day of impregnation. Therefore, time to impregnation plus gestation length was determined for each group. Since there were no significant differences between control and exposure groups for the combined impregnation/gestation length, dams with long impregnation times and short gestation lengths were excluded from the gestation length calculation. There were still no significant differences seen in gestation length for the remaining dams. The percentage of live pups on Day 1 for each dose group was not different from the control percent. The number of dams per treatment with at least one dead pup was not different between the dose groups and control.
No significant changes were found in urine parameters (total volume, specific gravity and creatinine concentration). There were no statistically significant changes in most hematology counts: neutrophil, eosinophil, basophil, lymphocyte and platelet. The leukocyte count was found to be significantly decreased in the 325 mg/kg/day dose group alone (p<0.05). This change was not dose dependent and has questionable biological significance. Clinical chemistry values (sodium, chloride, glucose, triglycerides, creatinine, alkaline phosphatase, AST, ALT) for treatment groups were not significantly different from control values. Data are not shown for urine, hematology and clinical chemistry parameters.
Samples of all collected tissues for each rat in the subsets were not available for histopathological examination. Significant pathological changes were limited to squamous hyperplasia of the stomach and perianal dermatitis. The incidence and severity of these changes were found to be dose-dependent and statistically significant at 1500 mg/kg/day for perianal dermatitis and stomach hyperplasia (p<0.05, see Table 6). Only the incidence and severity of the squamous hyperplasia of the stomach were significantly increased after oral exposure to 750 mg/kg/day JP-8 (p<0.05).
One day after weaning, the dams were euthanized. A subset from each group was necropsied. Due to sacrifices falling on weekends and the deaths of three animals not related to JP-8 dose (two from the 325 and one from the 750 mg/kg/day groups), the number of female rats per subset was limited. Treatment subsets had 7 or 8 rats while the control subset had 10 rats available. Liver weights were significantly increased, as were liver to body weight and liver to brain weight ratios (p<0.01 in 1500 mg/kg/day group). Kidneys to brain ratios were also significantly increased (p<0.05).
Mean Body Weights (g)
Week |
Negative Control |
Positive Control |
100 ppm |
300 ppm |
Initial |
289 |
281 |
283 |
284 |
Pre-treatment mating 1 |
331 |
325 |
328 |
328 |
Pre-treatment mating 2 |
365 |
362 |
367 |
363 |
Treatment 1 |
413 |
418 |
416 |
407 |
Treatment 2 |
438 |
449 |
441 |
428 |
Treatment 3 |
452 |
470 |
458 |
443 |
Treatment 4 |
470 |
487 |
475 |
459 |
Treatment 5 |
480 |
504 |
490 |
470 |
Treatment 6 |
484 |
516 |
502 |
479 |
Treatment 7 |
496 |
531 |
518 |
487 |
Treatment 8 |
504 |
538 |
527 |
500 |
Post-treatment mating 1 |
514 |
508 |
535 |
507 |
Post-treatment mating 2 |
523 |
518 |
544 |
516 |
Reproduction Data
Pregnancy Rate (%) |
||||
Week |
Negative Control |
Positive Control |
100 ppm |
300 ppm |
Pre-treatment mating 1 |
75.0 |
70.0 |
70.0 |
70.0 |
Pre-treatment mating 2 |
80.0 |
85.0 |
90.0 |
95.0 |
Post-treatment mating 1 |
85.0 |
75.0 |
80.0 |
65.0 |
Post-treatment mating 2 |
100.0 |
80.0 |
95.0 |
100.0 |
Mean Corpora Lutea |
||||
Pre-treatment mating 1 |
12.5 |
11.8 |
12.9 |
14.0 |
Pre-treatment mating 2 |
14.1 |
14.9 |
13.1 |
13.5 |
Post-treatment mating 1 |
13.1 |
11.1 |
13.9 |
13.4 |
Post-treatment mating 2 |
13.4 |
11.9 |
14.4 |
13.1 |
Mean Implantations |
||||
Pre-treatment mating 1 |
10.1 |
11.4 |
12.0 |
13.0 |
Pre-treatment mating 2 |
12.5 |
14.0 |
12.1 |
11.9 |
Post-treatment mating 1 |
11.9 |
8.8 |
12.6 |
12.6 |
Post-treatment mating 2 |
12.7 |
4.1 |
12.8 |
12.5 |
Implantation Efficiency |
||||
Pre-treatment mating 1 |
80.9 |
96.4 |
92.8 |
92.9 |
Pre-treatment mating 2 |
88.5 |
94.1 |
92.3 |
88.3 |
Post-treatment mating 1 |
91.0 |
79.0 |
91.0 |
94.3 |
Post-treatment mating 2 |
95.1 |
34.0 |
89.4 |
95.4 |
Mean Early Fetal Death |
||||
Pre-treatment mating 1 |
0.2 |
0.4 |
0.6 |
0.5 |
Pre-treatment mating 2 |
0.6 |
0.5 |
0.5 |
1.0 |
Post-treatment mating 1 |
0.8 |
5.9 |
0.5 |
0.8 |
Post-treatment mating 2 |
0.5 |
4.1 |
0.9 |
0.5 |
Mean Late Fetal Death |
||||
Pre-treatment mating 1 |
0.1 |
0.0 |
0.0 |
0.0 |
Pre-treatment mating 2 |
0.0 |
0.0 |
0.0 |
0.1 |
Post-treatment mating 1 |
0.0 |
0.1 |
0.0 |
0.0 |
Post-treatment mating 2 |
0.0 |
0.0 |
0.0 |
0.0 |
Viable Fetal Swellings |
||||
Pre-treatment mating 1 |
9.9 |
10.9 |
11.4 |
12.5 |
Pre-treatment mating 2 |
11.9 |
13.5 |
11.6 |
10.8 |
Post-treatment mating 1 |
11.1 |
2.8 |
12.1 |
11.8 |
Post-treatment mating 2 |
12.2 |
0.0 |
11.9 |
12.1 |
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 500 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- 2 weight of evidence studies from structural analogues available for assessment
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEC
- 1 720 mg/m³
- Study duration:
- subacute
- Experimental exposure time per week (hours/week):
- 30
- Species:
- rat
- Quality of whole database:
- 1 weight of evidence study from a structural analogue available for assessment
Effect on fertility: via dermal route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 494 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.
Additional information
No reproductive toxicity/fertility data is available for Hydrocarbons, C16-C20, n-alkanes, isoalkanes, cyclics, aromatics (2-30%). However, data is available for structural analogues, Hydrocarbons, C9-C12, n-alkanes, isoalkanes, cyclics, aromatics (2-25%), JP-8 and Kerosene. Petroleum substances of similar carbon number and aromatic content, principally kerosene and jet fuel, are typically in the range of C9-C16. These substances also contain similar types of molecules in similar proportions to those in C14-C20 aliphatic [2-30% Aromatics] Hydrocarbon solvents. In general, hydrocarbon solvents are more highly refined than petroleum substances. Accordingly, the petroleum substances typically represent a “worse case” with respect to hydrocarbon solvents and can be used for read across on that basis. 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, an OECD 443 test is proposed for Hydrocarbons, C16-C20, n-alkanes, isoalkanes, cyclics, aromatics (2-30%). This endpoint will be updated subsequent to ECHA's approval of the testing proposal and availability of data upon completion of the study.
Hydrocarbons, C9-C12, n-alkanes, isoalkanes, cyclics, aromatics (2-25%)
A read across OECD Guideline 421 screening reproductive toxicity study (ExxonMobil, 1980a), was conducted to assess the reproductive and developmental toxicity potential of the test material (Hydrocarbons, C9-C12, n-alkanes, isoalkanes, cyclics, aromatics (2-25%)) when administered to male rats. Male rats were cohabitated for two weeks with two female rats. Males were exposed for 6 hrs/day, 5 days/week, for 8 weeks. At the end of the 8 week exposure period, the male rats the cohabitated for 7 days with two virgin female rats. After this cohabitation, the males were again cohabitated with two new virgin females for another 7 days. 18 days after the beginning of cohabitation, the females were sacrificed. There were also a negative control group, and a positive control group exposed to triethylenemelamine prior to mating. Animals were examined for mortality, pharmacological observations, toxicological observations, physical observations, body weight, gross necropsy, and histopathology. Males proven fertile were then exposed to 100 or 300 ppm of test substance vapors via inhalation (10 males per concentration). The number of implantation sites, early resorption sites, late resorption sites, and viable fetal swellings were also examined. Pregnancy rates, implantation rate, and implantation efficiency were comparable between exposure groups and negative controls. The NOAEC for reproductive screening was determined to be ≥300 ppm for rats via inhalation.
JP-8
In a read across study (Mattie et al., 2000), male rats were given 0, 750, 1500 or 3000 mg/Kg neat JP-8 daily by gavage for 70 days prior to mating with naive females to assess fertility and sperm parameters. Males were allowed to mate while continuing to receive treatment. Aside from a decrement in male body weight, no clinical signs were observed. There were no statistical differences noted in any reproductive parameter measured. The reproductive NOAEL was ≥3000 mg/Kg/day for male rats.
In another read across study (Mattie et al., 2000), female rats were dosed with neat JP-8 (0, 325, 750, 1500 mg/Kg) daily by gavage for a total of 21 weeks (90-day plus mating with naive males, gestation and lactation) in an effort to assess general toxicity, fertility and reproductive endpoints. The NOAEL was ≥1500 mg/Kg/day for female fertility. The NOAEL was ≥1500 mg/kg/day for female fertility. The NOAEL for the pup was 750 mg/Kg/day based on a decrement in body weight which correlated with a decrease in maternal body weight at 1500 mg/Kg/day.
Kerosene
In a read across study (Schreiner et al., 1997), male and female rats were treated dermally with kerosene at doses of 0 (sham-treated and vehicle control groups, 165, 330 and 494 mg/kg from 14 days premating, during 14 days mating and through 20 days of gestation. No systemic or reproductive effects were noted. The NOAEL for reproductive toxicity is >494 mg/kg.
Effects on developmental toxicity
Description of key information
No developmental toxicity data is available for Hydrocarbons, C16-C20, n-alkanes, isoalkanes, cyclics, aromatics (2-30%). However, data is available for structural analogues, Hydrocarbons, C9-C12, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) and JP-8/Kerosene. Petroleum substances of similar carbon number and aromatic content, principally kerosene and jet fuel, are typically in the range of C9-C16. These substances also contain similar types of molecules in similar proportions to those in C14-C20 aliphatic [2-30% Aromatics] Hydrocarbon solvents. In general, hydrocarbon solvents are more highly refined than petroleum substances. Accordingly, the petroleum substances typically represent a “worse case” with respect to hydrocarbon solvents and can be used for read across on that basis. 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.
Hydrocarbons, C9-C12, n-alkanes, isoalkanes, cyclics, aromatics (2-25%)
NOAEC for developmental toxicity: ≥ 300 ppm (1575 mg/m3)
JP-8/Kerosene
NOAEL for developmental toxicity: 500 mg/kg bw/day
Additionally, OECD Guideline 414 rodent and non-rodent species tests are proposed for Hydrocarbons, C16-C20, n-alkanes, isoalkanes, cyclics, aromatics (2-30%). This endpoint will be updated subsequent to ECHA's approval of the testing proposals and availability of data upon completion of the studies.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 11 Sept. 1978 - 6 Oct. 1978
- 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:
- according to guideline
- Guideline:
- other: Guidelines for Reproduction Studies for Safety and Evaluation of Drugs for Human Use, Segment II (Teratology Study)
- GLP compliance:
- no
- Limit test:
- yes
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc.
- Age at study initiation: 7 weeks
- Fasting period before study: Animals were not given food during exposure.
- Housing: Individually, except during mating, in stainless steel cages, animals identified by ear tags
- Diet (e.g. ad libitum): Purina Lab Chow, ad libitum
- Water (e.g. ad libitum): Elizabethtown Water Company, ad libitum
- Acclimation period: Aug. 17, 1978-Sept. 4, 1978
ENVIRONMENTAL CONDITIONS
- Temperature (°C): monitored twice daily, room temperature
- Humidity (%): dry air
- Photoperiod (hrs dark / hrs light): 12 hrs light/12 hrs dark
IN-LIFE DATES: days 6-15 of gestation From: 11-27 Sept. 1978 To: 20 Sept. - 6 Oct. 1978 - Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: one cubic meter exposure chamber
- Temperature, humidity, pressure in air chamber: room temperature, dry air - Analytical verification of doses or concentrations:
- no
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: Overnight and removed in morning to check for pregnancy, this was repeated until females were pregnant
- Proof of pregnancy: vaginal plug and sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- 6 hrs/day
- Frequency of treatment:
- days 6-15 of gestation
- Duration of test:
- days 6-15 of gestation
- No. of animals per sex per dose:
- 20
- Control animals:
- yes, concurrent no treatment
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations: mortality, toxicological signs, pharmacological effects
BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 6-15, 21 of gestation
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #: 21
- Organs examined: uterus, ovaries - Ovaries and uterine content:
- The ovaries and uterine content were examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: number of live fetuses, number of dead fetuses - Fetal examinations:
- - External examinations: Yes: all per litter examined for sex, crown-rump distance, weighed, and malformations
- Soft tissue examinations: Yes: 2/3 per litter examined for gross dissection and examination of viscera, internal sex determination, ureter, kidneys, and heart
- Skeletal examinations: Yes: 2/3 per litter examined for skeletal malformations, and ossification
- Head examinations: Yes: 1/3 per litter examined for neural defects - Statistics:
- Analysis was done using the chi-square method, or the F-test and Student's t-test. When the variance differed significantly, the Student's t-test was modified suing Chochran's approximation. The mean number of live fetuses, resorptions, implantations, and corpora lutea were analyzed using the one-tailed t-test.
- Indices:
- implantation efficiency,
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
Details on maternal toxic effects:
There was no mortality in either of the dosage groups. Pregnancy rates were comparable between the exposure groups and negative controls. Weight gain was significantly higher in the exposure groups post-dosing. There were no significant clinical observations in either exposure group. The mean number of corpora lutea was significantly decreased in the 300 ppm group. Since ovulation occurred prior to exposure, this was not considered to be treatment related. The mean number of implantations was comparable between exposure groups and negative controls. The implantation efficiency values were actually significantly higher in exposure groups as compared to negative controls. The mean number of live fetuses, resorption sites, and number of dams with more than one resorption site were comparable between exposures and negative controls. The gross postmortem examination of dams showed no treatment related effects. - Key result
- Dose descriptor:
- NOAEC
- Effect level:
- >= 300 ppm
- Basis for effect level:
- other: Systemic toxicity
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
The body weights of fetal males in the 100 ppm group were significantly higher than negative controls. There were some statistically significant differences in mean crown-rump distance between both dosage levels and negative controls, these differences were slight and the effect inconsistant between dosages and sex. These differences were therefore not considered to be indicative of a treatment related effect. Mean numbers of male and female fetuses, and sex ratios were similar between exposure groups and negative controls. Ossification variations were similar in exposure groups and negative controls, as was the incidence of litters with fetuses containing ossification variations. No malformations externally or in the soft tissues were noted in the fetuses except in the positive controls. Though skeletal defects were noted in the exposure group, the types of malformations are common in rat fetus and not considered to be treatment related. - Key result
- Dose descriptor:
- NOAEC
- Effect level:
- >= 300 ppm
- Based on:
- test mat.
- Basis for effect level:
- other: Developmental Toxicity
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- The NOAEC for developmental toxicity in rats is >=300 ppm (1575 mg/m3) via inhalation. The test substance is also non-teratogenic.
- Executive summary:
This study determined the developmental toxicity of MRD-78 -25 in rats exposed via inhalation. Groups of 20 pregnant female rats were exposed 6 hrs/day during days 6 -15 of gestation. Test concentrations of 100 or 300 ppm test substance. In addition to a negative control group, there was also a positive control group that was exposed to acetylsalicylic acid on days 6 -15 of gestation. Dams were observed for toxicological signs and pharmacological effects. On day 21 of gestation, the animals were sacrificed, and examined for corpora lutea and uterine implantation parameters. Fetuses were examined for fetal size, sex ratio, and external, soft-tissue, and skeletal malformations. No adverse effects due to exposure to the test substance were seen in either dams or fetuses. No treatment related malformation effects were noted in the fetuses. The developmental NOAEC for rats by inhalation is >=300 ppm. The test substance is also not teratogenic.
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Study period:
- 1996
- 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:
- The justification for read across is provided 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:
- Time-mated Sprague-Dawley rats were dosed orally with JP-8 at 0, 500, 1000, 1500 and 2000 mg/kg/day on days 6-15 of pregnancy.
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Kingston, NY
- Age at study initiation: One hundred and fifty time-mated virus antibody-free rats were purchased on day 4 of pregnancy.
- Weight at study initiation: all groups contained dams of approximately equivalent body weight at the beginning of the study
- Diet (e.g. ad libitum): Purina Lab Chow, ad libitum
- Water (e.g. ad libitum): ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°F): 71-73°F
- Humidity (%): 45-55% relative humidity
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- On days 6-15 of pregnancy the animals assigned to each treatment group were administered one of the following doses of JP-8 by oral gavage: 500, 1000, 1500 and 2000mg/kg/day. The volume of JP-8 administered ranged from 1.1 to 7.3 ml daily, depending on the dam's body weight and dose group. Control animals received 1 ml of sterile water daily in order to emulate any stress that may have been associated with the dosing process. Animals were examined daily for evidence of toxicity. On day 20 of pregnancy all animals were euthanized with carbon dioxide.
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- GD 6-15
- Frequency of treatment:
- daily
- Duration of test:
- GD 6-15
- Remarks:
- Doses / Concentrations:
0, 500, 1000, 1500 and 2000mg/kg/day
Basis:
actual ingested - No. of animals per sex per dose:
- 30 females
- Control animals:
- yes, sham-exposed
- Maternal examinations:
- Animals were examined daily for evidence of toxicity.
- Ovaries and uterine content:
- The dam's body weight and the liver, kidney and gravid uterus weights were recorded. The total number of corpora lutea, live fetuses, dead fetuses and resorption sites were also recorded for each dam. Uteri that appeared to be non-gravid were placed in a 10% ammonium sulfate solution for 10 min and then reevaluated for the presence of early resorptions.
- Fetal examinations:
- Viable fetuses were sexed, weighed and examined for gross abnormalities. One-half of the fetuses were evaluations using the technique of Wilson. The remaining fetuses were placed in ethanol for later examination of skeletal anomalies using the procedure of Staples and Schnell.
- Statistics:
- Maternal body weight and average pup weights per litter were first analyzed using Bartlett's test for homogeneity of variance followed by one-way analysis of variance (ANOVA) procedures. Bonferoni's test was used to compare the body weights of maternal and fetal control animals with those of animals in the treatment groups. Non-parametric data (i.e. corpora lutea counts, number of live fetuses and the number of dead fetuses) were analyzed using the Kruskal- Wallis test followed by the Mann-Whitney U test when appropriate. The incidence of fetal malformations/variations per litter were compared using Fisher's exact test. In all cases P <= 0.05 was used as the level of significance.
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
Significant maternal toxicity was evidenced by a reduction in maternal body weight gain in the 1000, 1500 and 2000 mg/kg/day dose groups. Maternal necropsy weight (maternal body weight minus pregnant uterus's weight) was also significantly different from that of the control animals at doses of 1500 and 2000 mg/kg/day. No clinically apparent maternal toxicity was noted during the course of the study. Thirteen animals were found dead in their cage at various times during the dosing period and each was submitted to necropsy. In all cases the cause of death was found to be related to the presence of JP-8 in the lungs. Maternal observations at necropsy, including the number of females pregnant, number of corpora lutea per female, number of fetuses per female and post-implantation loss, were within the normal range for all treatment groups. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 500 mg/kg bw/day
- Basis for effect level:
- other: maternal toxicity
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
The average body weight of male and female fetuses was significantly reduced in the 1500 and 2000 mg/kg/day dose groups. A detailed examination of the fetal tissues revealed no significant increase in the incidence of malformations or variations in treated versus control animals. The sex ratio of male and female fetuses was also similar among the control and dose groups. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Basis for effect level:
- other: fetotoxicity
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 2 000 mg/kg bw/day (actual dose received)
- Basis for effect level:
- other: teratogenicity
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- The maternal NOAEL was determined to be 500 mg/kg/day based on reduced maternal body weight. The fetotoxicity NOAEL was determined to be 1000 mg/kg/day based on reduced fetal weight. There were no developmental or teratogenic effects noted (aside from body weight reduction) in any dose tested.
- Executive summary:
Time-mated Sprague-Dawley rats were dosed orally with JP-8 at 0, 500, 1000, 1500 and 2000 mg/kg/day on days 6-15 of pregnancy. The maternal NOAEL was determined to be 500 mg/kg/day based on reduced maternal body weight. The fetotoxicity NOAEL was determined to be 1000 mg/kg/day based on reduced fetal weight. There were no developmental or teratogenic effects noted (aside from body weight reduction) in any dose tested.
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study planned
- Study period:
- Will be completed in the timescale as indicated in the ECHA decision letter.
- Justification for type of information:
- This testing proposal has been presented in the lead registrant dossier for this substance submitted to ECHA in 2019. This is a source dossier where the overall approach should be seen in the context of a category of 108 different substances, where the substances are hydrocarbon solvents covering a carbon number range of C5-C20, based on alkane constituents and a range from approximately C8-C18 for aromatic constituents. The basis for this test proposal is set out in detail in the document ‘Hydrocarbon Solvents Test Proposals, Test Plans and Read-Across Strategy for Human Health Endpoints’, which is attached to this endpoint study record and in Section 13.2 of the IUCLID dossier.
TESTING PROPOSAL ON VERTEBRATE ANIMALS
[Please provide information for all of the points below. The information should be specific to the endpoint for which testing is proposed. Note that for testing proposals addressing testing on vertebrate animals under the REACH Regulation this document will be published on the ECHA website along with the third party consultation on the testing proposal(s).]
NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out : Hydrocarbons, C16-C20, n-alkanes, isoalkanes, cyclics, aromatics (2-30%) (EC# 919-006-8)
- Name of the substance for which the testing proposal will be used [if different from tested substance] : Not different
CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION [please address all points below]:
- Available GLP studies : There are no OECD Guideline 414 studies available on this substance to evaluate the developmental toxicity endpoint in both rodents and non-rodents.
- Available non-GLP studies : There are no ‘non-GLP’ studies available for this substance to evaluate the developmental toxicity endpoint in both rodent and non-rodent species.
- Historical human data : - No human data exist for this substance to evaluate developmental toxicity hazard.
- (Q)SAR : There are no recognised (Q)SAR methods available for reliable prediction of developmental toxicity.
- In vitro methods : There are no in vitro methods currently accepted by Regulatory Authorities for the reliable prediction of developmental toxicity.
- Weight of evidence : Currently there are insufficient data available to develop a robust weight of evidence approach for developmental toxicity.
- Grouping and read-across : This test proposal maybe used to help develop a category approach for a wider range of hydrocarbons.
- Substance-tailored exposure driven testing [if applicable] : Insufficient data available
- Approaches in addition to above [if applicable]: None applicable
- Other reasons [if applicable] : None identified
CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- As the registration dossier is submitted above 1000 tonnes, studies in both species will be conducted.
FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Details on study design / methodology proposed [if relevant]: See 'Materials and Methods' Section for further information. - Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes (incl. QA statement)
- Species:
- rat
- Route of administration:
- oral: unspecified
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study planned
- Study period:
- Will be completed in the timescale as indicated in the ECHA decision letter.
- Justification for type of information:
- This testing proposal has been presented in the lead registrant dossier for this substance submitted to ECHA in 2019. This is a source dossier where the overall approach should be seen in the context of a category of 108 different substances, where the substances are hydrocarbon solvents covering a carbon number range of C5-C20, based on alkane constituents and a range from approximately C8-C18 for aromatic constituents. The basis for this test proposal is set out in detail in the document ‘Hydrocarbon Solvents Test Proposals, Test Plans and Read-Across Strategy for Human Health Endpoints’, which is attached to this endpoint study record and in Section 13.2 of the IUCLID dossier.
TESTING PROPOSAL ON VERTEBRATE ANIMALS
[Please provide information for all of the points below. The information should be specific to the endpoint for which testing is proposed. Note that for testing proposals addressing testing on vertebrate animals under the REACH Regulation this document will be published on the ECHA website along with the third party consultation on the testing proposal(s).]
NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out : Hydrocarbons, C16-C20, n-alkanes, isoalkanes, cyclics, aromatics (2-30%) (EC# 919-006-8)
- Name of the substance for which the testing proposal will be used [if different from tested substance] : Not different
CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION [please address all points below]:
- Available GLP studies : There are no OECD Guideline 414 studies available on this substance to evaluate the developmental toxicity endpoint in both rodents and non-rodents.
- Available non-GLP studies : There are no ‘non-GLP’ studies available for this substance to evaluate the developmental toxicity endpoint in both rodent and non-rodent species.
- Historical human data : - No human data exist for this substance to evaluate developmental toxicity hazard.
- (Q)SAR : There are no recognised (Q)SAR methods available for reliable prediction of developmental toxicity.
- In vitro methods : There are no in vitro methods currently accepted by Regulatory Authorities for the reliable prediction of developmental toxicity.
- Weight of evidence : Currently there are insufficient data available to develop a robust weight of evidence approach for developmental toxicity.
- Grouping and read-across : This test proposal maybe used to help develop a category approach for a wider range of hydrocarbons.
- Substance-tailored exposure driven testing [if applicable] : Insufficient data available
- Approaches in addition to above [if applicable]: None applicable
- Other reasons [if applicable] : None identified
CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- As the registration dossier is submitted above 1000 tonnes, studies in both species will be conducted.
FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Details on study design / methodology proposed [if relevant]: See ‘Materials and Methods’ Section for further information. - Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes (incl. QA statement)
- Species:
- rabbit
- Route of administration:
- oral: unspecified
Referenceopen allclose all
Results - Dams
Endpoint |
Negative Control |
400 mg/kg ASA |
100 ppm |
300 ppm |
Pregnancy Rate (%) |
100.0 |
95.0 |
100.0 |
90.0 |
Mortality Rate (%) |
0.0 |
10.0 |
0.0 |
0.0 |
Mean Body Weight Gain (g) Dams - Days 15-21 |
84 |
32 |
108 |
103 |
Mean Corpora Lutea |
15.2 |
14.5 |
15.5 |
13.8 |
Mean No. Implantations |
13.0 |
13.2 |
13.8 |
13.2 |
Implantation Efficiency (%) |
85.8 |
91.1 |
88.7 |
95.6 |
Mean No. Live Fetuses |
12.5 |
7.4 |
12.9 |
12.6 |
Mean No. Dead Fetuses |
0.0 |
0.0 |
0.0 |
0.0 |
Mean No. Resorptions |
0.6 |
5.8 |
0.9 |
0.7 |
Dams with more than one Resorption (%) |
10.0 |
58.8 |
25.0 |
11.1 |
Results – Fetuses
Endpoint |
Negative Control |
400 mg/kg ASA |
100 ppm |
300 ppm |
Male Mean Fetal Weight (g) |
5.57 |
3.88 |
5.82 |
5.62 |
Female Mean Fetal Weight (g) |
5.29 |
3.62 |
5.44 |
5.33 |
Male Mean Crown-Rump Distance (cm) |
4.3 |
3.7 |
4.4 |
4.2 |
Female Mean Crown-Rump Distance (cm) |
4.2 |
3.6 |
4.2 |
4.1 |
Sex Ratio (%) |
91.5 |
98.4 |
88.3 |
105.5 |
Ossification Variations (%) |
70.7 |
100.0 |
79.4 |
79.3 |
Litters with Ossification Variations (%) |
100.0 |
100.0 |
95.0 |
100.0 |
Soft Tissue Malformations (%) |
2.4 |
26.8 |
1.1 |
3.9 |
Litters with Soft Tissue Malformations (%) |
10.0 |
54.5 |
5.0 |
16.7 |
Gross Evisceration Malformations (%) |
5.4 |
3.6 |
1.8 |
4.0 |
Litters with Gross Evisceration Malformations |
25.0 |
8.3 |
10.0 |
16.7 |
Skeletal Malformations (%) |
0.0 |
21.4 |
2.9 |
1.3 |
Litters with Skeletal Malformations |
0.0 |
66.7 |
15.0 |
11.1 |
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 500 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 developmental toxicity: via inhalation route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEC
- 1 575 mg/m³
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- 1 key study from a structural analogues available for assessment
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
No developmental toxicity data is available for Hydrocarbons, C16-C20, n-alkanes, isoalkanes, cyclics, aromatics (2-30%). However, data is available for structural analogues, Hydrocarbons, C9-C12, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) and JP-8/Kerosene. Petroleum substances of similar carbon number and aromatic content, principally kerosene and jet fuel, are typically in the range of C9 -C16. These substances also contain similar types of molecules in similar proportions to those in C14-C20 aliphatic [2-30% Aromatics] Hydrocarbon solvents. In general, hydrocarbon solvents are more highly refined than petroleum substances. Accordingly, the petroleum substances typically represent a “worse case” with respect to hydrocarbon solvents and can be used for read across on that basis. 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 rodent and non-rodent species tests are proposed for Hydrocarbons, C16-C20, n-alkanes, isoalkanes, cyclics, aromatics (2-30%). This endpoint will be updated subsequent to ECHA's approval of the testing proposals and availability of data upon completion of the studies.
Hydrocarbons, C9-C12, n-alkanes, isoalkanes, cyclics, aromatics (2-25%)
A key study (ExxonMobil, 1979b) determined the developmental toxicity of the test material (Hydrocarbons, C9-C12, n-alkanes, isoalkanes, cyclics, aromatics (2-25%)) in rats exposed via inhalation. Groups of 20 pregnant female rats were exposed 6 hrs/day during days 6 -15 of gestation. Test concentrations of 100 or 300 ppm test substance. In addition to a negative control group, there was also a positive control group that was exposed to acetylsalicylic acid on days 6 -15 of gestation. Dams were observed for toxicological signs and pharmacological effects. On day 21 of gestation, the animals were sacrificed, and examined for corpora lutea and uterine implantation parameters. Fetuses were examined for fetal size, sex ratio, and external, soft-tissue, and skeletal malformations. No adverse effects due to exposure to the test substance were seen in either dams or fetuses. No treatment related malformation effects were noted in the fetuses. The developmental NOAEC for rats by inhalation was determined to be >=300 ppm. The test substance is also not teratogenic.
JP-8/Kerosene
In a study (Cooper and Mattie, 1996), time-mated Sprague-Dawley rats were dosed orally with JP-8 at 0, 500, 1000, 1500 and 2000 mg/Kg/day on days 6-15 of pregnancy. The maternal NOAEL was determined to be 500 mg/Kg/day based on reduced maternal body weight. The fetotoxicity NOAEL was determined to be 1000 mg/Kg/day based on reduced fetal weight. There were no developmental or teratogenic effects noted (aside from body weight reduction) in any dose tested.
Justification for classification or non-classification
Based on available read across data from structural analogues, Hydrocarbons, C16-C20, n-alkanes, isoalkanes, cyclics, aromatics (2-30%) does not warrant the 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, further tests (OECD 443 and OECD 414 (rodent and 2nd species)) are proposed on the substance 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
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
