Registration Dossier
Registration Dossier
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EC number: - | CAS number: -
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
No study available with C12 -14 TMAC.
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 results of a pre-natal development toxicity study with 35% C12-14 TMAC in C14-15 AE7, the NOAEL for maternal toxicity and development toxicity was established at the highest tested dose of 8.4 mg a.i./kg bw/day. Similar absence of toxicity was observed in other development toxicity studies with read across substances, C12 TMAC and C16 TMAC up to highest tested doses of 24 and 40 mg/kg bw/day respectively. 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 40 mg/kg bw/day has been considered further for the hazard assessment.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- 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
- Qualifier:
- equivalent or similar to guideline
- 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
- Specific details on test material used for the study:
- Test substance: C12-14 TMAC
Purity: 35% C12-14 TMAC in C14-15 Pareth-7
Appreance: White cream, glossy paste - Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or test system 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
- Conclusions:
- Under study conditions, the NOAEL of test substance for maternal and embryotoxic effects/teratogenicty was determined to be 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 test substance, C12-14 TMAC (active ingredient 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 study conditions, the NOAEL of test substance for maternal and embryotoxic effects/teratogenicty in rabbits was determined to be 24 mg/kg bw/day (i.e., equivalent to 8.4 mg a.i./kg bw/day) (Fave 1980).
- 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
- 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, C12-14 TMAC, for maternal as well as developmental toxicity can be considered to be 40 mg/kg bw/d in rabbits.
- Executive summary:
A study was conducted to determine the developmental toxicity / teratogenicity of the read across substance, C16 TMAC, 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 study conditions, the NOAEL of the test substance, C12 -14 TMAC, for maternal as well as developmental toxicity was established at 40 mg/kg bw/d in rabbits (Albridge, 1985). Based on the results of the read across study, the NOAEL of the test substance, C12 -14 TMAC, for maternal as well as development toxicity in rabbits can be considered to be at 40 mg/kg bw/day.
Referenceopen allclose all
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 |
1/3 |
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, |
|
3468 |
3313 |
3450 |
3369 |
- |
Food consumption (g/day/dam) |
|
|
|
|
|
- |
Water consumption if test substance is applied with drinking water |
|
not recorded |
not recorded |
not recorded |
not recorded |
|
Pregnancies pregnancy rate or % |
|
11 |
8 |
11 |
13 |
+/- |
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 |
73 |
97 |
104 |
+/- |
Implantations number per pregnant female |
|
84 |
71 |
85 |
98 |
- |
Resorptions number per pregnant female |
|
1 |
4 |
2 |
7 |
- |
total number of foetuses |
|
83 |
67 |
83 |
91 |
+/- |
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 |
0 |
0 |
0 |
- |
Skeletal abnormal ossifications |
|
|
|
|
|
- |
incomplete ossifications sternebrae [%] |
|
32 |
29 |
30 |
36 |
- |
incomplete ossifications skull [%] |
|
23 |
9 |
11 |
15 |
- |
missing ossifications sternebrae [%] |
|
14 |
11 |
12 |
21 |
|
abnormal ossifications |
|
1 |
|
1 |
|
- |
Visceral abnormalities [%] |
|
1 |
1 |
0 |
0 |
- |
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 40 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rabbit
- 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 teratogenicity of test substance, C12-14 TMAC (active ingredient 35%), according to the method comparable to OECD 414. Duringgestation 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 study conditions, the NOAEL of test substance for maternal and embryotoxic effects/teratogenicty in rabbits was determined to be 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 2: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).
Study 3:A study was conducted to determine the developmental toxicity / teratogenicity of the read across substance, C16 TMAC, 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 h) 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. Based on the results of the read across study, the NOAEL of the test substance, C12 -14 TMAC, for maternal as well as developmental toxicity is considered to be 40 mg/kg bw/d in rabbits (Albridge, 1985).
Justification for classification or non-classification
Based on the available data from pre-natal development toxicity studies with C12 -14 TMAC as well as the read across substances, C12 TMAC and C16 TMAC, in rabbits, C12-14 TMAC is not expected to be a development toxicant. Therefore, no classification is required according to EU CLP criteria (Regulation EC 1272/2008).
Additional information
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