Registration Dossier

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
17 Feb - 07 April 2010
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP-Guideline study, tested with the source substance Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates (CAS 91052-13-0). According to the ECHA guidance document 'Practical guide 6: How to report read-across and categories' (ECHA, 2012), the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-aross 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:
other: Crl:WI(Han) (outbred, SPF-Quality)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories France, L'Arbresle Cedex, France
- Age at study initiation: approximately 12 weeks
- Weight at study initiation: 277-353 g (males), 180-228 g (females)
- Housing : 5 animals/sex/cage in Macrolon cages (MIV type, height 18 cm). This was also applicable for Main females and Recovery animals throughout the complete treatment period. Sterilised sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom) were supplied.
- Diet: pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany), ad libitum
- Water: tap-water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 3 (actual range: 19.7-21.9)
- Humidity (%): 40-70 (actual range: 22-71)
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

This species and strain of rat has been recognized as appropriate for general and reproduction toxicity studies. The testing laboratory has general and reproduction/developmental historical data in this species from the same strain and source. This animal model has been proven to be susceptible to the effects of reproductive toxicants.
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Formulations (w/w) were prepared daily within 6h prior to dosing and were homogenized to a visually acceptable level.
Adjustment was made for the density of the test substance (0.944), and the specific gravity of the vehicle (1.125).

VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on trial formulations performed at the testing laboratory.
- Purity: polyethylene glycol 400, specific gravity 1.125 (Merck, Darmstadt, Germany)

Dose volume: 5 mL/kg bw
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: max. 14 days
- Proof of pregnancy: evidence of sperm in the vaginal lavage, by staging of the estrous cycle and/or by the appearance of an intravaginal copulatory plug referred to as Day 0 of pregnancy
- After successful mating each pregnant female was caged individually in Macrolon cages (MIII type).

Following a minimum of 14 days of exposure for the males and females, one Repro female was cohabitated with one Main male of the same treatment group, avoiding sibling mating (Charles River supplied non-litter mates). Detection of mating was not confirmed for animal no. 98 which did deliver. The mating date of this animal was estimated at 21 days prior to the actual delivery date. This day was designated Day 0 post-coitum. Once mating had occurred, the males and females were separated. A maximum of 14 days was allowed for mating. After 14 days of mating, females who had not shown evidence of mating were separated from their males.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chemical analyses of formulations were conducted once during the study to assess accuracy, homogeneity and stability. Samples of formulations were analysed for homogeneity (highest and lowest concentration) and accuracy of preparation (all concentrations). Stability in vehicle over 6h at room temperature was also determined (highest and lowest concentration).
The accuracy of preparation was considered acceptable if the mean measured concentrations were 85-115% for suspensions. Homogeneity was demonstrated if the coefficient of variation was ≤10%. Formulations were considered stable if the relative difference before and after storage was maximally 10%.
The concentrations analysed in the formulations of Group 2, Group 3 and Group 4 were in agreement with target concentrations (i.e. mean accuracies between 85% and 115%). The formulations of Group 2 and Group 4 were homogeneous (i.e. coefficient of variation ≤10%) and formulations at the entire range were stable when stored at room temperature for at least 6h.
Duration of treatment / exposure:
41-49 days,
i.e. during 2 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation.
Frequency of treatment:
daily, 7 days/week
Details on study schedule:
Offspring were euthanized at the age of 4 days.
Remarks:
Doses / Concentrations:
100, 300 and 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on the results of a 10-day dose range finding study
Parental animals: Observations and examinations:
Male number paired with, mating date, confirmation of pregnancy, and delivery day were recorded.
Pregnant females were examined to detect signs of difficult or prolonged parturition, and cage debris of these females was examined to detect signs of abortion or premature birth. Any deficiencies in maternal care (such as inadequate construction or cleaning of the nest, pups left scattered and cold, physical abuse of pups or apparently inadequate lactation or feeding) were examined.

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes:

BODY WEIGHT: Yes

FOOD CONSUMPTION AND COMPOUND: Yes

for further details see Section 7.5.1
Oestrous cyclicity (parental animals):
Uterus epithelium was analysed histologically for estrus, proestrus and cystic endometrial glands.
Sperm parameters (parental animals):
Parameters examined in [all/P/F1/F2] male parental generations: testis weight, epididymis weight, histology of testes
Of the first 5 Main males of the control and high dose group, additional slides of the testes were prepared to examine staging of spermatogenesis.
The testes were processed, sectioned at 3-4 micrometers, and stained with PAS/haematoxylin.
Litter observations:
On Day 1 of lactation, all pups were randomized per litter and individually identified by means of subcutaneous injection of Indian ink.
Each litter was examined to determine the following, if practically possible:
Mortality / Viability: The numbers of live and dead pups on Day 1 of lactation and daily thereafter were determined. If possible, defects or cause of death were evaluated.
Clinical signs: At least once daily, detailed clinical observations were made in all animals.
Body weights: Live pups were weighed on Days 1 and 4 of lactation.
Sex: Sex was determined for all pups on Days 1 and 4 of lactation.
Postmortem examinations (parental animals):
SACRIFICE
- Maternal animals which delivered: on lactation Day 5
- Maternal animals which failed to deliver (4 animals): Post-coitum Day 26 (females with evidence of mating) or approximately 21 days after the last day of the mating period (females without evidence of mating).

GROSS NECROPSY
- Gross necropsy consisted of: see details under 7.5.1
The numbers of former implantation sites and corpora lutea were recorded for all paired females.

HISTOPATHOLOGY / ORGAN WEIGHTS
see details under 7.5.1
Postmortem examinations (offspring):
SACRIFICE
- Pups surviving to planned termination were killed by decapitation on lactation Day 5.

All pups were sexed and descriptions of all external abnormalities were recorded. The stomach was examined for the presence of milk. If possible, defects or cause of death were evaluated. Any abnormal pup, organ or tissue as well as pups from females that were killed in extremis were preserved in 10% buffered formalin for possible further examination.
Statistics:
See Section 7.5.1
Reproductive indices:
For each group the following calculations were performed:
- Mating (%): Number of females mated/Number of females paired x 100
- Fertility index (%): Number of pregnant females/Number of females paired x 100
- Conception index (%): Number of pregnant females/Number of females mated x 100
- Gestation index (%): Number of females bearing live pups/Number of pregnant females x 100
- Duration of gestation: Number of days between confirmation of mating and the beginning of parturition
- Percentage live males at First Litter Check: Number of live male pups at First Litter Check/ Number of live pups at First Litter Check x 100
- Percentage live females at First Litter Check: Number of live female pups at First Litter Check/Number of live pups at First Litter Check x 100
- Percentage of postnatal loss Days 0-4 of lactation: Number of dead pups on Day 4 of lactation/Number of live pups at First Litter Check x 100
- Viability index (%): Number of live pups on Day 4 of lactation/Number of pups born alive x 100
Offspring viability indices:
For each group the following calculations were performed:
- Percentage live males at First Litter Check: Number of live male pups at First Litter Check/ Number of live pups at First Litter Check x 100
- Percentage live females at First Litter Check: Number of live female pups at First Litter Check/Number of live pups at First Litter Check x 100
- Percentage of postnatal loss Days 0-4 of lactation: Number of dead pups on Day 4 of lactation/Number of live pups at First Litter Check x 100
- Viability index (%): Number of live pups on Day 4 of lactation/Number of pups born alive x 100
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not specified
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
as found by histological examination of uterus
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
as found by histological examination of testes
Reproductive performance:
no effects observed
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
The assessment of the integrity of the spermatogenetic cycle did not provide any evidence of impaired spermatogenesis, as explored by histological examination of testes.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
Histological examination of the uterus epithelium and endometrial glands did not reveal any treatment related influences on estrous cycle.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No treatment related effects on reproductive parameters were noted.
The mating, fertility and conception indices, precoital time, and number of corpora lutea and implantation sites were unaffected by treatment.

ORGAN WEIGHTS (PARENTAL ANIMALS)
No treatment-related effects observed.

GROSS PATHOLOGY (PARENTAL ANIMALS)
No treatment-related effects observed.

HISTOPATHOLOGY (PARENTAL ANIMALS)
No treatment-related effects observed.

For further details see 7.5.1
Dose descriptor:
NOAEL
Remarks:
parental fertility
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
no
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Number of pups: 432
No toxicologically relevant effects on gestation index and duration, parturition, maternal care and early postnatal pup development (mortality, clinical signs, body weight and macroscopy) were observed.
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: no adverse effects observed
Critical effects observed:
no
Reproductive effects observed:
not specified
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) and consistent 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).
The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII - IX, 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

Analogue justification

Data on the reproduction toxicity of glyceryl undecylenate (CAS 123759-97-7) are not available. The assessment was therefore based on studies conducted with analogue substances as part of a read across approach, which is in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5. For each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the read across approach is provided in the technical dossier (see IUCLID Section 13).

Toxicity to reproduction

CAS 91052-13-0

A combined repeated dose toxicity study with the reproduction / developmental toxicity screening test was performed according to OECD guideline 422 and under GLP conditions in Crl:WI(Han) Wistar rats receiving 100, 300 and 1000 mg/kg bw/day by gavage (Otterdijk, 2010). Dilutions of the test substance in polyethylene glycol or the vehicle alone were administered once daily to groups of 10 male and 5 female rats (main groups) via gavage. In addition, satellite groups of 5 males and 5 females (recovery animals) each for the control and high dose group were used to investigate the reversibility of effects during a 14-day post-exposure recovery period. Furthermore, 10 females (repro animals) were added to each group for the assessment of reproduction and developmental toxicity. The main and recovery groups were exposed for at least 28 days from start of treatment up to termination or start of recovery. Females used for the assessment of reproduction/developmental toxicity were exposed for 41-49 days (during 2 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation). In parental animals, no effects on reproductive function (spermatogenetic and oestrus cycle) or performance (mating, fertility and conception indices; precoital time; number of corpora lutea and implantation sites) were observed after treatment compared with the control animals. The maternal care level was comparable in all groups. The testis weight, epididymis weight, and histological examination of the testes in males as well as the histological examination of the uterus epithelium in females did not reveal any substance-related effects in the parental animals. Therefore, a NOAEL for parental fertility of1000 mg/kg bw/day was derived for male and female rats.

CAS 111-03-5

A GLP-compliant combined repeated dose toxicity study with the reproduction / developmental toxicity screening test was performed according to OECD 422 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: 7 males and 12 females) 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 (spermatogenetic and oestrus cycle) was observed compared to controls. Reproductive performance (copulation, fertility, gestation indices) in treated animals was 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.

 

Overall conclusion for toxicity to reproduction

There are no available studies on the toxicity to reproduction ofglyceryl undecylenate. Therefore analogue read across from 2 source substances was applied. No effects on reproductive parameters/organs were observed in the available screening studies. NOAEL values for reproduction toxicity were all at or above the currently applied limit dose value of 1000 mg/kg bw/day. Therefore, no hazard to reproduction was identified. Based on the available data and following the analogue approach,glyceryl undecylenateis not expected to be toxic to reproduction/fertility.


Short description of key information:
Oral: OECD 422, rat, NOAEL fertility ≥ 1000 mg/kg bw/day
Oral: OECD 422, rat, NOAEL systemic ≥ 1000 mg/kg bw/day

Justification for selection of Effect on fertility via oral route:
Hazard assessment is conducted by means of read-across from a structural analogue. 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
Oral: OECD 422, rat, NOAEL development ≥ 1000 mg/kg bw/day
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
17 Feb - 07 April 2010
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP-Guideline study, tested with the source substance Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates (CAS 91052-13-0). According to the ECHA guidance document 'Practical guide 6: How to report read-across and categories' (ECHA, 2012), the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-aross substance.
Qualifier:
according to guideline
Guideline:
other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
only external abnormalities and mainly macroscopic examination of soft tissues performed, no skeletal examination of pups
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Crl:WI(Han) (outbred, SPF-Quality)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories France, L'Arbresle Cedex, France.
- Age at study initiation: approximately 12 weeks.
- Weight at study initiation: 277-353 g (males), 180-228 g (females)
- Housing : 5 animals/sex/cage in Macrolon cages (MIV type, height 18 cm). This was also applicable for Main females and Recovery animals throughout the complete treatment period. Sterilised sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom) were supplied.
- Diet: pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany), ad libitum
- Water: tap-water, ad libitum
- Acclimation period: At least 5 days prior to start of treatment.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 3 (actual range: 19.7-21.9)
- Humidity (%): 40-70 (actual range: 22-71)
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

This species and strain of rat has been recognized as appropriate for general and reproduction toxicity studies. The testing laboratory has general and reproduction/developmental historical data in this species from the same strain and source. This animal model has been proven to be susceptible to the effects of reproductive toxicants.
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Formulations (w/w) were prepared daily within 6h prior to dosing and were homogenized to a visually acceptable level.
Adjustment was made for the density of the test substance (0.944), and the specific gravity of the vehicle (1.125).

VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on trial formulations performed at the testing laboratory.
- Purity: polyethylene glycol 400, specific gravity 1.125 (Merck, Darmstadt, Germany)

Dose volume: 5 mL/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chemical analyses of formulations were conducted once during the study to assess accuracy, homogeneity and stability. Samples of formulations were analyzed for homogeneity (highest and lowest concentration) and accuracy of preparation (all concentrations). Stability in vehicle over 6h at room temperature was also determined (highest and lowest concentration).
The accuracy of preparation was considered acceptable if the mean measured concentrations were 85-115% for suspensions. Homogeneity was demonstrated if the coefficient of variation was ≤10%. Formulations were considered stable if the relative difference before and after storage was maximally 10%.
The concentrations analyzed in the formulations of Group 2, Group 3 and Group 4 were in agreement with target concentrations (i.e. mean accuracies between 85% and 115%). The formulations of Group 2 and Group 4 were homogeneous (i.e. coefficient of variation ≤10%) and formulations at the entire range were stable when stored at room temperature for at least 6h.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: max. 14 days
- Proof of pregnancy: evidence of sperm in the vaginal lavage, by staging of the estrous cycle and/or or by the appearance of an intravaginal copulatory plug referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged individually in Macrolon cages (MIII type).
Duration of treatment / exposure:
41-49 days, i.e. during 2 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation.
Frequency of treatment:
daily, 7 days/week
Duration of test:
41-49 days
Remarks:
Doses / Concentrations:
100, 300 and 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on the results of a 10-day dose range finding study.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION: Yes

POST-MORTEM EXAMINATIONS: Yes

For further details see Section 7.5.1
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes

Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: No

The numbers of former implantation sites and corpora lutea were recorded for all paired females.
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes, partly (see details below)
- Skeletal examinations: No
- Head examinations: No

Each litter was examined to determine the following, if practically possible:
Mortality / Viability: The numbers of live and dead pups on Day 1 of lactation and daily thereafter were determined. If possible, defects or cause of death were evaluated.
Clinical signs: At least once daily, detailed clinical observations were made in all animals.
Body weights: Live pups were weighed on Days 1 and 4 of lactation.
Sex: Sex was determined for all pups on Days 1 and 4 of lactation.

Pups surviving to planned termination were killed by decapitation on lactation Day 5.
All pups were sexed and descriptions of all external abnormalities were recorded. The stomach was examined for the presence of milk. If possible, defects or cause of death were evaluated. Any abnormal pup, organ or tissue as well as pups from females that were killed in extremis were preserved in 10% buffered formalin for possible further examination.

Indices:
For each group the following calculations were performed:
- Mating (%): Number of females mated/Number of females paired x 100
- Fertility index (%): Number of pregnant females/Number of females paired x 100
- Conception index (%): Number of pregnant females/Number of females mated x 100
- Gestation index (%): Number of females bearing live pups/Number of pregnant females x 100
- Duration of gestation: Number of days between confirmation of mating and the beginning of parturition
- Percentage live males at First Litter Check: Number of live male pups at First Litter Check/ Number of live pups at First Litter Check x 100
- Percentage live females at First Litter Check: Number of live female pups at First Litter Check/Number of live pups at First Litter Check x 100
- Percentage of postnatal loss Days 0-4 of lactation: Number of dead pups on Day 4 of lactation/Number of live pups at First Litter Check x 100
- Viability index (%): Number of live pups on Day 4 of lactation/Number of pups born alive x 100
- Percentage live males at First Litter Check: Number of live male pups at First Litter Check/ Number of live pups at First Litter Check x 100
- Percentage live females at First Litter Check: Number of live female pups at First Litter Check/Number of live pups at First Litter Check x 100
- Percentage of postnatal loss Days 0-4 of lactation: Number of dead pups on Day 4 of lactation/Number of live pups at First Litter Check x 100
- Viability index (%): Number of live pups on Day 4 of lactation/Number of pups born alive x 100
Details on maternal toxic effects:
Maternal toxic effects:no effects
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Number of live pups: 432
Mortality: 1/119, 1/116. 1/126 and 1/71 for the control, 100, 300 and 1000 mg/kg bw/day groups, respectively. This is not considered to be treatment-related, as this falls within the expected range for this strain and age.
A statistically significant lower mean number of living pups at first litter check observed at 1000 mg/kg/day was due to a low number of pups (5 in total) for one female. Since the number of pups of other females of this dose group was within the range considered normal, no toxicological relevance was ascribed to this change.
Viability index, body weights of pups, external examination for abnormalities and clinical signs of pups did not indicate any treatment-related abnormalities
Dose descriptor:
NOAEL
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 observed
Abnormalities:
not specified
Developmental effects observed:
not specified
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 due to read-across) and consistent 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).
The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII - IX, 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
Additional information

Analogue justification

Data on the developmental toxicity/teratogenicity of glyceryl undecylenate are not available. The assessment was therefore based on studies conducted with analogue substances as part of a read across approach, which is in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5. For each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the read across approach is provided in the technical dossier (see IUCLID Section 13).

Developmental toxicity/teratogenicity

CAS 91052-13-0

A combined repeated dose toxicity study with the reproduction / developmental toxicity screening test was performed according to OECD guideline 422 and under GLP conditions in Crl:WI(Han) Wistar rats receiving 100, 300 and 1000 mg/kg bw/day (Otterdijk, 2010). Dilutions of the test substance in polyethylene glycol or the vehicle alone were administered once daily to groups of 10 male and 5 female rats (main groups) and 10 females (for the assessment of reproduction and developmental toxicity) via gavage. In addition, satellite groups of 5 males and 5 females (recovery animals) each for the control and high dose group were used to investigate the reversibility of effects during a 14-day post-exposure recovery period. The main and recovery groups were exposed for at least 28 days. Females used for the assessment of reproduction/developmental toxicity were exposed for 41-49 days (during 2 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation). Limited developmental data is assessed in the study, as pups are observed until Day 4 post-parturition. No toxicologically relevant changes in the offspring viability and post-natal loss were observed. The sex ratio, body weight, clinical signs observed and prevalence of external gross abnormalities were comparable between the treatment and control groups. Based on the results of the study, the NOAEL for developmental toxicity in offspring is ≥ 1000 mg/kg bw/day.

CAS 111-03-5

A GLP-compliant combined repeated dose toxicity study with the reproduction / developmental toxicity screening test was performed according to OECD 422 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: 7 males and 12 females) 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 offspring, the viability (delivery live birth, post-natal loss indices) in pups of treated dams were comparable to controls. The sex ratio, body weight, clinical signs observed and prevalence of external gross abnormalities were comparable between the treatment and control groups. Based on the results of the study, the NOAEL for developmental toxicity in offspring is ≥ 1000 mg/kg bw/day.

Overall conclusion for developmental toxicity/teratogenicity

There are no available studies on the developmental toxicity and teratogenicity of glyceryl undecylenate. Therefore analogue read across from 2 source substances was applied from a combined repeated dose toxicity study with the reproduction / developmental toxicity screening test. No hazard to development was identified. Based on the available data and following the analogue approach, the target substance glyceryl undecylenate is not expected to be hazardous for in utero development.


Justification for selection of Effect on developmental toxicity: via oral route:
Hazard assessment is conducted by means of read-across from a structural analogue. 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).

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the analogue concept is applied to glyceryl undecylenate, data will be generated from data available for reference source substance(s) to avoid unnecessary animal testing. Additionally, once the analogue read-across concept is applied, substances will be classified and labelled on this basis.

Based on the analogue read-across approach,the available data on toxicity to reproduction does not meet the classification criteria according to Regulation (EC) 1272/2008 and is therefore conclusive but not sufficient for classification. Under Regulation (EC) No. 1907/2006, Annex VIII,a pre-natal developmental toxicity study is not required if a (screening) study on toxicity to reproduction is available. Under these circumstances, the health hazard ‘reproductive toxicity’ as defined in Section 2.1 GHS and the reason for no classification (conclusive but not sufficient for classification) is considered to cover both the reproduction and developmental toxicity.

Additional information