Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Species:
rabbit
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

The test substance was tested for its prenatal developmental toxicity in two species, the rat and the rabbit both to full OECD guideline 414 and performed according to GLP

1.The test substance was tested firstly for its prenatal developmental toxicity in Wistar rats (OECD guideline 414, GLP).

The test substance was administered as an aqueous suspension to groups of 25 time-mated female Wistar rats by gavage at doses of 50, 150, and 500 mg/kg body weight/day (mg/kg bw/d) on gestation days (GD) 6 through 19. Under the conditions of this prenatal developmental toxicity study, the oral administration to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at a dose of 500 mg/kg bw/d caused no evidence of maternal toxicity. In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity is 500 mg/kg bw/d.

2. The test susbstance was subsequently tested for its prenatal developmental toxicity in New Zealand Rabbits (OECD guideline 414, GLP).

The test substance was tested for its prenatal developmental toxicity in New Zealand White rabbits.The test substance was administered as an aqueous suspension to groups of 25 inseminated female New Zealand White rabbits orally by gavage in doses of 15, 50 and 150 mg/kg body weight/day (mg/kg bw/d) on gestation days (GD) 6 through 28. The vehicle control group, consisting of 25 females, was dosed with the vehicle 0.5% Carboxymethylcellulose suspension in drinking water (0.5% CMC) in parallel. A standard dose volume of 10 mL/kg body weight was used for each test group.

Under the conditions of this prenatal developmental toxicity study, the oral administration of the test material to pregnant New Zealand White rabbits from implantation to one day prior to the expected day of parturition (GD 6-28) caused evidence of maternal toxicity at the high-dose (150 mg/kg bw/d), such as adverse clinical findings. In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity is 50 mg/kg bw/d.

Since there was no evidence for toxicologically relevant adverse effects of the test substance on fetal morphology at any dose, the no observed adverse effect level (NOAEL) for prenatal developmental toxicity is the highest dose of 150 mg/kg bw/d.

The rabbit is considered to be the more senstive species in this study and the lower of the NOAEL values has been taken as the definitive result.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
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:
- Source: Charles River Wiga GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: 10-12 weeks
- The body weight of the pregnant animals on gestation day 0 varied between 148.5 – 191.5 g
- Housing: singly
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: The animals were acclimated to the laboratory conditions between start of the study (beginning of the experimental phase) and first administration (GD 6).
- Fasting: 16h before administration

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
1%
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

The aqueous test substance preparations were prepared at the beginning of the administration period and thereafter at maximum intervals of 7 days, which took into account the period of established stability. The preparation was stored in a freezer.
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 1% Carboxymethylcellulose in drinking water over a period of a maximum of 7 days at room temperature were carried out prior to the start of the study. Samples of the test substance preparations were sent to the analytical laboratory at the beginning of administration for verification of the concentrations. The samples were also used to verify the homogeneity of the low and the high concentrations.
Details on mating procedure:
- Impregnation procedure: purchased timed pregnant
Duration of treatment / exposure:
gestation days 6 to 19
Frequency of treatment:
daily
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
150 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: range finding study in pregnant rats
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: wice a day on working days or once a day on Saturdays, Sundays or on public holidays (GD 0-20).

DETAILED CLINICAL OBSERVATIONS: Yes
A cage-side 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 (GD 0-20).

BODY WEIGHT: Yes
- Time schedule for examinations: GD 0, 1, 3, 6, 8, 10, 13, 15, 17, 19 and 20.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
The consumption of food was recorded for the intervals GD 0-1, 1-3, 3-6, 6-8, 8-10, 10-13, 13-15, 15-17, 17-19 and 19-20.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uteri and the ovaries

OTHER:
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: live fetuses, dead fetuses
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: all per litter
Statistics:
Dunnett Test, Fishers exact test, Wilcoxon test
Indices:
conception rate (in %), preimplantation loss (in %), postimplantation loss (in %)
Historical control data:
18 studies, from 2011 - 2013
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
Clinical examinations of the dams: Only pregnant dams were used for the calculations of mean maternal food consumption, body weight and body weight change. Only pregnant dams with scheduled sacrifice (GD 20) were used for the calculation of mean gravid uterine weights, corrected (net) body weight gain and summary of reproduction data. The following female was excluded from the above-mentioned calculations: Test group 3 (500 mg/kg bw/d): female No. 94 – not pregnant
Mortality: There were no test substance-related or spontaneous mortalities in any females of all test groups (0, 50, 150 or 500 mg/kg bw/d).
Clinical symptoms: Most females (20 out of 25) of the high-dose group (500 mg/kg bw/d) showed transient salivation during major parts of the treatment period. Salivation persisted in the respective animals for a few minutes after daily gavage dosing (i.e. about 10-15 minutes) and was initially observed on GD 9. Furthermore, high-dose female No. 95 (500 mg/kg bw/d) had an unsteady gait after treatment on GD 16. This finding persisted for approximately 2 hours. No clinical signs or changes of general behavior, which may be attributed to the test substance, were detected in any female at dose levels of 50 or 150 mg/kg bw/d during the entire study period.
Food consumption: The mean food consumption of the dams in test groups 1-3 (50, 150 or 500 mg/kg bw/d) was generally comparable to the concurrent control throughout the entire study period. This includes the statistically significantly increased food consumption value in the high-dose group on GD 15-19.
Body weight data: The mean body weights and the average body weight gains of the low-, mid- and high-dose rats (50, 150 or 500 mg/kg bw/d) were in general comparable to the controls throughout the entire study period. The statistically significantly increased body weight gain value in test group 2 on GD 0-6 (before start of treatment) is considered to be an incidental finding.
Corrected (net) body weight gain: The corrected body weight gain of test groups 1-3 (50, 150 and 500 mg/kg bw/d) revealed no difference of any biological relevance to the corresponding control group. Moreover, mean carcass weights remained also unaffected by the treatment.
Uterus weight The mean gravid uterus weights of the animals of test group 1-3 (50, 150 and 500 mg/kg bw/d) were not influenced by the test substance. The differences between these groups and the control group revealed no dose-dependency and were assessed to be without biological relevance.
Necropsy findings: No necropsy findings which could be attributed to the test substance were seen in any dam. There occurred two spontaneous findings in test group 1, i.e. one diaphragmatic hernia and one dilated renal pelvis. These findings were detected in single animals and therefore were not assessed to be treatment-related.
Reproduction data: The conception rate varied between 96% in test group 3 (500 mg/kg bw/d) and 100% in test groups 0-2 (0, 50 and 150 mg/kg bw/d). With these rates, a sufficient number of pregnant females were available for the purpose of the study (according to the test guidelines listed in chapter 2.3.). There were no test substance-related and/or biologically relevant differences between test groups 0, 1, 2 and 3 (0, 50, 150 and 500 mg/kg bw/d) in conception rate, in the mean number of corpora lutea and implantation sites or in the value calculated for the postimplantation loss, the number of resorptions and viable fetuses. However, the value calculated for the preimplantation loss was statistically significantly increased in the mid-dose group (150 mg/kg bw/d). Due to the lack of dose-response relationship and a historical control range which covers this value (HCD: 6.6% [3.2-15.8%]), this finding is considered as incidental and not related to treatment. All other observed differences are considered to reflect the normal range of fluctuations for animals of this strain and age.
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Sex distribution of the fetuses: The sex distribution of the fetuses in test groups 1-3 (50, 150 and 500 mg/kg bw/d) was comparable to the control fetuses. Any observable differences were without biological relevance.
Weight of the placentae: The mean placental weights in the high-dose group (500 mg/kg bw/d) were decreased (about 6-8% below control). Since the difference to the control was slight and as there were neither effects on intrauterine mortality nor on fetal weights, this apparent finding is not considered to be toxicologically relevant or adverse. The mean placental weights of the low- and mid-dose groups (50 and 150 mg/kg bw/d) were comparable to the corresponding control group.
Weight of the fetuses: The mean fetal weights of test groups 1, 2 and 3 (50, 150 and 500 mg/kg bw/d) were not influenced by the test substance and did not show any biologically relevant differences in comparison to the control group.
Fetal external malformations: No external malformations were recorded.
Fetal external variations: No external variations were recorded.
Fetal external unclassified observations: One unclassified external observation, i.e. blood coagulum around placenta, was recorded in two fetuses of the low-dose group (50 mg/kg bw/d). This finding was not considered biologically relevant.
Fetal soft tissue malformations: One soft tissue malformation was recorded for a control fetus. Male control fetus No. 13-08 had a situs inversus (abdominal and thoracic cavity). There were no soft tissue malformations in any of the treated groups.
Fetal soft tissue variations: Soft tissue variations were detected in all test groups including the control (0, 50, 150 or 500 mg/kg bw/d). The highest frequency was noted for dilated renal pelvis in all test groups including the control, and dilated ureter in the mid- and high-dose groups. The incidences of these findings were statistically significantly increased in the high-dose group. As a consequence, the total incidence of fetal soft tissue variations was also increased in this test group (Tab. 1.).
Fetal soft tissue unclassified observations: No unclassified soft tissue observations were recorded.
Fetal skeletal malformations: No skeletal malformations were recorded.
Fetal skeletal variations: For all test groups, skeletal variations of different bone structures were observed, with or without effects on corresponding cartilages. The observed skeletal variations were related to several parts of fetal skeleton and did not present a specific pattern. The overall incidences appeared without a relation to dosing and were comparable to the historical control data. For a better overview, all individual skeletal variations with statistically significant differences between the control and any treated group were compiled in the table below (Tab. 2). All incidences were expressed on a fetus per litter basis and any statistically significant differences, which were outside the historical control range were marked in bold types. As can be seen from Tab. 2. the rates of supernumerary thoracic vertebra and misshapen sternebra (unchanged cartilage) were statistically significantly increased in test group 3 (500 mg/kg bw/d) and slightly outside the historical control ranges. Concerning the other statistically significant findings, no dose dependency was observed and/or all values were clearly inside the historical control range, thus, an association to the test substance and a toxicological relevance is not assumed.
Fetal skeletal unclassified cartilage observations: Isolated cartilage findings without an impact on the respective bony structures, which were designated as unclassified cartilage observations, occurred in all test groups (Tab.3.). The observed unclassified cartilage findings were related to the skull, the sternum
and ribs and did not show any relation to dosing. However, the overall incidence of unclassified cartilage observations was statistically significantly increased in test group 3 (500 mg/kg bw/d), albeit only slightly above the historical control range (47.6 -80.3%).
Assessment of all fetal external, soft tissue and skeletal observations: External and skeletal malformations did not occur in any of the fetuses in this study. There was noted one soft tissue malformation in the control group, i.e. one situs inversus. External variations did not occur in any of the fetuses in this study. Some soft tissue variations and a range of skeletal variations were noted in all test groups including the controls. The majority of all variations were equally distributed about the different test groups, if normal biological variation is taken into account, and can be found in the historical control data at a comparable frequency. At the top dose (500 mg/kg bw/d) four different variations - dilated renal pelvis and dilated ureter as well as supernumerary thoracic vertebra and misshapen sternebra (unchanged cartilage) were statistically significantly increased and slightly above their historical control ranges. These rather minor increases resulted in a statistically significantly increased high-dose incidence if all different types of variations were summarized which just exceeded the historical control range (mean% affected fetuses per litter 50.44 - 56.61). Since these variations did not present a specific pattern and their rate was only slightly increased above an inherently high background rate, their toxicological significance is considered to be rather low. No unclassified soft tissue observations were recorded for any of the fetuses in this study. A spontaneous origin is assumed for the unclassified external observation and the unclassified skeletal cartilage observations which were observed in several fetuses of test groups 0, 1, 2 and 3 (0, 50, 150 and 500 mg/kg bw/d). The distribution and type of these findings do not suggest any relation to treatment. The total incidence of skeletal cartilage observations was slightly but statistically significantly higher in test group 3 (500 mg/kg bw/d) compared to control. However, since the control incidence was already at the upper limit of the historical control range (79.3 vs. 80.3 mean% affected fetuses per litter), this marginal increase is not considered to be biologically meaningful. Overall, fetal examinations revealed that there is no specific adverse effect of the test compound on fetal morphology at any of the tested dose levels. Particularly, there were no indications for a test substance-induced teratogenicity.
Remarks on result:
not determinable due to absence of adverse toxic effects
Abnormalities:
not specified
Developmental effects observed:
not specified

Stability analysis The stability of the test substance suspensions over a period of 7 days at room temperature was demonstrated

Homogeneity analysis of the test substance preparations The homogeneous distribution of the test substance in the vehicle (1% CMC) was demonstrated

Concentration control analyses of the test substance preparations The results of the analysis of the aqueous test substance preparations confirmed the correctness of the prepared concentrations. The analytical values of the samples corresponded to the expected values within the limits of the analytical method, i.e. were always above 90% and below 110% of the nominal concentrations.

Tab. 1 Total soft tissue variations

    Test group 0, 0 mg/kg bw/d Test group 1, 50 mg/kg bw/d  Test group 2, 150 mg/kg bw/d   Test group 3, 500 mg/kg bw/d 
 Litter Fetuses     N  25  25  25  24
 N  118  119  112  105
 Fetal incidence  N%  3 (2.5)  2 (1.7)  2 (1.8)  10 (9.5)
 Litter incidence  N%  3 (12)  2 (8.0)  2 (8.0)  8 (33)
  Affected fetuses/litter  Mean %  2.3  1.8  1.8  10.9*

mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent

* = p ≤ 0.05 (Wilcoxon-test [one-sided])

Tab. 2 Occurrence of statistically significantly increased fetal skeletal variations (expressed as mean percentage of affected fetuses/litter)

 Finding  Test group 0, 0 mg/kgbw/d Test group 1, 50 mg/kgbw/d  Test group 2, 150 mg/kgbw/d   Test group 3, 500 mg/kgbw/d  HCDMean %(range)
 Incomplete ossification ofnasal; unchanged cartilage  2.1 2.1  5.2  9.9*   1.4(0.0 – 10.1)
 Dumbbell ossification ofthoracic centrum;dumbbell-shaped cartilageof centrum 1.4  4.2  4.3  7.5*   4.9(0.0 – 19.4)
 Supernumerary thoracicvertebra  3.3 2.3  3.5  13.3**   3.9(0.8 – 8.0)
 Misshapen sternebra;unchanged cartilage  65.0 68.3  70.3  75.0*   52.7(29.5 – 66.8)
 Supernumerary rib (14th);cartilage present  3.5 9.2*  11.7*  6.8   5.9(1.4 – 11.7)

mg/kg bw/d = milligram per kilogram body weight per day; HCD = Historical control data; % = per cent

* = p ≤ 0.05 (Wilcoxon-test [one-sided])

** = p ≤ 0.01 (Wilcoxon-test [one-sided])

Tab. 3 Total unclassified cartilage observations

     Test group 0, 0 mg/kg bw/d  Test group 1, 50 mg/kg bw/d  Test group 2, 150 mg/kg bw/d  Test group 3, 500 mg/kg bw/d
 Litter  N  25  25  25  24
 Fetuses  N  130  129  128  121
 Fetal incidence  N (%)  103 (79)  97 (75)  107 (84)  107 (88)
 Litter incidence  N (%)  24 (96)  25 (100)  25 (100)  23 (96)
 Affectedfetuses/litter  Mean  79.3  76.2  85.1  87.1*

mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent

* = p ≤ 0.05 (Wilcoxon-test [one-sided])

Tab. 4 Total fetal variations

     Test group 0, 0 mg/kg bw/d  Test group 1, 50 mg/kg bw/d  Test group 2, 150 mg/kg bw/d  Test group 3, 500 mg/kg bw/d
 Litter  N  25  25  25  24
 Fetuses  N  248  248 240 226
 Fetal incidence  N (%)  133 (54)  130 (52)  130 (54)  131 (58)
 Litter incidence  N (%)  25 (100)  25 (100)  25 (100)  24 (100)
 Affectedfetuses/litter  Mean  53.4  52.6  54.8  58.5*

mg/kg bw/d = milligram per kilogram body weight per day; N = number; % = per cent

* = p ≤ 0.05 (Wilcoxon-test [one-sided])

Executive summary:

In this guideline (OECD 414) study conducted with GLP certification, the test material (EC xxx-xxx-x) was determined to have a NOAEL of >= 500 mg/kg bw/day. The test substance doses (50-500 mg/kg bw/day) were administered via oral gavage to pregnant rats on the day of implantation until one day before the expected day of parturition. No differences of toxicological relevance between the control and the treated groups were observed. The results of the study indicate that the test material does not meet the criteria to be considered mutagenic under the EU Classification, Labelling, and Packaging (CLP) regulation (1272/2008).

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
08 Nov 2016 - 15 Dec 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. certificate)
Limit test:
no
Specific details on test material used for the study:
Iracure 1173 (synonyms Darocur 1173, Omnirad 1173)
Chemical Identity: 2-hydroxy-2-methylpropiophenone
Batch number 0015591211
CAS number 7473-98-5
Expiry date 09 June 2019
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
Sexually mature, virgin New Zealand White Rabblits (Crl:KBL(NZW)) were supplied at 16-17 weeks old. Only animals free from clinical signs of disease were used. The rabbits were housed singly in Type 4X03B700CP cages. The animals were accommodated in fully air-conditioned rooms at a maintained temeperature of 20+/-2C and a range of relative humidity of 30-70% The air exchange was 15 times per hour. The day/night cycle was generally 12 hours.
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
The test substance preparations were prepared at the beginning of the administration period and thereafter at intervals, which took into account the period of established stability. The preparations were kept at room temparature.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of the test substance preparations were sent to the analytical laboratory once during the study period (at the beginning of administration) for verification of the concentrations. These were analysed using GC. The samples taken for the concentration control analyses were also used to verify the homogeneity of the samples of the low and high concentrations each (15 and 150 mg/kg bw/d).
It was concluded that Irgacure was distrubuted homogeneously in 0.5% carboxymethyl cellulose in drinking water. The results of the GC analysis demonstrated the correctness of the concentrationa of Irgacure 1173 in 0.5% carboxymethyl cellulose in drinking water.
Details on mating procedure:
After an acclimatization period of a least 5 days, the does were fertilzed by means of artifical insemination (AI). A synthetic hormone that stimulates release of LH and FSH from the anterior pituitary lobe was injected intramuscularly to the female rabbits about an hour before insemination. The ejaculate samples used for AI were obtained from male rabbits of the same breed as the females. The day of insemination was designated as GD 0 (beginning of the study) and the following day as GD1.
Duration of treatment / exposure:
The test substance was administered to the animals by oral gavage from implantation to one day prior to the expected day of parturition (GD 6-28) always at aprroximately the same time of day. The animals in the control group were treated in the same way with the vehicle (0.5% CMC) The volume administered eah day was 10 ml/kg body weight.
Frequency of treatment:
once a day
Duration of test:
28 days
Dose / conc.:
15 mg/kg bw/day (actual dose received)
Remarks:
low dose level
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Remarks:
mid-dose level
Dose / conc.:
150 mg/kg bw/day (actual dose received)
Remarks:
high-dose level
No. of animals per sex per dose:
25 female rabbits per dose
Control animals:
yes, concurrent vehicle
Details on study design:
The test material was tested for its prenatal developmental toxicity in New Zealand White rabbits. The test material was administered as an aqueous suspension to groups of 25 inseminated female rabbits orally by gavage in doses of 15,50 and 150 mg/kg body weight/day on gestation days (GD) 6 to 28. The vehicle control group, consisting of 25 females, was dosed with the vehicle 0.5% carboxymethylcellulose suspension in drinking water (0.5% CMC) in parallel. A standard dose volume of 10mL/kg body weight was used for each group. At terminal sacrifice on G 29, 22-25 females per group had implantation sites.
Maternal examinations:
A cage-side examination was conducted at least once a day for signs of morbidity,pertinent behavioral changes and signs of overt toxicity. If such signs were observed the animals were examined several times daily (GD 0-29). During the administration period (GD 6-28) all animals were checked daily for any abnormal clinical signs before the administration and within 5 hours after administration.
Ovaries and uterine content:
The uteri and ovaries were removed and the following data were recorded: weight of the unopened uterus, number of the corpora lutea, number and the distribution of implantation sites classified as, live fetuses or dead implantations. The dead implanations were classed as either early resorptions, late resorptions or dead fetuses.
Fetal examinations:
At necropsy each fetus was weighed and examined macroscopically for external findings. The viability of the fetuses and the condition of the placentas, umbilical cords, fetal membranes, and fluids were examined. Individual placental weights were recorded. After the fetuses had been sacrificed, the abdomen and thorax were opened in order to examine the organs in situ before they were removed. The heart and the kidneys were sectioned in order to evaluate the internal structure. The sex of the fetuses was determined by examination of the gonads in situ.


Transverse sections were prepared of the heads.of approximately half the fetuses per doe. Transversal incision into the frontal/parietal head bones was made of the intact fetues, After fixation in ethyl alcohol, the skeletons were stained and investigated individually.
Statistics:
Please see attachments titles Statistics
Historical control data:
Available for the following end points data collected between 1 Jan 2012 and 31 May 2017
Please see attachment entitled Historical control data
Mean Maternal Body weights during gestation (grams)
Reproduction data
Placenta weights (grams)
Mean fetal weights (grams)
Fetal external malformations
Fetal external variations
Fetal external unclassified findings
Fetal soft tissue malformations
Fetal soft tissue variations
Fetal soft tissue unclassified findings
Fetal skeletal variations
Fetal skeletal malformations
Fetal Skeletal cartilage
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Test group 3 - (150 mg/kg bw/d) unsteady gait and reduced attention shortly after treatment in all 25 females, splayed limbs after treatment in two females: all findings wore off between 2 and 5 hours post-dosing. Splayed limbs were recorded for 2 high-dose females shortly after treatment. These findings were considered as treatment related and adverse. However they disappeared 2-5 hours after dosing and were not observed before dosing the following day. Two females in mid range group had blood in bedding before and after treatment and subsequently died with in 48 hours.
Reduced defecation was observed in 4 control, 1 loe-dose, 4 mid-dose and two high dose females - displaying no dose related responce. There were no other clinical findings in the study.
Description (incidence and severity):
NA
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Test group 0 (0 mg/kg bw/d) - two animals died after gavage error
Test group 1 (15mg/kg bw/d)- one animal died after gavage error
Test group 2 (50 mg/kg bw/d) one aniimal died intercurrently
Test group 3 (150mg/kg bw/d) one animal died after gavage error
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
The mean body weights and the average body weight gain of the low-, mid- and high-dose groups (15, 50 and 150 mg/kg bw/d) were generally comparable to the concurrent control group throughout the entire study period. However, there were statistically significantly increased body weight gain values in the low- and the high-dose groups during GD 25-28 which were considered unrelated to treatment.
See illustration as attached - Mean body weight of pregnant animals
Also Table 3 - Mean Maternal body weight change during gestation (grams)
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The food consumption of the low-, mid- and high-dose rabbits (15, 50 and 150 mg/kg bw/d) was comparable to the concurrent control (0 mg/kg bw/d) throughout the entire study period.
Food efficiency:
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
Test group 3 - (150 mg/kg bw/d) unsteady gait and reduced attention shortly after treatment in all females, splayed limbs after treatment in two females: all finds wore off between 2 and 5 hours post-dosing.
Splayed limbs were recorded for 2 high-dose females shortly after treatment.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
The mean gravid uterus weight of the rabbits of the test groups was not influenced by the test substance.The differences between these groups and the control group showed no dose-dependency and were assessed to be without biological
relevance. Please also see table 4 - Mean Gravid weights and net maternal body weight change
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Some spontaneous findings were noted in individual females of test groups 0, 2 and 3 (0, 50 and 150 mg/kg bw/d). These gross findings were:

• small spleen (additionally misshapen) in one control doe (No. 14 - 0 mg/kg bw/d).
• single erosion in stomach in one mid-dose doe (No. 56 - 50 mg/kg bw/d).
• increased reddish fluid in uterus in one high-dose doe (No. 93 - 150 mg/kg bw/d).


Findings in test groups 0, 1 and 3, such as thoracic cavity filled with either blood or serous fluid,
in two control does, one low-dose doe and one high-dose doe were indicative of gavage errors and were thus associated with unscheduled maternal deaths.
Please see table 5 - Summary of maternal necropsy observations


Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Number of abortions:
effects observed, non-treatment-related
Description (incidence and severity):
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. All differences observed are considered to reflect the normal range of fluctuations for animals of this strain and age (see historical control dat as attached)
See Table 1 - summary of reproduction data
There were some foetues deaths found in test groups 0,1 and 3. None of these casualties were considered to be associated with treatment.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
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. All differences observed are considered to reflect the normal range of fluctuations for animals of this strain and age;
See Table 1 - summary of reproduction data
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
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. All differences observed are considered to reflect the normal range of fluctuations for animals of this strain and age;
See Table 1 - summary of reproduction data
Early or late resorptions:
effects observed, non-treatment-related
Description (incidence and severity):
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. All differences observed are considered to reflect the normal range of fluctuations for animals of this strain and age;
See Table 1 - summary of reproduction data
Dead fetuses:
effects observed, non-treatment-related
Description (incidence and severity):
Some dead fetuses were found in test groups 0, 1 and 3: one dead fetus in the litter of control, one in the litter of low-dose and two dead fetuses in the litter of high-dose. None of these casualties is considered to be associated with
treatment.
See Table 1 - summary of reproduction data

Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
There were no observed changes in any group on the pregnancy duration
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): There were no observed effects in any group on the pregnancy duration
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
There were no treatment related effects on the number of females becoming pregnant. Conception rate in groups 1-4 were 88,92,100 and 100% respectively. Please see table 1 - Summary of reproduction data
Other effects:
no effects observed
Description (incidence and severity):
No other effects observed
Details on maternal toxic effects:
Clinical observations revealed toxicologically relevant effects at a dose of 150 mg/kg bw/d. All 25 high-dose females (150 mg/kg bw/d) showed unsteady gait and reduced attention at least once during the treatment period. Two high-dose females additionally displayed splayed limbs.
These clinical observations were made shortly after treatment and disappeared in the affected animals between 2 and 5 hours post-dosing. There were no persistent clinical findings. These clinical findings were considered as treatment-related and adverse.

The does at the lower dose levels (15 and 50 mg/kg bw/d) remained clinically unaffected by the test item.
Neither food consumption nor body weights/body weight gain (gross and corrected) of the does were affected by the treatment at any dose.
Key result
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
clinical signs
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
The mean fetal weights of test groups 1, 2 and 3 were not influenced by the test substance and did not show any biologically relevant differences in comparison to the control group. Please see table 2 : mean placental and foeatal weights (on a litter basis)


Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Please see table 2 : mean placental and foeatal weights (on a litter basis)
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
Please see table 1 - Summary of reproduction data
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The sex distribution of the fetuses in test groups 1-3 (15, 50 and 150 mg/kg bw/d) was comparable to the control fetuses. Any observable differences were without biological
relevance. Please see table 1 - Summary of reproduction data

Changes in litter size and weights:
no effects observed
Description (incidence and severity):
Please see table 2 : mean placental and foeatal weights (on a litter basis)
Changes in postnatal survival:
no effects observed
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Three unclassified external observations were recorded in test groups 0, 1 and 3: hemorrhage in one fetus (150 mg/kg bw/d), placentae discolored in one dead fetus, each (0 mg/kg bw/d) and (15 mg/kg bw/d) and blood coagulum around placenta
in two dead fetuses (150 mg/kg bw/d). These findings are not considered to be related to treatment. Please see tables 6 and 7 Total Foetal external variation and total foetal external unclassified observations.

Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Skeletal malformations were detected in single fetuses of all test groups (0, 15, 50, 150 mg/kg bw/d), The incidence of these malformations was neither statisti-
cally significantly different from control nor dose-dependent and therefore, not considered biologically relevant. Please see table 11 - Total skeletal malformations.
For all test groups, skeletal variations of different bone structures were observed, with or without effects on corresponding cartilages. The observed skeletal variations were related to
several parts of fetal skeletons and appeared without a relation to dosing. The overall incidences of skeletal variations were comparable to the historical control data Please see table 12 and historical control data
For a better overview all skeletal variations with statistically significant differences between the control and the treated groups were complied in a table - please see table 13-statistically significant increses were not dose related and within historical control range.

Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were no external malformations in any foetus in the study. Soft tissue malformations occurred in all test groups including control (0, 15, 50 or 150 mg/kg bw/d). one Female low-dose fetus had multiple visceral malformations, i.e. high-arched
aortic arch, dilated aortic arch, narrowed pulmonary trunk and unexpanded lun, while one low dose foetus had a malpositioned kidney and a short ureter.Furthermore, female high-dose fetus showed microphthalmia on both eyes and severely fused sternebrae (bony plate). No ontogenetic pattern is recognizable for the individual malformations nor was there any cluster of any of these malformations seen in the other offspring of these test groups.

Other malformations, such as misshapen brain, small thymus, absent subclavian, cardiomegaly, absent gallbladder, fused cervical arch, thoracic hemivertebra and malpositioned and bipartite sternebra were scattered observations in individual fetuses of all test groups. They were not dose-related and some of them can be found in the historical control data. An associationof these findings to the treatment is not assumed.
Please see table 15 - total foetal malformations


The distribution of the findings about the test groups does not indicate an association to the treatment and no statistically significant differences between the groups were noted. The total
incidence of soft tissue malformations in treated animals did not differ significantly from the control group and was comparable to the historical control data.
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
The examination of the soft tissues revealed malpositioned carotid branches in individual fetuses of all test groups including the control group (0, 15, 50 or 150 mg/kg bw/d). An absent
lung lobe (Lobus inferior medialis) was noted in all substance-treated groups and showed a slightly but statistically significantly increased incidence in the low- and mid-dose groups (15
and 50 mg/kg bw/d). However, these are quite common findings in this rabbit strain, they can be found in the historical control data of the test facility at comparable incidences.



Other variations, such as cystic dilatation of the brain, dilated cerebral ventricle, malpositioned
subclavian artery origin, dilated aortic arch, blood-filled pericardium, small atrial chamber
(heart), enlarged atrial chamber (heart) and supernumerary gallbladder occurred in individual
offspring of all test groups including control (0, 15, 50 or 150 mg/kg bw/d). The incidences of
these variations were neither statistically significantly different from control nor dose-dependent
and, therefore, not considered biologically relevant . Some of them can be
found in the historical control data at comparable incidences
One unclassified soft tissue observation was recorded in one fetus of the high-dose group (150
mg/kg bw/d): blood coagulum around urinary bladder. This finding is not considered to be treat-
ment-related.


Details on embryotoxic / teratogenic effects:
No differences of toxicological relevance between the control and the treated groups (15, 50 and 150 mg/kg bw/d) were determined for any reproductive parameters, such as conception
rate, mean number of corpora lutea, mean number of implantations, as well as pre- and postimplantation loss and live litter size. Similarly, no adverse effect of the test substance on
uterine and placental weights as well as fetal weight and sex distribution of the fetuses was noted at any dose.



Overall, there were no toxicologically relevant adverse effects of the test substance on fetal
morphology at any dose.



Key result
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: here was no evidence for toxicologically relevant adverse effects of the test substance on fetal morphology at any dose, the no observed adverse effect level (NOAEL) for prenatal developmental toxicity is the highest dose of 150 mg/kg bw/d.
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
Irgacure 1173 was administered to pregnant New Zealand White rabbits daily by stomach tube from implantation to one day prior to the expected day of parturition (GD 6-28) at dose levels of 15, 50 and 150 mg/kg bw/day.
Analyses confirmed the correctness of the prepared concentrations, as well as the homogeneous distribution and the stability of the test substance in the vehicle
Clinical observations revealed toxicologically relevant effects at a dose of 150 mg/kg bw/d. All 25 high-dose females (150 mg/kg bw/d) showed unsteady gait and reduced attention at least once during the treatment period. Two high-dose females additionally displayed splayed limbs. These clinical observations were made shortly after treatment and disappeared in the affected animals between 2 and 5 hours post-dosing. There were no persistent clinical findings. These clinical findings were considered as treatment-related and adverse. The does at the lower dose levels (15 and 50 mg/kg bw/d) remained clinically unaffected by the test item.
Neither food consumption nor body weights/body weight gain (gross and corrected) of the does were affected by the treatment at any dose. No differences of toxicological relevance between the control and the treated groups (15, 50 and 150 mg/kg bw/d) were determined for any reproductive parameters, such as conception rate, mean number of corpora lutea, mean number of implantations, aswell as pre- and postimplantation loss and live litter size. Similarly, no adverse effect of the test substance on uterine and placental weights as well as fetal weight and sex distribution of the fetuses was noted at any dose. Overall, there were no toxicologically relevant adverse effects of the test substance on fetal morphology at any dose.

Under the conditions of this prenatal developmental toxicity study, the oral administration of Irgacure 1173 to pregnant New Zealand White rabbits from implantation to one day prior to the expected day of parturition (GD 6-28) caused evidence of maternal toxicity at the high-dose (150 mg/kg bw/d), such as adverse clinical findings. In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity is 50 mg/kg bw/d.

Since there was no evidence for toxicologically relevant adverse effects of the test substance on fetal morphology at any dose, the no observed adverse effect level (NOAEL)for prenatal developmental toxicity is the highest dose of 150 mg/kg bw/d.
Under the conditions of this prenatal developmental toxicity study, the oral administration of Irgacure 1173 to pregnant New Zealand White rabbits from implantation to one day prior tothe expected day of parturition (GD 6-28) caused evidence of maternal toxicity at the high-dose (150 mg/kg bw/d), such as adverse clinical findings. In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity is 50 mg/kg bw/d.

Executive summary:

Irgacure 1173 was tested for its prenatal developmental toxicity in New Zealand White rabbits.The test substance was administered as an aqueous suspension to groups of 25 inseminated female New Zealand White rabbits orally by gavage in doses of 15, 50 and 150 mg/kg bodyweight/day (mg/kg bw/d) on gestation days (GD) 6 through 28. The vehicle control group, consisting of 25 females, was dosed with the vehicle 0.5% Carboxymethylcellulose suspension in drinking water (0.5% CMC) in parallel. A standard dose volume of 10 mL/kg body weight was used for each test group.

At terminal sacrifice on GD 29, 22-25 females per group had implantation sites.

Food consumption and body weight of the animals were recorded regularly throughout the study period. The state of health of the animals was checked each day.

On GD 29, all females were sacrificed and assessed by gross pathology (including weight determinations of the unopened uterus and placentas). For each doe, corpora lutea were counted and number and distribution of implantation sites (differentiated between resorptions,live and dead fetuses) were determined. The fetuses were removed from the uterus, sexed, weighed and further investigated for any external, soft tissue and skeletal (inclusive cartilage) findings.

RESULTS

Analytics

• The stability of the test substance in 1% Carboxymethylcellulose suspension in drinking water was demonstrated over a period of 7 days at room temperature.

• The homogeneous distribution of the test substance in the vehicle was shown.

• The correctness of the prepared concentrations was shown. Effects

The following test substance-related adverse effects/findings were noted:

Test group 3 (150 mg/kg bw/d):

Does

• Unsteady gait and reduced attention shortly after treatment in all females, splayed limbs after treatment in two females; all findings wore off between 2 and 5 hours post-dosing

Fetuses

• No test substance-related adverse effects on fetuses.

Test group 2 (50 mg/kg bw/d):

• No test substance-related adverse effects on does, gestational parameters or fetuses.

Test group 1 (15 mg/kg bw/d):

• No test substance-related adverse effects on does, gestational parameters or fetuses.

Under the conditions of this prenatal developmental toxicity study, the oral administration of Irgacure 1173 to pregnant New Zealand White rabbits from implantation to one day prior to the expected day of parturition (GD 6-28) caused evidence of maternal toxicity at the high-dose (150 mg/kg bw/d), such as adverse clinical findings. In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity is 50 mg/kg bw/d.

Since there was no evidence for toxicologically relevant adverse effects of the test substance on fetal morphology at any dose, the no observed adverse effect level (NOAEL) for prenatal developmental toxicity is the highest dose of 150 mg/kg bw/d.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
150 mg/kg bw/day
Species:
rabbit
Quality of whole database:
There are two studies avaiilable for consideration, both were conducted according to OECD guideline 414 and to GLP, and both Klimisch code 1. One was conducted in the rat and one in the rabbit. The overall quality of the database is therefore considered to be high. The most senstive species is concluded to be the rabbit and the NOEAL observed in this study is the taken as the overall result.
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

OECD Guideline 414 with rats:

range finding study

In the course of a range finding study the test item was administered once daily by oral gavage to groups of 10 mated Wistar rats at dose levels of 0 (vehicle control; test group 0), 150 mg/kg bw/d (test group 1) and 400 mg/kg bw (test group 2) from gestation days (GD) 6 to 19. Effects of beginning systemic toxicity were limited to the high dose group, i.e. salivation in 6/10 animals, increased relative liver (110%) and kidney weights (108%) as well as increased alaninaminotransferase. Dose levels 50, 150 and 500 mg/kg bw/day were regarded to be appropriate to test the material in an OECD guideline 414 setup for its potential effects on rat offspring without causing exaggerated toxicity in their mothers.

main study OECD 414

The test substance was tested for its prenatal developmental toxicity in Wistar rats. The test substance was administered as an aqueous suspension to groups of 25 time-mated female Wistar rats by gavage at doses of 50, 150, and 500 mg/kg body weight/day (mg/kg bw/d) on gestation days (GD) 6 through 19. The control group, consisting of 25 females, was dosed with the vehicle (1% Carboxymethylcellulose suspension in drinking water (1% CMC)) in parallel. A standard dose volume of 10 mL/kg body weight was used for each test group. At terminal sacrifice on GD 20, 24-25 females per group had implantation sites.

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 GD 20, all females were sacrificed by cervical dislocation (under isoflurane anesthesia) 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 between resorptions, live and dead fetuses) were determined. The fetuses were removed from the uterus, sexed, weighed and further investigated for external findings. Thereafter, one half of the fetuses of each litter were examined for soft tissue findings and the remaining fetuses for skeletal (inclusive cartilage) findings.

The stability of the test substance preparations was demonstrated over a period of 7 days at room temperature. The homogeneous distribution of the test substance in the vehicle (1% CMC suspension in drinking water) was confirmed. The correctness of the prepared concentrations was shown.

Under the conditions of this prenatal developmental toxicity study, the oral administration to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at a dose of 500 mg/kg bw/d caused no evidence of maternal toxicity.

In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity is 500 mg/kg bw/d.

The no observed adverse effect level (NOAEL) for prenatal developmental toxicity is 500 mg/kg bw/d. There were no toxicologically relevant adverse fetal findings evident. Slightly higher rates of individual non-specific fetal variations at a dose of 500 mg/kg bw/d were considered to be an effect of the treatment, but not as adverse. Hence the no observed effect level (NOEL) for prenatal developmental toxicity is 150 mg/kg bw/d.

Toxicity to reproduction: other studies

Description of key information

OECD 414 with Rabbits

A range finding study was conducted and based on the results of thsi study and at the request of the sponsor three dose levels were selected for the main OECD 414 study.

The test substance was administered as an aqueous suspension to groups of 25 inseminated female New Zealand White rabbits orally by gavage in doses of 15, 50 and 150 mg/kg body

weight/day (mg/kg bw/d) on gestation days (GD) 6 through 28. The vehicle control group, consisting of 25 females, was dosed with the vehicle 0.5% Carboxymethylcellulose suspension in

drinking water (0.5% CMC) in parallel. A standard dose volume of 10 mL/kg body weight was used for each test group

Oral admisnistration of the test substance to pregnant New Zealand White rabbits from implantation to one day prior to the expected day of parturition (GD 6-28) caused evidence of maternal toxicity at the highdose (150 mg/kg bw/d), such as adverse clinical findings. In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity is 50 mg/kg bw/d.

Since there was no evidence for toxicologically relevant adverse effects of the test substance on fetal morphology at any dose, the no observed adverse effect level (NOAEL)

for prenatal developmental toxicity is the highest dose of 150 mg/kg bw/d.

Justification for classification or non-classification

The test material is not classified as a reproductive toxicant.

Reproductive toxicity includes adverse effects on sexual function and fertility as well as developmental toxicity in the offspring.

Weight of evidence from both the study results indicate that there are no relevant adverse effects on either fertility or relelvent fetal findings i.e fertility and developmental toxicty even at the highest doses so there is no evidence that the test material is a reproductive toxicant and so classifation is not required.