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REACH

2,2,6,6-Tetramethylpiperidin-4-yl dodecanoate

EC number: 700-503-1 | CAS number: 101238-01-1

Life Cycle description
Uses advised against

Toxicological information

Endpoint summary

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:: screening for reproductive / developmental toxicity
Remarks:: based on test type (migrated information)
Type of information:: migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:: supporting study
Reliability:: 2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:: other: Guideline study. A reliability of 2 is assigned because of read-across.
Reason / purpose for cross-reference:: reference to same study
Qualifier:: according to guideline
Guideline:: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:: yes
Remarks:: Biosafety Research Center, Food, Drugs and Pesticides (An-Pyo Center), Japan
Limit test:: no
Species:: rat
Strain:: Crj: CD(SD)
Sex:: male/female
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Age at study initiation: 10 weeks old for female and male animals
- Weight at study initiation: 359 - 400g for males; 227 - 282g for females
Route of administration:: oral: gavage
Vehicle:: water
Details on mating procedure:: - M/F ratio per cage: 1/1
- Length of cohabitation: at most 3 days, until proof of pregnancy
- Proof of pregnancy: vaginal plug or sperm in vaginal smear
Analytical verification of doses or concentrations:: yes
Duration of treatment / exposure:: Male: for 48 days from 2 weeks prior to mating
Female: for 41-52 days from 2 weeks prior to mating to day 3 postpartum throughout mating and pregnancy
Frequency of treatment:: once daily
Remarks:: Doses / Concentrations:
0, 60, 200, 600
Basis:
actual ingested
No. of animals per sex per dose:: 12
Control animals:: yes, concurrent vehicle
Parental animals: Observations and examinations:: CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once a day

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once a day

BODY WEIGHT: Yes
- Time schedule for examinations: for males: once a week, the first and the last day of the administration, the sacrificed day; for pregnant females: on day 0, 14 and 20 of gestation, on day 0 and 4 of lactation

FOOD CONSUMPTION: Yes
- Time schedule: once a week, on the same day when body wt. determined
Oestrous cyclicity (parental animals):: estrus cycle assessed during study
Sperm parameters (parental animals):: Parameters examined in P male parental generations:
testis weight, epididymis weight
Litter observations:: STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no
- If yes, maximum of [...] pups/litter ([...]/sex/litter as nearly as possible); excess pups were killed and discarded

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead.

OTHER: General appearance once a day
Postmortem examinations (parental animals):: SACRIFICE
- Male animals: All surviving animals after 49 days
- Maternal animals: All surviving animals after the last litter of each generation was weaned

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
Organ weights (brain, thymid gland, liver, kidney, spleen, adrenal, thymus and for males, testes and epididymis. Dead animals in 60 and 600 mg/kg group, and the parent from which all pups died in 600 mg/kg group : brain, spinal cord, pituitary gland, eyeball, harderian gland, salivary gland, tongue, thyroid gland (including parathyroid gland), thymus, heart, trachea, bronchus, esophagus, lung, liver, kidney, adrenal, spleen, stomach, duodenum, small intestine, large intestine, pancreas, urinary bladder, sternum, bone marrow, sciatic nerve, lymph node, testes, epididymis, prostate, seminal vesicle, ovary, uterus, vagina, mammary gland, skin. All pregnant males and females in 60 and 200 mg/kg group: kidney and any organs which might be expected to have histopathological changes at the higher doses.
Postmortem examinations (offspring):: SACRIFICE
- The F1 offspring were sacrificed at #4 days of age.
- These animals were subjected to postmortem examinations (macroscopic examination) as follows: Full macroscopic examination on all of pups

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
Statistics:: Dunnett's or Scheffe's test for continuous data and Chi square test for quantal data
Reproductive indices:: copulation index (No. of pairs with successful copulation/No. of pairs mated x 100), fertility index (No. of pregnant animals/No. of pairs with successful copulation x 100), implantation index (No. of implantation sites/No. of corpora lutea x 100), gestation index (No. of females wilth live pups/No. of living pregnant females x 100), delivery index (No. of pups born/No. of implantation sites x 100)
Offspring viability indices:: live birth index (No. of live pups on day 0/No. ofpups born x 100), viability index (No. of live pups on day 4/No. of live pups on day 0 x 100)
Clinical signs:: effects observed, treatment-related
Body weight and weight changes:: effects observed, treatment-related
Food consumption and compound intake (if feeding study):: effects observed, treatment-related
Dose descriptor:: LOEL
Remarks:: systemic toxicity
Effect level:: 60 mg/kg bw/day (actual dose received)
Based on:: test mat.
Sex:: male/female
Basis for effect level:: other: clinical signs at 60 mg/kg bw : 8/12 of the male and in all female rats blepharoptosis was found. The substance caused mortality in four rats of the high dose group (600 mg/kg bw) and strongly affected body weight gain in both genders.
Dose descriptor:: NOEL
Remarks:: fertility
Effect level:: 200 mg/kg bw/day (actual dose received)
Sex:: female
Basis for effect level:: other: other: estrus cycle increased significantly in the 600mg/kg group. Incidences of mortality occured at 600 mg/kg bw.
Dose descriptor:: NOEL
Remarks:: developmental toxicity
Generation:: F1
Effect level:: 200 mg/kg bw/day (actual dose received)
Sex:: male/female
Basis for effect level:: other: pups of the 600mg/kg group showed lower body weight on day 4 of lactation
Reproductive effects observed:: not specified
Conclusions:: On the basis of these findings, NOEL of 2,2,6,6-tetramethyl-4-hydroxypiperidine for reproductive and developmental toxicity was considered to be 200 mg/kg/day. Higher doses caused slight effects on reproductive parameters (increased estrous cycle length, reduced pup weight on day 4), but also incidences of mortality in parental animals. Therefore, these effects are considered secondary to the poor condition of the parental animals and no specific hazard for reproductive/developmental toxicity is identified.

Effect on fertility: via oral route

Endpoint conclusion:: no adverse effect observed
Species:: rat
Quality of whole database:: valid with restriction. Screening study with active metabolite.

Effect on fertility: via inhalation route

Endpoint conclusion:: no study available

Effect on fertility: via dermal route

Endpoint conclusion:: no study available

Additional information

Subchronic feed dosing at dose levels of up to 10000 ppm did not cause adverse effects on reproductive organs, nor did it affect the estrous cycle or sperm parameters (BASF 2014). The study followed OECD guideline 408 and was performed under GLP. This indicates absence of adverse effects on fertility.

Additional evidence is available from a screening study (OECD 422, GLP) with the relevant ester hydrolysis product HTMP (MHLW 1998). As the other fragment generated by hydrolysis is a food-borne fatty acid, no further assessment is required.

HTMP is a stronger base than the substance itself and classified for corrosive properties. Subacute gavage dosing of 600 mg/kg bw caused mortality in four parental animals..

Short description of key information:
The test substance undergoes enzymyatic and pH-dependent hydrolysis to HTMP and a short-chain fatty acid. HTMP was found to have no adverse effects on fertility in a GLP-compliant screening study (OECD 422). No adverse effects on reproductive organs were observed in the 90-day study (OECD 408).

Effects on developmental toxicity

Description of key information

The substance did not cause developmental toxicity or teratogenicity in rats (GLP, OECD 414).

Link to relevant study records

Reference

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:: other: OECD 414 and GLP compliant study
Qualifier:: according to guideline
Guideline:: OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:: no
GLP compliance:: yes (incl. QA statement)
Limit test:: no
Species:: rat
Strain:: other: Crl:WI (Han)
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Age at study initiation: About 10-12 weeks
- Weight at study initiation: 146.5 – 189.0 g
- Housing: single caging
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: six days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30 - 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2013-06-25 To: 2013-07-16
Route of administration:: oral: gavage
Vehicle:: corn oil
Details on exposure:: PREPARATION OF DOSING SOLUTIONS: The oily test substance preparations were prepared at the beginning of the administrationperiod and thereafter at maximum intervals of 7 days, which took into account the period of established stability. For the test substance preparations, the specific amount of test substance were weighed, topped up with corn oil in a graduated flask and intensely mixed by shaking until it is dissolved.

VEHICLE
- Justification for use and choice of vehicle (if other than water): the test item is soluble in the vehicle. It is not soluble in water.
- Amount of vehicle (if gavage): 4 ml/kg body weight
Analytical verification of doses or concentrations:: yes
Details on analytical verification of doses or concentrations:: HPLC-method
Details on mating procedure:: - Impregnation procedure: purchased timed pregnant
The day of evidence of mating (= detection of vaginal plug/sperm) was referred to as GD 0. The animals arrived on the same day (GD 0) at the experimental laboratory.
Duration of treatment / exposure:: gestation days 6- 19
Frequency of treatment:: daily
Duration of test:: 14 days
Remarks:: Doses / Concentrations:
0, 30 ,100 and 300 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:: 25
Control animals:: yes
Details on study design:: - Dose selection rationale: Based on range-finder study with pregnant rats
Maternal examinations:: CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Mortality/Morbidity, pertinent behavioral changes and/or signs of overt toxicity. were checked twice daily from Mondays to Fridays and once daily on Saturdays, Sundays and public holidays (GO 0 to 20).

DETAILED CLINICAL OBSERVATIONS: No

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

POST-MORTEM EXAMINATIONS: Gross pathology
- Sacrifice on gestation day: GD 20
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: Site of implantations in the uterus
Fetal examinations:: - External examinations: Yes: [all per litter ]
- Soft tissue examinations: Yes: [ half per litter ]
- Skeletal examinations: Yes: [ half per litter ]

In the present study the glossary of WISE et al. (1997) and its updated version of MAKRIS et al. (2009) was essentially used to describe findings in fetal morphology. Classification of these findings was based on the terms and definitions proposed by CHAHOUD et al. (1999) and SOLECKI et al. (2001, 2003):

Malformation
A permanent structural change that is likely to adversely affect the survival or health.

Variation
A change that also occurs in the fetuses of control animals and/or is unlikely to adversely affect the survival or health. This includes delays in growt or morphogenesis that have otherwise followed a normal pattern of development.

The term "unclassified observation" was used for those fetal findings, which could not be classified as malformations or variations.
Statistics:: DUNNETT's test: Food consumption, body weight, body weight change, DUNNETT's test
corrected body weight gain, carcass weight, weight of
the unopened uterus, weight of the placentas and
fetuses, corpora lutea, implantations, pre- and
postimplantation losses, resorptions and live fetuses

FISHER's exact test
Number of pregnant animals at the end of the study, FISHER's exact test mortality rate (of the dams) and number of litters with fetal findings

WILCOXON test
Proportion of fetuses with findings per litter
Indices:: sex ratio
conception rate (in %)
preimplantation loss (in %)
postimplantation loss (in %)
Historical control data:: Included in the final report.
Details on maternal toxic effects:: Maternal toxic effects:yes

Details on maternal toxic effects:
High-dose female No. 94 (300 mg/kg bw/d) died on GD 15. The gross pathological examination of this animal revealed findings indicative of a gavage error. There were no further substance-related or spontaneous mortalities in any females of all test groups (0, 30, 100 or 300 mg/kg bw/d).

All females of the high-dose group (300 mg/kg bw/d), nearly all females (23 out of 25) of the mid-dose group (100 mg/kg bw/d) and 16 females of the low-dose group (30 mg/kg bw/d) showed transient salivation during major parts of the treatment period. Salivation persisted in the respective animals for some minutes after daily gavage dosing (i.e. up to 10 minutes) and was initially observed on GD 7. No further clinical signs or changes of general behavior, which may be attributed to the test substance, were detected in any female at dose levels of 100, 300 or 1000 mg/kg bw/d during the entire study period.

The mean food consumption of the high-dose dams (300 mg/kg bw/d) was statistically significantly reduced on GD 6-10 and GD 15-17. If calculated for the entire treatment period (GD 6-19) or the entire study period (GD 0-20), the dams of test group 3 consumed 12% or 7% less food, respectively, in comparison to the concurrent control group. Furthermore, the mean food consumption of the mid-dose dams (100 mg/kg bw/d) was statistically significantly reduced on GD 6-8. If calculated for the entire treatment period (GD 6-19) or the entire study period (GD 0-20), the dams of test group 2 consumed 4% less food, respectively, in comparison to the concurrent control group. The mean food consumption of the dams in test group 1 (30 mg/kg bw/d) was generally comparable to the concurrent control throughout the entire study period.

The mean body weights of the high-dose females (300 mg/kg bw/d) were statistically significantly reduced from GD 8 onwards until terminal sacrifice on GD 20. At the beginning of treatment these dams even lost weight, thus, the average body weight gain was statistically significantly reduced on GD 6-8 and GD 17-19. If calculated for the entire treatment period (GD 6-19) or entire study period (GD 0-20), these dams gained 21% or 13% less weight than the concurrent control animals, respectively.
The mean body weights of the mid-dose group (100 mg/kg bw/d) were slightly lower than the concurrent control values (without attaining statistical significance), mainly caused by the statistically significantly reduced mean body weight gain value on GD 6-8. If calculated for the
entire treatment period (GD 6-19) or entire study period (GD 0-20), these dams gained 8% or 7% less weight than the concurrent control animals (without attaining statistical significance). The impairments of body weights in the mid- and high-dose groups were considered to be treatment-related, whereas the statistically significantly increased body weight gain value on GD 1-3 (test group 3) was an incidental occurrence.
The mean body weights and the average body weight gains of the low-dose rats (30 mg/kg bw/d) were in general comparable to the controls throughout the entire study period. This includes the statistically significantly reduced body weight gain value on GD 17-19 which was considered as an accidental finding.

The corrected body weight gain (terminal body weight on GD 20 minus weight of the unopened uterus minus body weight on GD 6) was distinctly and statistically significantly lower in test groups 2 (100 mg/kg bw/d – about 20% below the concurrent control value) and 3 (300
mg/kg bw/d – about 29% below the concurrent control value). Furthermore, the carcass weight of the high-dose dams was statistically significantly lower in comparison to the control group (about 5% below controls).
These effects are assessed as direct, test substance-related signs of maternal toxicity.
The corrected body weight gain of test group 1 (30 mg/kg bw/d) revealed no difference of any biological relevance to the corresponding control group. Mean carcass weights remained also unaffected by the treatment.

No necropsy findings which could be attributed to the test substance were seen in any dam. One finding indicative for misgavaging, i.e. thoracic cavity filled with serous fluid, was recorded for dam No. 94 (300 mg/kg bw/d), which died on GD 15.

Although without attaining statistical significance, the mean gravid uterus weight of the animals of test group 3 (300 mg/kg bw/d) was reduced in comparison to the control group (about 10% below controls), which is likely to be a subsequent effect of the increased number of resorptions in this test group (see 4.2.2.3. Reproduction data). The mean gravid uterus weights of the low- and mid-dose animals (30 and 100 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.
Dose descriptor:: NOAEL
Effect level:: 30 mg/kg bw/day (actual dose received)
Based on:: test mat.
Basis for effect level:: other: maternal toxicity
Dose descriptor:: NOAEL
Effect level:: 100 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:
There were statistically significant differences in the values calculated for the postimplantation loss (5.2%/4.5%/4.0%/13.8%** [p<=0.01] in test groups 0-3), the number of resorptions and viable fetuses (94.8%/95.5%/96.0%/86.2%** [p<=0.01]. These differences were exclusively caused by an increased number of early resorptions in this dose group. All values were outside of the historical control range of the test facility.

There were no test substance-related and/or biologically relevant differences between the test groups 0, 1 and 2 in the values calculated for the pre- and postimplantation losses, the number of resorptions and viable fetuses.

The sex distribution of the fetuses in test groups 1-3 (30, 100 and 300 mg/kg bw/d) was comparable to the control fetuses. Any observable differences were without biological relevance.
The mean placental weights of the low-, mid- and high-dose groups (30, 100 and 300 mg/kg bw/d) were comparable to the corresponding control group.
The mean fetal weights of test groups 1, 2 and 3 (30, 100 and 300 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.

The high-dose of the test item (300 mg/kg bw/d) caused a significant increase of early resorptions and, subsequently, postimplantation loss as well as a decrease in the number of viable fetuses. All values for these parameters were outside of the historical control range of the test facility. This effect is considered to be treatment–related. However, it occurred exclusively in the presence of distinct maternal toxicity, which was most pronounced during the early phase of the treatment, i.e. in the days shortly after implantation (GD 6-8). A relationship between the profound disturbance of maternal nutritive status during this sensitive window of development and an adverse effect on the number of surviving early implants is assumed.
No influence of the test compound on fetal weight and sex distribution of the fetuses was noted at any dose. Particularly, the surviving high-dose fetuses showed a normal prenatal development in terms of fetal weight gain, which is correlated to the lower average litter size in these animals.
Overall, there was no evidence for toxicologically relevant adverse effects of the test substance on fetal morphology at any dose.
Dose descriptor:: NOAEL
Effect level:: >= 300 mg/kg bw/day (actual dose received)
Based on:: test mat.
Basis for effect level:: other: teratogenicity
Abnormalities:: not specified
Developmental effects observed:: not specified
Conclusions:: The substance does not cause developmental toxicity or teratogenicity in rats.

Effect on developmental toxicity: via oral route

Endpoint conclusion:: adverse effect observed
Dose descriptor:: NOAEL
: 100 mg/kg bw/day
Species:: rat
Quality of whole database:: valid without restriction

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

The substance was tested for its prenatal developmental toxicity in Wistar rats. The test substance was administered as an oily solution to groups of 25 time-mated female Wistar rats by gavage at doses of 30, 100, and 300 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 (corn oil) in parallel. A standard dose volume of 4 mL/kg body weight was used for each test group. At terminal sacrifice on GD 20, 24-25 females per group had implantation sites. 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 analytically over a period of 7 days at room temperature.

The following test substance-related, adverse effects/findings were noted for dams at the high dose group:

• Reduced food consumption; if calculated for GD 6-19 or GD 0-20: -12% or -7% less

consumed food than control.

• Reduced body weights from GD 8-20; reduced body weight gain, if calculated for GD 6-19

or GD 0-20: -21% or -13% less gained weight.

• Lower corrected body weight gain (about 29% below control).

• Reduced carcass weight (about 5% below controls)

• Increased number of early resorptions; consequentially increased postimplantation loss

(13.8%** [p<=0.01] vs. 5.2% in control), as well as reduced number of viable fetuses

(86.2%** vs. 94.8% in control).

At the beginning of treatment dams even lost weight, thus, the average body weight gain was statistically significantly reduced on GD 6-8 and GD 17-19.

The following test substance-related, adverse effects/findings were noted for dams at the intermediate dose group:

• Reduced food consumption on GD 6-8, if calculated for GD 6-19 or GD 0-20: -4% less

food.

• Reduced mean body weight gain on GD 6-8.

• Lower corrected body weight gain (about 20% below control).

No effects were noted on the fetuses. No effects were noted at the low dose group for either dams or fetuses.

From other studies it is known that the highly irritating substance affects the stomach and intestine. Salivation after treatment was observed in a dose-dependent manner.

No differences of toxicological relevance between the control and treated groups 1 and 2 (30 or 100 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. The high-dose of the test item (300 mg/kg bw/d) caused a significant increase of early resorptions and, subsequently, postimplantation loss as well as a decrease in the number of viable fetuses. All values for these parameters were outside of the historical control range of the test facility. This effect is considered to be treatment–related. However, it occurred

exclusively in the presence of distinct maternal toxicity, which was most pronounced during the early phase of the treatment, i.e. in the days shortly after implantation (GD 6-8). A relationship between the profound disturbance of maternal nutritive status during this

sensitive window of development and an adverse effect on the number of surviving early implants is assumed.

No influence of the test compound on fetal weight and sex distribution of the fetuses was noted at any dose. Particularly, the surviving high-dose fetuses showed a normal prenatal development in terms of fetal weight gain, which is correlated to the lower average litter size in these animals.

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

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available developmental toxicity study is considered reliable and suitable for classification purposes under 67/548/EEC. No adverse effects on development or malformations were noted at the highest tolerable dose. The slight increase in post-implantation loss is considered to be secondary to the significant maternal toxicity during the first days of treatment.

There is no suspicion for an adverse effect on fertilty based on the outcome of a subchronic feeding study and a screening study with the relevant ester hydrolysis product.

As a result the substance is not considered to be classified for fertility or developmental toxicity under Directive 67/548/EEC, as amended for the 31st time in Directive2009/2/EG.

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The OECD 414 study is reliable and suitable for classification purposes under Regulation 1272/2008. No adverse effects on development or malformations were noted at the highest tolerable dose. The slight increase in post-implantation loss is considered to be secondary to the significant maternal toxicity during the first days of treatment.

There is no suspicion for an adverse effect on fertilty based on the outcome of a subchronic feeding study and a screening study with the relevant ester hydrolysis product.

As a result the substance is not considered to be classified for fertility or developmental toxicity under Regulation (EC) No. 1272/2008, as amended for the fifth time in Directive EC944/2013.

Additional information

Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.

Dose level (mg/kg/day)	0	60	200	600
No. of pairs mated	12	11	12	10
No. of pairs mated with successful copulation	12	11	12	10
Copulation index (%)	100	100	100	90.9
No. of pregnant females	12	11	12	10
Fertility index (%)	100	100	100	100
Pairing days until copulation (mean ± S.D.)	2.9±1.1	2.3±0.9	2.4±0.7	3.1±0.8
No. of corpora lutea (mean ± S.D.)	18.8±1.5	20.6±2.9	19.6±2.5	18.6±1.7
No. of implantation sites (mean ± S.D.)	17.6±1.6	17.2±3.3	18.2±1.9	17.0±2.3
Implantation index (%, Mean ± S.D.)	93.4±5.4	83.5±14.3	93.2±7.5	91.3±8.0
No. of pregnant females with parturition (mean ± S.D.)	12	11	12	10
Gestation length (days, mean ± S.D.)	22.7±0.5	22.3±0.5	22.6±0.5	22.4±0.5
Gestation index (%)	100	100	100	100
Estrus cycle (days, mean ± S.D.)	4.1±0.3	4.1±0.3	4.3±0.5	4.5±0.4?

Dose level (mg/kg/day)	0	60	200	600
No. of pups born	16.3±2.0	15.3±3.3	15.4±1.5	15.7±2.7
Delivery index (%)	92.9±7.0	90.3±16.2	85.2±6.9	92.1±6.0
No. of pups alive on day 0 of lactation
Total	16.3±2.0	15.2±3.3	15.3±1.4	15.7±2.7
Male	8.2±2.2	7.7±2.3	7.9±1.8	7.0±3.0
Female	8.2±1.5	7.5±2.6	7.4±2.2	8.7±2.3
Live birth index (%)	100±0.0	99.5±1.8	99.5±1.7	100±0.0
Sex ratio (Male/Female)	1.05±0.37	1.15±0.46	1.22±0.60	0.90±0.57
No. of pups alive on day 4 of lactation
Total
Male	7.8±2.0	7.5±2.2	6.5±2.7	4.3±2.9
Female	7.4±1.1	6.5±2.5	6.3±2.5	6.4±3.7
Viability index (%)
Total	96.1±7.5	96.8±5.4	82.7±28.4	67.2±39.2
Male	91.9±9.9	86.2±10.4	85.8±20.3	70.7±35.0
No. of total dead pups born (mean±S.D.)	0.0±0.0	0.1±0.3	0.1±0.3	0.0±0.0
Stillbirth	0.0±0.0	0.0±0.0	0.0±0.0	0.0±0.0
cannibalism	0.0±0.0	0.1±0.3	0.1±0.3	0.0±0.0

		Test group 0 0 mg/kg bw/d	Test group 1 30 mg/kg bw/d	Test group 2 100 mg/kg bw/d	Test group 3 300 mg/kg bw/d
Litter Fetuses	N N	25 261	25 243	25 267	23 218
Fetal incidence	N (%)	2 (0.8)	0.0	0.0	0.0
Litter incidence	N (%)	2 (8.0)	0.0	0.0	0.0
Affected fetuses/litter	Mean%	0.7	0.0	0.0	0.0

		Test group 0 0 mg/kg bw/d	Test group 1 30 mg/kg bw/d	Test group 2 100 mg/kg bw/d	Test group 3 300 mg/kg bw/d
Litter Fetuses	N N	25 121	25 114	25 127	23 105
Fetal incidence	N (%)	0.0	0.0	0.0	2 (1.9)
Litter incidence	N (%)	0.0	0.0	0.0	2 (8.7)
Affected fetuses/litter	Mean%	0.0	0.0	0.0	2.0

		Test group 0 0 mg/kg bw/d	Test group 1 30 mg/kg bw/d	Test group 2 100 mg/kg bw/d	Test group 3 300 mg/kg bw/d
Litter Fetuses	N N	25 121	25 114	25 127	23 105
Fetal incidence	N (%)	5 (4.1)	3 (2.6)	6 (4.7)	0.0
Litter incidence	N (%)	5 (20)	3 (12)	6 (24)	0.0
Affected fetuses/litter	Mean%	3.9	2.8	5.3	0.0