6-methylhept-5-en-2-one

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

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

Prenatal Developmental Toxicity Study (OECD Guideline 414): NOAEL for maternal and prenatal developmental toxicity = 200 mg/kg body weight/day

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well conducted guideline study under GLP conditions.

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes (incl. QA statement)

Remarks:

BASF Aktiengesellschaft; Experimentelle Toxikologie und Ökologie; Ludwigshafen

Limit test:

no

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Germany
- Strain: CrIGIxBrIHan:WI- Age at study initiation: 70 - 84 days
- Weight at study initiation: 149.2 - 184.6 g- Identification: ear tattoo
- Housing: singly from day 0 - 20 p.c. in type DK 111 stainless steel wire mesh cages supplied by BECKER & CO., Castrop-Rauxel, FRG (height: 15 cm, length: 37,5 cm, width: 21 cm; floor area about 800 cm^2).
- Diet: ad libitum, ground Kliba maintenance diet rat/mouse/hamster meal, supplied by PROVIMI KLIBA SA, Kaiseraugst, Switzerland.
- Water: ad libitum, drinking water of tap water quality from water bottles- Acclimation period: animals were mated by the breeder (time-mated") and supplied on day 0 post coitum (= detection of vaginal plug / sperm).

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

oral: gavage

Vehicle:

olive oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: The oily test substance suspensions were prepared at the beginning of the administration period and thereafter at intervals which took into account the analytical results of the stability verification. For the preparation of the suspensions, an appropriate amount of the test substance was weighed depending on the dose group, in calibrated beakers, topped up with olive oil Ph.Eur./DAB and subsequently thoroughly mixed using a magnetic stirrer. This devise was also used to keep the suspensions homogeneous during treatment of the animals.

VEHICLE
- Concentration in vehicle: 10, 40, 200 mg/ml
- Amount of vehicle (if gavage): 5 ml/kg bw/d

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analytical verifications of the stability of the test substance in olive oil for a period of at least 7 days at room temperature were carried out before the study was initiated.Samples of the test substance suspensions were sent to the analyticat laboratory twice during the study period (at the beginning and towards the end) for verification of concentrations. The samples which were taken for the first concentration control analyses at the beginning of the administration period were also used to verify the homogeneity for the samples of the low and the high concentrations (50 and 1,000 mg/kg bw/day). 3 samples (one from the top, middle and bottom in each case) were taken for each of these concentrations from the beaker with a magnetic stirrer running.

Details on mating procedure:

- Impregnation procedure: purchased timed pregnant
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

Days 6 - 19 post conception

Frequency of treatment:

once daily

Duration of test:

until day 20 post conception

No. of animals per sex per dose:

25

Control animals:

yes, concurrent vehicle

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day on working days or once a day (Saturday, Sunday or on public holidays) (days 0 - 20 p.c.).

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once a day, or more often when clinical signs of toxicity were elicited (days 0 - 20 p.c.).

BODY WEIGHT: Yes
- Time schedule for examinations: on days 0, 1, 3, 6, 8, 10, 13, 15, 17, 19 and 20 p.c.. The body weight change of the animals was calculated from these results. Corrected body weight gain was calculated after terminal sacrifice (terminal body weight on day 20 p.c. minus weight of the unopened uterus minus body weight on day 6 p.c.).

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: gross pathology

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: YesExaminations included:- Gravid uterus weight: Yes- Number of corpora lutea: Yes- Number of implantations: Yes- Number of early resorptions: Yes- Number of late resorptions: Yes

Fetal examinations:

All fetal analyses were conducted without knowledge of treatment group in order to minimize bias:
- External examinations: Yes: all litter. At necropsy each fetus was weighed, sexed and examined macroscopically for any external findings. The sex was determined by observing the distance between the anus and the base of the genital tubercle and was later confirmed in all fetuses fixed in BOUIN'S solution by internal examination. lf there were discrepancies between the "external" and the "internal" sex of a fetus, the fetus was finally sexed according to the appearance of its gonads.Furthermore, the viability of the fetuses and the condition of the placentae, the umbilical cords, the fetal membranes and fluids were examined.
Individual placental weights were recorded.
- Soft tissue examinations: Yes: one half of the fetuses per dam
- Skeletal examinations: Yes: one half of the fetuses per dam

Statistics:

Statistical analyses were performed according to following schedule:
- DUNNETT-test (two-sided): Food consumption, body weight, body weight change, corrected body weight gain, carcass weight, weight of unopened uterus, number of corpora lutea, number of implantations, number of resorptions, number of live fetuses, proportions of preimplantation loss, pro-portions of postimplanta-tion loss, proportions of resorptions, proportion of live fetuses in each litter, litter mean fetal body weight, litter mean placental weight
- FISHER'S EXACT test (one-sided): Female mortality, females pregnant at terminal sacrifice, number of litters with fetal findings
- WILCOXON-test (one-sided): Proportions of fetuses with malformations, variations and/or unclassified observations in each litter

Indices:

- The conception rate (in %) was calculated according to the following formula: number of pregnant animals / number of fertilized animals x 100
- The preimplantation loss (in %) was calculated according to the following formula:(number of corpora lutea - number of implantations) / number of corpora lutea x 100
- The postimplantation loss (in %) was calculated from the following formula:(number of implantations - number of live fetuses) / number of implantations x 100

Historical control data:

The historical control data used for interpretation of findings refer to the same test facility, the same rat strain and supplier of the animals.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Several high dose rats showed abdominal position, ataxia and/or unsteady gait shortly after treatment. These findings were only observed on the first days of dosing. Moreover, all high dose and several mid dose rats showed transient salivation, being considered to be substance-related and probably induced by bad taste of the test substance, local affection of the upper digestive tract or as a conditioning phenomenon. No disturbances of the general behavior occurred in the dams of control and low dose group.

Mortality:

no mortality observed

Description (incidence):

There were no substance-related or spontaneous mortalities in any of the groups.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights were not affected. Mean body weight gains of the high dose dams were statistically significantly lowered (about 14% below if calculated for days 6 - 19 p.c.) which is considered to be a clear test substance-related sign of maternal toxicity. Body weight gains of the dams at 50 and 200 mg/kg bw were similar to those of controls.

Corrected body weight gain (net maternal body weight change): The net weight change of the high dose rats was about 29% below controls which is considered to be a clear test substance-related sign of maternal toxicity.The corrected body weight gains of the dams at 50 and 200 mg/kg bw revealed no differences of any biological relevance to the corresponding control group.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

The mean food consumption of the high dose dams was statistically significantly reduced on most days of the treatment and during the posttreatment period. For the entire treatment phase (days 6 - 19 p.c.): about 7% below controls. Food consumption of the mid and low dose rats was not affected by the test substance administration.

Food efficiency:

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Uterus weight: Mean gravid uterus weights of the animals of all test groups were not influenced by the administration of the test substance.

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

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 specified

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed

Changes in number of pregnant:

no effects observed

Details on maternal toxic effects:

Details on maternal toxic effects:
- Mortality and day of death: There were no substance-related or spontaneous mortalities in any of the groups.
- Clinical symptoms: Several high dose rats showed abdominal position, ataxia and/or unsteady gait shortly after treatment. These findings were only observed on the first days of dosing. Moreover, all high dose and several mid dose rats showed transient salivation, being considered to be substance-related and probably induced by bad taste of the test substance, local affection of the upper digestive tract or as a conditioning phenomenon. No disturbances of the general behavior occurred in the dams of control and low dose group.
- Food consumption: The mean food consumption of the high dose dams was statistically significantly reduced on most days of the treatment and during the posttreatment period. For the entire treatment phase (days 6 - 19 p.c.): about 7% below controls. Food consumption of the mid and low dose rats was not affected by the test substance administration.
- Body weight data: Mean body weights were not affected. Mean body weight gains of the high dose dams were statistically significantly lowered (about 14% below if calculated for days 6 - 19 p.c.) which is considered to be a clear test substance-related sign of maternal toxicity. Body weight gains of the dams at 50 and 200 mg/kg bw were similar to those of controls.
- Corrected body weight gain (net maternal body weight change): The net weight change of the high dose rats was about 29% below controls which is considered to be a clear test substance-related sign of maternal toxicity. The corrected body weight gains of the dams at 50 and 200 mg/kg bw revealed no differences of any biological relevance to the corresponding control group.
- Uterus weight: Mean gravid uterus weights of the animals of all test groups were not influenced by the administration of the test substance.
- Necropsy findings: There were no substance-related observations at necropsy in any of the dams.
- Reproduction data of dams: There were no substance-related and/or biologically relevant differences between the test groups in conception rate, in the mean number of corpora lutea and implantation sites or in the values calculated for the pre- and the postimplantation losses, the number of resorptions and viable fetuses.

Key result

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Key result

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

Weight of fetuses: The mean body weights of the high dose fetuses were statistically significantly reduced (about 9% below controls if both sexes are combined). The mean fetal body weights at 50 and 200 mg/kg bw were not influenced.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Weight of fetuses: The mean body weights of the high dose fetuses were statistically significantly reduced (about 9% below controls if both sexes are combined). The mean fetal body weights at 50 and 200 mg/kg bw were not influenced.

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not examined

External malformations:

effects observed, non-treatment-related

Description (incidence and severity):

There appeared only one kind of external malformations. Cleft palate was seen in 2 10w dose littermates (female fetus No. 5 and male fetus No. 6 from dam No. 43). This isolated and not dose-related finding is considered to be spontaneous in nature.

Skeletal malformations:

effects observed, treatment-related

Description (incidence and severity):

Skeletal variations (primarily delays in the ossification process of skull, vertebral column and sternum) occurred at statistically significantly increased rates in the high dose fetuses at incidences above the upper historical control values. These variations were:
- lncomplete ossification of supraoccipital; unchanged cartilage: 14.8%, 19.8%, 20.4%, 28.9% (mean percentage of affected fetus/litter) at 0, 50, 200, 1000 mg/kg bw/d.
- Dumbbell ossification of thoracic centrum; dumbbell-shaped cartilage of centrum: 8.5%, 6.5%, 9.3%, 20.1% (mean percentage of affected fetus/litter) at 0, 50, 200, 1000 mg/kg bw/d.
- Incomplete ossification of sacral arch; cartilage present: 28.1%, 28.3%, 41.2%, 65.1% (mean percentage of affected fetus/litter) at 0, 50, 200, 1000 mg/kg bw/d.
- Unossified sternebra; unchanged cartilage: 20.4%, 21.3%, 24.2%, 40.8% (mean percentage of affected fetus/litter) at 0, 50, 200, 1000 mg/kg bw/d. These delays in skeletal maturation are in-line with marked impairments of the fetal body weights at the high dose level. The increased occurrence of some skeletal variations at 1,000 mg/kg represents common findings on fetal morphology most probably due to fetal growth retardations and/or due to maternal stress. These variations are, however, not indicative for selective effects on the fetal organism as they only occurred at a dose, which already induced overt maternal toxicity.

Total variations: 111 of the 196 examined control fetuses [= 57%] in all 24 litters [= 100%], 105 of the 187 examined low dose fetuses [= 56%] in all 21 litters [= 100%], 125 out of 219 mid dose fetuses [= 57%] in all 23 litters [= 100%] and 118 out of 204 high dose fetuses [= 58%] in all 23 litters [= 100%]. The mean percentages of affected fetuses/litter with total variations amounted to 59.4, 56.5, 57.5 and 57.8% at 0; 50; 200 or 1000 mg/kg bw respectively.

The incidences at 50 and 200 mg/kg do not suggest any treatment-relationship, but reflect the usual biological variation inherent in the strain of rats used for this experiment. The increased occurrence of some skeletal variations at the top dose level is considered to be substance-induced and related to the lower fetal body weights in this group, although the rate of overall variations does not suggest a treatment-relationship.

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

Two kinds of soft tissue malformations were recorded for one fetus of the control and the mid dose group (0 and 200 mg/kg body weight/day). Malpositioned subclavian branch occurred in female fetus No. 6 from control dam No. 6 and a situs inversus was seen in male fetus No. 5 from mid dose dam No. 59. The isolated occurrence of these soft malformations does not suggest any relation to dosing.

Other effects:

effects observed, treatment-related

Description (incidence and severity):

Weight of placentae: The mean placental weights at 1000 mg/kg bw were statistically significantly reduced (13% lower than controls if both sexes are combined), to be seen in association with the reduced mean fetal body weights in this group. The mean placental weights at the low and mid dose were not influenced.

Details on embryotoxic / teratogenic effects:

Details on embryotoxic / teratogenic effects:
- Sex distribution of fetuses: The sex distribution of the fetuses in all test groups was comparable to control.
- Weight of placentae: The mean placental weights at 1000 mg/kg bw were statistically significantly reduced (13% lower than controls if both sexes are combined), to be seen in association with the reduced mean fetal body weights in this group. The mean placental weights at the low and mid dose were not influenced.- Weight of fetuses: The mean body weights of the high dose fetuses were statistically significantly reduced (about 9% below controls if both sexes are combined). The mean fetal body weights at 50 and 200 mg/kg bw were not influenced.
- Fetal external, soft tissue and skeletal observations: The scattered occurrence of the few observed external, soft tissue and skeletal malformations in single fetuses of all test groups including the controls were without a consistent pattern, without a clear dose-response relationship and/or at incidences, which are similar to historical control rates. All malformations, in total 2 of the 196 examined control fetuses [= 1.0%] in 2 out of 24 litters [= 8.3%], 2 of the 187 examined low dose fetuses [= 1.1%] in one out of 21 litters [= 4.8%], 2 out of 219 mid dose fetuses [= 0.9%] in 2 out of 23 litters [= 8.7%] and 3 out of 204 high dose fetuses [= 1.5%] in 2 out of 23 litters [= 8.7%] showed malformations. The mean percentages of affected fetuses/litter with total malformations amounted to 1.1, 1.1, 0.9 and 1.4% at 0; 50; 200 or 1000 mg/kg bw respectively. These incidences do not suggest any treatment-relationship.External variations did not occur in any of the fetuses in this study. Soft tissue variations, exclusively in the form of dilated renal pelvis and ureter, occurred in all test groups including the controls without a clear relation to dosing and at incidences, which are fully within the historical control data range. Indications for substance-induced effects on the high dose group fetuses were found, taking fetal and litter incidences as well as mean percentages of affected fetuses/litter with skeletal variations into account. Skeletal variations (primarily delays in the ossification process of skull, vertebral column and sternum) occurred at statistically significantly increased rates in the high dose fetuses at incidences above the upper historical control values. These variations were:
- lncomplete ossification of supraoccipital; unchanged cartilage: 14.8%, 19.8%, 20.4%, 28.9% (mean percentage of affected fetus/litter) at 0, 50, 200, 1000 mg/kg bw/d.
- Dumbbell ossification of thoracic centrum; dumbbell-shaped cartilage of centrum: 8.5%, 6.5%, 9.3%, 20.1% (mean percentage of affected fetus/litter) at 0, 50, 200, 1000 mg/kg bw/d.
- Incomplete ossification of sacral arch; cartilage present: 28.1%, 28.3%, 41.2%, 65.1% (mean percentage of affected fetus/litter) at 0, 50, 200, 1000 mg/kg bw/d.
- Unossified sternebra; unchanged cartilage: 20.4%, 21.3%, 24.2%, 40.8% (mean percentage of affected fetus/litter) at 0, 50, 200, 1000 mg/kg bw/d.These delays in skeletal maturation are in-line with marked impairments of the fetal body weights at the high dose level.
Total variations: 111 of the 196 examined control fetuses [= 57%] in all 24 litters [= 100%], 105 of the 187 examined low dose fetuses [= 56%] in all 21 litters [= 100%], 125 out of 219 mid dose fetuses [= 57%] in all 23 litters [= 100%] and 118 out of 204 high dose fetuses [= 58%] in all 23 litters [= 100%]. The mean percentages of affected fetuses/litter with total variations amounted to 59.4, 56.5, 57.5 and 57.8% at 0; 50; 200 or 1000 mg/kg bw respectively. The incidences at 50 and 200 mg/kg do not suggest any treatment-relationship, but reflect the usual biological variation inherent in the strain of rats used for this experiment. The increased occurrence of some skeletal variations at the top dose level is considered to be substance-induced and related to the lower fetal body weights in this group, although the rate of overall variations does not suggest a treatment-relationship.

Key result

Dose descriptor:

NOAEL

Effect level:

> 1 000 mg/kg bw/day

Based on:

test mat. (total fraction)

Sex:

not specified

Basis for effect level:

other: teratogenicity

Remarks on result:

other: The increase in skeletal variations at 1,000 mg/kg represent common findings on fetal morphology probably due to fetal growth retardations and/or due to maternal stress. These variations only occurred at a dose, which already induced maternal toxicity.

Abnormalities:

not specified

Key result

Developmental effects observed:

yes

Lowest effective dose / conc.:

200 mg/kg bw/day

Treatment related:

yes

Relation to maternal toxicity:

developmental effects as a secondary non-specific consequence of maternal toxicity effects

Dose response relationship:

yes

Relevant for humans:

not specified

Conclusions:

Based on the results of this prenatal developmental toxicity study, the NOAEL for maternal and prenatal developmental toxicity is 200 mg/kg body weight/day. Thus signs of prenatal developmental toxicity did only occur at a dose level, which was also clearly toxic to the dams. There were no indications for teratogenicity up to and including 1000 mg/kg body weight/day. Therefore, Methylheptenone does not need to be classified for developmental toxicity in accordance with the criteria outlined in Annex I of the CLP Regulation (1272/2008/EC).

Executive summary:

6-Methylhept-5-en-2-one (Methylheptenon) was tested for its prenatal developmental toxicity in Wistar rats. The test substance was administered as an oily suspension to 25 time-mated female Wistar rats/group by stomach tube at doses of 50; 200 and 1,000 mg/kg body weight on day 6 through day 19 post coitum (p.c.). A standard dose volume of 5 ml/kg body weight was used for each group. The control group, consisting of 25 females, was dosed with the vehicle only (olive oil Ph.Eur./DAB). Food consumption and body weights of the animals were recorded regularly throughout the study period. The state of health of the animals was checked each day. On day 20 post coitum, all females were sacrificed and assessed by gross pathology (including weight determinations of the unopened uterus and the placentae). For each dam, corpora lutea were counted and number and distribution of implantation sites (differentiated as resorptions, live and dead fetuses) were determined. The fetuses were removed from the uterus, sexed, weighed and further investigated for any external findings. Thereafter, nearly one half of the fetuses of each litter was examined for soft tissue findings and the remaining fetuses for skeletal (incl. cartilage) findings.

The following substance-related findings were obtained:

Test group 3 (1,000 mg/kg body weight/day):

-       transient salivation in all dams between days 6 - 19 p.c.

-       transient occurrence of abdominal position and ataxia (in 3 out of 25 rats) and/or unsteady gait (in 5 out of 25 rats) shortly after treatment at initiation of dosing (days 7 -11 p.c.)

-       statistically significantly decreased food consumption on most days of the treatment period (about 7% less food intake as in the concurrent control group if calculated for days 6 -19 p.c.)

-       statistically significantly impaired body weight gain on days 6 - 8, 15 - 17, 19 - 20, 6 - 19 and 0 - 20 p.c. (about 14% below the concurrent control value if calculated for days 6 - 19 p.c.)

-       statistically significantly lower corrected body weight gain (about 29% below controls)

-       statistically significantly lower mean placental (about 13% below controts) and fetal body weights (about 9% below controls)

-       statistically significantly increased rates of fetuses/litter with certain skeletal variations (i.e. delays in the ossification of parts of the skull, the vertebral column and the sternum)

 

Test group 2 (200 mg/kg body weight/day):

-       Transient salivation in 9out of 25 dams between treatment days 10- 19 p.c.

-       no substance-related effects on gestational parameters or fetuses

 

Test group 1 (50 mg/kg body weight/day):

-       no substance-related effects on dams, gestational parameters or fetuses

Thus, under the conditions of this prenatal developmental toxicity study, the oral administration of 6-Methylhept-5-en-2-one (Methylheptenon) to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (days 6 - 19 p.c.) elicited clear signs of mnaternal toxicity at 1,000 mg/kg body weigh/day. No signs of substance-induced maternal toxicity occurred at the low and the mid dose level (50 or 200 mg/kg body weight/day). There were no substance-related influences on the gestational parameters up to and including the highest dose level (1,000 mg/kg body weight/day). Conception rate, mean number of corpora lutea, total implantations, resorptions and live fetuses, fetal sex ratio or the values calculated for the pre- and the postimplantation losses were unaffected by treatment. Some signs of substance-induced prenatal developmental toxicity, but no indications tor teratogenicity occurred exclusively at the high dose level. The mean placental and fetal body weights were diminished. Correspondingly, the rates for certain skeletal variations (i.e. indications for delays in the ossification process) were statistically significantly increased and outside historical control ranges. These variations mirror common findings on fetal morphology due to growth retardations, but are not indicative for selective effects on the fetal organism. No substance-induced signs of embryo-/fetotoxicity were observed at 50 and 200 mg/kg body weight/day. Based on these results, the no observed adverse effect level (NOAEL) for maternal and prenatal developmental toxicity is 200 mg/kg body weightlday. Thus signs of prenatal developmental toxicity did only occur at a dose level, which was also toxic to the dams. There were no indications for teratogenicity up to and including 1,000 mg/kg body weight/day. Therefore, Methylheptenone does not niet to be classified for developmental toxicity in accordance with the criteria outlined in Annex I of the CLP Regulation (1272/2008/EC).

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Study was conducted according to OECD 414 and under GLP conditions.

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

6-Methylhept-5-en-2-one (Methylheptenon) was tested for its prenatal developmental toxicity in Wistar rats. The test substance was administered as an oily suspension to 25 time-mated female Wistar rats/group by stomach tube at doses of 50; 200 and 1,000 mg/kg body weight on day 6 through day 19 post coitum (p.c.). A standard dose volume of 5 ml/kg body weight was used for each group. The control group, consisting of 25 females, was dosed with the vehicle only (olive oil Ph.Eur./DAB). Under the conditions of this prenatal developmental toxicity study, the oral administration of 6-Methylhept-5-en-2-one (Methylheptenon) to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (days 6 - 19 p.c.) elicited clear signs of mnaternal toxicity at 1,000 mg/kg body weigh/day. No signs of substance-induced maternal toxicity occurred at the low and the mid dose level (50 or 200 mg/kg body weight/day). There were no substance-related influences on the gestational parameters up to and including the highest dose level (1,000 mg/kg body weight/day). Conception rate, mean number of corpora lutea, total implantations, resorptions and live fetuses, fetal sex ratio or the values calculated for the pre- and the postimplantation losses were unaffected by treatment. Some signs of substance-induced prenatal developmental toxicity, but no indications tor teratogenicity occurred exclusively at the high dose level. The mean placental and fetal body weights were diminished. Correspondingly, the rates for certain skeletal variations (i.e. indications for delays in the ossification process) were statistically significantly increased and outside historical control ranges. These variations mirror common findings on fetal morphology due to growth retardations, but are not indicative for selective effects on the fetal organism. No substance-induced signs of embryo-/fetotoxicity were observed at 50 and 200 mg/kg body weight/day. Based on these results, the no observed adverse effect level (NOAEL) for maternal and prenatal developmental toxicity is 200 mg/kg body weightlday. Thus signs of prenatal developmental toxicity did only occur at a dose level, which was also toxic to the dams. There were no indications for teratogenicity up to and including 1,000 mg/kg body weight/day.

Justification for classification or non-classification

Based on the available data on developmental toxicity, the substance does not need to be classified in accordance with the criteria outlined in Annex I of the CLP Regulation (1272/2008/EC).