[No public or meaningful name is available]

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

Oral (OECD 422), rat (m/f): NOAEL fertility = 1000 mg/kg bw/day (highest dose tested); NOAEL developmental toxicity = 1000 mg/kg bw/day (highest dose tested)

Read-across from structural analogue source substances 1,2,3 -propanetriol, homopolymer, diisooctadecanoate (CAS 63705-03 -3) and 2,3 -dihydroxypropyl oleate (CAS 111-03-5).

Link to relevant study records

Reference

Reference 1

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

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 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc., Yokohama, Japan
- Age at study initiation: 10 weeks
- Weight at study initiation: 352 - 426 g (males; mean: 372 g), 192 - 249 g (females; mean: 224 g)
- Housing: individual in stainless steel cages
- Diet: ad libtum
- Water: ad libitum
- Acclimation period: 11 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.1 - 23.2
- Humidity (%): 48 - 61
- Air changes (per hr): more than 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The test substance was diluted in appropritate amounts of corn oil for each dose level. Aliquots of the dosing solution corresponding to the amount of daily administration were stored in the dark at 2 - 6 °C. The stability of the dosing solution was 7 days in a refrigerator and 1 day at room temperature. Therefore, the dosing solution was used within 7 days.

VEHICLE
- Justification for use and choice of vehicle (if other than water): the test substance showed low solubility in water.
- Amount of vehicle (if gavage): 5 mL/kg
- Lot/batch no. (if required): V4N3566

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: up to 14 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: individually in a polycarbonate cage with animal bedding for nesting

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

No details reported.

Duration of treatment / exposure:

males: 42 days (14 days prior to mating and 28 days thereafter)
females: 42-52 days (from 14 days before mating to day 4 of lactation)
satellite males and females: 42 days and 14 days post-exposure observation period

Frequency of treatment:

once daily, 7 days/week

Details on study schedule:

- Age at mating of the mated animals in the study: 12 weeks

Remarks:

Doses / Concentrations:
100, 300 and 1000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

12 females in control and test groups
7 males in control and 1000 mg/kg bw groups
12 males in 100 and 300 mg/kg bw groups
5 animals per sex in satellite control and test groups

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:
Two dose range finding studies were performed. 2000 mg/kg bw of test substance was administered for 3 days in male and female rats. No abnormalities were found in general condition and body weight. The second study was performed at dose levels of 0, 330, 100, 300 and 1000 mg/kg bw/day for 14 days. No abnormalities of general condition, body weight, food consumption, hematological findings, blood biochemical findings, gross pathology and organ weight were found. Therefore, 1000 mg/kg bw/day was selected as the highest dose.
- Post-exposure recovery period in satellite groups: 14 days

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once prior to the first exposure and weekly thereafter

BODY WEIGHT: Yes
- Time schedule for examinations:
Males: Day 1 (before administration), 7, 14, 21, 28, 35 and 42 (before sacrifice)
Females: Day 1 (before administration), 7, 14, during pregnancy on Day 0, 7 14 and 21, during lactation on Days 0 and 4 (before sacrifice)
Satellite males and females: Day 1 (before administration), 7, 14, 21, 28, 35, 42, 49 (Day 7 of recovery period) and 56 (Day 14 of recovery period, before sacrifice)

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

Oestrous cyclicity (parental animals):

Numbers of times in estrous before and during administration till mating confirmed.

Sperm parameters (parental animals):

Parameters examined in P male parental generations:
testis weight and abnormality, epididymis weight and abnormality, prostate weight and abnormality

Litter observations:

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, body weight, physical abnormalities

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was determined for pups born or found dead.

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals one day after the last administration (Day 43)
- Maternal animals: All surviving animals on Day 5 of lactation

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
The following tissues were prepared for microscopic examination and weighed, respectively:
brain, pituitary, thyroid, thymus, lung trachea (after liquid immersion fixation), stomach, intestines, heart, liver, spleen, kidney, adrenal gland, bladder, testis, epididymis, prostate, seminal vesicles, ovaries, uterus, spinal cord (cervical, thoracic, lumbar), sciatic nerve, bone marrow (femur), lymph nodes (cervical lymph node, mesenteric lymph nodes), mammary gland, and other gross abnormalities.
Spermatogenic cycle (Stage II, III, V, VII, and XII) was also investigated.

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring were sacrificed at 4 days of age.
- These animals were subjected to postmortem examinations (macroscopic).

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the thoracic, and abdominal viscera.

Statistics:

ANOVA, Barlettm Kruskal-Willis, Dunnett, F test, Studen t-test, Aspin-Welch t-test, Mann-Whitney U-test, Fisher's exact test

Reproductive indices:

Copulation index = (No. of pairs with successful copulation/No. of pairs mated) x 100
Fertility index = (No. of pregnant females/No. of pairs with successful copulation) x 100
Gestation index = (No. of females with live pups / No. of pregnant females) x 100

Offspring viability indices:

Delivery index = (No. of pups born / No. of implantation sites) x 100
Live birth index = (No. of live pups on day 0 / No. of pups born) x 100
Viability index = (No. of live pups on day 4 / No. of live pups on day 0) x 100
Sex ratio = total No. of male pups / total No. of female pups

Clinical signs:

no effects observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

1000 mg/kg bw/day (satellite group, males): significant increase was observed (non adverse)

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

1000 mg/kg bw/day (satellite group, males): significant increase was observed (non adverse)

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

control and 1000 mg/kg bw/day: low incidence of commonly found microscopic changes, evenly distributed between groups (not treatment-related);300 mg/kg bw/day: benign fibroadenoma of the mammary gland in one female (not treatment-related)

Other effects:

not examined

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No abnormalities and no mortality were observed.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
No change of body weight and weight gain was observed during the administration period. During the recovery period, a significant increase in body weight was noted in males at 1000 mg/kg bw/day. This was caused by a tendency of the control group animals to lose weight. One male in control group showed a significant decrease in body weight during the recovery period. However, no other abnormalities were observed in this male.
No change was observed during the administration period in the test groups. A significant increase in food consumption was found in satellite females of the 1000 mg/kg bw/day group on Day 14 of administration. However, it was regarded as an incidental finding since the food consumption of the corresponding control group was relatively small on that day. Therefore, this change was not regarded as a compound-related effect.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
No differences were observed between control group and test groups.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
Decreased sperm was observed in one male in control group and whose pair was not pregnant.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No changes were observed both in control and test groups.

ORGAN WEIGHTS (PARENTAL ANIMALS)
After the administration period, a significant decrease in the absolute weight of seminal vesicles in males given and a significant decrease in relative weight of spleen in females were observed in the 100 mg/kg bw/day group. However, this change was not compound-related because no abnormalities were found at histopathological examination and there was no dose-dependency.
After the recovery period, a significant decrease in relative weight of pituitary in males of the 1000 mg/kg bw/day group and relative weight of thyroid in females of the 1000 mg/kg group bw/day was observed. Nevertheless, this effect was not compound-related because no abnormality was reported regarding these organs after administration period.

GROSS PATHOLOGY (PARENTAL ANIMALS)
No test substance-related changes were found. No abnormalities were found in breeding pairs which were not successful at mating and in those which were successful at mating but not pregnant.
After administration period, reddish thymus was noted in one male of the control group and subcutis mass was found in one female of 300 mg/kg by/day group (see also HISTOPATHOLOGY: NEOPLASTIC). After the recovery period, larger spleen and capsular thickening in spleen was found in one male and reddish area in thymus was observed in one female at 1000 mg/kg bw/day.

HISTOPATHOLOGY (PARENTAL ANIMALS)
No test substance-related changes were observed. There were also no changes regarding spermatogenic cycle.
Myocardial degeneration/fibrosis, foam cell accumulation in lung, mineralization in artery in lung, fatty degeneration of hepatocyte, microgranuloma in liver, solitary cyst in kidney, hyaline cast in kidney, lymphocyte infiltration in cortex of kidney, mineralization of cortico-medullary junction in kidney, fibrosis of cortex in kidney and haemorrhage in thymus were observed both in the control and 1000 mg/kg bw/day groups or only in the control group with low incidence. Hyaline droplet of proximal tubular epithelium in kidney was found in all males of the control and 1000 mg/kg bw/day groups. Brown deposit pigment and extramedullary haematopoiesis in spleen were found in all males and females of the control and 1000 mg/kg bw/day groups. However, there were no differences between control and test group. In the 1000 mg/kg bw/group, lymphocyte interstitium infiltration in prostate was found in one male, interstitial focal inflammation in lung and focal necrosis in liver was observed in one female. These changes occur naturally and were not compound-related.
No abnormalities were found in uterus and ovary in the non-pregnant females and the unsuccessful copulation females of the control and 1000 mg/kg bw/day groups, respectively. Degeneration of seminiferous tubules of testis, decrease in sperm and atrophy in prostate was observed in one control male.
Mass on abdomen was found in a female after 40 days of administration in the 300 mg/kg bw/day group. However, this subcutaneous tumour of the mammary gland was a benign fibroadenoma and generated naturally.

Dose descriptor:

NOAEL

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: overall effects

Dose descriptor:

NOAEL

Remarks:

fertility

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

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:

effects observed, treatment-related

Description (incidence and severity):

control and test groups: low incidence of commonly found visceral variations (not compound-related)

Histopathological findings:

not examined

VIABILITY (OFFSPRING)
No changes were observed.

CLINICAL SIGNS (OFFSPRING)
No effects were observed.

GROSS PATHOLOGY (OFFSPRING)
Thymic remnant in neck was observed in one, one and two pups in the control, 300 and 100 mg/kg bw/day groups, respectively. Persistent left umbilical artery was found in one and two pups at 100 and 1000 mg/kg bw/day, respectively. Convoluted ureter was found in one, three and two pups at 100, 300 and 1000 mg/kg bw/day, respectively. Dilatation of renal pelvis was observed in one pup at 300 mg/kg bw/day. Dilatation of ureter was observed in one and two pups in 100 and 300 mg/kg bw/day, respectively. However, these changes were regarded as not-compound related, since they could occur naturally and there was no significant difference between control and test groups.

Dose descriptor:

NOAEL

Remarks:

development

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: overall effects

Reproductive effects observed:

not specified

Reference 2

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP - guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: EPA OPPTS 870.3650 “Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test”

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: Harlan Laboratories, B.V., Kreuzelweg 53, 5961 NM Horst / Netherlands
- Age at study initiation: 11 weeks
- Weight at study initiation: 260 - 390 g (males), 175 - 240 g (females)
- Housing: in groups of three to five in Makrolon type-4 cages with wire mesh tops during acclimatisation and afterwards individually in Makrolon type-3 cages with wire mesh tops and sterilized standard softwood bedding with paper enrichment. During the pre-pairing period, cages with males were interspersed amongst those holding females to promote the development of regular estrus cycles.
- Diet (ad libitum): pelleted standard Harlan Teklad 2018C rodent maintenance diet (Provimi Kliba SA, 4303 Kaiseraugst / Switzerland)
- Water (ad libitum): community tap-water
- Acclimation period: at least seven days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): Based on an observation on 01-Feb-2013, the automatic light cycle of 12h on / 12 h off was not functional within a block of rooms including room numbers 015A and 011B. Due to the breeding performance from November 2012 onwards during this and other studies conducted in rooms which belong to the affected block, it was considered probable that the animals hab been maintained under constant lightning throughout the study period for the first delivery animals. From 01-Feb-2013 onwards, the automatic light cycle was restored.

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: daily. The test substance was weighed into a glass beaker on a tared precision balance and approximately 80% of the vehicle was added (w/v). Using an appropriate homogenizer, a homogeneous suspension was prepared. Having obtained a homogeneous mixture, the remaining vehicle was added. Separate formulations were prepared for each concentration.
Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.

VEHICLE
- Amount of vehicle (if gavage): 4 mL/kg bw (dose volume)

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: until evidence of copulation was observed
- Proof of pregnancy: copulation plug or sperm in vaginal smear referred to day 0 of pregnancy
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no, if mating was not recorded during the additional pairing period of a maximum of 14 days, the female was sacrificed and, if indicated, the reproductive organs examined histopathologically in order to ascertain the reason for the infertility.
- After successful mating each pregnant female was caged (how): individually

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

On the first dose formulation day samples from the control group as well as three samples (top, middle and bottom) of about 1 g of each concentration were taken prior to dosing for analysis of concentration and homogeneity. Samples of about 1 g of each test item concentration were taken from the middle to confirm the stability (4 hours). Towards the end of the study, samples were taken from the middle to confirm concentration. The aliquots for analysis of dose formulations were frozen (-20 ± 5 °C) and stored at -20 ± 5 °C until analysis.
The samples were analyzed by derivatisation with MSTFA and analysis by GC-FID. The test item was used as the analytical standard. Analyzed samples were not discarded without written consent from the study director.
Duplicates were taken of all samples and stored at Harlan Laboratories Ltd., Füllinsdorf / Switzerland. The samples were not discarded without written consent from the study director.

Duration of treatment / exposure:

Males: Minimum 28 days
Females: Approximately 6 weeks

Frequency of treatment:

once daily (within four hours)

Remarks:

Doses / Concentrations:
100, 300, 1000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

at least 12 (see any other information on materials and methods)

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: - Dose selection rationale: Based on single dose toxicity data of the test compound and repeated dose toxicity data of chemically similar compounds, the results of a 14-day range-finding study the dose levels of 100, 300, and 1000 mg/kg bw per day were selected for the present study.

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once prior to the first administration of the test item and weekly thereafter (in the gestation period on day 0, 6, 13 and 20 post coitum).
- detailed clinical observations were performed outside the home cage in a standard arena and the animals were observed for the following changes in: skin, fur, eyes, mucous membranes, occurrence of secretions and excretions, and autonomic activity (e.g. lacrimation, piloerection, pupil size, unusual respiratory pattern). Changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypies or bizarre behavior were also reported.

BODY WEIGHT: Yes
- Time schedule for examinations: daily from treatment start to day of necropsy.

FOOD CONSUMPTION: Yes
- Males: Pre-pairing period days 1 - 4, 4 - 8, 8 - 11 and 11 - 14; after pairing period weekly.
- Females: Pre-pairing period days 1 - 4, 4 - 8, 8 - 11 and 11 - 14; gestation days 0 – 7, 7 14 and 14 – 21 and days 1 - 4 of the lactation
No food consumption was recorded during the pairing period.

Sperm parameters (parental animals):

Parameters examined in all male parental generations:
testis weight, epididymis weight, daily sperm production, seminal vesicles, stages of spermatogenesis

Litter observations:

STANDARDISATION OF LITTERS
The litters were examined for litter size, live births, still births and any gross anomalies. The sex ratio of the pups was recorded. Pups were weighed
individually (without identification) on days 1 and 4 post partum.

PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring:
[number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, other:]

Postmortem examinations (parental animals):

GROSS PATHOLOGY: Yes
The following organs were trimmed from any adherent tissue, as appropriate, and their wet weight was taken: adrenal glands (weighed as pairs), brain, epididymides, heart, kidneys (weighed as pairs), liver, ovaries (weighed as pairs), prostate, seminal vesicles (inclusive coagulating gland), spleen, testes, thymus, thyroid (after fixation), uterus (including cervix)
HISTOPATHOLOGY: Yes
The following tissues from all parental animals were preserved in neutral phosphate buffered 4% formaldehyde solution if not otherwise described: adrenals, brain, bone marrow (femur), epididymides (in Bouin’s fixative), gross lesions, heart, kidneys, liver, lymph nodes (axillary and mesenteric), ovaries (with oviduct), peripheral nerve (sciatic), prostate, seminal vesicles with coagulating gland, small and large intestines (incl. Peyer’spatches; duodenum, jejunum, ileum, colon, caecum, rectum), spinal chord (cervical, thoracic, lumbar), spleen, stomach (forestomach and glandular stomach), testes (in Bouin’s fixative), thymus, thyroids, and parathyroids if possible, trachea and lungs (preserved by inflation with fixative and then immersion), uterus (with vagina), urinary bladder
The following tissues were only examined by histopathology in case of macroscopic findings indicative of potential toxicity: aorta, esophagus, eyes with optic nerve and harderian gland, femur with knee joint, lacrimal gland, larynx, mammary gland (male and female), nasal cavity, pancreas, pharynx, pituitary gland, salivary glands – mandibular, sublingual, skeletal muscle, sternum with bone marrow.

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring were sacrificed at day 4 post partum.
- These animals were subjected to postmortem examinations (macroscopic examination) as follows:

GROSS NECROPSY
All parent animals and pups were examined macroscopically for any structural changes at the
scheduled necropsy.

Statistics:

The following statistical methods were used to analyze food consumption, body weights and reproduction data:
• The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables were assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
• The Steel-test (many-one rank test) was applied instead of the Dunnett-test when the data could not be assumed to follow a normal distribution.
• Fisher's exact-test will be applied if the variables could be dichotomized without loss of information

Reproductive indices:

Percentage mated = (Females mated/Females paired)*100
Fertility index = (Females achieving a pregnancy/Females paired) *100
Conception rate = (Females achieving a pregnancy/Females mated)*100
Gestation index = (Number of females with living pups / Females pregnant) * 100

Offspring viability indices:

Birth index = (pups born alive/number of implantations)*100
Viability index = (pups alive before cullig on day 4 post partum/pups born alive)*100

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

see details on results

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

see details on results

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

see details on results

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

see details on results

Other effects:

effects observed, treatment-related

Description (incidence and severity):

Test substance intake: see details on results

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

effects observed, treatment-related

Description (incidence and severity):

see details on results

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

see details on results

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
At a dose level of 1000mg/kg bw/day, one male (no. 171, third animal delivery) died spontaneously on day 1 of the after pairing period. No clinical signs were observed and a normal body weight gain was recorded until day 13 of the pairing period. One day before it died, it showed a body weight loss of 3%. During necropsy, a dark red discolored thymus was recorded.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Males:
Mean body weight gain was statistically significantly lower at 1000mg/kg bw/day during pre-pairing period, resulting in slightly reduced mean body weights (-3% at the end of this period compared to the controls). This was a result of the minor body weight loss (1%) between days 1 and 2. During the pairing period, body weight gain at the high dose level was similar to the control value. Due to this fact, teh reduction in mean body weight gain ans body weights were considered to be not adverse. The overall differences in mean body weight gain at the dose levesl of 0, 100, 300 and 1000mg/kg bw/day were: +13%, +12%, +11% and +11% during the pre-pairing period, +5%, +5%, +3% and +4% during the pairing period and +7%, +9%, +7% and +8% during the after pairing period (percentages refer to the body weight gain within the period).
At 1000mg/kg bw/day, mean food consumption was statistically significantly reduced during the first 11 days of treatment in males of the first and second delivery (-9,3% on day 11 of prepairing when compared with controls). Thereafter, the food consumption remained slightly lower than in controls, but without reaching statistical signifincance. Fod consumption was also lower in males of the third delivery, but not to a statistically significant degree. Since this reduction in food consumption occured only transiently, the reduction was considered to be not adverse.

Females: No effect of the test item on mean body weights and mean body weight gain was noted for females at any dose level. Towards the end of the gestation period, body weights and body weight gain were reduced in females at 1000mg/lg bw/day (statistically significantly different body weight gains drom day 17 post coitum onwards). These differences were considered to be a result of the increased post implantation loss and low number of pups, which were noted for dams at this dose level. The overall differences in mean body weight gain at the dose levels of 0, 100, 300 and 1000mg/kg bw/day were: +8%, +9%, +8% and +7% during the pre-pairing , +63%, +57%, +57% and +51% during the gestation period and +4%, +7%, +4% and +3% during days 1 to 4 of the lactation period (percentage refer to the body weight gain within the period.
There were no effects on mean food consumption at any dose level and in any study phase.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
The fertility index and conception rate were low across all groups in females of the first animal delivery only. This poor mating performance was considered to be due to a disturbance of the light / dark cycle during the conduct of this study and not test item-related. In females at 1000 mg/kg bw/day, the mean duration of gestation was slightly higher than in controls (22.1 days versus 21.3 days in the controls for first and second animal delivery, 21.7 days versus 21.3 days in the controls for third animal delivery) and not in the range or borderline to the historical control data (21.2 to 21.7 days). Also, the post-implantation loss was increased (16.2% versus 6.6% in controls for first and second animal delivery, 14.2% versus 3.3% in
controls for third animal delivery), which was borderline regarding the historical control data (3.3% - 14.4% as a percentage of total implantations).
Due to the higher post-implantation loss, mean litter size at first check was reduced at the high dose level.

ORGAN WEIGHTS (PARENTAL ANIMALS)
Treatment with the test item at 1000mg/kg bw/day resulted in statistically significantly higher absolute and relative liver and kidney weights in animals of bith genders, which was confirmed in animals of the third delivery except for kidney weights in females. Since there was no evidence for an impairment of organ function by clinical pathology and histopathology, these findings were not considered to be adverse. Additionally, in females, absolute and relative heart weights were also increased. This finding was without histopathological correlate, and was therefore considered to be incidental. There were no effects of treatment at 100 and 300mg/kg bw/day.

GROSS PATHOLOGY (PARENTAL ANIMALS)
All findings were typical of this strain and age of rat and were considered to be incidental.

HISTOPATHOLOGY (PARENTAL ANIMALS)
There were no treatment-related findings. In particular, qualitative examination of the stages of spermatogenesis in the testis did not reveal any treatment-related abnormalities in the integrity of various cell types present within the different stages of the sperm cylce. No treatment-related microscopic abnormalities were observed in the evaluation of the ovarian follicles and corpora lutea of the ovaries or the evaluation of the uterus. All findings were typical of this strain and age of rat and were considered to be incidental.

Key result

Dose descriptor:

NOAEL

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 adverse effects

Key result

Dose descriptor:

NOEL

Remarks:

sytemic

Effect level:

300 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects observed

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

see details on results

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

see details on results

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

see details on results

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

see details on results

Histopathological findings:

not examined

VIABILITY AND CLINICAL SIGNS (OFFSPRING)
No test item-related findings were noted in pups during first litter check and during lactation at any dose level.
Three control pups from the litter no. 129 showed no milk in the stomach on the first day post partum. Those three pups were then missing at litter check on day 2 post partum, along with a further female pup. One pup of this litter had already been found dead at first litter check. The
remaining 10 pups from this litter survived until their necropsy on day 4 post partum.
At 1000 mg/kg bw/day, one pup showed a black discolored exophthalmos on the first day post partum. This animal was free from clinical signs from day 2 post partum onwards and survived until necropsy on day 4. A further pup showed a wound on the head on days 3 and 4 post partum.

BODY WEIGHT (OFFSPRING)
Mean pup weights on day 1 and day 4 post partum were unaffected by treatment with the test item.
On day 1 post partum mean pup weights were 5.7, 6.1, 6.0 and 5.9 g in order of ascending dose level. Also mean body weight gain was similar in all groups on day 4 post partum and no effects on mean body weights were recorded.

GROSS PATHOLOGY (OFFSPRING)
No test item-related findings were noted at macroscopic examination of F1 pups.
One male pup treated at 100 mg/kg bw/day had a missing right testicle at planned necropsy and two pups treated at 1000 mg/kg bw/day showed sores on the skin. These isolated findings were incidental and unrelated to treatment.

OTHER FINDINGS (OFFSPRING)
Sex ratios at first litter check and on day 4 post partum were unaffected by exposure to the test item.
The proportion of males at first litter check was 56, 53, 50 and 51%, in order of ascending dose level.

Key result

Dose descriptor:

NOEL

Remarks:

reproduction and development

Generation:

F1

Effect level:

300 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:

Based on these results, the NOAEL (No Observed Adverse Effect Level) for general toxicity was considered to be 1000 mg/kg body weight/day. The NOEL (No Observed Effect Level) for general toxicity and for reproduction and development was established at 300 mg/kg bw/day.

Reference 3

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

refer to the analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Description (incidence and severity):

see details on results

Description (incidence and severity):

see details on results

Key result

Dose descriptor:

NOAEL

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 adverse effects

Remarks on result:

other:

Remarks:

Source CAS 63705-03-3

Key result

Dose descriptor:

NOEL

Remarks:

sytemic

Effect level:

300 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects obversed

Remarks on result:

other:

Remarks:

Source CAS 63705-03-3

Key result

Dose descriptor:

NOAEL

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 adverse effects

Remarks on result:

other:

Remarks:

Source CAS 111-03-5

Key result

Dose descriptor:

NOEL

Remarks:

systemic

Effect level:

300 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects obversed

Remarks on result:

other:

Remarks:

Source CAS 111-03-5

Description (incidence and severity):

see details on results

Description (incidence and severity):

see details on results

Key result

Dose descriptor:

NOEL

Remarks:

reproduction and development

Generation:

F1

Effect level:

300 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Overall effects

Remarks on result:

other:

Remarks:

Source CAS 63705-03-3

Key result

Dose descriptor:

NOAEL

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: overall effects. Source CAS 111-03-5

Reproductive effects observed:

not specified

Conclusions:

As detailed in the analogue justification, it is considered that the target and the source substances are unlikely to lead to differences in reproduction toxicity potential. With both source substances, the NOEL (No Observed Effect Level) for reproduction toxicity was established at 300 mg/kg bw/day or higer. Therefore, the NOEL for reproduction toxicity for the target substance is also expected to be equal or greater than 300 mg/kg body weight/day.

Reference 4

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the extended one-generation reproductive toxicity study does not need to be conducted because there are no results from available repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (refer to the endpoint discussion for further details). Taken together, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VIII-X, 8.7, in accordance with Annex XI, 1.5, 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

There are no data on the toxicity to reproduction available for Fatty acids, C16-18 (even numbered), esters with glycerol oligomers. However, in EFSA’s scientific opinion on the re-evaluation of polyglycerol esters of fatty acids (PEPA, E 475), as a food additive, it is stated that the safety of polyglycerols and specific fatty acids has recently been assessed and no adverse effects were identified in the available studies. The reproductive toxicity studies showed no adverse effects of PEFA but had major limitations (EFSA, 2017). The reproductive toxicity of the registered substance was assessed based on the available data from the source substances 1,2,3 -propanetriol, homopolymer, diisooctadecanoate (CAS 63705-03-3) and 2,3-dihydroxypropyl octadec-9-enoate (CAS 111-03-5). In accordance with Regulation (EC) No. 1907/2006 Annex XI, 1.5 “Grouping of substances and read across” and following the Read across assessment framework (RAAF, ECHA 2017) read across from analogue substances have been applied to support the human health hazard assessment of Fatty acids, C16-18 (even numbered), esters with glycerol oligomers.

 

CAS 63705-03-3

 

A study investigating the toxicological effects of the test item 1,2,3 -Propanetriol, homopolymer, diidoctadecanoate (CAS 63705-03-3) to rats according to OECD guideline 422 is available. 1,2,3 -Propanetriol, homopolymer, diidoctadecanoate was administeredto the rats by gavage, using corn oil as vehicle, at doses of 100, 300 and 1000 mg/kg bw/day; the control group received the vehicle only. To meet guideline requirements concerning number of pregnant females per group, male and female rats were added in a second delivery for breeding due to reduced fertility observed in all groups of the first delivery. It is believed, that a disturbance of the light / dark cycle was the reason for the reduced mating rate of the females of the first delivery. The additional animals ran through the whole study as the animals from the first delivery with the exception that the males went to necropsy on day 24 after mating period and not on day 16 as the males of the first delivery (logistical reasons). Therefore, 1,2,3-Propanetriol, homopolymer, diisooctadecanoate was administered to male rats for up to 28 days (first delivery) and up to 41 days (second delivery) and to female rats for 14 days prior to mating, through the mating and gestation periods until the F1 generation reached day 4 post partum.

Because an impact of the light/dark cycle disturbance during the study on these results (a prolonged duration of gestation and an increased post-implantation loss was observed at the high dose) could not be excluded, the study was repeated with a third animal delivery of control and high-dose (1000 mg/kg bw/day) groups under proper light conditions. Test item was administered to 12 male rats per group for up to 33 days and to 12 female rats per group for 14 days prior to mating, through the mating and gestation periods until the F1 generation reached day 4 post partum. All animals survived until scheduled necropsy. There were no treatment-related clinical signs or effects on fuctional observation battery or locomotor activity. No test-titem related findings were noted during the clinical laboratory investigations.

At necropsy, liver and kidney weights were slightly increased at 1000 mg/kg bw/day in both sexes of the first and second delivery, which was confirmed in animals of the third delivery except for kidney weights in females. These changes were considered compound-related, but not adverse, since there was no evidence for an impairment of organ functional by clinical pathology and histopathology. There were no test item-related gross pathological or histopathological abnormalities.

Overall at 1000 mg/kg bw/day, food consumption and body weight gain were transiently reduced in males only at the beginning of the treatment period which was considered to be not adverse.

The mean duration of gestation was slightly higher than in controls and the post-implantation loss was increased (up to 16.2% versus 6.6% in controls), which was borderline regarding the historical control data (3.3% - 14.4% as a percentage of total implantations). At 1000 mg/kg bw/d some changes in clinical biochemistry were noted in females. Although these effects were not dose-dependant and within the historical control range, a test item-related effect can´t be excluded. Therefore it is possible that the higher implantation losses and reduced litter size at 1000 mg/kg bw/d were induced by maternal toxicity, even if the observed effects are not regarded as adverse to the parental animals. According to the applicant, the borderline effects on post-implantation losses and litter size, should not be regarded a separate toxicity to reproduction.

Based on these results, the NOAEL (No Observed Adverse Effect Level) for parental toxicity and for reproduction and development toxicity was considered to be 1000 mg/kg body weight/day. There was no evidence for reproduction toxicity and the effects reported with respect to developmental toxicity were related to maternal toxicity.

 

CAS 111-03-5

 

A GLP-compliant reproductive toxicity screening study according to OECD 422 was performed with 2,3-dihydroxypropyl oleate at dose levels of 100, 300 and 1000 mg/kg bw/day (Yamaguchi, 2005). Male and female Sprague Dawley rats (12 per sex and group, except for 1000 mg/kg bw/day: only 7 males) received the test substance in corn oil once daily via gavage. A control group, consisting of 7 males and 12 females, was treated with the vehicle alone. The duration of treatment was 42 days (14 days prior to mating and 28 days thereafter) in males and 42-52 days (from 14 days before mating to day 4 of lactation) in females, respectively. Satellite groups of 5 animals per sex, each for the control and test groups, were used to investigate reversibility of effects during a 14-day post-exposure recovery period. In parental animals, no difference in reproductive function was observed compared to controls. Reproductive performance (copulation, fertility, gestation indices) and offspring viability (delivery, live birth, sex ratio and viability indices) in treated animals were comparable to controls. No substance-related changes in organ weights and histopathology of reproductive organs in males and females were observed. Based on the results of the study, the NOAEL for reproductive toxicity in male and female Sprague Dawley rats is ≥1000 mg/kg bw/day. The NOAEL for developmental toxicity was 1000 mg/kg bw/day under the test condition used (screening test).

 

Conclusions:

In conclusion, according to the available data on reproductive toxicity for the source substances 1,2,3 -propanetriol, homopolymer, diisooctadecanoate (CAS 63705-03-3) and

2,3-dihydroxypropyl oleate (CAS 111-03-5) no reproduction toxicity is to be expected.

Effects on developmental toxicity

Description of key information

Oral (OECD 414), rat (m/f): NOAEL developmental = 4280 mg/kg bw/day

Read-across from structural analogue source substance Medium Chain Triglycerides (MCT).

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions Parenteral route of application, only two dose levels, number of corpora lutea not reported

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

parenteral route of application, only two dose levels, number of corpora lutea not reported

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

other: Crl:CD BR rats

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Portage, MI, USA
- Weight at study initiation: 150 - 200 g
- Housing: individually housed in suspended stainless steel cages
- Diet: Certified Rodent Chow 5002 meal (PMI Feeds, Inc.), ad libitum; except during dose administration
- Water: ad libitum; except during dose administration

ENVIRONMENTAL CONDITIONS
Environmental controls in the animal rooms were set to maintain temperature, relative humidity, and light/dark cycle

Route of administration:

intravenous

Vehicle:

other: 20% lipid emulsion was created, no further specified

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The dose was administered daily to rats by intravenous infusion via a caudal vein using a Quik-Cath Teflon catheter connected to a syringe using an extension set. Doses for rats and rabbits were delivered using syringe pumps.

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

Time-mated Crl:CD BR rats were shipped by the supplier on GD 4.

Duration of treatment / exposure:

Day 6-15 of gestation

Frequency of treatment:

4 h/day, 7 days/week

Duration of test:

Day 20 of gestation / post mating

Remarks:

Doses / Concentrations:
1000 and 4280 mg/kg bw/day
Basis:
nominal conc.

No. of animals per sex per dose:

25 or 29 females (P)

Control animals:

other: 0.9% saline

Details on study design:

- Dose selection rationale: The dose rate was based on previous preclinical studies (unpublished). The 1 g/kg dose approximates the proposed clinical dosage. The 4.28 g/kg dose is the highest dose administered in preclinical studies that did not produce narcosis (unpublished).
- Selection of exposure route: The intravenous route of administration was used because the lipid emulsion is intended for intravenous human administration as a component of parenteral nutrition. The dose was administered daily to rats by intravenous infusion for approximately 4 h/day on GD 6 through 15 via a caudal vein using a Quik-Cath Teflon catheter connected to a syringe using an extension set.
- Dose volumes: 5 and 21.4 mL/kg bw

Maternal examinations:

CLINICAL SIGNS AND CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were observed twice daily (AM and PM) for mortality and moribundity. On dosing days, animals were observed predose, immediately (within 5 min) postdose, and approximately 1 h after completion of dosing.

BODY WEIGHT: Yes
- Time schedule for examinations: daily on GD 5 - 20

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule for examinations: Food consumption data were collected daily beginning on the day of receipt

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day GD 20

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

Fetal examinations:

- External examinations: half litter; live fetuses were weighed, examined externally, sexed, then euthanatised
- Soft tissue examinations: half litter; Following completion of fetal examinations, soft tissue malformations were preserved in 10% phosphate-buffered formalin
- Skeletal examinations: half litter; Viscera were removed and discarded, and fetuses were processed and examined for skeletal variations and malformations; skeletal specimens were retained in glycerine
- Head examinations: half litter; A mid-coronal slice of the head was made to expose the internal structure of the brain for examination; the eyes were excised and examined.

Statistics:

The litter was the experimental unit for evaluation. All comparisons were made with the control group (Group 1). For rats, feed consumption, dam body weights, and fetal body weights were summarized with means and standard deviations calculated using an Excel spreadsheet program (Microsoft Corporation). For rabbit data, Levene's test (Levene, 1960) was done to test for variance homogeneity. In the case of heterogeneity of variance at p « 0.05, rank transformation was used to stabilize the variance. Analysis of variance [ANOVA (Winer, 1971a)] was done on the homogeneous or transformed data. If the ANOVA was significant, Dunnett's t test (Dunnett, 1964) was used for pairwise comparisons between groups. One-way ANOVA was used to analyze body weights, body weight changes, feed consumption, and cesarcan section data. As appropriate, rat and rabbit fetal abnormality data were analyzed by the Cochran-Armitage test (Thalcur et al, 1985) for trend and departure and by the Fisher-Irwin exact test (Thalcur et al., 1985). One-way analysis of covariance [ANCOVA (Winer, 1971b)] was used to analyze fetal body weights (males, females, and combined) with the number of fetuses in the litter as the covariate. As appropriate, for values calculated to analyze litter data or mean fetal weight data, values were first derived within the litter, and the group mean values were derived as a mean of individual litter values. Group comparisons were analyzed at the 5.0 and 1.0% two-tailed probability levels.

Indices:

early and late resorptions, % fetuses dead/live, % postimplantation loss

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: effects in the highest dose group

Details on maternal toxic effects:
The only test article-related findings observed were associated with tail lesions in both test article groups and the occasional occurrence of red tinged urine (8 of 29) and vaginal bleeding (1 of 29) in the high-dose group. The tail findings were predominantly those of discoloration and ulceration. Incidences were 1/25, 14/25, and 23/29 for these tail lesions in the control, low-, and high-dose groups, respectively, and ranged from mild to severe with some necrosis and partial loss of the tail.
These findings were generally considered to be related to occurrences of observed extravasation of the MCT:LCT lipid test article into perivascular areas. Evaluation of urine collected from one high-dose animal suggested a bacterial infection of the urogenital tract. Clinical observations for this animal included occasional red-tinged urine and vaginal bleeding. This rat was noted as having a large urinary bladder stone and kidney hydronephrosis at necropsy.
There were no marked differences in mean body weights or feed consumption for the low-dose group compared with those of the control group. However, the high-dose group consistently exhibited lower body weights beginning 1 day after dose administration throughout the remainder of the study. Feed consumption was also notably lower for nine of the ten days during dosing, with an increase in feed consumption after completion of dose administration (GD 15). The decrease in feed consumption at the high-dose level was expected based on the high-caloric nature of the test article.
Necropsy findings were primarily related to tail effects and were observed for most rats in the high-dose group and some rats in the low-dose group. In addition to tail effects, there was a trend toward an increasing incidence of necropsy findings in the high-dose group, including enlarged lymph nodes, enlarged spleen, hydronephrosis/enlarged renal pelvis, small thymus, and small red lung foci. These changes indicated that the high-dose group was likely exhibiting test article effects.
There was a slight trend toward decreasing mean gravid uterine weights in proportion to increasing test article dose; however, due to the large variability between groups, group mean uterine weights appeared to be similar. With the exception of one control dam, all females were pregnant and had at least one viable fetus/litter (i.e., no dams had total resorptions).

Key result

Dose descriptor:

NOAEL

Effect level:

4 280 mg/kg bw/day

Based on:

test mat.

Remarks:

(i.v. application)

Basis for effect level:

other: developmental toxicity

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Remarks:

(i.v. application)

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There were no significant group differences in preimplantation or postimplantation loss or in the mean percentage of live or resorbed fetuses; no dead fetuses were present. Mean fetal sex ratios of the test article-treated groups were comparable with those of controls. There were no apparent effects on mean fetal body weight (combined, males, or females). There were no test article-related fetal external, soft tissue, or skeletal observations.
A high incidence of folded retina in control and test article-treated groups was attributed to shrinkage of the retina during storage in alcohol prior to being transferred to Bouin's fixative.
Omphalocele and cleft palate were observed in one fetus each in the control and high-dose groups, respectively. The only fetal skeletal malformation observed (malformed/misshapen skull bones) was present in one fetus each from two control litters. Fetal skeletal variations were present in control and test article-treated groups in a nondose-related pattern.

Key result

Dose descriptor:

NOAEL

Effect level:

4 280 mg/kg bw/day

Based on:

test mat.

Remarks:

(i.v. application)

Sex:

male/female

Basis for effect level:

other: developmental toxicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

Upon intravenous application of 4280 mg/kg bw/day during gestational Days 6 - 15, medium chain triglycerides exerted no teratogenic effects in rats.

Reference 2

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Remarks:

Summary of available data used for the endpoint assesssment of the target substance

Adequacy of study:

key study

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Control animals:

other: 0.9% saline

Key result

Dose descriptor:

NOAEL

Effect level:

4 280 mg/kg bw/day

Based on:

test mat.

Remarks:

(i.v. application)

Basis for effect level:

other: developmental toxicity

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Remarks:

(i.v. application)

Basis for effect level:

other: maternal toxicity

Key result

Dose descriptor:

NOAEL

Effect level:

4 280 mg/kg bw/day

Based on:

test mat.

Remarks:

(i.v. application)

Sex:

male/female

Basis for effect level:

other: developmental toxicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

As detailed in the analogue justification, it is considered that the target and the source substances are unlikely to lead to differences in reproduction toxicity potential. Upon intravenous application of 4280 mg/kg bw/day during gestational Days 6 - 15, the source substance exerted no teratogenic effects in rats. Therefore, the target substance is also not expected to be teratogenic in rats.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

4 280 mg/kg bw/day

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable (Klimisch score 2) study from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (refer to the endpoint discussion for further details). Taken together, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VIII-X, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Toxicity to reproduction: other studies

Description of key information

There are no data on the developmental toxicity available for Fatty acids, C16-18 (even numbered), esters with glycerol oligomers. However, in EFSA’s scientific opinion on the re-evaluation of polyglycerol esters of fatty acids (PEPA, E 475) as a food additive, it is stated that the safety of polyglycerols and specific fatty acids has recently been assessed and no adverse effects were identified in the available studies.The developmntal toxicity studies showed no adverse effects of PEFA but had major limitations(EFSA, 2017).

The developmental toxicity of the registered substance was assessed based on the available data from the source substance medium Chain Triglycerides (MCT). In accordance with Regulation (EC) No. 1907/2006 Annex XI, 1.5 “Grouping of substances and read across” and following the Read across assessment framework (RAAF, ECHA 2017) read across from an analogue substance has been applied to support the human health hazard assessment of Fatty acids, C16-18 (even numbered), esters with glycerol oligomers.

 

 

Medium Chain Triglycerides (MCT): 

In a prenatal developmental toxicity study performed similar to OECD guideline 414, the effects of medium Chain Triglycerides (MCT) on pregnant Crl:CD BR rats were investigated following treatment from gestation day 6 to 15 (Henwood, 1997). The animals (25 or 29 for the low and high dose, respectively) received the test substance in 20% emulsion containing a 3:1 ratio of MCT:LCT (Long Chain Triglycerides) at doses of 1000 and 4280 mg/kg bw/d by intravenous infusion via the caudal vein for a 4-h period per day. A control group of 25 animals received 0.9% saline. On Day 20 of gestation, dams were sacrificed and maternal as well as foetal examinations were performed. At 4280 mg/kg bw/day, maternal toxicity occurred and involved an increased incidence of necropsy findings on the tail, which was considered to be due to extravasation of the MCT:LCT lipid test article into perivascular areas. In addition to tail effects, there was a trend toward an increasing incidence of necropsy findings in the high-dose group, including enlarged lymph nodes, enlarged spleen, hydronephrosis/enlarged renal pelvis, small thymus, and small red lung foci. There were no significant group differences in pre-implantation or post-implantation loss or in the mean percentage of live or resorbed foetuses in treated animals. No dead foetuses were found and the mean foetal sex ratios and the mean foetal body weight of the treated animals were comparable to those of controls. No test substance-related external, soft tissue, or skeletal malformations were noted in the foetuses of exposed dams. Based on the results of the study, the NOAEL for developmental toxicity was established at ≥ 4280 mg/kg bw/day. With respect to maternal toxicity, the NOAEL was set at 1000 mg/kg bw/day.

 

In the same study, 15 pregnant Hra:(NZW)SPF rabbits were treated daily with MCT (Medium Chain Triglycerides) by a 5-h intravenous infusion via a marginal ear vein at doses of 1000 and 4280 mg/kg bw/d from gestation day (GD) 6 through 19 (Henwood, 1997). A similar constituted control group was injected with 0.9% saline. Administration of the test substance resulted in lower maternal food consumption and significant body weight loss during treatment at 4280 mg/kg bw/day. All pregnant animals had at least one viable foetus at scheduled caesarean section on GD 29. The observed foetal effects (i.e. increased resorptions, decreased foetal body weights, and increased incidence of morphological anomalies) were assumed to be the result of dietary deprivation, maternal toxicity, or both, rather than a direct teratogenic effect of the test article. Based on these results, the NOAEL for maternal as well as developmental toxicity was set at 1000 mg/kg bw/day in rabbits.

Justification for classification or non-classification

Based on read-across from structurally similar substances, the available data on reproductive and developmental toxicity do not meet the criteria for classification according to Regulation (EC) No. 1272/2008, and are therefore conclusive but not sufficient for classification