Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No study available with Oleyl TMAC.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because a pre-natal developmental toxicity study is available
Reason / purpose:
data waiving: supporting information
Reason / purpose:
data waiving: supporting information
Reason / purpose:
data waiving: supporting information
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

Based on the available data from pre-natal development toxicity studies with read across substances in rats and rabbits, Oleyl TMAC is not expected to be a development toxicant. Overall, in the absence of toxicologically significant systemic effects with all the assessed TMACs in either repeated dose or development toxicity studies, the higher NOAEL of 50 mg/kg bw/day has been considered further for the hazard assessment.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Study period:
1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Justification for type of information:
Refer to the Quaternary ammonium salts (QAS) category or section 13 of IUCLID for details on the category justification. The study with the read across substance is considered sufficient to fulfil the information requirements as further explained in the provided endpoint summary.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
other: Strain: CFY
Details on test animals and environmental conditions:
- Four groups (caged individually)
- Temperature: 20°C +/- 2°C, Relative humidity: 55 +/- 10%
- 12/12 hours dark/light
-Free access to food (Spratts Laboratory Animals Diet No 1) and tp water
Route of administration:
dermal
Vehicle:
other: distilled water
Details on exposure:
On Days 4 or 5 of pregnancy, an area (4x4 cm) of fur in the scapular region was removed by electric clippers. (Shaving was repeated when necessary but no depilatory agents were used). Dosing started on Day 6 and continued up to and including Day 15 of gestation. On each day, the test substance was applied to the shaved area at the rate of 0.5 mL/rat, and at a speed minimising 'run off' into surrounding fur. The exposed area was neither washed nor occluded at any time.
Analytical verification of doses or concentrations:
yes
Remarks:
no further details
Duration of treatment / exposure:
From Gestation Day 6 to 15
Frequency of treatment:
each day
Dose / conc.:
0 other: %
Remarks:
corresponding to 0 mg/kg bw/day
Dose / conc.:
0.9 other: %
Remarks:
corresponding to 18 mg/kg bw/day
Dose / conc.:
1.5 other: %
Remarks:
corresponding to 30 mg/kg bw/day
Dose / conc.:
2.5 other: %
Remarks:
corresponding to 50 mg/kg bw/day
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle
Details on study design:
Concentrations: 0.0, 0.9, 1.5, and 2.5% in distilled water administered per 0.5 mL/rat/day (2 mL/kg bw/day for a weight of ca. 250g).
Maternal examinations:
Signs of systemic reaction and local reaction of the exposed area of skin (scores: 1-4): daily.
Body weights: on Days 1, 3, 6, 10, 17, and 20 of pregnancy.
Food and water consumption: at regular intervals throughout the study.
Ovaries and uterine content:
On Day 20 of pregnancy:
- congenital abnormalities and macroscopic pathological changes in maternal organs
- ovaries and uteri: number of corpora lutea, number/distribution of live young and embryo/foetal deaths (early and late, stages of implantation) and post implantation loss ((No. of implantations - No. of live young) x 100 / No. of implantations)
Fetal examinations:
On Day 20 of pregnancy:
- litter weight from which the mean pup weight was calculated, foetal abnormalities (external and internal + classification) and post implantation loss ((No. of implantations - No. of live young) x 100 / No. of implantations)
- sex determination
Statistics:
- Group mean values were calculated from individual litter values and, where expressed as a percentage, were calculated as the mean of the percentages within individual litters (and not from group totals for foetuses)
- Non-parametric methods (analysis of litter and abnormalities), analysis of variance (body weight, food or water consumption), and Kruskal-Wallis test (where significant heterogenicity was recorded)
Clinical signs:
no effects observed
Description (incidence and severity):
No systemic signs of reaction
Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
- In terms of incidence of animals affected, and degree of reaction.
- In all cases, initial reaction was evident within a day of the first administration. It reached a peak of severity around the mid point of the dosing period, and stabilized or showed a decline thereafter. This phenomenon was frequently associated with scab formation.
- Local reactions (erythema and oedema).
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
no macroscopic pathological changes in internal organs
Histopathological findings: neoplastic:
not examined
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Changes in number of pregnant:
not examined
Other effects:
no effects observed
Description (incidence and severity):
No differences in the number of corpora lutea were recorded.
Details on maternal toxic effects:
Only dermal irritation was observed
Key result
Dose descriptor:
NOAEL
Remarks:
systemic effect
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: overall no systemic toxicity except "dermal irritation"
Key result
Dose descriptor:
NOAEL
Remarks:
local effect
Effect level:
18 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
dermal irritation
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
other: dermal
Description (incidence and severity):
- In terms of incidence of animals affected, and degree of reaction.
- In all cases, initial reaction was evident within a day of the first administration. It reached a peak of severity around the mid point of the dosing period, and stabilized or showed a decline thereafter. This phenomenon was frequently associated with scab formation.
- Local reactions (erythema and oedema).
Fetal body weight changes:
no effects observed
Description (incidence and severity):
The mean foetal weight was not modified by the treatment
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
not examined
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
The litter weight was not modified by the treatment
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Details on embryotoxic / teratogenic effects:
In all groups, the incidence of affected litters and foetuses was within the limits of historical control values. The types of malformations or anomaly observed were compatible with the types of abnormality recorded among concurrent or historical control vlaues and there was no unusual clustering of a particular type of abnormality in any one test group.
Key result
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: no effects
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
Under the study conditions, a dermal application of the test substance did not induce toxic effects on dams or foetuses, except for a local irritation (erythema and oedema) on the skin of pregnant animals. The maternal NOAELs (systemic and local) were therefore established at 50 and 18 mg/kg bw/day, respectively. The developmental NOAEL was determined at 50 mg/kg bw/day.
Executive summary:

A study was conducted to determine the developmental toxicity of the read across substance, C18 TMAC (active: 98.8%), according to a method similar to OECD Guideline 414. Pregnants rats were exposed dermally to the test substance from Day 6 to Day 15 of gestation. Volumes of 0.5 mL were applied on shaved skin. The concentrations of the test substance ranged from 0.0 to 2.5% (i.e., corresponding to 0, 18, 30 and 50 mg/kg bw/day). Signs of systemic reaction and local reaction of the exposed area of skin were assessed on a daily basis. Body weights were recorded on Days 1, 3, 6, 10, 17, and 20 of pregnancy. Food and water consumption were measured at regular intervals throughout the study. On Day 20 of pregnancy, congenital abnormalities and macroscopic pathological changes in maternal organs as well as in ovaries and uteri (number of corpora lutea, number/distribution of live young and embryo/foetal deaths (early and late, stages of implantation)) and post implantation loss were evaluated. Litter weights (from which the mean pup weight was calculated), foetal abnormalities (external and internal), and sex determination were also recorded on Gestation Day 20. Under the study conditions, a dermal application of the test substance did not induce toxic effects on dams or foetuses, except for a local irritation (erythema and oedema) on the skin of pregnant animals. The maternal NOAELs (systemic and local) were therefore established at 50 and 18 mg/kg bw/day, respectively. The developmental NOAEL was determined at 50 mg/kg bw/day (Palmer, 1983). Based on the results of the read across study, similar NOAELs for maternal and development toxicity is considered for the test substance, Oleyl TMAC.

Endpoint:
developmental toxicity
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
1985
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
Refer to the Quaternary ammonium salts (QAS) category or section 13 of IUCLID for details on the category justification. The study with the read across substance is considered sufficient to fulfil the information requirements as further explained in the provided endpoint summary.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
see 'Principles of method if other than guideline'
Deviations:
yes
Remarks:
short exposure time i.e., on gestation Days 7-18 only
Principles of method if other than guideline:
- 20 mated female rabbits per group were exposed for Days 7 - 18 of gestation to 2.0 mL/kg bw/day of the test substance topically (2h per day) at concentrations of 0, 0.5, 1.0, or 2.0% (i.e., equivalent to 0, 10, 20 and 40 mg/kg bw/day, respectively). The control group was treated with deionised water.
- Animals were observed twice daily for signs of toxicity, including skin irritation from Days 7 to 29. Body weights and food consumption were recorded. A gross necropsy was conducted on animals that died. Foetuses less than 28d old were fixed in buffered neutral formalin and those 28d or older were cleared and stained. All surviving dams were sacrificed at study termination on gestation Day 29. An examination of the uterus and ovaries was conducted. Following removal of the foetuses the abdominal and thoracic cavities and organs of the dams were examined. At sacrifice foetuses were identified, weighed and examined externally for defects. Gross dissection and examination of viscera, and internal sex determination also were conducted on each foetus. Finally, an examination of the skeleton for anomalies and ossification variations was conducted after clearing and alizarin red staining of the foetuses.
GLP compliance:
yes
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Route of administration:
dermal
Vehicle:
water
Details on exposure:
TEST SITE:
Shaved dorsal area.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Rinsed with water and dried.
- Time after start of exposure: 2 h.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2 mL/kg
- Concentration (if solution): 0, 0.5, 1.0 and 2.0%
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Days 7 - 18 of gestation.
Frequency of treatment:
Once daily (2 hours).
Duration of test:
Days 0 - 29 of gestation.
Remarks:
Concentrations: 0, 0.5, 1.0, or 2.0% (i.e., equivalent to 0, 10, 20 and 40 mg/kg bw/day, respectively)
No. of animals per sex per dose:
20 pregnant females per dose.
Control animals:
yes, concurrent vehicle
Maternal examinations:
Dams were observed twice daily for signs of toxicity, including skin irritation from Days 7 through 29. Body weights were taken on gestation Days 0, 3, 6, 9, 12, 15, 18, 21, 24, 27 and 29. Individual food consumption was measured daily. A gross necropsy was conducted on dams that died in an attempt to determine the cause of death. All surviving dams were sacrificed at study termination on gestation Day 29. An examination of the uterus (including the number and location of live and dead foetuses, early and late resorptions, and implantation sites) and ovaries (including the number of corpora lutea) was conducted. Following removal of the foetuses the abdominal and thoracic cavities and organs of the dams were examined. Uteri from females that appeared non-gravid were placed in 10% ammonium sulphide solution for confirmation of pregnancy.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
Statistics:
Body weight changes and food consumption and number of early and late resorptions, dead foetuses, total implantations, corpora lutea, skeletal abnormalities, and mean fetal body weight were compared by analysis of variance (Bartlette's). If variance was not significant, then treatment-control comparisons were made using the least significant difference (LSD) criterion. If variance was significant, then comparison was made using the t-test for unequal variances and the Wilcoxon, Mann-Whitney rank sum test. Additionally, a regression and lack of fit were performed on each of these parameters. The number of pregnancies per group, the percentage of skeletal abnormalities and soft tissue malformations were analysed by Fisher's exact test.
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
Skin irritation was observed at all doses with the severity and duration of erythema, oedema, desquamation, atonia and coriaceousness increased in a dose-dependent manner.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Two control, one intermediate and one high dose doe died during the study. The cause of death could not be determined. Two of the does that died aborted prior to death (one control and one intermediate dose group animal).
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
A slight increase in congested lungs was observed for the high dose group at necropsy.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Number of abortions:
effects observed, non-treatment-related
Description (incidence and severity):
Two additional abortions occurred, one each in the intermediate and high dose groups. None of these deaths or abortions were considered related to test substance toxicity.
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Changes in number of pregnant:
not examined
Details on maternal toxic effects:
Maternal toxic effects: no test substance related significant effects.
Key result
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
40 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Basis for effect level:
other: no significant treatment-related maternal toxic effects were observed up to the highest tested dose.
Key result
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Effect level:
40 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Basis for effect level:
other: no significant treatment-related foetal development effects were observed up to the highest tested dose.
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
not examined
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects: no effects

Details on embryotoxic / teratogenic effects:
The incidence of foetal malformations, as well as genetic and developmental variations in the treated groups were comparable to that of the control group.
Key result
Dose descriptor:
NOAEL
Remarks:
general toxicity
Effect level:
40 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: no effects observed up to the highest dose tested
Key result
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Effect level:
40 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: no developmental effects observed up to the highest dose tested
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
Based on the results of the read across study, the NOAEL of the test substance, Oleyl TMAC, for maternal as well as development toxicity in rabbits can be considered to be at 40 mg/kg bw/day.
Executive summary:

A study was conducted to determine the developmental toxicity / teratogenicity of the read across substance, C16 TMAC (active: 25%), according to a method similar to OECD Guideline 414, in compliance with GLP. This experiment was performed in New Zealand White rabbits. Twenty mated female rabbits per group were exposed topically (daily for 2 hours) from Days 7 to 18 of gestation at concentrations of 0, 0.5, 1.0, or 2.0% (equivalent to 0, 10, 20 and 40 mg a.i./kg bw/day, respectively). The control group was treated with deionised water only. Clinical condition and reactions to treatment were recorded at least once daily. Body weights were recorded on Days 0, 3, 6, 9, 12, 15, 18, 21, 24, 27 and 29 of gestation. All surviving females were sacrificed on Day 29 of gestation and the foetuses were removed by caesarean section. At necropsy the females were examined macroscopically. Live foetuses were weighed, sexed and were examined for visceral and skeletal abnormalities. Two control animals, one intermediate and one high dose died during the study. Two of the rabbits that died, aborted prior to death (one control and one intermediate dose). Two additional abortions occurred, one each in the intermediate and high dose groups. Deaths or abortions were not considered to be related to the test substance. No treatment-related maternal body weight or food intake effects were noted. The incidence of foetal malformations, as well as genetic and developmental variations in the treated groups was comparable to that of the control group. No other treatment-related effects were noted.Under the conditions of the study, the NOAEL of the test substance for maternal as well as developmental toxicity was established at 40 mg/kg bw/day in rabbits (Albridge, 1985). Based on the results of the read across study, similar NOAELs for maternal and development toxicity is considered for the test substance, Oleyl TMAC.

Endpoint:
developmental toxicity
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
From June 19, 1979 to June 12, 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Justification for type of information:
Refer to the Quaternary ammonium salts (QAS) category or section 13 of IUCLID for details on the category justification. The study with the read across substance is considered sufficient to fulfil the information requirements as further explained in the provided endpoint summary.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
No macroscopic or microscopic examination of sacrificed dams
GLP compliance:
not specified
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
Animal supplier source: Accredited breeder - Oury, Domaine De la Chesnaie, 45230 Chatilloon-Coligny
Body weight: 2.7 to 2.9 kg
Sex: Female
Pre-trail period: The animal were maintained under conditions as close as possible to those of the trial for one month pre-trial and were vaccinated against myxomatosis on May 12, 1979. The male rabbits used for mating were supplied from the same breeder and placed under the same experimental conditions as the females
Housing: Animals were placed in individual caging (70×50×30 cm) with plastic perforated floor
Temperature: 21ºC ± 10ºC
Relative humidity: 50 ± 10%
Air changes: 10 times/hour
Allocation to the groups: 13 animals each were grouped to control, test group 1, test group 2 and test group 3.
Tap water: ad libitum
Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
The first mating started on September 04, 1979.
Duration of treatment / exposure:
The day of mating was considered as day 0 and the animals were dosed daily from day 6 to day 18 inclusive (for 13 consecutive days).
Frequency of treatment:
once a day
Duration of test:
28 d
Dose / conc.:
2 mg/kg bw/day
Remarks:
0.35 mg a.i./kg bw/day
Dose / conc.:
8 mg/kg bw/day
Remarks:
1.4 mg a.i./kg bw/day
Dose / conc.:
24 mg/kg bw/day
Remarks:
8.4 mg a.i./kg bw/day
No. of animals per sex per dose:
13 female rabbits per dose
Control animals:
yes
Details on study design:
Preliminary study
Animal details: 3 female New Zealand rabbits for each dose group, weighing about 3 kg
Route of administration: Oral by stomach tube
Dose levels (mg/kg bw/day): 25 mg/kg bw/day (Test group 1), 50 mg/kg bw/day (Test group 2), 100 mg/kg bw/day (Test group 3), 200 mg/kg bw/day (Test group 4), 400 mg/kg bw/day (Test group 5)
Test substance was administered as an aqueous solution at following concentration:
Test group 1: 1.25 %
Test group 2: 2.50 %
Test group 3: 5 %
Test group 4: 10 %
Test group 5: 20 %
The solution were prepared every 3rd or 4th d and stored at 4ºC. 2 mL/kg bw was administered for each group. The preliminary test results obtained indicated that the test substance was toxic at the dose levels of 100, 200 and 400 mg/kg bw/day by oral route. 50 mg/kg did seem to be the threshold of an indirect embryotoxic action.

Main study
Based on preliminary testing results, following dose levels were selected for main study:
Test group 1: 1 mg/kg bw/day
Test group 2: 5 mg/kg bw/day
Test group 3: 25 mg/kg bw/day
Maternal examinations:
- Behaviour and clinical symptoms: daily
- Body weight: every 3 days during pregnancy
- Food consumption: daily
- Number of corpora lutea, implantations, resorptions
Ovaries and uterine content:
Staining of implantation sites with ammonium sulphide
- Number of corpora lutea
- Number of implantations
- Number of absorptions
Fetal examinations:
- Number of viable and dead foetuses
- Macroscopic external observations
- Individual weights
- Sex
- 2/3 of foetuses stained with alizarin for skeletal examination
- 1/3 of foetuses immersed on Bouin: sections cut for examination of visceral abnormalities (method adapted from Wilson technique)
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No difference of growth curve of treated groups compared to controls was observed.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No difference of growth curve of treated groups compared to controls was observed.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
No mortality, no difference of growth curve of treated groups compared to controls, no difference in food consumption.
Number of abortions:
no effects observed
Early or late resorptions:
no effects observed
Description (incidence and severity):
The rate of resorptions was considered low and comparable in all groups.
Dead fetuses:
no effects observed
Details on maternal toxic effects:
There was a higher number of non-pregnant females in group I. The rate of resorptions is considered low, and comparable in all groups. No histopathology was performed on the sacrificed dams end of term.
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 24 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: No effects were observed at highest test dose
Remarks on result:
other:
Remarks:
NOAEL 8.4 mg a.i./kg bw/day
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
External malformations:
no effects observed
Description (incidence and severity):
In the high dose group, one foetus showed a torsion of the fore limbs. No other external abnormality was observed in any of the dose groups.
Skeletal malformations:
no effects observed
Description (incidence and severity):
Incidence in treated groups were comparable to controls.
Visceral malformations:
no effects observed
Description (incidence and severity):
- Dilated and haemorrhagic cerebral ventricles in one foetus of control group
- Left hydro-ureter in one foetus of low dose group
- Retinal folds in region of optic nerve in 13 foetuses: Control: 3 (11%); low dose: 2 (9%); mid dose: 4 (14%); and high dose: 4 (16%). These were considered to be caused by fixation artefact.
Details on embryotoxic / teratogenic effects:
No foetal mortality was observed.

External abnormalities:
In the high dose group, one foetus showed a torsion of the fore limbs. No other external abnormality was observed in any of the dose groups.

Visceral abnormalities:
- dilated and haemorrhagic cerebral ventricles in one foetus of control group
- left hydro-ureter in one foetus of low dose group.
- retinal folds in region of optic nerve in 13 foetuses: Control: 3 (11%); low dose: 2 (9%); mid dose: 4 (14%); and high dose: 4 (16%). These were considered to be caused by fixation artefact.

Skeletal abnormalities: See table: Incidence in treated groups are comparable to controls.
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 24 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects were observed at highest test dose
Remarks on result:
other: NOAEL: 8.4 mg a.i./kgbw/day
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Lowest effective dose / conc.:
24 mg/kg bw/day
Treatment related:
no

Maternal toxic Effects

 

Preliminary study

25, 50, 100, 200, and 400 mg test material /kg bw/day using 3 animals per dose group.

 

Mortality

Dose of test substance (mg/kg bw/day)

25

50

100

200

400

mortality

1/3
(day 26)

1/3
(day 18)

2/3 (day 18,26)

3/3 (all day 10)

3/3 (all day 7)

At 50 and 100 mg groups, a clear fall in body weight was observed between days 12 and 18. At 25 mg, two of the three females showed anorexia. From first day of treatment food consumption was clearly decreased at 50 and 100 mg/kg.

 

Final study

No mortality, no difference of growth curve of treated groups compared to controls, no difference in food consumption. There was a higher number of non-pregnant females in group I. The rate of resorptions is considered low, and comparable in all groups. No histopathology was performed on the sacrificed dams end of term.

 

Teratogenic/embryotoxic effects

 

Preliminary study on 25, 50, 100, 200, and 400 mg test material/kg bw/day using 3 animals per dose group. At 50 mg, the two females showed resorption sites. The weight of foetuses of the 50 mg group were low. Macroscopic examination, number and mean weight of foetuses of the 25 mg group showed no embryotoxic effect. 50 mg/kg/day seems to be the threshold for an indirect embryotoxic action.

 

Final study

No foetal mortality was observed.

External abnormalities
In the high dose group, one foetus showed a torsion of the fore limbs. No other external abnormality was observed in any of the dose groups.

Visceral abnormalities

- Dilated and haemorrhagic cerebral ventricles in one foetus of control group

- left hydro-ureter in one foetus of low dose group.

- Retinal folds in region of optic nerve in 13 foetuses: Control: 3 (11%); low dose: 2 (9%); mid dose: 4 (14%); and high dose: 4 (16%). These were considered to be caused by fixation artefact.
Skeletal abnormalities: Incidence in treated groups are comparable to controls.

Table for Maternal effects (separate data for all dosage groups) 

Maternal effects

Parameter

control data

low dose

medium dose

high dose

dose-response
+ / -

historical

study

Number of dams examined

 

13

14

13

13

 

Clinical findings during application of test substance

 

no

no

no

no

 

Mortality of dams

state %

 

0

0

0

0

 

Abortions

 

0

0

0

0

 

Body weight (day 28) g

gain day 0-28 (end of test) g,
gain day 6-18 (treatment) g,

 

3468
541
205

3313
638
206

3450
645
246

3369
650
231

-

Food consumption (g/day/dam)
day 0-5
day 6-18 (treatment)
day 19-29

 


165
152
111


148
139
118


148
143
124


157
152
134

-

Water consumption

if test substance is applied with drinking water

 

not recorded

not recorded

not recorded

not recorded

 

Pregnancies

pregnancy rate or %

 

11
85%

8
57%

11
85%

13
100%

+/-

Necropsy findings in dams dead before end of test

 

none died

none died

none died

none died

 


 Table for developmental effects (separate data for all dosage groups)

Litter response (Caesarean section data)

Parameter

control data

low dose

medium dose

high dose

dose-response
+ / -

historical

study

Number full-term pregnant females

 

11

8

11

13

+/-

Corpora lutea

number per pregnant female

 

98
8.91

73
9.13

97
8.82

104
8.00

+/-

Implantations

number per pregnant female

 

84
7.64

71
8.87

85
7.73

98
7.54

-

Resorptions

number per pregnant female

 

1
0.09

4
0.50

2
0.18

7
0.54

-

total number of foetuses
number per pregnant female

 

83
7.55

67
8.37

83
7.55

91
7.00

+/-

pre-implantation loss

state %

 

14%

3%

12%

6%

-

post-implantation loss

state %

 

1%

6%

2%

7%

-

total number of litters

 

11

8

11

13

+/-

fetuses / litter

 

7.55

8.37

7.55

7.00

+/-

live fetuses / litter

state ratio

 

7.55

8.37

7.55

7.00

+/-

dead fetuses / litter

state ratio

 

0

0

0

0

 

fetus weight (mean)

[g]

 

33.63

31.73

34.21

35.17

+/-

placenta weight (mean)

[g]

 

not recorded

not recorded

not recorded

not recorded

 

crown-rump length (mean)

[mm]

 

not recorded

not recorded

not recorded

not recorded

 

Fetal sex ratio

[state ratio m/f]

 

40/38

26/34

39/39

48/34

+/-

 Table for developmental effects (separate data for all dosage groups)

Examination of the foetuses

Parameter

control data

low dose

medium dose

high dose

dose-response
+ / -

historical

study

External abnormalities

[%]

 

1
3.7%

0

0

0

-

Skeletal abnormal ossifications
12thpair complete [%]
13ribs left side [%]
13ribs right side [%]
13thpair complete [%]

 


47.1%
3.9%
5.9%
43.1%


8.9%


11.1%


30.9%
10.9%
10.9%
47.3%


45.0%
10.0%
6.7%
38.3%

-

incomplete ossifications sternebrae

[%]

 

32
63%

29
64%

30
55%

36
60%

-

incomplete ossifications skull

[%]

 

23
45%

9
20%

11
20%

15
25%

-

missing ossifications sternebrae

[%]

 

14
27%

11
24%

12
22%

21
35%

 

abnormal ossifications

 

1
2%

 

1
1.8%

 

-

Visceral abnormalities

[%]

 

1
3.7%

1
4.5%

0

0

-

Conclusions:
Based on the results of the read across study, the NOAEL of test substance for maternal and embryotoxic effects/teratogenicty can be considered to be at 24 mg/kg bw/day (i.e., equivalent to 8.4 mg a.i./kg bw/day).
Executive summary:

A study was conducted to determine the teratogenicity of read across substance, C12-14 TMAC (active: 35%), according to the method comparable to OECD 414. During gestation Days 6 -18, four groups of 13 female New Zealand White rabbits were dosed by stomach tube at dose levels of 0, 2, 8 and 24 mg/kg bw/day of test substance (35% C12-14 TMAC in dobanol 45E7 (i.e., C14 -15 AE7)), in 2 mL/kg bw/day daily prepared solutions in water. Animals were sacrificed on Day 29. Examinations included daily observations of behaviour and clinical symptoms, daily food consumption, and body weight every three days. Upon sacrifice, number of corpora lutea, implantations and resorptions were examined. For foetuses, number of viable and dead, macroscopic external examinations, sex, individual weights, skeletal examinations (2/3), and visceral abnormalities (1/3) were conducted. A preliminary study was undertaken under similar conditions, applying 5 dose groups: 0, 25, 50, 100, 200 and 400 mg/kg bw/day using three animals per dose group. At 50 mg, the two females showed resorption sites. The weight of foetuses of the 50 mg group were low. Macroscopic examination, number and mean weight of foetuses of the 25 mg group showed no embryotoxic effect. 50 mg/kg/day did seem to be the threshold for an indirect embryotoxic action. In the final study, no signs of maternal toxicity was observed. Also no foetal mortality was observed. Numbers of corpora lutea and resorptions were comparable. The number of pregnancies at the low dose group did seem to be diminished, but this was considered an incidental observation. There was no change in frequency of external, visceral and skeletal observations. No maternal toxic or embryotoxic/teratogenic effects were seen up to hightest tested dose of 24 mg/kg bw/day (i.e., equivalent to 8.4 mg a.i./kg bw/day). Under the conditions of the study, the NOAEL of read across substance for maternal and embryotoxic effects/teratogenicty was at 24 mg/kg bw/day (i.e., equivalent to 8.4 mg a.i./kg bw/day) (Fave 1980). Based on the results of the read across study, similar NOAELs for maternal and development toxicity is considered for the test substance, Oleyl TMAC.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Good quality.
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

Study 1: A study was conducted to determine the developmental toxicity of the read across substance, C18 TMAC (active: 98.8%), according to a method similar to OECD Guideline 414. Pregnants rats were exposed dermally to the test substance from Day 6 to Day 15 of gestation. Volumes of 0.5 mL were applied on shaved skin. The concentrations of the test substance ranged from 0.0 to 2.5% (i.e., corresponding to 0, 18, 30 and 50 mg/kg bw/day). Signs of systemic reaction and local reaction of the exposed area of skin were assessed on a daily basis. Body weights were recorded on Days 1, 3, 6, 10, 17, and 20 of pregnancy. Food and water consumption were measured at regular intervals throughout the study. On Day 20 of pregnancy, congenital abnormalities and macroscopic pathological changes in maternal organs as well as in ovaries and uteri (number of corpora lutea, number/distribution of live young and embryo/foetal deaths (early and late, stages of implantation)) and post implantation loss were evaluated. Litter weights (from which the mean pup weight was calculated), foetal abnormalities (external and internal), and sex determination were also recorded on Gestation Day 20. Under the study conditions, a dermal application of the test substance did not induce toxic effects on dams or foetuses, except for a local irritation (erythema and oedema) on the skin of pregnant animals. The maternal NOAELs (systemic and local) were therefore established at 50 and 18 mg/kg bw/day, respectively. The developmental NOAEL was determined at 50 mg/kg bw/day (Palmer, 1983).

Study 2: A study was conducted to determine the developmental toxicity / teratogenicity of the read across substance, C16 TMAC (active: 25%), according to a method similar to OECD Guideline 414, in compliance with GLP. This experiment was performed in New Zealand White rabbits. Twenty mated female rabbits per group were exposed topically (daily for 2 hours) from Days 7 to 18 of gestation at concentrations of 0, 0.5, 1.0, or 2.0% (equivalent to 0, 10, 20 and 40 mg a.i./kg bw/day, respectively). The control group was treated with deionised water only. Clinical condition and reactions to treatment were recorded at least once daily. Body weights were recorded on Days 0, 3, 6, 9, 12, 15, 18, 21, 24, 27 and 29 of gestation. All surviving females were sacrificed on Day 29 of gestation and the foetuses were removed by caesarean section. At necropsy the females were examined macroscopically. Live foetuses were weighed, sexed and were examined for visceral and skeletal abnormalities. Two control animals, one intermediate and one high dose died during the study. Two of the rabbits that died, aborted prior to death (one control and one intermediate dose). Two additional abortions occurred, one each in the intermediate and high dose groups. Deaths or abortions were not considered to be related to the test substance. No treatment-related maternal body weight or food intake effects were noted. The incidence of foetal malformations, as well as genetic and developmental variations in the treated groups was comparable to that of the control group. No other treatment-related effects were noted. Under the conditions of the study, the NOAEL of the read across substance for maternal as well as developmental toxicity was established at 40 mg/kg bw/day in rabbits (Albridge, 1985).

Study 3: A study was conducted to determine the teratogenicity of read across substance, C12-14 TMAC (active: 35%), according to the method comparable to OECD Guideline 414. During gestation Days 6 -18, four groups of 13 female New Zealand White rabbits were dosed by stomach tube at dose levels of 0, 2, 8 and 24 mg/kg bw/day of test substance (35% C12-14 TMAC in dobanol 45E7 (i.e., C14 -15 AE7)), in 2 mL/kg bw/day daily prepared solutions in water. Animals were sacrificed on Day 29. Examinations included daily observations of behaviour and clinical symptoms, daily food consumption, and body weight every three days. Upon sacrifice, number of corpora lutea, implantations and resorptions were examined. For foetuses, number of viable and dead, macroscopic external examinations, sex, individual weights, skeletal examinations (2/3), and visceral abnormalities (1/3) were conducted. A preliminary study was undertaken under similar conditions, applying 5 dose groups: 0, 25, 50, 100, 200 and 400 mg/kg bw/day using three animals per dose group. At 50 mg, the two females showed resorption sites. The weight of foetuses of the 50 mg group were low. Macroscopic examination, number and mean weight of foetuses of the 25 mg group showed no embryotoxic effect. 50 mg/kg/day did seem to be the threshold for an indirect embryotoxic action. In the final study, no signs of maternal toxicity was observed. Also no foetal mortality was observed. Numbers of corpora lutea and resorptions were comparable. The number of pregnancies at the low dose group did seem to be diminished, but this was considered an incidental observation. There was no change in frequency of external, visceral and skeletal observations. No maternal toxic or embryotoxic/teratogenic effects were seen up to hightest tested dose of 24 mg/kg bw/day (i.e., equivalent to 8.4 mg a.i./kg bw/day). Under the study conditions, the NOAEL of read across substance for maternal and embryotoxic effects/teratogenicty was considered to be at 24 mg/kg bw/day (i.e., equivalent to 8.4 mg a.i./kg bw/day) (Fave 1980). Based on the absence of reproductive and developmental effects of C14-15 AE7 in a 2-generation study conducted in Charles River CD rats, no impact of the solvent is expected on the endpoint.

Study 4: A study was conducted to evaluate the development toxicity potential of the read across substance, C12 TMAC, in New Zealand White rabbits. Based on the range finding study, pregnant rabbits were orally administered at dose levels of 0, 2, 8 and 24 mg/kg bw/day from Day 6 through 18 of pregnancy. The dams were killed on Day 19 and necropsied. There were no adverse effects reported for the dams and no developmental or teratogenic effects observed (CIR, 2012).

Overall, based on the available data from pre-natal development toxicity studies with read across substances in rats and rabbits, Oleyl TMAC is not expected to be a development toxicant.

Justification for classification or non-classification

Based on the available data from pre-natal development toxicity studies with read across substances, in rats and rabbits, Oleyl TMAC is not expected to be a development toxicant. Therefore, no classification is required according to CLP criteria (Regulation EC 1272/2008).