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Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
26 Mar 2013 - 21 May 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to the appropriate OECD test guideline and in compliance with GLP.
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
(1995)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
The Department of Health of the Government of the United Kingdom
Limit test:
no
Species:
rat
Strain:
other: Wistar Han(TM):RccHan(TM):WIST
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK, Ltd., Oxon, UK
- Age at study initiation: 12 weeks
- Weight at study initiation: 300 - 344 g (males), 192 – 223 g (females)
- Housing: Initially, all animals were housed in groups of four in solid floor polypropylene cages with stainless steel mesh lids and softwood flake bedding (Datesand Ltd., Cheshire, UK). During the pairing phase, the animals were transferred to polypropylene grid floor cages suspended over trays lined with absorbent paper on a one male/one female basis. Following evidence of successful mating, the males were returned to their original cages. Mated females were housed individually during gestation and lactation in solid floor polypropylene cages with stainless steel mesh lids and softwood flakes.
- Diet: Rodent 2018C Teklad Global Certified Diet (Harlan Laboratories UK, Oxon, UK), ad libitum
- Water: (tap/filtered) water, ad libitum
- Acclimation period: five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Test item formulations were prepared daily during the study period due to the chemical characteristics of the test item and its limited solubility in organic and aqueous media.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Due to the chemical characteristics of the test item and its limited solubility in organic and aqueous media, arachis oil was chosen as the vehicle.
- Concentration in vehicle: 7.5, 75 and 250 mg/mL
- Amount of vehicle (if gavage): 4 mL/kg
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: Animals were paired on a 1 male/1 female basis within each dose group, for a period of up to fourteen days.
- Proof of pregnancy: vaginal plug/sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): Mated females were housed individually during gestation and lactation in solid floor polypropylene cages with stainless steel mesh lids and softwood flakes.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analytical validation of the test item was previously determined using an earlier batch of ST1797KS in Harlan Study No. 41203177. In this earlier study, verification work carried out by Harlan Laboratories Ltd., Shardlow, UK Analytical Services established that due to the chemical characteristics of the test item a chromatographic method of analysis could not be developed due to the test items limited solubility in typical HPLC/GC solvents (for this reason there was no alternative but to use the gravimetric approach which involves weighing a set amount of test item into arachis oil (vehicle) to make the required formulation concentration and then analyzing by taking an aliquot onto a glass sintered crucible and then rinsing with a solvent i.e. acetone to remove the oil. The insoluble test item is then retained on the crucible and weighed to confirm the concentration present. The homogeneity determinations were performed using an earlier batch of ST1797KS under Harlan Laboratories Ltd. Study number 41203177. The test item formulations were sampled and analyzed within two days of preparation. The accuracy determinations were performed under Harlan Laboratories Ltd. Study number 41203177. The analytical method has been considered to be sufficiently accurate for the purpose of this study. The test sample results have not been corrected for recovery. The analytical method has been satisfactorily validated in terms of accuracy for the purposes of the study. The results indicate that the prepared formulations were within ± 9 % of the nominal concentration.
Duration of treatment / exposure:
(P) Males: for up to 43 days (beginning during 14 days of pre-mating period)
(P) Females: maximum period of 8 weeks (14 days pre-mating until post-natal day 5)
Frequency of treatment:
daily, 7 days/week
Remarks:
Doses / Concentrations:
30, 300, 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
12 P males, 12 P females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels were chosen based on the results of previous work (Harlan Laboratories Ltd., Project No: 41203177). The oral route was selected as the most appropriate route of exposure, based on the physical properties of the test item, and the results of the study are believed to be of value in predicting the likely toxicity of the test item to men.
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were examined for overt signs of toxicity, ill-health and behavioural change immediately before dosing, soon after dosing, and one hour and five hours after dosing during the working week. Animals were observed immediately before dosing, soon after dosing and one hour after dosing at weekends and public holidays (except for females during parturition where applicable).

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded on Day 1 (prior to dosing) and then weekly for males until termination and weekly for females until mating was evident. Body weights were then recorded for females on Days 0, 7, 14 and 20 post coitum, and on Days 1 and 4 post partum.
Oestrous cyclicity (parental animals):
No data
Sperm parameters (parental animals):
Parameters examined in P male parental generations:
- testis weight, epididymis weight, sperm morphology, spermatogenesis
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, live births, stillbirths, postnatal mortality, surface righting, weight gain, clinical signs, presence of gross anomalies
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals were killed on Day 43.
- Maternal animals: All surviving animals were killed on Day 5 post partum.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations.

HISTOPATHOLOGY / ORGAN WEIGHTS
- The tissues of coagulating gland, epididymides, ovaries, mammary gland, pituitary, prostate, seminal vesicles, testes (including spermatogenesis), uterus cervix, vagina were prepared for microscopic examination.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring was sacrificed at 5 days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination).

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations.
Statistics:
The homogeneity of variance from mean values was analyzed using Bartlett’s test. Intergroup variance were assessed using suitable ANOVA, or if required, ANCOVA with appropriate covarities. Any transformed data were analyzed to find the lowest treatment level that showed a significant effect using the Williams Test for parametric data or the Shirley Test for nonparametric data. If no dose response was found but the data shows non-homogeneity of means, the data were analyzed by a stepwise Dunnett’s (parametric) or Steel (non-parametric) test to determine significant difference from the control group. Where the data were unsuitable for these analyses, pair-wise tests was performed using the Student t-test (parametric) or the Mann-Whitney U test (non-parametric). Data not analyzed by the Provantis data capture system were assessed separately using the SPSS statistical package. Initially, the homogeneity of the data was assessed using Levene’s test. Where Levene’s test was shown to be non-significant (p=0.05), parametric analysis of the data was applied, incorporating analysis of variance (ANOVA). If this data was shown to be significant, this analysis was followed by pair-wise comparisons using Dunnett’s test. Where Levene’s test was significant, non-parametric analysis of the data was analyzed incorporating the Kruskal-Wallis test which if significant, was followed by the Mann-Whitney U test. Dose response relationship was also be investigated by linear regression. Where the data was unsuitable for these analyses, then pair-wise tests were performed using the Student t-test (parametric) or the Mann-Whitney U test (non-parametric). Due to the preponderance of non-normally distributed data, reproductive parameters (implantation losses, offspring sex ratio and offspring surface righting) were analyzed using nonparametric analyses. Probability values (p) are presented as follows: p<0.001 ***, p<0.01 **, p<0.05 *, p>0.05 (not significant).
Reproductive indices:
- Pre-coital interval = Calculated as the time elapsing between initial pairing and the observation of positive evidence of mating
- Mating index [%] = Number of animals mated/Number of animals paired x 100
- Pregnancy index [%] = Number of pregnant females/Number of animals mated x 100
- Gestation length = Calculated as the number of days of gestation including the day for observation of mating and the start of parturition
- Parturition index [%] = Number of females delivering live offspring/Number of pregnant females x 100
Offspring viability indices:
- Live Birth Index [%] = Number of pups born alive on day 1/Total number born (live + dead) x 100
- Viability Index [%] = Number of pups alive on day 4/Number of pups live on day 1 x 100
- Pre-implantation loss [%] = Corpora lutea - implantations/Corpora lutea x 100
- Post-implantation loss [%] = Implantations - number of pups born alive/Implantations x 100
- Sex ratio: [% males] = Number of male offspring/Total number of offspring x 100
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:
no effects observed
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No treatment-related clinical findings were observed throughout the study. Incidental findings were characterized by sporadic episodes of pilo-erection observed in two 30 mg/kg bw/day males and in a similar number of males treated at 1000 mg/kg bw/day between Weeks 4 and 5. In addition, noisy respiration was observed in one control female (Day 9) and in one female at 30 mg/kg bw/day (Day 42). It is reasonable given the isolated nature and absence of a dose related trend that both findings be considered a result of biological variability and not to be a result of treatment. One 300 mg/kg bw/day female developed a small swelling on the left side of the thorax from Day 19 persisting through to termination. This may have resulted from a mal-dose although there was no evidence of the lesion at necropsy. One 1000 mg/kg bw/day male was observed between Days 28 and 34 to have developed a small scab in otherwise unaffected skin, this minor lesion had regressed by the start of the fifth week of treatment. Given the transient and isolated nature of this finding it was considered to be incidental and not related to treatment. No unscheduled mortality occurred during the study period.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
There was no convincing evidence or dose dependent trend to indicate an adverse body weight response to treatment in any of the male test animals when compared to controls. No adverse effects on body weight change were detected for female test animals during the pre-mating, gestation or lactation phases of the study when compared to controls.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
No treatment-related adverse effect on dietary intake or for food efficiency (the ratio of body weight gain to dietary intake) was identified for either sex of test animals in comparison with controls throughout the treatment-period. The sporadic instances of variances that did occur were considered attributable to biological variability. Daily visual inspection of water bottles did not reveal any significant intergroup differences between control and treated animals.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No treatment-related effects were detected in mating performance. The majority of paired animals mated within the first four days of pairing. Statistical analysis of the pre-coital interval data did not reveal any significant intergroup differences. No treatment-related effects on fertility were detected for treated animals when compared to controls. Three control females, one female at 30 and one female at 300 mg/kg bw/day did not achieve pregnancy following evidence of mating. In the absence of any histopathological correlates in the reproductive organs to elucidate the cause of the non-pregnancy in either the paired female or male partner which did not produce a pregnancy, these intergroup differences were considered to be incidental and of no toxicological importance. No treatment-related effects were detected in the length of gestation for treated females when compared to controls. All animals showed gestation lengths between 22 to 23½ days. Statistical analysis of the data did not reveal any significant intergroup differences.

ORGAN WEIGHTS (PARENTAL ANIMALS)
No treatment related effects were detected in the reproductive organs weighed in males from any treatment group.

GROSS PATHOLOGY (PARENTAL ANIMALS)
There were no treatment-related macroscopic abnormalities detected in animals killed at study termination. Incidental findings were confined to one control male observed to have small and flaccid testes and small epididymides. Such observations represent common sporadic findings amongst rats of the strain and age used in the study and as such was considered to have arisen fortuitously.

HISTOPATHOLOGY (PARENTAL ANIMALS)
Under the conditions of this study, the test item ST1797KS produced no histological evidence of toxicological properties in the organs and tissues examined in this study. No treatment-related effects on the testicular histomorphology were identified including spermatogenesis and interstitial cell structure.
Dose descriptor:
NOEL
Remarks:
systemic
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No mortality and no clinical signs of toxicity occurred during the study period
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
VIABILITY (OFFSPRING)
In total nine females from control, eleven females from 30 and 300 mg/kg bw/day dose groups and twelve females from 1000 mg/kg bw/day dose group gave birth to a live litter and successfully reared young to Day 5 of age. No significant differences were detected for corpora lutea counts for treated animals when compared to controls. Litter sizes and viability for treated groups were also comparable to controls. There were no convincing treatment-related intergroup differences in sex ratio (percentage male offspring) for litters from treated groups compared to controls.

CLINICAL SIGNS (OFFSPRING)
No clinical observable signs of toxicity were detected for offspring from all treatment groups.

BODY WEIGHT (OFFSPRING)
Offspring body weight gain and litter weights at birth and subsequently on Day 1 and Day 4 post partum were comparable to controls. There were no significant differences in litter weights or mean offspring body weights between control and treated animals. Statistical analysis of the data did not reveal any significant intergroup differences.

GROSS PATHOLOGY (OFFSPRING)
No treatment-related macroscopic abnormalities were detected for interim death or terminal kill offspring. The incidental findings observed were those occasionally observed in reproductive studies of this type and were considered to be unrelated to toxicity of the test item.
Dose descriptor:
NOAEL
Remarks:
reproduction
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects observed
Reproductive effects observed:
not specified
Conclusions:
The oral administration of ST1797KS to rats for a period of up to eight weeks (including two weeks pre-mating, gestation and early lactation period for females) at dose levels of up to 1000 mg/kg bw/day resulted in no treatment related effects. There were no convincing treatment-related responses observed throughout the study nor treatment-related effects detected in the reproductive parameters observed namely for mating performance or fertility. Furthermore, there was no evidence of any developmental effects observed in offspring from treated litters and no effect on the reproductive organs was evident following post mortem assessments or during histopathological assessments. On this basis, the ‘No Observed Effect Level’ (NOEL) for systemic toxicity and reproduction for either sex was considered to be greater than 1000 mg/kg bw/day.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Study duration:
subacute
Species:
rat
Quality of whole database:
The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.7, of Regulation (EC) No 1907/2006.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Effect on reproduction/developmental toxicity screening test: via oral route

A key reproduction/developmental toxicity screening test performed according to OECD TG 421 and in compliance with GLP with Didocosyl sebacate (CAS 42233-75-0) is available (McRae, L.A., 2013c).Groups of 12 Wistar rats of each sex per dose were administered doses of 30, 300 and 1000 mg/kg bw/day of the test substance or vehicle (arachis oil) via oral gavage. Treatment was carried out once daily starting with a 14 days pre-mating period for both sexes up to 43 days (males) and a maximum period of 8 weeks until post-natal day 5 (females). Animals were observed for mortalities andovert signs of toxicity, ill-health and behavioural changeat least twice a day. Individual body weights were recorded on Day 1 (prior to dosing) and then weekly for males until termination and weekly for females until mating was evident. Body weights were then recorded for females on Days 0, 7, 14 and 20 of gestation, and on Days 1 and 4 of lactation. Upon sacrifice on Day 43 (males) and Day 5 post-partum (females, offspring) macroscopic examination for structural abnormalities or pathological changes were performed includingtissues of coagulating gland, epididymides, ovaries, mammary gland, pituitary, prostate, seminal vesicles, testes, uterus cervix and vagina. Reproductive indices including pre-coital interval, mating index, pregnancy index, gestation length and parturition index were calculated as well as offspring viability indices such as livebirth index, viability index, pre/post-implantation loss and sex ratio. No treatment-related clinical findings and no unscheduled mortality occurred during the study period. There was no convincing evidence or dose dependent trend to indicate an adverse body weight response to treatment in male and female test animals during the pre-mating, gestation or lactation phases of the study when compared to controls. No treatment-related adverse effect on dietary intake or for food efficiency was identified for either sex of test animals in comparison with controls throughout the treatment-period. No treatment-related effects were detected in mating performance, fertility and in reproductive organs for treated animals when compared to controls. Gross pathology and histological investigation revealed no treatment-related macroscopic abnormalities in the organs and tissues examined in animals killed at study termination. No treatment-related effects on the testicular histomorphology including spermatogenesis, interstitial cell structure and corpora lutea counts for treated animals were recorded when compared to controls. Litter sizes and viability for treated groups were also comparable to controls. There were no convincing treatment-related intergroup differences in sex ratio for litters from treated groups compared to controls. No clinical observable signs of toxicity were detected for offspring from all treatment groups. Offspring body weight gain and litter weights at birth and subsequently on Day 1 and Day 5 post-partum were comparable to controls. There were no significant differences in litter weights or mean offspring body weights between control and treated animals. Gross pathology revealed no treatment-related macroscopic abnormalities for interim death or terminal kill offspring.In summary, oral administration of Didocosyl sebacate (CAS 42233-75-0) at doses of 30, 300 or 1000 mg/kg bw/day to Wistar rats for a period up to 8 weeks via oral gavage resulted in no treatment-related effects.No convincing treatment-related responses were observed for reproductive parameters throughout the study period. Furthermore, there was no evidence of any developmental effects observed in offspring from treated dams and no effect on the reproductive organs was evident following post mortem assessments or during histopathological assessments. Therefore, the ‘No Observed Effect Level’ (NOEL) for systemic toxicity and reproduction for either sex was considered to be greater than 1000 mg/kg bw/day.

 

According to Regulation (EC) No 1907/2006, Annex IX, 8.7.3, column 1, an extended one-generation reproductive toxicity study is not indicated unless repeated dose toxicity studies demonstrate adverse effects on reproductive organs or tissues. Two repeated dose toxicity studies (28 and 90 days) are available forDidocosyl sebacate (CAS 42233-75-0).No test item related effects on reproductive organs and tissue were noted at the end of the treatment of this study. In addition, a reproduction/developmental toxicity screening test for a period of up to eight weeks is available forDidocosyl sebacate andresulted in no treatment related effects detected in the reproductive parameters such as mating performance or fertility. No evidence of any developmental effects was observed in offspring from treated litters and no effect on the reproductive organs was evident following post mortem assessments or during histopathological assessments. Thus, an extended one-generation reproductive toxicity study does not need to be conducted based on no observed adverse effects with the test substance.


Short description of key information:
Reproduction/Developmental Toxicity Screening Test (OECD guideline 421), rat NOEL > 1000 mg/kg bw/day
Waiving – Extended one-generation reproductive toxicity study

Justification for selection of Effect on fertility via oral route:
The reliable GLP compliant OECD Guideline study was choosen.

Effects on developmental toxicity

Description of key information
Developmental Toxicity / teratogenicity (OECD guideline 414), rat NOAEL ≥ 1080 mg/kg bw/day
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
15 Sep - 16 Oct 1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP - Guideline study. According to the ECHA guidance document "Practical guide 6: How to report read-across and categories (March 2010)", the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Alpk:APfSD (Wistar derived)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: SPF colony maintained at the Animal Breeding Unit, ICI Pharmaceuticals, Alderley Park, Cheshire, UK.
- Age at study initiation: 12 weeks
- Weight at study initiation: 218-278 g
- Housing: individually in stainless steel cages with absorbent paper over collecting trays.
- Diet (e.g. ad libitum): CTI diet, Special Diets Services Ltd., Essex, UK.
- Water (e.g. ad libitum): yes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-24
- Humidity (%): 44-70
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light):12/12

IN-LIFE DATES: From: 15 Sept - 16 Oct 1987.
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The experimental diets were prepared in 30 kg batches from premixes.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chemical stability was observed at 300 ppm up to at least 32 days. This interval was in excess of the maximum period of use of the first batch of diet (21 days from preparation). The achieved concentration was within 8% of target and the doses received by the test groups were approximately 28, 170 and 1080 mg/kg bw/day.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: not reported
- Length of cohabitation: overnight
- Proof of pregnancy: sperm in vaginal smear referred to as day 1 of pregnancy

Successfully mated females were delivered to the experimental unit.
A total of 96 mated females was supplied over a two week period.
Duration of treatment / exposure:
days 1-22 of gestation.
Frequency of treatment:
Continuous feeding
Duration of test:
22 days
No. of animals per sex per dose:
24
Control animals:
yes, plain diet
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: on arrival and daily

BODY WEIGHT: Yes
- Time schedule for examinations: daily during days 1-22 of gestation

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 22
- Organs examined: uterus, ovaries, liver, spleen, kidney, stomach, rectum, abdominal cavity, pelvic cavity,
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes, in each ovary.
- Number of implantations: Yes
- Number of early resorptions: Yes (early intra-uterine deaths)
- Number of late resorptions: Yes (late intra-uterine deaths)
- Other: Each foetus was weighed and individually identified within the litter by means of a cardboard tag. After weighing the foetuses were killed with an intra-cardiac injection of pentobarbitone.
Fetal examinations:
- External examinations and cleft palate: Yes, each foetus
- Soft tissue examinations: Yes, all
- Skeletal examinations: Yes, all
- Head examinations: Yes, the head of each foetus was cut along the fronto-parietal suture line and the brain was examined for macroscopic abnormalities.
Statistics:
Analysis of variance, Student's t-test, Fisher's Exact Test
Indices:
- Pre-implantation loss (No. of corpora lutea / No. of implantations)
- Post implantation loss (No. of implantations / No. of live foetuses)
Historical control data:
Yes, data on variants and frequency of occurence in rats of this strain were given.
Defects like bipartite 5th sternebrae, slightly dilated ureters and kinked ureters were seen in historical controls of this strain.
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
At 12000 ppm a small but statistically significant reduction in maternal bodyweight gain was observed.
There was also a small but statistically significant reduction in food consumption at this dose level from days 2-18 inclusive of gestation.
There was no evidence of maternal toxicity at 300 or 1800 ppm.
Dose descriptor:
NOAEL
Remarks:
maternal
Effect level:
ca. 170 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: Equivalent to 1800 ppm in diet.
Dose descriptor:
LOAEL
Remarks:
maternal
Effect level:
ca. 1 080 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: Equivalent to 12000 ppm in diet. Reduced bodyweight gain and food consumption.
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes. Remark: (non-adverse)

Details on embryotoxic / teratogenic effects:
There was no effect at any dose on foetal weight, litter weight, gravid uterus weight, numbers of intra-uterine deaths or numbers of external abnormalities. At 12000 ppm there was a minimal increase of pre-implantation loss with an associated decrease in litter size.
Six major abnormalities (in five foetuses) were seen in the treated groups and eight in the control group (of which seven consisted of multiple minor skull defects in one litter). There was no evidence that the type or distribution of these abnormalities was related to treatment with the test substance.
Overall, minor skeletal defects were increased in a dose-related manner at 1800 and 12000 ppm of the test substance, while skeletal variants (as a percentage of foetuses affected) were increased at the top dose only. These findings indicated slightly poorer ossification at dose levels of 1800 and 12000 ppm, which were considered to be the result of slight fetotoxicity. However, the slightly poorer ossification is not considered as adverse effect.
Dose descriptor:
NOAEL
Remarks:
developmental
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Equivalent to 12000 ppm in diet. No relevant developmental effects.
Dose descriptor:
LOEL
Remarks:
developmental
Effect level:
170 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Equivalent to 1800 ppm in diet. Reduced ossification, non-adverse effect, typically reversible.
Dose descriptor:
NOEL
Remarks:
developmental
Effect level:
28 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Equivalent to 300 ppm in diet. Reduced ossification, non-adverse effect, typically reversible.
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1: Foetal defects and variants - Intergroup comparison of foetal defects and variants

 

Dietary conc. of DEHA (ppm)

0

300

1800

12000

No. of litters examined

24

23

24

23

External and visceral defects

No. of foetuses examined

282

263

278

243

No. of foetuses showing major defects

1

2

0

2

No. of foetuses showing minor defects only

7

8

9

3

Variants

No. of foetuses showing variants

69

69

81

78*

Skeletal defects

No. of foetuses examined

282

263

278

243

No. of foetuses showing major defects

7

0

1

1

No. of foetuses showing minor defects only

70

78

97**

120**

Variants

No. of foetuses showing variants

270

257

268

243**

 

Table 2: Summary of the type and incidence of major defects

 

Dietary conc. of DEHA (ppm)

0

300

1800

12000

External/Visceral

Situs inversus totalis

0

0

0

1

Left adrenal, kidney and ureter absent

1

0

0

0

Cysts attached to liver

0

1

0

0

Small right kidney

0

1

0

0

Umbilical hernia

0

0

0

1

Skeletal

Skull: Multiple minor defects

7

0

0

0

3rdand 7thribs (left) not ossified0

0

0

0

1

1strib (right) partially ossified

0

0

1

0

 There was no evidence that the test substance is teratogenic to the rat at any of the dose levels tested (up to 12000 ppm -approximately 1000 mg/kg/day). Administration of 12000 ppm DEHA resulted in slight maternal toxicity and slight foetotoxicity.

At 1800 ppm, there was no evidence of maternal toxicity although minimal foetotoxicity was observed. A dietary level of 300 ppm DEHA was a clear no-effect level for embryonic development. 

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 080 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) and consistent studies from a reference substance with similar structure and intrinsic properties. Read-across is justified based on structural similarity between the source and target substance.
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

Justification for grouping of substances and read-across

There are only limited data available on developmental toxicity of Didocosyl sebacate (CAS 42233-75-0). In order to fulfil the standard information requirements set out in Annex VII and VIII, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was conducted. In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across). Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

Overview of developmental toxicity

CAS

Developmental toxicity

42233-75-0 (a)

RA: CAS 103-23-1

103-23-1 (b)

OECD 414: NOAEL≥ 1080 mg/kg bw/day

(a) The substance subject to registration is indicated in bold font. (b) Reference (read-across) substances are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

The above mentioned substances are considered to be similar on the basis of the structural similar properties and/or activities. The available endpoint information is used to predict the same endpoints for Didocosyl sebacate (CAS 42233-75-0). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

CAS 103-23-1

In a prenatal developmental toxicity study according to OECD guideline 414, the effects of bis(2-ethylhexyl) adipate (CAS 103-23-1) on mated female Alpk:APfSD (Wistar derived) rats were investigated during Days 1 to 22 of gestation (Hodge, 1988). Groups of 24 females received the test substance at dietary concentrations of 300, 1800 and 12000 ppm, which approximately corresponded to dose levels of 28, 170 and 1080 mg/kg bw/day. A further group of 24 mated females received the plain diet and served as controls. On Day 22 of gestation, dams were sacrificed and maternal as well as fetal examinations were performed. Maternal toxicity occurred at 12000 ppm and involved a small, but statistically significant decrease in body weight gain compared to controls. This effect was accompanied by slight, statistically significant reduction in food consumption between Days 2 to 18 of gestation. No treatment-related clinical signs were observed during the study and no adverse findings were noted at macroscopic examination of dams. There was no effect at any dose level on fetal weight, litter weight, gravid uterus weight, numbers of intra-uterine deaths or numbers of external abnormalities. At 12000 ppm, a minimal increase of pre-implantation loss associated with a decrease in litter size was observed. Six major abnormalities (in five fetuses) were seen in the treated groups and eight in the control group (of which seven consisted of multiple minor skull defects in one litter). There was no evidence that the type or distribution of these abnormalities was related to test substance treatment. Overall, minor skeletal defects were increased in a dose-related manner at 1800 and 12000 ppm, while skeletal variants (as a percentage of fetuses affected) were increased at the 12000 ppm only. These findings indicated slightly poorer ossification at dose levels of 1800 and 12000 ppm, which were considered to be the result of slight fetotoxicity. However, the slightly poorer ossification is not considered as adverse effect. There was no evidence at any dose level, that the test substance was teratogenic in rats. 

Based on the results of the study, the NOEL for developmental toxicity in male and female Alpk:APfSD (Wistar derived) rats was established at 300 ppm, which approximately corresponded to 28 mg/kg bw/day. The NOAEL for developmental toxicity in Alpk:APfSD (Wistar derived) rats was ≥ 12000 ppm, which is equivalent to ca. ≥ 1080 mg/kg bw/day. The NOAEL for maternal toxicity in Alpk:APfSD (Wistar derived) rats was 1800 ppm, which is equivalent to ca. 170 mg/kg bw/day.

 

Conclusion for developmental toxicity/teratogenicity

Overall, no adverse effects indicating developmental toxicity/teratogenicity toxicity have been observed with the structural analogue substance CAS 103-23-1 resulting in a NOAEL≥ 1080 mg/kg bw/day. Due to the trend in toxicokinetic behavior and comparable metabolism of the hydrolysis products ofdidocosyl sebacate (CAS 42233-75-0) and bis(2-ethylhexyl) adipate (CAS 103-23-1) (for further information refer toIUCLID Section 13) the provided study is regarded as suitable worst case approach for the assessment of developmental toxicity of the target substance. Based on the available data no developmental toxicity is expected for didocosyl sebacate (CAS 42233-75-0).


Justification for selection of Effect on developmental toxicity: via oral route:
Hazard assessment is conducted by means of read-across from structural analogues. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substances and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Justification for classification or non-classification

The available data on reproductive/developmental toxicity of the registered substance do not meet the criteria for classification according to Regulation 1272/2008, and are therefore conclusive but not sufficient for classification.

Additional information