Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

The Rodent Hershberger Assay was performed in accordance with OECD Protocol and Guidance, Phase 2 of the test validation.

Clinical examinations revealed no substance-related findings in both treatment groups (300 and 1,000 mg/kg bw/day). Concerning hormone levels, co-administration of 1,000 mg/kg bw/day of the test substance and 0.4 mg/kg bw/day of testosterone propionate did not affect testosterone, dihydrotestosterone and luteinizing hormone in the serum of castrated male rats when compared with castrated animals given 0.4 mg/kg bw/day of testosterone propionate as reference androgen, only.

In the uterotrophic assay two doses (500 mg/kg bw/d and 1000 mg/kg bw/d) of the test item were administered to 10 immature Wistar female rats (age: 22 days) for 4 consecutive days twice daily. Animals of the control group received the vehicle alone (sesame oil). A positive control group was treated with diethylstilbestrol-dipropionate (5 µg/kg bw/d), a known uterotrophic agent.

The administration of 500 mg/kg bw/d of the test item had no effect on body weight and body weight gain of the treated animals, whereas 1000 mg/kg bw/d of the test substance elicited statistically significantly decreased body weight gain at the beginning of the administration period. However, no further findings on body weight, body weight gain and clinical findings were recorded in the course of the study and there were no substance-related effects on the absolute and relative uterine weights.

In comparison to the vehicle control group administration of the positive control resulted in an approximate 3.3-fold increase in absolute and in relative uterine weights, consistent with the known efficacy as an uterotrophic agent.

In conclusion, under the conditions of the uterotrophic assay, the test item did not promote growth of the uterus in immature female rats and was therefore considered not to possess any estrogenic activity.

Effects seen in the 90d oral feeding study with mice and rats on sperm and estruous cycle length were only noted at the highest dose tested (50000 ppm, equivalent 3656 mg/kg bw/d in male rats, 3261 mg/kg bw/d female rats, 18624 mg/kg bw/d male mice and 22968 mg/kg bw/d female mice) and thus not relevant to real life exposure.


Short description of key information:
The substance has been assessed in a Hershberger assay for anti-androgen activity and was found negative of such effects. In addition an uterotrophic assay was performed, also turning out negative, not showing any effects on uteri of test animals. Within the 90 day oral toxicity study using mice and rats slight effects on sperm and estrous cycle were only noted at the highest dose groups (50000 ppm). As a result no adverse effects on fertility by oral route are anticipated.

Effects on developmental toxicity

Description of key information
NOAEL for prenatal development 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:
from November 1, 2004 to May 2, 2005
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: guideline test with GLP
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
Species and strain
Time-mated Wistar rats (Crl:WI(Han) [fomner: CrlGlxBrlHan:WI]) supplied by Charles River Laboratories, Germany that were free from clinical signs of disease, were used for the investigations,
Animal identification
The animals were paired by the breeder and supplied on day 0 post coitum (= detection of vaginal plug / sperm). They were randomly allocated to the test groups by withdrawal from the transport box at random and placed in to a random distribution of groups. After randomization the rats were identified uniquely by ear tattoo.
Reason for species selection
This strain was selected since extensive experience is available on Wistar rats and this strain has been proven to be sensitive to substances with a teratogenic potential.
HOUSING AND DIET
The rats were housed singly from day 0 - 20 p.c. in type DK III stainless steel wire mesh cages supplied by BECKER & CO., Castrop-Rauxel, Germany (height: 15 cm, length: 37,5 cm, width: 21 cm; floor area about 800 cm2).
The animals were accommodated in fully air- conditioned rooms in which central air conditioning maintained a range of temperature of 20 - 24 °C and a range of relative humidity of 30 - 70%. There were no deviations from these limits.
The day/night rhythm was 12 hours (12 hours light from 6.00 a.m. to 6.00 p.m. and 12 hours darkness from 6.00 p.m. to 6.00 a.m.).
Before the study started, the animal room was completely disinfected using a disinfector ("AUTEX", fully automatic, formal in-ammonia - based terminal disinfection). In general, each week the walls and the floor were cleaned with water containing about 0.5% Mikro-Quat (supplied by ECOSAN GmbH, Germany).
The food used was ground Kliba maintenance diet mouse/rat “GLP", supplied by PROVIMI KLIBA SA, Kaiseraugst, Switzerland. Food was available to the animals ad libitum throughout the study (from the day of supply to the day of necropsy), as was drinking water of tap water quality from water bottles.
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Test article was tested for its prenatal developmental toxicity in Wistar rats. The test substance was administered as a suspension in corn oil to 25 time-mated female Wistar rats per group by gavage at doses of 40, 200 and 1000 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 (corn oil) in parallel. At terminal sacrifice 22 - 24 females/group had implantation sites.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytical verification of the stability of the test substance in corn oil for a period of at least 10 days at room temperature was carried prior to the study.
Samples of the test substance suspensions were sent to the analytical laboratory twice during the study period (at the beginning and towards the end) for verification of the concentrations. The samples which were taken for the first concentration control analysis at the beginning of the administration period were also used to verify the homogeneous distribution of the test compound in corn oil. For this purpose three samples were taken for the low and high concentrations from the top, middle and bottom of the beaker with a magnetic stirrer running.
Details on mating procedure:
The animals were paired by the breeder ("time-mated") and supplied on day 0 post coitum (= detection of vaginal plug / sperm). The animals arrived on the same day (i.e. day 0 p.c.) at the experimental laboratory. The following day was designated “day 1" post coitum (p.c.). Between start of the study (beginning of the experimental phase) and first administration (day 6 p.c.) the animals were acclimated to the laboratory conditions.
Duration of treatment / exposure:
14 days (days 6 -19)
Frequency of treatment:
once a day
Duration of test:
20 days
Remarks:
Doses / Concentrations:
40, 200, 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Details on study design:
The animals were supplied at an age of about 70 - 84 days.
Based on the pregnant animals the body weight on day 0 varied between 143.3 - 176.6 g.
The test substance suspensions were administered to the animals orally (by gavage) once a day from implantation to one day prior to the expected day of parturition (day 6 to day 19 p.c.) always at approx. the same time of day (in the morning). The animals of the control group were treated with the vehicle (corn oil) in the same way. The volume administered each day was 5 ml/kg body weight. The calculation of the volume administered was based on the most recent individual body weight.
On day 20 p.c. all females were sacrificed in a randomized order and examined macroscopically. The fetuses were removed from the uterus and further investigated with different methods.
Due to technical reasons, the study was carried out in 2 cohorts. Each dose group was represented in each cohort. For further details.

Maternal examinations:
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).
1.Clinical examinations
1.1.Mortality
A check was made twice a day on working days or once a day (Saturday, Sunday or on public holidays) (days 0 - 20 p.c.).
1.2.Clinical symptoms
A cageside examination was conducted at least once daily for any signs of morbidity, pertinent behavioral changes and signs of overt toxicity, If such signs occurred, the animals were examined several times daily (days 0 through 20 p.c.).
1.3.Body weight data
All animals were weighed 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.
1.4.Food consumption
With the exception of day 0, the consumption of food was determined on the same days as was body weight.
1.5.Corrected body weight gain (net maternal body weight change)
Furthermore, the 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.).
2.Examinations of the dams at termination
2.1.Necropsy
On day 20 p.c., the dams were sacrificed in randomized order by cervical dislocation (after Isoflurane anesthesia) and the fetuses were removed from the uterus.

Ovaries and uterine content:
After the dams had been sacrificed, they were necropsied and assessed by gross pathology, in randomized order to minimize bias. The uterus and the ovaries were removed and the following data were recorded:
-Weight of the unopened uterus
-Number of corpora lutea
-Number and distribution of implantation sites classified as:
•live fetuses
•dead implantations:
a) early resorptions (only decidual or placental tissues visible or according to SALEWSKI (Salewski, 1964) from uteri from apparently non-pregnant animals and the empty uterus horn in the case of single-horn pregnancy)
b) late resorptions (embryonic or fetal tissue in addition to placental tissue visible)
c) dead fetuses (hypoxemic fetuses which did not breathe spontaneously after the uterus had been opened)
Fetal examinations:
1. Examination of the fetuses after dissection from the uterus
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 Harrison’s fluid by internal examination. If 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.
Thereafter, the fetuses were sacrificed by subcutaneous injection of a pentobarbital (Narcoren®, Fa. Rhone Merieux GmbH, 88471 Laupheim, Germany; Dose: 0.1 ml/fetus).
After these examinations, approximately one half of the fetuses per dam were eviscerated, skinned and placed in ethyl alcohol, the other half was placed in Harrison's fluid for fixation and further evaluation.
2. Soft tissue examination of the fetuses
The fetuses fixed in Harrison's fluid were examined for any visceral findings. After this examination these fetuses were discarded.
3. Skeletal examination of the fetuses
The skeletons of the fetuses fixed in ethyl alcohol were stained. Thereafter, the skeletons of these fetuses were examined under a stereomicroscope. After this examination the stained fetal skeletons were retained individually.
4. Evaluation criteria for assessing the fetuses
-Malformation
A permanent structural change that is likely to adversely affect the survival or health.
-Variation
A change that occurs also in fetuses of control animals and is unlikely to adversely affect the survival or health. This includes delays in growth or morphogenesis that has otherwise followed a normal pattern of development.
Statistics:
1, Food consumption, body weight, body weight change, corrected body weight gain (net maternal body weight change), carcass weight, weight of unopened uterus, number of corpora lutea, number of implantations, number of resorptions, number of live fetuses, proportions of preimplantation loss, proportions of postimplantation loss, proportion of resorptions, proportion of live fetuses in each litter, litter mean fetal body weight, litter mean placental weight:
Simultaneous comparison of all dose groups with the control group using the DUNNETT-test (two- sided) for the hypothesis of equal means

2, Female mortality, females pregnant at terminal sacrifice, number of littera with fetal findings:
Pairwise comparison of each dose group with the control group using FISHERS EXACT test (one-sided) for the hypothesis of equal proportions

3, Proportions of fetuses with malformations, variations and/or unclassified observations in each litter:
Pairwise comparison of each dose group with the control group using the WILCOXON-test (one-sided) for the hypothesis of equal medians
Indices:
1, The conception rate (in %) was calculated according to the following formula:
number of pregnant animals / number of fertilized animals × 100
2, The preimplantation loss (in %) was calculated according to the following formula:
(number of corpora lutea - number of implantations)/ number of corpora lutea × 100
3, The postimplantation loss (in %) was calculated from the following formula:
(number of implantations- number of live fetuses) / number of implantations × 100
Historical control data:
see table 1 in the field for any other information on results.
Details on maternal toxic effects:
Maternal toxic effects:yes. Remark: All high dose (1,000 mg/kg body weight/day) and individual (3 out of 25) of the mid dose (200 mg/kg body weight/day) dams showed transient salivation during major parts of the treatment period.

Details on maternal toxic effects:
1.Clinical examinations
1.1. Mortality
There were no test substance-related or spontaneous mortalities in any of the groups.
1.2.Clinical symptoms
All high dose (1,000 mg/kg body weight/day) and individual (3 out of 25) of the mid dose (200 mg/kg body weight/day) dams showed transient salivation during major parts of the treatment period. Salivation persisted in the respective females only for a few minutes after daily gavage dosing. This symptom was initially observed for high dose female No. 97 on day 7 p.c. and for mid dose rat No. 65 on day 12 p.c. After cessation of treatment on day 19 p.c. salivation did not occur any longer.
The observed temporary salivation is considered to be test substance-induced. It is likely, that this finding was induced by bad taste of the test substance or local affection of the upper digestive tract. Salivation itself is not assessed as an adverse or toxic effect.
Reddish discolored urine was recorded in 10 females of test group 3 (1,000 mg/kg body weight/day) from day 13 p.c. onwards until terminal sacrifice (day 20 p.c.). This urine discoloration mirrors the systemic availability of the test substance rather than being an adverse effect. It is most likely due to the excreted test compound or its metabolites.
Furthermore, 16 high dose dams showed urine stained fur on gestation days 7-20. This clinical finding is a sign of discomfort of the rats and is probably test substance-induced.
High dose female No. 80 had alopecia on its right flank from gestation day 17 onwards.
No clinical observations at all were noted in the dams of test group 1 (40 mg/kg body weight/day).
1.3.Food consumption
Average food consumption of the high dose dams (1,000 mg/kg body weight/day) was statistically significantly reduced on treatment days 6-10 p.c.. Thereafter, food consumption of those rats recovered and was comparable to the control values. If calculated for the entire treatment period (days 6-20 p.c.), mean food consumption of test group 3 was 9% below the concurrent control group.
Food consumption of the females of test groups 1 and 2 <40 and 200 mg/kg body weight/day) was unaffected and did not show any statistically significant or biologically relevant differences in comparison to the controls.
1.4.Body weight data
The average body weights during the whole study were comparable among control and treated groups (0, 40, 200 and 1,000 mg/kg body weight/day).
Body weight gain of the high dose rats was statistically significantly reduced at initiation of treatment (days 6-8 p.c.; about 60% below the concurrent control value). If calculated for the entire treatment phase (days 6-19 p.c.), the reduction in mean body weight gain of these rats amounted to about 7%.
Body weight gain of the dams of test groups 1 and 2 (40 and 200 mg/kg body weight/day) was comparable to the concurrent controls. All observable differences in these 2 groups in comparison to the controls are without any biological relevance.
1.5.Corrected body weight gain (net maternal body weight change)
The corrected body weight gain (terminal body weight on day 20 p.c. minus weight of the unopened uterus minus body weight on day 6 p.c.) of the dams of test groups 1 and 2 (40 and 200 mg/kg body weight/day) showed no difference of biological relevance to the corresponding control group. The net weight change of the 1,000 mg/kg rats, however, was statistically significantly below (-21%) the concurrent control value. This correlates well to the temporarily decreased food consumption and absolute weight gain in these rats.
2.Examinations of the dams at termination
2.1.Uterus weight
The mean gravid uterus weights of the animals of test groups 1-3 (40, 200 or 1,000 mg/kg body weight/day) were not influenced by the test substance. The differences between these groups and the control group were assessed to be without biological relevance.
2.2.Necropsy findings
There were no test substance-related or spontaneous findings at necropsy in any of the dams.
2.3.Reproduction data of dams
The conception rate reached 96% in test groups 0 and 3 (0 and 1,000 mg/kg body weight/day) and 88% in test groups 1 and 2 (40 and 200 mg/kg body weight/day). A sufficient number of pregnant females was available for the purpose of the study (according to test guidelines listed in chapter 2.4.).
There were no test substance-related and/or biologically relevant differences between the different 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. Gestaiional parameters in the various test groups were within the normal range for animals of this strain and age; see also Volume III (Supplement) for historical control data.


Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes. Remark: all fetal pathology findings were indicative for a minor disturbance and delay of ossification at high dose level tested (1,000 mg/kg body weight/day).

Details on embryotoxic / teratogenic effects:
The scattered occurrence of a few external , soft tissue , and skeletal malformations in test groups 0, 1, 2 and 3 (0, 40, 200 and 1,000 mg/kg body weight/day) without a consistent pattern, without a clear dose- response relationship and/or at incidences, which are similar to historical control rates does not suggest any substance-induced origin of these findings. The following malformations were recorded: misshapen humerus (in two control fetuses), anasarca, right-sided aortic arch, muscular ventricular septum defect (heart) and abnormal lung lobation (in one low dose fetus), situs inversus (in another low dose fetus) and malpositioned and bipartite sternebrae (in one high dose fetus).
If all the different types of malformations are summarized, in total 2 of the 208 examined control fetuses [= 1.0%] in 2 out of 24 litters [= 8.3%], 2 out of 175 low dose fetuses [= 1.1%, in one out of 22 litters [= 4.5%], none of the 182 mid dose fetuses from 22 litters and one out of 211 high dose fetuses [= 0.5%] in one out of 24 litters [=4.2%] showed malformations. The mean percentages of affected fetuses/litter with total malformations amounted to 0.9, 1.5, 0.0, and 0.4% at 0, 40, 200 or 1,000 mg/kg body weight/day respectively. These low, non dose-related incidences do not suggest any relationship to the test substance.
External variations did not occur in any of the fetuses in this study , Soft tissue variations, in the form of an enlarged ventricular chamber (heart), an absent lung lobe, dilated renal pelvis and ureters occurred in all test groups including the controls.
The few skeletal variations consisted primarily in transient delays of ossification. The vast majority of the skeletal variations was equally distributed among the different test groups including controls, if normal biological variation is taken into account.
Only in 2 skeletal structures - skull bones and cervical arch - retarded ossification was more frequently observed in the 1,000 mg/kg litters and at incidences, which were mainly slightly above the respective historical control range . This ossification delay is considered to be secondary to the distinct maternal toxicity noted in this dose group. Furthermore, as the associated cartilaginous structures remained unchanged, reversibility of these isolated findings of delayed skeletal maturation can be anticipated shortly after birth.
The incidence of fetuses with supernumerary 14th rib(s) without cartilage was also higher in the top dose litters (1,000 mg/Kg body weight/day) than in either the concurrent or historical control. The expectation would be, if other teratogenic effects did not occur at that dose level, that at a higher dose, frank embryotoxicity would become evident". Therefore, the statistically significantly increased number of 1,000 mg/kg fetuses with supernumerary 14th rib(s) in the present study is finally assessed as an embryo-/fetotoxic effect representing a manifestation of a non-specific stress on the dams; it is, however, not interpreted as being a teratogenic effect of the test substance at this dose level.
If all variations are summarized, in total 111 of the 208 examined control fetuses [= 53%] in all 24 litters [= 100%], 94 of the 175 examined low dose fetuses [=54%] in all 22 litters [= 100%], 98 out of 182 mid dose fetuses [= 54%] in all 22 litters [=100%] and 115 out of 211 high dose fetuses [= 55%] in all 24 litters [= 100%] showed variations. The mean percentages of affected fetuses/litter with total variations amounted to 54.8, 57.3, 53.7, and 54.6% at 0, 40, 200 or 1,000 mg/kg body weight/day, respectively. These incidences do not suggest a treatment-relationship, but reflect the usual biological variation inherent in the strain of rats used for this experiment.
A spontaneous origin is also assumed for the unclassified external observation and the few unclassified cartilage observations which were recorded for several fetuses of test groups 0, 1, 2 and 3 (0, 40, 200 or 1,000 mg/kg body weight/day). Distribution and type of these findings do not suggest any relation to treatment.
Finally, all fetal pathology findings were indicative for a minor disturbance and delay of ossification at high dose level tested (1,000 mg/kg body weight/day). Test article does not possess any selective teratogenic properties. The slightly increased incidence in few skeletal variations at the high dose fetuses mirror common minor effects on fetal morphology, being obviously secondary to maternal toxicity. No test substance-induced effects on fetal morphology occurred at low and the mid dose levels (40 or 200 mg/kg body weight/day).
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1.Occurrence of statistically significantly increased fetal skeletal variations (expressed as mean percentage of affected fetuses/litter)

Finding

0 mg/Kg bw/d

40 mg/kg bw/d

200 mg/kg bw/d

1,000 mg/kg bw/d

HCD Mean % (range)

Incomplete ossification of interparietat; unchanged cartilaga

12.4

25.8

27.3*

34.0*

21.4

(12.5-33.3)

Incomplete ossification of parietal; unchanged cartilage

9.0

18.3

19.2

23.5*

15.2 (3.1 -27.6)

Incomplete ossification of supraocoipitai; unchanged cartilage

7.1

13.9

10-8

19.6*

13.9

(6.2-21.2)

Incomplete ossification of cervical arch; cartilage present

0,0

1.5

0.0

2.9*

0,1 {0.0-1.1)

Supernumerary rib(14th)

; cartilage present

2.9

16.4*

1.8

5.6

4.0

(0,0-10.2)

Supernumerary rib (14th); cartilage not present

42,1

41.2

47.1

61.3*

41,6 (32.4 - 58.8)

Total fetal skeletal variations

97.3

96,3

96.4

100.0*

94.4

(87.0-99.2)

 mg/kg bw/d = mg/kg body weight/day * = p<=0.05, ** = p < 0.01; HCD=Historicalcontroldata



Conclusions:
Based on the experimental data given in this study, it is concluded that the no observed adverse effects level (NOAEL) for maternal and prenatal developmental toxicity is 200 mg/kg body weight/day. The test article did not possess any selective teratogenic properties.
Executive summary:

This prenatal toxicity study was performed to evaluate the effects of test article on embryonic and fetal development in Wistar rats by orallly at dose levels of 40, 200, 1000 mg/kg bw/dayon day 6 through day 19 post coitum (p.c.).

Signs of test substance related maternal toxicity were observed during the study. In particular, the high dose dams showed an impaired health status indicated by urine stained fur, transiently affected food consumption and body weight and a decreased net maternal body weight gain but without any influence on the uterine content. This demonstrates an adverse effect of the test compound on all pregnant rats of this dose group. In addition, reddish discolored urine as sign for systemic substance availability and transient salivation were noted in the dams of this group. The only substance-induced finding in the mid dose dams (200 mg/kg body weight/day) consisted in transitory salivation in individual rats. However, salivation by itself is not assessed as an adverse or toxic effect.

The oral administration of test article to the dams at all 3 dose levels had no influence on gestational parameters.Conception rate, mean number of corpora lutea, total implantations, resorptions and live fetuses, fetal sex ratio or the values calculated for pre- and the postimplantation losses were unaffected by the treatment. No test substance-related differences were recorded for placental and fetal body weights.

All fetal pathology findings were indicative for a minor disturbance and delay of ossification at high dose level tested (1,000 mg/kg body weight/day). Test article does not possess any selective teratogenic properties. The slightly increased incidence in few skeletal variations at the high dose fetuses mirror common minor effects on fetal morphology, being obviously secondary to maternal toxicity. No test substance-induced effects on fetal morphology occurred at low and the mid dose levels (40 or 200 mg/kg body weight/day).

Therefore, it can be concluded that the no observed adverse effect level (NOAEL) of test article for maternal and prenatal developmental toxicity is 200 mg/kg body weight/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
subacute
Species:
rat
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

One animal study (Dr.S. Schneider,2005) was available to assess the developmental toxicity of test article.

This prenatal toxicity study was performed to evaluate the effects of test article on embryonic and fetal development in Wistar rats by oral administration at dose levels of 40, 200, 1000 mg/kg bw/dayon day 6 through day 19 post coitum (p.c.).

The oral administration of test article to the dams at all 3 dose levels had no influence on gestational parameters. conception rate, mean number of corpora lutea, total implantations, resorptions and live fetuses, fetal sex ratio or the values calculated for pre- and the post-implantation losses were unaffected by the treatment. No test substance-related differences were recorded for placental and fetal body weights.

All fetal pathology findings were indicative for a minor disturbance and delay of ossification at high dose level tested (1,000 mg/kg body weight/day). Test article does not possess any selective teratogenic properties. The slightly increased incidence in few skeletal variations at the high dose fetuses mirror common minor effects on fetal morphology, being obviously secondary to maternal toxicity. No test substance-induced effects on fetal morphology occurred at low and the mid dose levels (40 or 200 mg/kg body weight/day).

Therefore, it can be concluded that the no observed adverse effect level (NOAEL) of test article for prenatal developmental toxicity is 200 mg/kg body weight/day.

Justification for classification or non-classification

Based on the pre-natal developmental toxicity study in which no teratogenic effects had been observed as well as on the study on anti-androgenic effects and uterotrophic assay, both turning out negative, the substance does not require classification according to CLP (Regulation (EC) No. 1272/2008) or DSD (Directive 67/548/EEC) respectively.