Dodecanoic acid, ester with oxybis[propanediol]

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP-Guideline study, tested with the source substance glycerol monooleate (CAS No. 111-03-5). 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), 192-249 g (females)
- Housing: animals were housed individually 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): > 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Aliquots of the dosing solution (prepared in corn oil) corresponding to the amount of daily administration were stored at 2-6 °C in the dard. The stability of the dosing solution was 7 days in a refrigerator and one day at room temperature. Thus, the dosing solutions were used within 7 days.

VEHICLE
- Justification for use and choice of vehicle: 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 2 weeks
- 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

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

Males: 42 days (14 days before 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 males and females (including 5 males of the control and high-dose group as recovery group )
5 additional females (in satellite control and high-dose group)

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:
Prior to the main study, two dose range finding studies were performed. In the first study, 2000 mg/kg bw of test substance were administered for 3 days in male and female rats. No abnormalities were found in general condition and body weight. In the second study, dose levels of 330, 100, 300 and 1000 mg/kg bw/day were administered for 14 days. No abnormalities of general condition, body weight, food consumption, haematological findings, blood biochemical findings, gross pathology and organ wight were found. Therefore, 1000 mg/kg bw/day was selected as the highest dose level for the main study.
- 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: prior to the first administration and weekly thereafter

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

Estrous cycle number before and during administration untill mating were observed (no further information).

Sperm parameters (parental animals):

Parameters examined in P male parental generations:
testis weight and epididymis weight and any 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 on Day 43
- Maternal animals: all surviving animals on Day 5 of lactation

GROSS NECROPSY
- Gross necropsy consisted of body surface, mucous membranes and internal organs.

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 was 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 males (satellite group): significant increase, non-adverse

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

1000 mg/kg bw/day males (satellite group): significant increase, 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):

300 mg/kg bw/day females: benign fibroadenoma of the mammary gland in one animal, 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 mortalities and no clinical signs of toxicity were observed.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
No changes in body weight and weight gain were observed during the treatment period.
During the recovery period, in males of the high-dose group a significant increase in body weight was noted, probably due to a tendency of the control group animals to lose body weight. One male in the control group showed a significant decrease in body weight during the recovery period. However, no other abnormalities were observed in this male.

FOOD CONSUMPTION (PARENTAL ANIMALS)
No differences in food consumption were observed during the administration period in the test groups.
In satellite females of the high-dose, a significant increase in food consumption was found on Day 14 of administration. However, the finding was regarded as incidental and not substance-related, since the food consumption of the corresponding control group was relatively low on the respective day.

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

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
No test substance-related changes were observed within the study. Only one control animal had decreased sperm and the respective pair animal was not pregnant.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No test substance-related changes were observed during the study period.

ORGAN WEIGHTS (PARENTAL ANIMALS)
In males of the low-dose group, after the administration period a significant decrease in the absolute weight of seminal vesicles was observed. Furthermore, a significant decrease in the relative spleen weight of females in the low dose group was apparent. These changes were considered not to be compound-related as no corresponding findings were apparent in the histopathological examination and no dose-relationship was observed.
After the recovery period, the relative weight of pituitary in males of the high-dose group was significantly decreased. In addition, high-dose females showed a decrease in the relative thyroid weight. These effects were also not considered to be substance-related because no abnormalities of were reported regarding these organs after the administration period.

GROSS PATHOLOGY (PARENTAL ANIMALS)
Gross pathology showed no substance-related changes. No differences were found in breeding pairs which were not successful at mating and in those which were successful at mating but not pregnant.
After the administration period, in one male of the control reddish thymus was noted and in one female of the mid-dose group subcutis mass was found. 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 of the high dose group.

HISTOPATHOLOGY (PARENTAL ANIMALS)
No test substance-related changes were observed in histopathological examinations.
Furthermore, no differences were found regarding spermatogenic cycle.
In male control animals, accumulation of foam cell, microgranuloma in the liver, solitary cyst in the kidnes and haemorrhage of the thymus were observed with low incidence. In female animals of the control group, artery mineralization of the lung, hyaline cast and cortex fibrosis of the kidney were apparent with low incidence in control animals only. Both in the high-dose group and in the control group, myocardial degeneration/fibrosis, extramedullary haematopoiesis of the spleen, foam cell accumulation of the lung, and focal liver necrosis, were found with low incidence in control and test groups. In all males of the high-dose and control group, hyaline droplet of proximal tubular epithelium in the kidney was found. Furthermore, in all males and females of the control and high dose group, brown deposit pigment and extramedullary haematopoiesis in spleen were found without differences between control and test group.
Incidental not substance-related findings of lymphocyte interstitium infiltration in prostate were found in one male of the high-dose group and interstitial focal inflammation in the lung and focal necrosis in the liver of one female of the high dose group were observed.
No abnormalities were found in the uterus and ovaries in the non-pregnant females and the unsuccessful copulation females of the control and high-dose groups, respectively. Degeneration of seminiferous tubules of testis, decrease in sperm and atrophy in prostate was observed in one control male only.

HISTOPATHOLOGY: NEOPLASTIC (PARENTAL ANIMALS)
In the mid-dose group, mass on abdomen was found in one female after 40 days of administration. This subcutaneous tumour of the mammary gland was a benign fibroadenoma and generated naturally and was therefore not considered to be substance related.

OTHER FINDINGS (PARENTAL ANIMALS)
HAEMATOLOGY
No changes in the observed parameters were noted. However, a significant decrease in APTT was observed in males of the low and mid-dose groups in comparison to the control group. The finding was considered not to be of toxicological relevance; no dose-relationship was observed and the value was still within the reference range.

CLINICAL CHEMISTRY
A significant decrease in inorganic phosphate was observed in females of the low and high-dose group. However, this change was not regarded as test substance-related, since no dose-relationship was observed and most of the individual data were within the reference ranges. Furthermore, choline esterase was increased in females of the high dose group after the recovery period but was still was within the reference range. Since the difference was only slight and no change was observed after the administration period, the effect was considered not to be substance related.

URINALYSIS
No significant changes in urine parameters were found during the administration and recovery periods.

NEUROBEHAVIOUR
No abnormalities were observed for the sensory/reflex function, landing foot, grip strength and motor activity during the administration period. During the recovery period, motor activity increased from 0 to 60 min, but not from 0 to 30 min in high dose females. This effect was not considered to be substance-related since the observed difference was slight and no change was observed during and after the administration period.

Dose descriptor:

NOAEL

Remarks:

reproduction

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:

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

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 visceral variations, not substance related

Histopathological findings:

not examined

VIABILITY (OFFSPRING)
No differences in viability between control and test groups were observed.

CLINICAL SIGNS (OFFSPRING)
No clinical signs were observed in any animal.

GROSS PATHOLOGY (OFFSPRING)
No substance-related effects were found during gross necropsy. Several visceral variations were found with low incidence in the control and test groups (see Table 1 under “Any other information on results incl. tables”).

Dose descriptor:

NOAEL

Remarks:

developmental

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

Table 1. Visceral findings of pups.

Dose [mg/kg bw/day]	Control	100	300	1000
No. of pups examined	161	169	165	153
No of pups with visceral malformations	0	0	0	0
No. of pups with visceral variations	1	3	5	6
Visceral variations
Thymic remnant in neck	1	0	1	2
Persistent left umbilical artery	0	1	0	2
Convoluted ureter	0	1	3	2
Dilatation of renal pelvis	0	0	1	0
Dilatation of ureter	0	1	2	0

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2 due to read-across) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common functional group(s) and common precursors/breakdown products (refer to the endpoint discussion for further details).

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No data are available on the toxicity to reproduction of Reaction product of lauric acid and oxybis(propanediol) (List No. 700-672-1). In order to fulfil the standard information requirements set out in Annex VIII, 8.7.1, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006 read-across from the structurally related surrogate substance, glycerol oleate (CAS No. 111-03-5) was considered for read-across and assessment was conducted based on an analogue approach.

Glycerol oleate (CAS No. 111-03-5) was tested for toxicity to reproduction in a 28-day screening study according to OECD guideline 422 under GLP conditions (Yamaguchi).

Prior to the main study, two dose range finding studies were performed. Based on the results of the preliminary studies, 1000 mg/kg bw/day was selected as the highest dose level for the main study. Groups of 12 Sprague-Dawley rats per sex were given the test substance by gavage at dose levels of 100, 300 and 1000 mg/kg bw/day including 5 males of the control and high-dose group which were allowed 14 days of recovery. For the assessment of reproduction and developmental toxicity 5 females were added to a satellite control and high-dose group. A concurrent negative control group receiving the vehicle corn oil only was included in the testing as well.

Examinations revealed no clinical signs or mortality in relation to the test substance. No changes in body weight (gain) and food consumption were observed during the treatment period which were considered to be of toxicological relevance. Furthermore, findings in haematology and clinical chemistry in single groups were considered to be of no toxicological relevance. No toxicological relevant changes were noted neurobehavioural parameters (for further details refer to “Repeated dose toxicity”). In low-dose males, a significant decrease in absolute weight of seminal vesicles and in the low-dose female group a significant decrease in the relative weight of spleen was observed. These changes were considered not to be compound-related as no corresponding findings were apparent in the histopathological examination and no dose-relationship was observed. Moreover, gross pathology and histopathology showed no substance-related changes in any animal. Furthermore, no differences were found regarding spermatogenic cycle and no abnormalities were found in the uterus and ovaries in the non-pregnant females and the unsuccessful copulation females of the control and high-dose groups, respectively. In addition, no treatment-related effects on oestrous cycle and reproductive performance were observed within the study.

Moreover, viability of the offspring was not affected by treatment. There were no toxicologically relevant clinical signs in the offspring. Furthermore, viability, viability index and sex ratio remained unaffected by the treatment. At pathology no treatment-related macroscopic findings were observed in the offspring. Several visceral variations were found with low incidence in the control and test groups. However, the variations were considered to be not treatment-related effects.

Based on the lack of toxicological relevant effects, a NOAEL of 1000 mg/kg bw/day (m/f) for reproduction toxicity was identified in this study. Furthermore, no adverse effects in the offspring were observed and a NOAEL of 1000 mg/kg bw/day for developmental toxicity was considered.

Short description of key information:
Based on read-across from a surrogate substance the oral NOAEL (fertility) of the test substance is 1000 mg/kg bw/day (OECD 422, GLP).

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

Effects on developmental toxicity

Description of key information

Based on read-across and a weight of evidence approach the NOAEL for developmental toxicity/ teratogenicity (oral exposure) is 1000 mg/kg bw/day (OECD 414)

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2) and consistent studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common functional group(s) and common precursors/breakdown products (refer to endpoint discussion for further details).

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

No data are available on the developmental toxicity of Reaction product of lauric acid and oxybis(propanediol) (List No. 700-672-1).

Therefore, in order to fulfil the standard information requirements set out in Annex VIII, 8.7.2, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006 read-across from on the structural surrogates medium chain triglycerides and dipropylene glycol (CAS No. 25265-71-8) were considered for read-across and assessment was conducted based on an analogue and weight of evidence approach.

In a study on prenatal developmental toxicity, medium chain triglycerides (MCT) were administered to rats and rabbits in a protocol similar to OECD guideline 414 (Henwood, 1997). The test substance was given to Crl:CD BR rats intravenously via the caudal vein and to Hra:(NZW)SPF rabbits via a marginal ear vein as a 20% lipid emulsion containing a 3:1 ratio of MCT : LCT (Long Chain Triglycerides). Doses of 1000 and 4280 mg/kg bw/day were daily administered to groups of 25 or 29 female rats from Day 6-15 of gestation and from Day 7-19 to 15 female rabbits, respectively. Concurrent control animals received a 0.9% saline solution.

In the maternal rats, lower body weights and decreased food consumption in the high-dose group were apparent during administration, possibly due to the high-caloric nature of the test material.

Furthermore, red tinged urine (8/29) and vaginal bleeding (1/29) as well as tail lesions were observed in the high-dose group. Substance-related incidences of tail lesions (1/25, 14/25, and 23/29) in the control, low-, and high-dose groups ranged from mild to severe discoloration and ulceration with some necrosis and partial loss of the tail. The tail lesions were probably the result of the observed extravasation of the lipid test article into perivascular areas.

At necropsy, findings on tail effects were confirmed. Additionally, in the high-dose group a probably treatment-related trend towards increased incidence of necropsy findings was observed, including enlarged lymph nodes, enlarged spleen, hydronephrosis/enlarged renal pelvis, small thymus, and small red lung foci.

In maternal rabbits one control and one animal in the high- dose group died during the study. No treatment-related findings were observed at necropsy in any parental animal. Clinical signs in the treatment groups were limited to faecal findings i.e. increased incidence of few or no faeces.

Similarly to the findings in rats, maternal rabbits showed lower body weights and decreased food consumption in the high-dose group during administration and during the early post-treatment period, probably due to the high-caloric nature of the test material.

Fetal examinations in rats, including litter size and weights, sex ratio, external or soft tissue and skeletal abnormalities, preimplantation or postimplantation loss and the mean percentage of live or resorbed foetuses, revealed no toxicological relevant effects.

In rabbits, post-implantation loss was significantly higher and the mean percentage of live fetuses/litter was correspondingly lower in the high-dose group as well as the mean fetal body weights. Reduced fetal weights may have been secondary to the decreased maternal feed consumption observed at this dose level. Because treated females were consuming significantly less feed than control females, the fetal effects noted (especially the postimplantation loss and decreased fetal weights) may have been due to dietary deprivation, as opposed to a direct effect by the test article.

Furthermore, in this group significantly more fetuses had external morphological abnormalities in comparison to the control group. The most notable findings were rachischisis and short tail formation. Soft tissue abnormalities were present in the treatment groups as single fetal or litter incidences restricted to three or four litters/group, suggesting a litter-related occurrence. Also skeletal abnormalities were significantly higher in the high-dose group and incidence of fetuses/litters with vertebral column malformations was higher, even though not statistically significant, than that of the control group.

Due to the decreased maternal food consumption in the high-dose group, the reduced fetal weights and the fetal effects noted for rabbits were assumed to be the result of dietary deprivation and/or maternal toxicity, rather than a direct teratogenic effect.

In this study, the NOAEL for maternal toxicity for rats and rabbits was considered to be 1000 mg/kg bw/day. Moreover, the NOAEL for developmental toxicity was considered to be 4280 mg/kg bw/day for rats. In rabbits the NOAEL for developmental toxicity was considered to be 1000 mg/kg bw/day due to the adverse fetal findings in the high-dose group.

Additionally, prenatal developmental toxicity with the surrogate substance dipropylene glycol was investigated in rats and rabbits equivalent to OECD guideline 414 under GLP conditions (Bates, 1992).

The test substance was orally applied by gavage to Crl:CD® rats and to New Zealand White rabbits. Doses of 800, 2000 and 5000 mg/kg bw/day for rats and 200, 400, 800 and 1200 mg/kg bw/day for rabbits were daily administered to groups of 26 or 27 female rats from Day 6-15 of gestation and to groups of 24 female rabbits from Day 6-19, respectively. Concurrent control animals received distilled and filtered water.

In rats, maternal lethality was observed in one and two animals of the 2000 and 5000 mg/kg bw/day group, respectively. As necropsy of these animals failed to determine the reason of death, mortalities were considered to be related to test substance exposure. Clinical signs observed in confirmed-pregnant animals during and after exposure to 2000 and 5000 mg/kg bw/day included ataxia, weight loss, lethargy, unstable gait, piloerection and morbidity. Moreover, maternal body weights were significantly decreased from GD 9-20 in high-dose animals and concurrently, body weight gains of high-dose animals was significantly reduced during treatment and gestation period when compared to controls. In these animals, the corrected maternal weight gain was significantly reduced, as well. A significant decrease in absolute and relative food consumption accompanied the reduction in body weight in the high-dose group during treatment (GD 6-15) and across gestation (GD 0-20). The relative water consumption by animals of the high-dose group was increased for all measurement periods between GD 9 and GD 18, as well. Organ weight examinations showed significantly increased relative liver weight of maternal animals of the mid- and high-dose groups.

At necropsy, 74% (20/27), 74% (20/27), 96% (24/26), and 83.0% (20/26) of the mated animals in the control and treatment groups (800, 2000 and 5000 mg/kg bw/day, respectively), were confirmed to be pregnant after uterine examination, and thus did not reveal any treatment-related changes.

In maternal rabbits, no mortality and no dose-related clinical signs of toxicity occurred during the study in any animal. No significant changes in pregnancy rates were observed and maternal body weights and food consumption were not significantly different in treated groups when compared to controls. Moreover, organs weights of kidney and liver were not changed in the treated animals. One control animal and one animal of the 1200 mg/kg bw/day group aborted prior to GD 30. All of the remaining pregnant animals had one or more live fetuses on GD 30. In the high-dose group, examination of the ovaries from pregnant animals revealed a significant decrease in the number of corpora lutea compared to control animals. This observation was considered to be not treatment-related, since exposure of the maternal animals did not begin until approximately 6 days after ovulation. The number of ova produced by the animals in the high-dose group was less than in control animals. However, the fertility rate among these animals was high. Thus, the mean number of implantation sites in exposed groups was equivalent to control. The two factors low corpora lutea and normal implantation rate caused the decrease in the preimplantation loss rate of the high-dose group compared to controls.

Fetal examinations in rats, revealed no treatment-related effects on pre- or post-implantation loss and no significant differences in the average of corpora lutea, implants, live foetuses, early deaths, late deaths, or non-live implants per litter. Mean body weights, per litter of treated animals were associated with a significant decreasing linear trend, but did not show a significant difference from control. Body weights in treated groups were not significantly different from control. No significant incidences of malformations or variations were observed in external, visceral and skeletal examinations of the fetuses. The percentage of malformed fetuses per litter was somewhat higher in the exposed groups than in the control (10.49, 9.01, and 11.61% in the 800, 2000 and 5000 mg/kg bw/day group compared to 6.61% in the control group). This increase was due to the visceral finding of enlarged lateral ventricles of the brain in approximately 8, 15, 14, and 16% of the fetuses examined in the control, 800, 2000 and 5000 mg/kg bw/day group, respectively. No significant effects were noted in the prevalence of variations in the examined fetuses.

Fetal examinations in rabbit, showed no significant differences between treated groups and the control group in the average number of implants, live fetuses, early deaths, late deaths, or non-live implants per litter. No alterations in the percentage of post-implantation loss per litter and average fetal body weight per litter or in the percentage of male fetuses per litter were observed. External, visceral, or skeletal examination of morphological abnormalities did not reveal any statistically significant, treatment-related effects. The only exception was a significant linear trend associated with the number of litters showing visceral malformations. No significant effects were noted in the prevalence of variations in the fetuses of this study.

In the study, the NOAEL for maternal toxicity for rats was considered to be 800 mg/kg bw/day and 1200 mg/kg bw/day for rabbits, respectively. Moreover, the NOAEL for developmental toxicity was considered to be 1000 mg/kg bw/day for rats. In rabbits the NOAEL for developmental toxicity was considered to be 1200 mg/kg bw/day.

 

Justification for selection of Effect on developmental toxicity: via oral route:
Hazard assessment is conducted by means of read-across from structural surrogates in a weight of evidence approach. No study was selected since all available studies are equally reliable and provide dose descriptors above the limit dose value (> 1000 mg/kg bw/day).

Justification for classification or non-classification

Based on the available data of the surrogate substances following an analogue and weight of evidence approach, the available data on toxicity to reproduction of Reaction product of lauric acid and oxybis(propanediol) (List No. 700-672-1) do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.

No information is available on effects via lactation.