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Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Remarks:
based on test guideline (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant, near guideline study.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: specific pathogen free (SPF) colony at the Alderley Park Breeding Unit, ICI
- Age at study initiation: 28 days
- Weight at study initiation: (P) Males: 72.5 g; Females: 71.1 g
- Housing: 2 females or 1 male per cage
- Diet (ad libitum): CTI diet supplied by Special Diets Servies Limited
- Water (ad libitum): filtered tap water
- Acclimatisation period: 6-7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 21
- Humidity (%): 45-60
- Air changes (per hr): 15 - 25
- Photoperiod (hrs dark / hrs light): 12 /12

IN-LIFE DATES: From: 3-4 August 1987 To: 12 January 1988
Route of administration:
oral: feed
Vehicle:
other: hexane
Details on exposure:
DIET PREPARATION
- Mixing appropriate amounts with (Type of food):
Dose level 300 ppm: 9.07g/30 kg
Dose level 1800 ppm: 54.44g/30 kg
Dose level 12000 ppm: 362.90g/30 kg
Details on mating procedure:
- M/F ratio per cage: 1 male and 2 females per cage
- Length of cohabitation: 10 days
- Proof of pregnancy: vaginal smears were examined daily.
- After 10 days of unsuccessful pairing replacement of first male by another male with proven fertility
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): separately
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Mean concentrations within 2% of target concentration for all groups. Diethylhexyladipat was not detected in any control diet (detection limit 10 ppm). Chemical stability of Diethylhexyladipat in diet was determined on three batches of diet at nominally 300 ppm and 12000 ppm. Satisfactory chemical stability was established. Homogeneity of Diethylhexyladipat in diet mixtures was satisfactorily demonstraded on the first diet batch at nominally 300 and 12000 ppm Diethylhexyladipat.
Duration of treatment / exposure:
10 weeks
Frequency of treatment:
The rats in each generation were fed experimental diets continuously until termination.
Remarks:
Doses / Concentrations:
0, 300, 1800, 12000 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0, 28, 170, 1080 mg/kg bw/day
Basis:
nominal in diet
No. of animals per sex per dose:
30 females and 15 males per group in total 4 groups.
Control animals:
yes, plain diet
Details on study design:
According to randomisation the rats were housed.
Positive control:
no
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes, at least once daily

DETAILED CLINICAL OBSERVATIONS: Yes, once weekly

BODY WEIGHT: Yes, of all rats were recored at weekly intervals throughout the premating period.

FOOD CONSUMPTION AND COMPOUND INTAK:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg/day: Yes, each cage of rats was recorded throughout the premating periods and calculated on a weekly basis. The food utilisation value per cage was calculated as the weight gained by the animals in the cage per 100 g of food eaten.
Oestrous cyclicity (parental animals):
no data
Sperm parameters (parental animals):
no data
Litter observations:
STANDARDISATION OF LITTERS
A count of all live and dead pups was made within 24 hours (day 1), at days 5, 11, 22, 29 and 36 post partum. The sexes of the pups were also recorded at these times.
Postmortem examinations (parental animals):
SACRIFICE
All animals at scheduled kills and those killed during the study were anaesthetised by inhalation of halothane BP vapour and killed by exsanguination. All surviving males were killed after completion of mating. All females were killed after weaning their litters.

Histological examination:cervix, epididymis, liver, mammary gland, ovary, prostate, seminal vesicle, testis, uterus, abnormal tissues.
Postmortem examinations (offspring):
All pups were killed as soon as possible after Day 36 post partum.

Histological examination: cervix,epididymis, liver, mammary gland, ovary, prostate, seminal vesicle, testis, uterus, abnormal tissues.
Statistics:
Mean bodyweight gain, food consumption and food utilisation during the premating period, female bodyweight gain during pregnancy, parental liver weights and pup (litter) bodyweight gain until Day 36 post partum.
Reproductive indices:
Mean lenght of gestation, mean pre-coital interval
Offspring viability indices:
Mean live born index, mean survival index, mean litter size, total litter weight and whole litter losses.
Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
effects observed, treatment-related
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
TEST SUBSTANCE INTAKE
There was a slight increase in food consumption in males dosed with 12000ppm DEHA from 6-10 weeks of the study, the effect being statistically significant at weeks 6-9. Food utilisation was slightly less efficients overall for males receiving 12000ppm DEHA.

ORGAN WEIGHTS
An increase in liver weight was observed for both male and female parents receiving 12000ppm DEHA. No other treatment group was effected. This increase in liver weight has been reported previously and is associated with peroxisome proliferation (Moody and Reddy 1978).
Dose descriptor:
NOAEL
Effect level:
ca. 170 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: increased absolute liver weights, and reduced body weight gain in females at 12000 ppm (1080 mg/kg bw/day)
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
BODY WEIGHT
Mean pup weight gain and total litter weight for both male and female offspring receiving 12000ppm (1080 mg/kg bw/day) Diethylhexyladipat were reduced throughout the whole of the post partum phase. There was no effect on either male or female pup weight gain in any other dose group in comparison with the control animals.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
ca. 170 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
170 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Additional information

No data on reproduction/developmental toxicity are available for Dipropylheptyladipat. However, Diethylhexyladipat, a structural analogue to Dipropylheptyladipat (for more details please refer to the read across statement in chapter 13), was investigated in a one-generation study (CEFIC, 1988, equivalent to OECD guideline 415). In this study, male and female Wistar rats were fed Diethylhexyladipat in the diet from 10 weeks before mating up to 36 days postpartum at levels of 28, 170 and 1080 mg/kg bw/day (300, 1800 or 12 000 ppm). At 1080 mg/kg bw/day, body weight gain was marginally reduced in females, and liver weights of both male and female parental animals were significantly increased. There were no effects on male or female fertility or on gestation length. At the highest dose level (1080 mg/kg), total litter weights and body weight gain of pups were reduced. No effect on pup survival was found at any treatment level. No treatment-related macroscopic abnormalities were found in the pups. Therefore, the NOAEL was set at 1800 ppm, 170 mg/kg bw/day, for both parental toxicity and for fetal toxicity.

Diethylhexyladipat was further tested in a study according to OECD 422 (combined repeated dose toxicity study with the reproduction / developmental toxicity screening test) (Miyata et al. 2006). Sprague-Dawley rats (10 per sex and dose) were orally gavaged with 0, 40, 200 or 1000 mg/kg/ bw/day of the test material in corn oil at least 28 days from 8 weeks of age onwards. The doses were selected on the basis of a preliminary test. A vehicle control group was gavaged with corn oil alone. The dose volume was 10 mL/kg bw. The concentration and stability of the test material in the vehicle were confirmed. Animals were killed by exsanguination under ether anesthesia, and blood samples were obtained from the abdominal aorta and examined for hematological, clinical biochemistry and hormonal parameters. In two rats in the 1,000 mg/kg group, the estrous stage persisted until the day of sacrifice 4 and 10 days later. In the male rats, increased eosinophilic bodies and hyaline droplets were observed in the kidneys of the 1,000 mg/kg group. In the female rats, increased ovarian follicle atresia was detected in four rats in the 1,000 mg/kg group, and prolongation of the estrous stage was detected in two of these four rats. In addition, on male rats increased kidney weight was observed in the 200 and 1000 mg/kg group. In female rats, increased liver, kidney, and adrenal weights were observed in the 1000 mg/kg group. In conclusion, a prolonged estrous stage associated with histopathological changes in the ovary was detected by this assay and therefore a NOAEL of 200 mg/kg bw was deduced for female, parental animals.

The publication by Dalgaard et al. (Reprod. Tox., 2003) was disregarded for the assessment, because the data presented is unreliable. In this non-GLP study, DEHA was fed by gavage to 20 pregnant Wistar rats per group at doses of 200, 400, and 800 mg/kg bw/day from GD 7 to day 17 after parturition. Data on pups are presented for days 3, 13, and 21, but it is unclear, if pups were directly exposed to Diethylhexyladipat or only indirectly via lactation. According to the authors the study design was similar to an OECD 426 study, but there are no similarities between the publication and the OECD 426 guideline. For example, there was no assessment of gross neurologic and behavioural abnormalities, including the assessment of physical development, behavioural ontogeny, motor activity, motor and sensory function, and learning and memory. Instead, additional parameters were included to detect effects on male sexual maturation.

No antiandrogenic effects were found, but the authors state that they observed prolonged gestation time and an increase in postnatal death and decreased body weight in the pubs in the absence of maternal toxicity. These results are questionable due to some severe flaws in the study.

• The assessment of maternal toxicity is not possible based on the data presented, i.e., absence of clinical signs. No further data on hematology, clinical chemistry, or histopathology are available.

• There is limited data on maternal body weight gain from GD 7 – 21 showing no significant difference between groups, but dams were not randomly assigned to the treatment groups, but based on their body weight. An evaluation of the data on body weight gain is not possible without individual animal data prior to treatment. Since it is unknown, if this led to selection of pregnant animals for the high dose that were significantly lighter or heavier than control animals, further effects on reproductive parameters cannot be excluded.

• The acclimatization period was very short (4 days, starting on GD3) considering a full reversal of the dark-light cycle and the use of pregnant animals.

• Pup weights cannot be compared between groups. Pups were all weighed on the same day, independent of their age. Postnatal day 0 was defined as gestation day 21, even if pups were not yet born. On average, pups were born 0.9 days later in the high dose group compared to control animals, so that weight differences might solely be due to difference in age.

• The increase in postnatal deaths was slight and not dose dependent – 400mg/kg bw/day led to a higher percentage of postnatal deaths than 800mg/kg bw/day. Additionally, the percentage of postnatal deaths at 800mg/kg bw/day in the pre-study was no different from the controls. The same is true for the stated increase of perinatal deaths. This is not surprising, because of the unusual definition of perinatal death in the publication, which includes all postnatal deaths until day 21.

• No historical control data or data on individual animals are available, making it impossible to judge the biological significance of the differences.

Overall, many effects observed in the study might be due to poor study design (e.g., animal assignment and data acquisition). An assessment of the remaining differences is impossible, since key information is missing. For all these reasons and because these effects were not observed at a higher dose in a guideline conform one-generation GLP study (CEFIC 1988), the publication from Dalgaard et al. (2003) is considered invalid.

In conclusion, valid data from the reproduction toxicity studies on Diethylhexyladipat, a structural surrogate to Dipropylheptyladipat, elicited no critical effect. In the one-generation study no effects on the reproductive organs were noted (cervix, epididymis, mammary gland, ovary, prostate, seminal vesicle, testis, uterus). In addition, in the 90-day studies conducted with Dipropylheptyladipat and its structural surrogate Diethylhexyladipat, also no effects were noted for the reproductive organs (prostate, seminal vesicles, uterus, testis, epididymides, ovaries, mammary glands, cervix). The NOAEL (170 mg/kg bw/day) derived from the one-generation study was based on both maternal and F1 offspring effects seen at a relatively high dose of 1080 mg/kg which exceeds limit dose. The F1 effects (reduced total litter weight) were considered to be secondary to the maternal toxic effects (increased absolute liver weights, and reduced body weight gain in females). In addition no differences were seen in litters or litter size, survival or clinical signs.  


Short description of key information:
No data on reproduction / fertility are available for Dipropylheptyladipat. The toxicity to reproduction/fertility was investigated for Diethylhexyladipat, a structural analogue to Dipropylheptyladipat, in a one-generation reproduction study in rats (comparable to OECD guideline 415). In this study Wistar rats were fed Diethylhexyladipat in the diet from 10 weeks before mating up to 36 days postpartum at levels of 300, 1800 or 12000 ppm ( at 28, 170 and 1080 mg/kg bw/day, respectively). The NOAEL was determined to be 170 mg/kg bw/day.

Justification for selection of Effect on fertility via oral route:
Most reliable study

Effects on developmental toxicity

Description of key information
Dipropylheptyladipat was tested in a prenatal developmental toxicity study according to OECD test guideline 414 (WIL 2015). Pregnant rats were treated via oral gavage with doses up 600 mg/kg bw/d. The NOAEL of the study was 200 mg/kg bw/d for maternal and developmental toxicity. Diethylhexyladipat, a close structural analogue to Dipropylheptyladipat (for more details please refer to the read across statement in chapter 13), was investigated in teratogenicity study (CEFIC, 1988, eqivalent to OECD guideline 414). In this study pregnant rats were treated with Diethylhexyladipat in the diet throughout gestation (gestation day 1-22) at 300, 1800 or 12000 ppm (corresponding to 28, 170 or 1080 mg/kg bw/d, respectively) leading to a NOAEL of 170 mg/kg bw/d. In a further study pregnant rabbits were treated with Diethylhexyladipat via their diet according to OECD test guideline 414 (BASF 2014). The NOAEL of this study was the highest tested dose of 160 mg/kg bw/d. 
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2014-2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories B.V., Venray, The Netherlands
- Age at study initiation: Age at delivery: Females were approximately 10 to 14 weeks.
- Weight at study initiation: 17.6 - 22.2 g (group means)
- Fasting period before study: no
- Housing: individually housed in Macrolon plastic cages (MIII type)
- Diet (e.g. ad libitum):ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period: at least 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 24 °C
- Humidity (%): 40 - 70%
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12-hour light/12-hour dark cycle

IN-LIFE DATES: From: 25 December 2014 To: 14 January 2015
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Formulations (w/w) were prepared daily within 5 hours prior to dosing and
were homogenized to a visually acceptable level

VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on trial formulations
Analytical verification of doses or concentrations:
yes
Details on mating procedure:

Untreated females were mated at the supplier, and were at Day 0, 1 or 2
post-coitum on arrival at the test facility (Day 0 post-coitum was the day
of successful mating; confirmed by vaginal plug).
Duration of treatment / exposure:
From Day 6 to Day 20 post-coitum, inclusive
Frequency of treatment:
once daily
Duration of test:
treatment from Day 6 to Day 20 post-coitum, inclusive; necropsy on day 21 post-coitum
Remarks:
Doses / Concentrations:
0, 60, 200, 600 mg/kg bw/d
Basis:
actual ingested
No. of animals per sex per dose:
22 females per dose group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: prestudy
- Rationale for animal assignment: random
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations:Days 3, 6, 9, 12, 15, 18 and 21 post-coitum.

FOOD CONSUMPTION: Yes
Days 3-6, 6-9, 9-12, 12-15, 15-18 and 18-21 post-coitum.


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Organs examined: organ weights: (gravid) uterus, liver, spleen, necrospy: Gross lesions, ovary and uterine horn, spleen, liver, Identification marks

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
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: number and distribution of live and dead fetuses, weight of each fetus, sex of each fetus from the ano-genital distance (during necropsy) and also from gonadal inspections (during further fetal examination), weight of each placenta.
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: half per litter
Statistics:
The following statistical methods were used to analyze the data:
- If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-toone
t-test) based on a pooled variance estimate was applied for the comparison of the treated
groups and the control group.
- The Steel-test (many-to-one rank test) was applied if the data could not be assumed to follow
a normal distribution.
- The Fisher Exact-test was applied to frequency data.
- The Mann Whitney test was used to compare mean litter proportions (percent of litter) of the
number of viable and dead fetuses, early and late resorptions, total resorptions, pre- and postimplantation
loss, and sex distribution.
- Mean litter proportions (percent per litter) of total fetal malformations and developmental variations
(external, visceral and skeletal), and each particular external, visceral and skeletal malformation or
variation were subjected to the Kruskal-Wallis nonparametric ANOVA test to determine
intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance,
Dunn’s test was used to compare the compound-treated groups to the control group.
All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance.
Group means were calculated for continuous data and medians were calculated for discrete data
(scores) in the summary tables. Test statistics were calculated on the basis of exact values for means
and pooled variances. Individual values, means and standard deviations might be rounded off before
printing. Therefore, two groups might display the same printed means for a given parameter, yet
display different test statistics values.
No statistics were applied for data on maternal survival, pregnancy status, group mean numbers of
dead fetuses, early and late resorptions, and pre- and post-implantation loss.
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
-increased absolute and/or relative liver weights at 200 and 600 mg/kg bw/d
- lower total protein and increased urea at 600 mg/kg bw/d
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
At 600 mg/kg bw/day, reduced fetal body weights were noted (approximately 8% lower than control levels, combined for both sexes) along with a correspondingly higher incidence of reduced ossification parameters. An increase in unossified metacarpal(s) and/or metatarsal(s) was the most pronounced effect and an increase in reduced ossification of the skull also occurred, but to a lesser degree.
An increase in skeletal variations at 600 mg/kg bw/day that were not body weight dependent included increased incidence of 14th rudimentary rib(s), 14th full rib(s), 7th cervical rudimentary rib(s), and caudal shift of the pelvic girdle.
These effects indicate a generalized delay in ossification, a well documented effect often associated with maternal toxicity of various different mechanisms and/or affected homeostasis. In the present study, increased maternal liver weights and changes in clinical chemistry parameters indicate an adversely disturbed liver homeostasis. In addition, a generalized delay in ossification is expected to be readily repairable during early postnatal development and is therefore not considered as specific developmental toxicity.
There were no treatment-related effects on fetal external, visceral or skeletal malformations, on
external and visceral variations and on litter size, male:female ratios and placenta weights up to and including 600mg/kg bw/day. No developmental toxicity was observed in the 60 and 200 mg/kg bw/day groups.
Dose descriptor:
NOAEL
Effect level:
> 600 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

At 600 mg/kg bw/day, reduced fetal body weights were noted (approximately 8% lower than control levels, combined for both sexes) along with a correspondingly higher incidence of reduced ossification parameters. An increase in unossified metacarpal(s) and/or metatarsal(s) was the most pronounced effect and an increase in reduced ossification of the skull also occurred, but to a lesser degree. An increase in skeletal variations at 600 mg/kg bw/day that were not body weight dependent included increased incidence of 14th rudimentary rib(s), 14th full rib(s), 7th cervical rudimentary rib(s), and caudal shift of the pelvic girdle. These effects indicate a generalized delay in ossification, a well documented effect often associated with maternal toxicity of various different mechanisms and/or affected homeostasis. In the present study, increased maternal liver weights and changes in clinical chemistry parameters indicate an adversely disturbed liver homeostasis. In addition, a generalized delay in ossification is expected to be readily repairable during early postnatal development and is therefore not considered as specific developmental toxicity. There were no treatment-related effects on fetal external, visceral or skeletal malformations, on external and visceral variations and on litter size, male:female ratios and placenta weights up to and including 600mg/kg bw/day. No developmental toxicity was observed in the 60 and 200 mg/kg bw/day groups.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Species:
rat
Additional information

Dipropylheptyladipat was tested in a prenatal developmental toxicity study according to OECD test guideline 414 (WIL 2015). Pregnant rats were treated with doses of 0, 60, 200 or 600 mg/kg bw/d via oral gavage from gestation day 6 to 20 (inclusive). Females at 200 and 600 mg/kg bw/d showed higher absolute and/or relative liver weights. Relative liver weights were increased with approximately 7 and 22% at 200 and 600 mg/kg bw/d, respectively. Clinical biochemistry examinations revealed decreased total protein and higher urea levels in high dose dams. At this dose level, the changes in clinical biochemistry parameters and liver weights were considered to be adverse treatement-related effects. The liver was also shown to be the target organ of Dipropylheptyladipat in a 90d study (BASF SE 2015) were the highest tested dietary levels of 12000ppm for males (corresponding to 875 mg/kg bw/d) and 15000 ppm for females (corresponding to 1361 mg/kg bw/d) caused changes in respective clinical biochemistry parameters as well as increased absolute and relative liver weights and diffuse hepatocellular hypertrophy indicating a liver cell swelling because of liver enzyme induction. At 600 mg/kg bw/d, the highest tested dose in the prenatal toxicity study where marked maternal toxicity was observed, Dipropylheptyladipat caused reduced fetal body weights (approximately 8% lower than concurrent control) along with a correspondingly higher incidence of reduced ossification parameters. An increase in unossified metacarpal(s) and/or metatarsal(s) was the most pronounced effect and an increase in reduced ossification of the skull also occurred, but to a lesser degree. An increase in skeletal variations at 600 mg/kg bw/day that were not body weight dependent included increased incidence of 14th rudimentary rib(s), 14th full rib(s), 7th cervical rudimentary rib(s), and caudal shift of the pelvic girdle. These effects indicate a generalized delay in ossification, a well documented effect often associated with maternal toxicity of various different mechanisms and/or affected homeostasis (Carney and Kimmel 2007) . In the present study, increased maternal liver weights and changes in clinical chemistry parameters indicate an adversely disturbed liver homeostasis. As concluded by Carney and Kimmel (2007) a generalized delay in ossification is expected to be readily repairable during early postnatal development and is not mechanistically linked to malformation. Furthermore, the observed developmental effects occurred associated with maternal toxicity and are therefore not considered as specific developmental toxicity. There were no treatment-related effects on fetal external, visceral or skeletal malformations, on external and visceral variations and on litter size, male:female ratios and placenta weights up to and including 600mg/kg bw/day. No developmental toxicity was observed in the 60 and 200 mg/kg bw/day groups. Thus, the NOAEL for maternal and developmental toxicity under the conditions of this study was 200 mg/kg bw/d.

Diethylhexyladipat, a structural analogue to Dipropylheptyladipat (for more details please refer to the read across statement in chapter 13), was investigated in a teratogenicity study (CEFIC, 1988, eqivalent to OECD guideline 414). In this study pregnant Wistar rats were fed Diethylhexyladipat in the diet at levels of 300, 1800 or 12000 ppm, corresponding to daily doses of 28, 170 or 1080 mg/kg bw/day, on days 1–22 of gestation. Administration of 12000 ppm resulted in slight maternal toxicity, expressed as a small reduction in body weight gain. 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 the highest dose level, a small increase in pre-implantation loss as well as a minimal increase in post-implantation loss was noted. Incidence of minor external and visceral defects was unaffected by treatment although two visceral variants were increased at the top two dose levels, kinked ureter being increased in the 1800 and 12000 ppm groups and slightly dilated ureter being increased in the 12000 ppm group. Overall, minor skeletal defects were increased in a dose-related manner at 1800 and 12000 ppm, while skeletal variants and pes score were increased at the top dose only. These findings indicated slightly poorer ossification at the 1800 and 12000 ppm dose levels. The reduced ossification and increase in the incidence of visceral variants are considered to be the result of slight foetotoxicity only, and as results from the one-generation study did not indicate any adverse outcome at 1800 ppm. Therefore, based on this study a NOAEL for maternal and foetal toxicity was set at 1800 ppm (170 mg/kg bw/day).

In a study according to GLP and OECD 414 pregnant rabbits were treated with Diethylhexyladipat in the diet at 0, 40, 80 and 160 mg/kg bw/day(BASF 2014). No maternal toxicity was observed in all dose groups. 20 control and 19 litters per treatment group were available for evaluation. There was no difference between treated and control animals with regard to implantation loss, corpora lutea, litter size, sex distribution, fetal body weight, and external and visceral malformations or variations. Doses were based on a preliminary range finding study, in which 5 mated females were exposed to 100, 300, and 1000mg/kg from days 7 -29 post coitum. Severe toxicity (e.g., body weight loss) was noted after treatment with 300mg/kg in the diet and via gavage (to exclude palatability problems), so that the maximum dose in the main study was app. one half of 300mg/kg.

Based on the results in this prenatal developmental toxicity study the maternal and developmental No Observed Adverse Effect Level (NOAEL) was established as being at least 160mg/kg bw/dayin the diet (dose level approximation).

Diethylhexyladipat was tested for its embronic-fetal toxicity and teratogenic effects in rats (Singh et al. 1973). Five female rats per group were injected intraperitoneally on Days 5, 10, and 15 of gestation at three dosage levels of 1, 5 and 10 mL/kg bw. For the highest dose distilled water, normal saline and cotton seed oil were use, the other concentrations were used undiluted. Dams were sacrificed on Day 20, and the uterine horns and the ovaries were removed. The numbers of corpora lutea, resorption site and viable and dead fetuses were counted. Individual fetal weights were measured, and all fetuses (dead and viable) were examined for gross anomalies. Half the fetuses were examined for skeletal anomalies and the other half for visceral anomalies. The numbers of corpora lutea, resorption sites, viable and dead fetuses were not different compared to the controls. Mean fetal weights were slightly lower compared to the control in the mid and high dose levels. Diethylhexyladipat produced a few gross, skeletal, and visceral abnormalities in the mid and high dose levels. However, the incidences are in the range of the controls or do not exceed 4%. The reliability of this study was indicated as 4, not assignable, since the a route of exposure that was not relevant (i.p.) and essential endpoints were not reported (e.g. maternal toxicity).

In conclusion, three prenatal develomental toxicity studies conducted according to GLP and OECD test guideline 414 with Dipropylheptyladipat and its structural analogue Diethylhexyladipat did not reveal any teratogenic effects or specific developmental toxicity in rats and rabbits.

References:

Carney EW and Kimmel CA, Interpretation of skeletal variations for human risk assessment: delayed ossification and wavy ribs, Birth Defects Research (Part B) 80:473 -496 (2007)


Justification for selection of Effect on developmental toxicity: via oral route:
Most reliable study

Justification for classification or non-classification

The available developmental and one-generation reproduction toxicity data for Dipropylheptyladipat and the read across substance Diethylhexyladipat, a close structural analogue to Dipropylheptyladipat, do not trigger classification for reproduction or developmental toxicity according to EU Directive 67/548/EEC or Regulation (EC) No. 1272/2008 (CLP, GHS).

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