Registration Dossier
Registration Dossier
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EC number: 947-394-9 | CAS number: -
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
No adverse effects were observed in two OECD 422 studies involving close analogues of the registered substance. The key study determined the NOAEL for reproduction/developmental toxicity to be 300 mg/kg bw/day for male and female rats (the highest dose tested). These data are supported by NOEL values of 740 mg/kg bw/day (male) and 1039 mg/kg bw/day (female) for a second analogue of the registered substance.
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2002
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Crj: CD(SD)IGS
- Sex:
- male/female
- Route of administration:
- oral: gavage
- Vehicle:
- olive oil
- Details on exposure:
- - Pre-mating exposure period: 14 days (males and females)
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- - Males: 47 days
- Females: 42-45 days (from 14 days before mating to Day 4 of lactation) - Frequency of treatment:
- Once daily
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 5 mg/kg bw/day (nominal)
- Dose / conc.:
- 20 mg/kg bw/day (nominal)
- Dose / conc.:
- 80 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 5 males and 5 females
- Control animals:
- yes, concurrent vehicle
- Parental animals: Observations and examinations:
- CLINICAL OBSERVATIONS
- General condition was observed once a day.
BODYWEIGHT
- Bodyweights of males were determined on Day 1 (before dosing) and on Days 8, 15, 22, 29, 36, 43 and 49 of treatment.
- Bodyweights of females were determined on Day 1 (before dosing), on Days 1, 8 and 15 of treatment, on Days 0, 7, 14 and 20 of gestation, on Days 0 and 4 of lactation, and on the day of autopsy.
FOOD CONSUMPTION
- Food consumption by males was determined on Days 1, 8, 15, 22, 29, 36, 43 and 48 of treatment.
- Food consumption by females was determined on Days 1, 8 and 15 of treatment, on Days 0, 7, 14 and 20 of gestation, and on Days 0 and 4 of lactation.
- Food consumption of males and females was not determined during the mating period.
URINALYSIS
- Urinalysis was performed for all males on Day 41 or Day 42 of the administration period.
HEAMATOLOGY AND BIOCHEMISTRY
- Investigations were performed at the time of necropsy (after 48 days for males and 5 days after delivery for females). - Oestrous cyclicity (parental animals):
- - Effects on estrous cyclicity were considered.
- Sperm parameters (parental animals):
- - Effects on sperm parameters were considered.
- Litter observations:
- - Number, sex ratio, body weight and viability of pups were considered.
- Postmortem examinations (parental animals):
- ORGAN WEIGHTS
- Organ weights from male animals measured at the time of necropsy were brain; heart; liver; kidney; spleen; adrenal; thymus; testis and epididymis.
- Organ weights from female animals measured at the time of necropsy were brain; heart; liver; kidney;spleen; adrenal; thymus.
- Organ weight was determined for 10 males from the control group; 10 males from the 5 mg/kg bw/daygroup; 9 males from the 20 mg/kg bw/day group; 10 males from the 80 mg/kg bw/day group; 10 malesfrom the 300 mg/kg bw/day group.
- Organ weight was determined for 7 females from the control group; 8 females from the 5 mg/kg bw/day group; 9 females from the 20 mg/kg bw/day group; 10 females from the 80 mg/kg bw/day group; 9 females from the 300 mg/kg bw/day group.
MICROSCOPIC EXAMINATION
- Organs examined in all animals were brain; spinal cord; intestine; liver; kidney; adrenal; spleen; heart; thymus; thyroid; parathyroid; trachea; lung; uterus; ovary; urinary bladder; ischiadic nerve; bone marrow; mesentery lymph node; mandibular lymph node; submandibular gland.
- The sublingual gland from 5 males and 5 females in the 0 and 300 mg/kg bw/day groups was examined.
- The stomach from 5 males and 5 females in the 5, 20 and 80 mg/kg bw/day groups was examined. - Postmortem examinations (offspring):
- - Pups were examined for external and internal malformations.
- Statistics:
- STATISTICAL METHODS
- Dunnett's or Scheffe's test for continuous data.
- Chi square test for quantal data. - Reproductive indices:
- - Number of pairs with successful copulation.
- Number of pregnant females.
- Copulation index (number of pairs with successful copulation / number of pairs mated * 100).
- Fertility index (number of pregnant animals / number of animals with successful copulation * 100).
- Estrous cycle.
- Number of pregnant females with live pups.
- Gestation length.
- Number of corpora lutea.
- Number of implantation sites.
- Sex ratio.
- Gestation index (number of females with live pups / number of pregnant females * 100).
- Implantation index (number of implants / number of corpora lutea * 100). - Offspring viability indices:
- - Number of pups born.
- Number of pups alive on Day 0 of lactation.
- Number of dead pups.
- Live birth index (number of live pups born / number of pups born * 100)
- Viability index on Day 4 (number of live pups on Day 4 after birth / number of live pups born * 100). - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- - Transitional softening stools were observed in a few males and females in the 80 and 300 mg/kg bw/day groups.
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- - No animal deaths related to treatment with test material took place.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - There were no statistically significant changes for males or females.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- - No statistically significant changes for males or females.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - No statistically significant changes for males or females.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- - An increase in GPT levels and a decrease in triglyceride levels was observed in males from the 300 mg/kg bw/day group.
- No statistically significant differences were observed in females.
- Mean GPT was reported as 41 i.u./L (10 animals; 0 mg/kg bw/day; SD 4 i.u./L); 40 i.u./L (10 animals; 5mg/kg bw/day; SD 6 i.u./L); 38 i.u./L (9 animals; 20 mg/kg bw/day; SD 3 i.u./L); 44 i.u./L (10 animals; 80 mg/kg bw/day; SD 6 i.u./L); 53 i.u./L (10 animals; 300 mg/kg bw/day; SD 7 i.u./L; statistically significant p < 0.01).
- Mean triglyceride was reported as 63 mg/dL (10 animals; 0 mg/kg bw/day; SD 28 mg/dL); 43 mg/dL (10 animals; 5 mg/kg bw/day; SD 18 mg/dL); 50 mg/dL (9 animals; 20 mg/kg bw/day; SD 22 mg/dL); 49 mg/dL (10 animals; 80 mg/kg bw/day; SD 18 mg/dL); 29 mg/dL (10 animals; 300 mg/kg bw/day; SD 13 mg/dL; statistically significant p < 0.05). - Urinalysis findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - No statistically significant changes.
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Description (incidence and severity)
- Squamous hyperplasia, erosion and lamina propria and/or submucosa edema and inflammatory infiltration were observed in the forestomach of males and females in the 80 and 300 mg/kg bw/day groups (see table, below). - Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Reproductive function: oestrous cycle:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - No test item-related effect on estrous cyclicity was observed.
- Reproductive function: sperm measures:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - Three females in the control group did not become pregnant due to abnormality of spermatogenesis in paired males.
- Reproductive performance:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - Three females in the control group did not become pregnant due to abnormality of spermatogenesis in paired males.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reproductive performance
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Critical effects observed:
- no
- Clinical signs:
- no effects observed
- Mortality / viability:
- mortality observed, non-treatment-related
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
- Other effects:
- not examined
- Behaviour (functional findings):
- not examined
- Developmental immunotoxicity:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Critical effects observed:
- no
- Key result
- Reproductive effects observed:
- no
- Conclusions:
- The NOAEL for reproduction/developmental toxicity was determined to be 300 mg/kg bw/day in rats.
- Executive summary:
In a study involving an analogue substance, a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test [OECD 422] was used to assess the effect of test material administered to Crj:CD (SD) IGS rats (10 animals/sex/dose) by gavage at 0, 5, 20, 80, or 300 mg/kg bw/day. Males were dosed for 47 days from day 14 before mating and females were dosed for 42-45 days from day 14 before mating to day 4 of lactation throughout the mating and pregnancy period.Three females in the control group did not become pregnant due to abnormality of spermatogenesis in paired males. No decrease in fertility index was observed in the groups given this compound. There was no compound-related effect on the estrous cyclicity, copulation index, gestation length, numbers of corpora lutea, or number of implantation sites found in dams. No compound-related effects on the number, sex ratio, body weight, or viability were detected in pups on days 0 and 4 of lactation. No abnormal findings considered to be attributable to administration of the test material were observed in dead pups during lactation and pups at scheduled sacrifice. No external or internal malformations were also noted in pups of any groups. Based on these findings, the NOAEL for reproductive/developmental toxicity was considered to be 300 mg/kg bw/day in rats.Reproduction/developmental parameters, i.e. mating, pregnancy, delivery, lactation, and viability and body weight of pups, were not affected by the test material up to 300 mg/kg bw/day. The NOAEL for reproduction/developmental toxicity was considered to be 300 mg/kg bw/day in rats.
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Justification for type of information:
- A screening study for reproductive/developmental toxicity does not need to be conducted because available data indicate that variation in alkyl chain length does not influence test results or the adverse effect profile of structurally similar substances when relevant endpoints are investigated (see attached justification).
- Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- read-across: supporting information
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reproductive performance
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Critical effects observed:
- no
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Critical effects observed:
- no
- Key result
- Reproductive effects observed:
- no
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 2005
- Reliability:
- 4 (not assignable)
- Rationale for reliability incl. deficiencies:
- secondary literature
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Crj: CD(SD)IGS
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Source: Charles River Japan, Inc (Atsugi, Japan).
- Age: Eight weeks (males and females)
- Acclimatisation period: 14 days prior to treatment.
- Environmental conditions: Animal rooms were maintained at 20 to 26 °C with relative humidity of 41 to 68 % and a 12 hour light/dark cycle. - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- - Groups of 12 rats were fed test material in an NMF powder diet (Oriental Yeast Co Ltd, Japan).
- Details on mating procedure:
- - Each male was placed in the cage of his paired female overnight until pregnancy occurred.
- Female rats were examined each morning for the presence of sperm and the day sperm was seen was defined as Day 0.
- Pregnant females were caged individually in plastic cages (340 mm width x 400 mm depth x 185 mm height) from Day 17 of pregnancy until Day 4 post-partum. - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- - Males were dosed for 56 days including prior to mating, and during the mating and post-mating periods.
- Females were dosed for 41-51 days from 14 days prior to mating until postpartum Day 4. - Frequency of treatment:
- - test material provided to animals in feed.
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- equivalent to 0 % in feed
- Dose / conc.:
- 175 mg/kg bw/day (nominal)
- Remarks:
- equivalent to 0.3 % in feed
- Dose / conc.:
- 360 mg/kg bw/day (nominal)
- Remarks:
- equivalent to 0.6 % in feed
- Dose / conc.:
- 740 mg/kg bw/day (nominal)
- Remarks:
- equivalent to 1.2 % in feed
- No. of animals per sex per dose:
- Six males and six females
- Control animals:
- yes, plain diet
- Parental animals: Observations and examinations:
- - Rats were observed daily for clinical signs and mortality throughout the study.
- With the exception of males during the mating period, animal bodyweights and food consumption were measured at least once per week.
- Blood samples were collected under light ether anaesthesia from the abdominal aorta after 16 hours starvation (anticoagulant used was EDTA-2K for haematological examination or sodium citrate for measuring clotting time and fibrinogen level).
- Instruments used were Coulter T890 analyser (Beckman Coulter Inc) for haematological analysis; light microscope for differential leucocyte counts; automated coagulation analyser (ACL 100, Instrumentation Laboratory, Barcelona, Spain) for prothrombin time (PT) and activated partial prothrombin time (APTT).
- Blood chemistry was investigated using a Clinical Laboratory System TBA-120FR (Toshiba Medical Systems, Tochigi, Japan).
- Albumin/globulin (A/G) ratio was calculated from total protein and albumin concentrations.
- Organs were excised at necropsy, weighed and processed routinely for histological examination. - Postmortem examinations (parental animals):
- - Animals were necropsied at the end of the experiment.
- Statistics:
- - Bartlett's test for homogeneity of variance between groups.
- Dunnet multiple comparison if Bartlett's test found no significant heterogeneity.
- Dunnet type mean rank test if significant heterogeneity of varience was detected.
- Lesion incidence was analysed using the chi square test with Yates' continuity correction or Fisher's exact test. - Reproductive indices:
- - Reproductive and developmental parameters recorded were duration of mating, mating rate, pregnancies, deliveries, corpus luteum counts, implantations, lactation, maternal nursing behaviour.
- Offspring viability indices:
- - Pup viability and pup body weight.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - No significant differences between groups (see Table 1 and Figure 2, attached).
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- - No significant differences between groups (see Figure 3, attached).
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- - Decreased fibrinogen levels and increased prothrombin times were observed in females at the 740 mg/kg bw/day (1.2 %) dose level (see Table 2, attached).
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- - Triglyceride levels were observed to decrease in both sexes at the 360 mg/kg bw/day (0.6 %) and 740 mg/kg bw/day (1.2 %) dose levels (see Table 3, attached).
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- - Hepatocyte enlargement was observed in the centrolobular area of the liver in five treated females with slight anisonucleosis in one animal, slight focal necrosis in one animal and slight atrophy of the thymus cortex in two animals (data not reported).
- No liver or thymus abnormalities were observed in the five corresponding males. - Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- - The reproduction and developmental parameters were essentially the same in all treatment groups and the control.
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 740 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Remarks on result:
- other: reproductive/developmental toxicity
- Remarks:
- feed concentration1.2 %
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 1 039 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Remarks on result:
- other: reproductive/developmental toxicity
- Remarks:
- feed concentration 1.2 %
- Dose descriptor:
- NOEL
- Effect level:
- 175 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Remarks on result:
- other: repeated dose oral toxicity
- Remarks:
- feed concentration 0.3 %
- Dose descriptor:
- NOEL
- Effect level:
- 249 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Remarks on result:
- other: repeated dose oral toxicity
- Remarks:
- feed concentration 0.3 %
- Conclusions:
- In an OECD combined repeated dose toxicity study with the reproduction/developmental toxicity screening test, the NOEL for reproductive/developmental toxicity was determined to be 740 mg/kg bw/day (feed concentration 1.2 %) in males and 1039 mg/kg bw/day (feed concentration 1.2 %) in females. The NOEL for repeated dose oral toxicity was reported as 175 mg/kg bw/day (feed concentration 0.3 %) in males and 249 mg/kg bw/day (feed concentration 0.3 %) in females.
- Executive summary:
In a study involving an analogue substance, a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test [OECD 422] was used to assess the effect of test material administered to Crj:CD (SD) IGS rats (12 animals/sex/dose) in the diet at 0, 175, 300 and 740 mg/kg bw/day. Males were dosed for 56 days including prior to mating, and during the mating and post-mating periods. Females were dosed for 41-51 days from 14 days prior to mating until postpartum Day 4. The reproduction and developmental parameters were considered to be essentially the same in all treatment groups and the control. Based on these findings, the NOEL for reproductive/developmental toxicity was determined to be 740 mg/kg bw/day (feed concentration 1.2 %) in males and 1039 mg/kg bw/day (feed concentration 1.2 %) in females. The NOEL for repeated dose oral toxicity was reported as 175 mg/kg bw/day (feed concentration 0.3 %) in males and 249 mg/kg bw/day (feed concentration 0.3 %) in females.
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- supporting study
- Reliability:
- 4 (not assignable)
- Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- read-across: supporting information
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 740 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Remarks on result:
- other: reproductive/developmental toxicity
- Remarks:
- feed concentration1.2 %
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 1 039 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Remarks on result:
- other: reproductive/developmental toxicity
- Remarks:
- feed concentration 1.2 %
- Dose descriptor:
- NOEL
- Effect level:
- 175 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Remarks on result:
- other: repeated dose oral toxicity
- Remarks:
- feed concentration 0.3 %
- Dose descriptor:
- NOEL
- Effect level:
- 249 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Remarks on result:
- other: repeated dose oral toxicity
- Remarks:
- feed concentration 0.3 %
- Conclusions:
- In an OECD combined repeated dose toxicity study with the reproduction/developmental toxicity screening test, the NOEL for reproductive/developmental toxicity was determined to be 740 mg/kg bw/day (feed concentration 1.2 %) in males and 1039 mg/kg bw/day (feed concentration 1.2 %) in females. The NOEL for repeated dose oral toxicity was reported as 175 mg/kg bw/day (feed concentration 0.3 %) in males and 249 mg/kg bw/day (feed concentration 0.3 %) in females).
- Executive summary:
In a study involving an analogue substance, a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test [OECD 422] was used to assess the effect of test material administered to Crj:CD (SD) IGS rats (12 animals/sex/dose) in the diet at 0, 175, 300 and 740 mg/kg bw/day. Males were dosed for 56 days including prior to mating, and during the mating and post-mating periods. Females were dosed for 41-51 days from 14 days prior to mating until postpartum Day 4. The reproduction and developmental parameters were considered to be essentially the same in all treatment groups and the control. Based on these findings, the NOEL for reproductive/developmental toxicity was determined to be 740 mg/kg bw/day (feed concentration 1.2 %) in males and 1039 mg/kg bw/day (feed concentration 1.2 %) in females. The NOEL for repeated dose oral toxicity was reported as 175 mg/kg bw/day (feed concentration 0.3 %) in males and 249 mg/kg bw/day (feed concentration 0.3 %) in females).
Referenceopen allclose all
- No decrease in fertility index was observed in the groups receiving test material.
- No test item-related effect was observed with respect to estrous cyclicity, copulation index, gestation length, numbers of corpora lutea or number of implantation sites in dams.
- There were no test material-related effects on the number, sex ratio, body weight or viability of pups on Day 0 and Day 4 of lactation.
- No abnormal findings considered to be attributable to administration of test item were observed in dead pups during lactation or at scheduled sacrifice.
- No external or internal malformation were noted in pups from any group.
Histopathology results |
|||||
Males |
|
|
|
|
|
Dose (mg/kg bw/day) |
0 |
5 |
20 |
80 |
300 |
Number of animals examined |
5 |
5 |
5 |
5 |
5 |
Forestomach |
|
|
|
|
|
Hyperplasia, squamous (slight to severe) |
0/5 |
0/5 |
0/5 |
4/5 |
5/5 (p < 0.01) |
Erosion (slight to moderate) |
0/5 |
0/5 |
0/5 |
0/5 |
3/5 |
Edema, lamina propria/ submucosa (slight to moderate) |
0/5 |
0/5 |
0/5 |
0/5 |
4/5 (p < 0.05) |
Cellular infiltration, inflammatory cell, lamina propria/ submucosa (slight to moderate) |
0/5 |
0/5 |
0/5 |
0/5 |
4/5 (p < 0.05) |
Females |
|
|
|
|
|
Dose (mg/kg bw/day) |
0 |
5 |
20 |
80 |
300 |
Number of animals examined |
5 |
5 |
5 |
5 |
5 |
Forestomach |
|
|
|
|
|
Hyperplasia, squamous (slight to moderate) |
0/5 |
0/5 |
0/5 |
4/5 (p < 0.05) |
5/5 (p < 0.01) |
Erosion (moderate) |
0/5 |
0/5 |
0/5 |
0/5 |
1/5 |
Edema, lamina propria/ submucosa (slight to moderate) |
0/5 |
0/5 |
0/5 |
2/5 |
5/5 (p < 0.01) |
Cellular infiltration, inflammatory cell, lamina propria/ submucosa (slight) |
0/5 |
0/5 |
0/5 |
1/5 |
2/5 |
Reproductive and developmental parameters |
|||||
Dose (mg/kg bw/day) |
0 |
5 |
20 |
80 |
300 |
Estrous cycle (days) |
Mean 4.2 |
Mean 4.0 |
Mean 4.0 |
Mean 4.0 |
Mean 4.0 |
SD 0.6 |
SD 0.00 |
SD 0.0 |
SD 0.1 |
SD 0.1 |
|
Number of pairs mated |
10 |
10 |
10 |
10 |
10 |
Number of pairs copulated |
10 |
10 |
9 |
10 |
10 |
Copulation index (%) |
100 |
100 |
90 |
100 |
100 |
Number of pregnant females |
7 |
10 |
9 |
10 |
10 |
Fertility index (%) |
70 |
100 |
100 |
100 |
100 |
Number of pregnant females with parturition |
7 |
8 |
9 |
10 |
10 |
Number of pregnant females with live pups |
7 |
8 |
9 |
10 |
10 |
Gestation length (days) |
Mean 22.4 |
Mean 22.5 |
Mean 22.4 |
Mean 22.6 |
Mean 22.5 |
SD 0.5 |
SD 0.5 |
SD 0.5 |
SD 0.5 |
SD 0.5 |
|
Number of corpora lutea |
Mean 19.7 |
Mean 18.4 |
Mean 19.3 |
Mean 17.5 |
Mean 18.2 |
SD 2.8 |
SD 4.1 |
SD 3.3 |
SD 1.9 |
SD 2.6 |
|
Number of implantation sites |
Mean 15.6 |
Mean 13.2 |
Mean 14.9 |
Mean 15.9 |
Mean 15.3 |
SD 1.6 |
SD 6.3 |
SD 2.4 |
SD 1.5 |
SD 2.4 |
|
Number of pups born |
Mean 15.0 |
Mean 11.9 |
Mean 13.1 |
Mean 14.8 |
Mean 13.9 |
SD 1.7 |
SD 6.4 |
SD 4.0 |
SD 2.0 |
SD 1.7 |
|
Delivery index (%) |
Mean 96.3 |
Mean 73.8 |
Mean 85.4 |
Mean 93.3 |
Mean 91.4 |
SD 4.8 |
SD 39.4 |
SD 20.0 |
SD 10.1 |
SD 6.1 |
|
Sex ratio (male/female) |
0.78 |
0.98 |
0.97 |
0.85 |
0.88 |
Number of pups alive on Day 0 of lactation |
Mean 15.0 |
Mean 14.9 |
Mean 13.0 |
Mean 14.4 |
Mean 12.3 |
SD 1.7 |
SD 1.6 |
SD 3.9 |
SD 2.0 |
SD 4.2 |
|
Live birth index (%) |
Mean 100 |
Mean 100 |
Mean 99.3 |
Mean 97.4 |
Mean 88.3 |
SD 0 |
SD 0 |
SD 2.1 |
SD 4.6 |
SD 27.2 |
|
Number of pups alive on Day 4 of lactation |
Mean 14.7 |
Mean 14.9 |
Mean 12.9 |
Mean 14.2 |
Mean 12.0 |
SD 1.4 |
SD 1.6 |
SD 3.8 |
SD 1.8 |
SD 4.7 |
|
Viability index (%) |
Mean 98.3 |
Mean 100 |
Mean 99.3 |
Mean 98.7 |
Mean 89.3 |
SD 2.9 |
SD 0 |
SD 2.2 |
SD 2.7 |
SD 31.5 |
|
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 300 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
In a key study involving an analogue substance, hexadecanoic acid, 2-sulfo-, 1-methylester, sodium salt,a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test [OECD 422] was used to assess the effect of test material administered to Crj:CD (SD) IGS rats (10 animals/sex/dose) by gavage at 0, 5, 20, 80, or 300 mg/kg bw/day. Males were dosed for 47 days from day 14 before mating and females were dosed for 42-45 days from day 14 before mating to day 4 of lactation throughout the mating and pregnancy period. Three females in the control group did not become pregnant due to abnormality of spermatogenesis in paired males. No decrease in fertility index was observed in the groups given this compound. There was no compound-related effect on the estrous cyclicity, copulation index, gestation length, numbers of corpora lutea, or number of implantation sites found in dams. No compound-related effects on the number, sex ratio, body weight, or viability were detected in pups on days 0 and 4 of lactation. No abnormal findings considered to be attributable to administration of the test material were observed in dead pups during lactation and pups at scheduled sacrifice. No external or internal malformations were also noted in pups of any groups. Based on these findings, the NOAEL for reproductive/developmental toxicity was considered to be 300 mg/kg bw/day in rats. Reproduction/developmental parameters, i.e. mating, pregnancy, delivery, lactation, and viability and body weight of pups, were not affected by the test material up to 300 mg/kg bw/day. The NOAEL for reproduction/developmental toxicity was considered to be 300 mg/kg bw/day in rats.
In a supporting study involving an analogue substance,tetradecanoic acid, 2-sulfo-, 1-methyl ester, sodium salt,a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test [OECD 422] was used to assess the effect of test material administered to Crj:CD (SD) IGS rats (12 animals/sex/dose) in the diet at 0, 175, 300 and 740 mg/kg bw/day. Males were dosed for 56 days including prior to mating, and during the mating and post-mating periods. Females were dosed for 41-51 days from 14 days prior to mating until postpartum Day 4. The reproduction and developmental parameters were considered to be essentially the same in all treatment groups and the control. Based on these findings, the NOEL for reproductive/developmental toxicity was determined to be 740 mg/kg bw/day (feed concentration 1.2 %) in males and 1039 mg/kg bw/day (feed concentration 1.2 %) in females. The NOEL for repeated dose oral toxicity was reported as 175 mg/kg bw/day (feed concentration 0.3 %) in males and 249 mg/kg bw/day (feed concentration 0.3 %) in females.
Effects on developmental toxicity
Description of key information
No adverse effects were observed in two OECD 422 studies involving close analogues of the registered substance. The key study determined the NOAEL for reproduction/developmental toxicity to be 300 mg/kg bw/day for male and female rats (highest dose tested). These data are supported by NOEL values of 740 mg/kg bw/day (male) and 1039 mg/kg bw/day (female) for a second analogue of the registered substance.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2002
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Crj: CD(SD)IGS
- Route of administration:
- oral: gavage
- Vehicle:
- olive oil
- Details on exposure:
- - Pre-mating exposure period: 14 days (males and females)
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- - Males: 47 days
- Females: 42-45 days (from 14 days before mating to Day 4 of lactation) - Frequency of treatment:
- Once daily
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 5 mg/kg bw/day (nominal)
- Dose / conc.:
- 20 mg/kg bw/day (nominal)
- Dose / conc.:
- 80 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 5 males and 5 females
- Control animals:
- yes, concurrent vehicle
- Maternal examinations:
- CLINICAL OBSERVATIONS
- General condition was observed once a day.
BODYWEIGHT
- Bodyweights of males were determined on Day 1 (before dosing) and on Days 8, 15, 22, 29, 36, 43 and 49 of treatment.
- Bodyweights of females were determined on Day 1 (before dosing), on Days 1, 8 and 15 of treatment, on Days 0, 7, 14 and 20 of gestation, on Days 0 and 4 of lactation, and on the day of autopsy.
FOOD CONSUMPTION
- Food consumption by males was determined on Days 1, 8, 15, 22, 29, 36, 43 and 48 of treatment.
- Food consumption by females was determined on Days 1, 8 and 15 of treatment, on Days 0, 7, 14 and 20 of gestation, and on Days 0 and 4 of lactation.
- Food consumption of males and females was not determined during the mating period.
URINALYSIS
- Urinalysis was performed for all males on Day 41 or Day 42 of the administration period.
HEAMATOLOGY AND BIOCHEMISTRY
- Investigations were performed at the time of necropsy (after 48 days for males and 5 days after delivery for females).
ORGAN WEIGHTS
- Organ weights from male animals measured at the time of necropsy were brain; heart; liver; kidney; spleen; adrenal; thymus; testis and epididymis.
- Organ weights from female animals measured at the time of necropsy were brain; heart; liver; kidney;spleen; adrenal; thymus.
- Organ weight was determined for 10 males from the control group; 10 males from the 5 mg/kg bw/day group; 9 males from the 20 mg/kg bw/day group; 10 males from the 80 mg/kg bw/day group; 10 males from the 300 mg/kg bw/day group.
- Organ weight was determined for 7 females from the control group; 8 females from the 5 mg/kg bw/day group; 9 females from the 20 mg/kg bw/day group; 10 females from the 80 mg/kg bw/day group; 9 females from the 300 mg/kg bw/day group.
MICROSCOPIC EXAMINATION
- Organs examined in all animals were brain; spinal cord; intestine; liver; kidney; adrenal; spleen; heart; thymus; thyroid; parathyroid; trachea; lung; uterus; ovary; urinary bladder; ischiadic nerve; bone marrow; mesentery lymph node; mandibular lymph node; submandibular gland.
- The sublingual gland from 5 males and 5 females in the 0 and 300 mg/kg bw/day groups was examined.
- The stomach from 5 males and 5 females in the 5, 20 and 80 mg/kg bw/day groups was examined. - Ovaries and uterine content:
- - Numbers of corpora lutea and number of implantation sites were considered.
- Fetal examinations:
- - Pups were examined for external and internal malformations.
- Statistics:
- STATISTICAL METHODS
- Dunnett's or Scheffe's test for continuous data.
- Chi square test for quantal data. - Indices:
- - Number of pairs with successful copulation.
- Number of pregnant females.
- Copulation index (number of pairs with successful copulation / number of pairs mated * 100).
- Fertility index (number of pregnant animals / number of animals with successful copulation * 100).
- Estrous cycle.
- Number of pregnant females with live pups.
- Gestation length.
- Number of corpora lutea.
- Number of implantation sites.
- Number of pups born.
- Number of pups alive on Day 0 of lactation.
- Sex ratio.
- Number of dead pups.
- Gestation index (number of females with live pups / number of pregnant females * 100).
- Implantation index (number of implants / number of corpora lutea * 100).
- Live birth index (number of live pups born / number of pups born * 100)
- Viability index on Day 4 (number of live pups on Day 4 after birth / number of live pups born * 100). - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- - Transitional softening stools were observed in a few males and females in the 80 and 300 mg/kg bw/day groups.
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- - No animal deaths related to treatment with test material took place.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - There were no statistically significant changes for males or females.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- - No statistically significant changes for males or females.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - No statistically significant changes for males or females.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- - An increase in GPT levels and a decrease in triglyceride levels was observed in males from the 300 mg/kg bw/day group.
- No statistically significant differences were observed in females.
- Mean GPT was reported as 41 i.u./L (10 animals; 0 mg/kg bw/day; SD 4 i.u./L); 40 i.u./L (10 animals; 5mg/kg bw/day; SD 6 i.u./L); 38 i.u./L (9 animals; 20 mg/kg bw/day; SD 3 i.u./L); 44 i.u./L (10 animals; 80 mg/kg bw/day; SD 6 i.u./L); 53 i.u./L (10 animals; 300 mg/kg bw/day; SD 7 i.u./L; statistically significant p < 0.01).
- Mean triglyceride was reported as 63 mg/dL (10 animals; 0 mg/kg bw/day; SD 28 mg/dL); 43 mg/dL (10 animals; 5 mg/kg bw/day; SD 18 mg/dL); 50 mg/dL (9 animals; 20 mg/kg bw/day; SD 22 mg/dL); 49 mg/dL (10 animals; 80 mg/kg bw/day; SD 18 mg/dL); 29 mg/dL (10 animals; 300 mg/kg bw/day; SD 13 mg/dL; statistically significant p < 0.05). - Urinalysis findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - No statistically significant changes.
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - No statistically significant changes were observed for males or females.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- - Thickening of the forestomach mucosa was observed in the 80 mg/kg bw/day group (effect seen in 6 out of 10 males and 10 out of 10 females).
- Thickening of the forestomach mucosa was observed in the 300 mg/kg bw/day group (effect seen in 10 out of 10 males and 9 out of 9 females). - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- - Squamous hyperplasia, erosion and lamina propria and/or submucosa edema and inflammatory infiltration were observed in the forestomach of males and females in the 80 and 300 mg/kg bw/day groups (see table, below).
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Details on results:
- - Reproductive and developmental parameters are shown in the table below.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other:
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Abnormalities:
- no effects observed
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other:
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Abnormalities:
- no effects observed
- Key result
- Developmental effects observed:
- no
- Treatment related:
- no
- Conclusions:
- The NOAEL for reproduction/developmental toxicity was determined to be 300 mg/kg bw/day in rats.
- Executive summary:
In a study involving an analogue substance, a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test [OECD 422] was used to assess the effect of test material administered to Crj:CD (SD) IGS rats (10 animals/sex/dose) by gavage at 0, 5, 20, 80, or 300 mg/kg bw/day. Males were dosed for 47 days from day 14 before mating and females were dosed for 42-45 days from day 14 before mating to day 4 of lactation throughout the mating and pregnancy period.Three females in the control group did not become pregnant due to abnormality of spermatogenesis in paired males. No decrease in fertility index was observed in the groups given this compound. There was no compound-related effect on the estrous cyclicity, copulation index, gestation length, numbers of corpora lutea, or number of implantation sites found in dams. No compound-related effects on the number, sex ratio, body weight, or viability were detected in pups on days 0 and 4 of lactation. No abnormal findings considered to be attributable to administration of the test material were observed in dead pups during lactation and pups at scheduled sacrifice. No external or internal malformations were also noted in pups of any groups. Based on these findings, the NOAEL for reproductive/developmental toxicity was considered to be 300 mg/kg bw/day in rats. Reproduction/developmental parameters, i.e. mating, pregnancy, delivery, lactation, and viability and body weight of pups, were not affected by the test material up to 300 mg/kg bw/day. The NOAEL for reproduction/developmental toxicity was considered to be 300 mg/kg bw/day in rats.
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Justification for type of information:
- A screening study for reproductive/developmental toxicity does not need to be conducted because available data indicate that variation in alkyl chain length does not influence test results or the adverse effect profile of structurally similar substances when relevant endpoints are investigated (see justifcation attached in Section 13).
- Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- read-across: supporting information
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: no test-tem related effect reported with respect to fertility or reproductive performance
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Abnormalities:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no abnormal findings noted in pups following administration of test item to parent animals i
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Developmental effects observed:
- no
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- supporting study
- Justification for type of information:
- A screening study for reproductive/developmental toxicity does not need to be conducted because available data indicate that variation in alkyl chain length does not influence test results or the adverse effect profile of structurally similar substances when relevant endpoints are investigated (see attached justification).
- Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- read-across: supporting information
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 1 039 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Remarks on result:
- other: reproductive/developmental toxicity feed concentration 1.2 %
- Key result
- Abnormalities:
- no effects observed
- Dose descriptor:
- NOEL
- Effect level:
- 1 039 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no developmental effects reported
- Key result
- Developmental effects observed:
- no
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 2005
- Reliability:
- 4 (not assignable)
- Rationale for reliability incl. deficiencies:
- secondary literature
- Qualifier:
- according to guideline
- Guideline:
- other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Crj: CD(SD)IGS
- Details on test animals or test system and environmental conditions:
- - Source: Charles River Japan, Inc (Atsugi, Japan).
- Age: Eight weeks (males and females)
- Acclimatisation period: 14 days prior to treatment.
- Environmental conditions: Animal rooms were maintained at 20 to 26 °C with relative humidity of 41 to 68 % and a 12 hour light/dark cycle. - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- - Groups of 12 rats were fed test material in an NMF powder diet (Oriental Yeast Co Ltd, Japan).
- Analytical verification of doses or concentrations:
- no
- Details on mating procedure:
- - Each male was placed in the cage of his paired female overnight until pregnancy occurred.
- Female rats were examined each morning for the presence of sperm and the day sperm was seen was defined as Day 0.
- Pregnant females were caged individually in plastic cages (340 mm width x 400 mm depth x 185 mm height) from Day 17 of pregnancy until Day 4 post-partum. - Duration of treatment / exposure:
- - Males were dosed for 56 days including prior to mating, and during the mating and post-mating periods.
- Females were dosed for 41-51 days from 14 days prior to mating until postpartum Day 4. - Frequency of treatment:
- - test material provided to animals in feed.
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- equivalent to 0 % in feed
- Dose / conc.:
- 175 mg/kg bw/day (nominal)
- Remarks:
- equivalent to 0.3 % in feed
- Dose / conc.:
- 360 mg/kg bw/day (nominal)
- Remarks:
- equivalent to 0.6 % in feed
- Dose / conc.:
- 740 mg/kg bw/day (nominal)
- Remarks:
- equivalent to 1.2 % in feed
- No. of animals per sex per dose:
- Six males and six females
- Control animals:
- yes, plain diet
- Maternal examinations:
- - Rats were observed daily for clinical signs and mortality throughout the study.
- With the exception of males during the mating period, animal bodyweights and food consumption were measured at least once per week.
- Blood samples were collected under light ether anaesthesia from the abdominal aorta after 16 hours starvation (anticoagulant used was EDTA-2K for haematological examination or sodium citrate for me
asuring clotting time and fibrinogen level).
- Instruments used were Coulter T890 analyser (Beckman Coulter Inc) for haematological analysis; light microscope for differential leucocyte counts; automated coagulation analyser (ACL 100, Instrumentation Laboratory, Barcelona, Spain) for prothrombin time (PT) and activated partial prothrombin time (APTT).
- Blood chemistry was investigated using a Clinical Laboratory System TBA-120FR (Toshiba Medical Systems, Tochigi, Japan).
- Albumin/globulin (A/G) ratio was calculated from total protein and albumin concentrations.
- Animals were necropsied at the end of the experiment.
- Organs were excised at necropsy, weighed and processed routinely for histological examination. - Statistics:
- - Bartlett's test for homogeneity of variance between groups.
- Dunnet multiple comparison if Bartlett's test found no significant heterogeneity.
- Dunnet type mean rank test if significant heterogeneity of varience was detected.
- Lesion incidence was analysed using the chi square test with Yates' continuity correction or Fisher's exact test. - Indices:
- - Reproductive and developmental parameters recorded were duration of mating, mating rate, pregnancies, deliveries, corpus luteum counts, implantations, lactation, maternal nursing behaviour, pup viability and pup body weight.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - No significant differences between groups (see Table 1 and Figure 2, attached).
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- - No significant differences between groups (see Figure 3, attached).
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- - Decreased fibrinogen levels and increased prothrombin times were observed in females at the 740 mg/kg bw/day (1.2 %) dose level (see Table 2, attached).
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- - Triglyceride levels were observed to decrease in both sexes at the 360 mg/kg bw/day (0.6 %) and 740 mg/kg bw/day (1.2 %) dose levels (see Table 3, attached).
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- - A slight increase in absolute and relative weight of testes was observed in males at the 740 mg/kg bw/day (1.2 %) dose level (see Table 4, attached).
- Females receiving a dose of 740 mg/kg bw/day (1.2 %) showed an increased liver weight (absolute and relative) and kidneys (relative). The weight of adrenals (absolute and relative) and thymus (absolute), heart (absolute) and spleen (absolute) were decreased in females from this group (see Table 5, attached). - Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - No treatment-related changes were observed at necropsy in any treatment group.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- - Hepatocyte enlargement was observed in the centrolobular area of the liver in five treated females with slight anisonucleosis in one animal, slight focal necrosis in one animal and slight atrophy of the thymus cortex in two animals (data not reported).
- No liver or thymus abnormalities were observed in the five corresponding males. - Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Details on results:
- - The reproduction and developmental parameters were essentially the same in all treatment groups and the control.
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 1 039 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Remarks on result:
- other: reproductive/developmental toxicity
- Remarks:
- feed concentration 1.2 %
- Dose descriptor:
- NOEL
- Effect level:
- 1 039 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no developmental effects reported
- Key result
- Developmental effects observed:
- no
- Conclusions:
- In an OECD combined repeated dose toxicity study with the reproduction/developmental toxicity screening test, the NOEL for reproductive/developmental toxicity was determined to be 740 mg/kg bw/day (feed concentration 1.2 %) in males and 1039 mg/kg bw/day (feed concentration 1.2 %) in females. The NOEL for repeated dose oral toxicity was reported as 175 mg/kg bw/day (feed concentration 0.3 %) in males and 249 mg/kg bw/day (feed concentration 0.3 %) in females).
- Executive summary:
In a study involving an analogue substance, a combined repeated dose toxicity study with the reproduction/ developmental toxicity screening test [OECD 422] was used to assess the effect of test material administered to Crj:CD (SD) IGS rats (12 animals/sex/dose) in the diet at 0, 175, 300 and 740 mg/kg bw/ day. Males were dosed for 56 days including prior to mating, and during the mating and post-mating periods. Females were dosed for 41-51 days from 14 days prior to mating until postpartum Day 4. The reproduction and developmental parameters were considered to be essentially the same in all treatment groups and the control. Based on these findings, the NOEL for reproductive/developmental toxicity was determined to be 740 mg/kg bw/day (feed concentration 1.2 %) in males and 1039 mg/kg bw/day (feed concentration 1.2 %) in females. The NOEL for repeated dose oral toxicity was reported as 175 mg/kg bw/day (feed concentration 0.3 %) in males and 249 mg/kg bw/day (feed concentration 0.3 %) in females.
Referenceopen allclose all
Histopathology results |
|||||
Males |
|
|
|
|
|
Dose (mg/kg bw/day) |
0 |
5 |
20 |
80 |
300 |
Number of animals examined |
5 |
5 |
5 |
5 |
5 |
Forestomach |
|
|
|
|
|
Hyperplasia, squamous (slight to severe) |
0/5 |
0/5 |
0/5 |
4/5 |
5/5 (p < 0.01) |
Erosion (slight to moderate) |
0/5 |
0/5 |
0/5 |
0/5 |
3/5 |
Edema, lamina propria/ submucosa (slight to moderate) |
0/5 |
0/5 |
0/5 |
0/5 |
4/5 (p < 0.05) |
Cellular infiltration, inflammatory cell, lamina propria/ submucosa (slight to moderate) |
0/5 |
0/5 |
0/5 |
0/5 |
4/5 (p < 0.05) |
Females |
|
|
|
|
|
Dose (mg/kg bw/day) |
0 |
5 |
20 |
80 |
300 |
Number of animals examined |
5 |
5 |
5 |
5 |
5 |
Forestomach |
|
|
|
|
|
Hyperplasia, squamous (slight to moderate) |
0/5 |
0/5 |
0/5 |
4/5 (p < 0.05) |
5/5 (p < 0.01) |
Erosion (moderate) |
0/5 |
0/5 |
0/5 |
0/5 |
1/5 |
Edema, lamina propria/ submucosa (slight to moderate) |
0/5 |
0/5 |
0/5 |
2/5 |
5/5 (p < 0.01) |
Cellular infiltration, inflammatory cell, lamina propria/ submucosa (slight) |
0/5 |
0/5 |
0/5 |
1/5 |
2/5 |
Reproductive and developmental parameters |
|||||
Dose (mg/kg bw/day) |
0 |
5 |
20 |
80 |
300 |
Estrous cycle (days) |
Mean 4.2 |
Mean 4.0 |
Mean 4.0 |
Mean 4.0 |
Mean 4.0 |
SD 0.6 |
SD 0.00 |
SD 0.0 |
SD 0.1 |
SD 0.1 |
|
Number of pairs mated |
10 |
10 |
10 |
10 |
10 |
Number of pairs copulated |
10 |
10 |
9 |
10 |
10 |
Copulation index (%) |
100 |
100 |
90 |
100 |
100 |
Number of pregnant females |
7 |
10 |
9 |
10 |
10 |
Fertility index (%) |
70 |
100 |
100 |
100 |
100 |
Number of pregnant females with parturition |
7 |
8 |
9 |
10 |
10 |
Number of pregnant females with live pups |
7 |
8 |
9 |
10 |
10 |
Gestation length (days) |
Mean 22.4 |
Mean 22.5 |
Mean 22.4 |
Mean 22.6 |
Mean 22.5 |
SD 0.5 |
SD 0.5 |
SD 0.5 |
SD 0.5 |
SD 0.5 |
|
Number of corpora lutea |
Mean 19.7 |
Mean 18.4 |
Mean 19.3 |
Mean 17.5 |
Mean 18.2 |
SD 2.8 |
SD 4.1 |
SD 3.3 |
SD 1.9 |
SD 2.6 |
|
Number of implantation sites |
Mean 15.6 |
Mean 13.2 |
Mean 14.9 |
Mean 15.9 |
Mean 15.3 |
SD 1.6 |
SD 6.3 |
SD 2.4 |
SD 1.5 |
SD 2.4 |
|
Number of pups born |
Mean 15.0 |
Mean 11.9 |
Mean 13.1 |
Mean 14.8 |
Mean 13.9 |
SD 1.7 |
SD 6.4 |
SD 4.0 |
SD 2.0 |
SD 1.7 |
|
Delivery index (%) |
Mean 96.3 |
Mean 73.8 |
Mean 85.4 |
Mean 93.3 |
Mean 91.4 |
SD 4.8 |
SD 39.4 |
SD 20.0 |
SD 10.1 |
SD 6.1 |
|
Sex ratio (male/female) |
0.78 |
0.98 |
0.97 |
0.85 |
0.88 |
Number of pups alive on Day 0 of lactation |
Mean 15.0 |
Mean 14.9 |
Mean 13.0 |
Mean 14.4 |
Mean 12.3 |
SD 1.7 |
SD 1.6 |
SD 3.9 |
SD 2.0 |
SD 4.2 |
|
Live birth index (%) |
Mean 100 |
Mean 100 |
Mean 99.3 |
Mean 97.4 |
Mean 88.3 |
SD 0 |
SD 0 |
SD 2.1 |
SD 4.6 |
SD 27.2 |
|
Number of pups alive on Day 4 of lactation |
Mean 14.7 |
Mean 14.9 |
Mean 12.9 |
Mean 14.2 |
Mean 12.0 |
SD 1.4 |
SD 1.6 |
SD 3.8 |
SD 1.8 |
SD 4.7 |
|
Viability index (%) |
Mean 98.3 |
Mean 100 |
Mean 99.3 |
Mean 98.7 |
Mean 89.3 |
SD 2.9 |
SD 0 |
SD 2.2 |
SD 2.7 |
SD 31.5 |
|
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 300 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
In a key study involving an analogue substance, hexadecanoic acid, 2-sulfo-, 1-methylester, sodium salt, a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test [OECD 422] was used to assess the effect of test material administered to Crj:CD (SD) IGS rats (10 animals/sex/dose) by gavage at 0, 5, 20, 80, or 300 mg/kg bw/day. Males were dosed for 47 days from day 14 before mating and females were dosed for 42-45 days from day 14 before mating to day 4 of lactation throughout the mating and pregnancy period.Three females in the control group did not become pregnant due to abnormality of spermatogenesis in paired males. No decrease in fertility index was observed in the groups given this compound. There was no compound-related effect on the estrous cyclicity, copulation index, gestation length, numbers of corpora lutea, or number of implantation sites found in dams. No compound-related effects on the number, sex ratio, body weight, or viability were detected in pups on days 0 and 4 of lactation. No abnormal findings considered to be attributable to administration of the test material were observed in dead pups during lactation and pups at scheduled sacrifice. No external or internal malformations were also noted in pups of any groups. Based on these findings, the NOAEL for reproductive/developmental toxicity was considered to be 300 mg/kg bw/day in rats. Reproduction/developmental parameters, i.e. mating, pregnancy, delivery, lactation, and viability and body weight of pups, were not affected by the test material up to 300 mg/kg bw/day. The NOAEL for reproduction/developmental toxicity was considered to be 300 mg/kg bw/day in rats.
In a supporting study involving an analogue substance, tetradecanoic acid, 2-sulfo-, 1-methyl ester, sodium salt,a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test [OECD 422] was used to assess the effect of test material administered to Crj:CD (SD) IGS rats (12 animals/sex/dose) in the diet at 0, 175, 300 and 740 mg/kg bw/day. Males were dosed for 56 days including prior to mating, and during the mating and post-mating periods. Females were dosed for 41-51 days from 14 days prior to mating until postpartum Day 4. The reproduction and developmental parameters were considered to be essentially the same in all treatment groups and the control. Based on these findings, the NOEL for reproductive/developmental toxicity was determined to be 740 mg/kg bw/day (feed concentration 1.2 %) in males and 1039 mg/kg bw/day (feed concentration 1.2 %) in females. The NOEL for repeated dose oral toxicity was reported as 175 mg/kg bw/day (feed concentration 0.3 %) in males and 249 mg/kg bw/day (feed concentration 0.3 %) in females.
Justification for classification or non-classification
No adverse effect was reported at the highest dose level when two close analogues of the test item were assessed via the combined repeated dose with reproductive/developmental toxicity screening test. Classification of the test material under the terms of Regulation (EC) No 1272/2008 (CLP) is therefore not required.
Additional information
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