Registration Dossier

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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Jasmal (read across from Florosa in a 90 -day dermal toxicity study): No adverse effects on fertility: NOAEL > 1000 mg/kg bw

Link to relevant study records
Reference
Endpoint:
fertility, other
Remarks:
Repeated-dose 90-day dermal toxicity study.
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Januari 2014 - November 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
other: OECD 411 Subchronic dermal toxicity: 90-day study (1981)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: EU method B.28 sub-chronic dermal toxicity study (2008)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
other: Crl:WI(Han)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services GmbH, Sulzfeld, Germany
- Age at study initiation: 63 ± 1 days
- Weight at study initiation: Males: 245.0-275.6 g; Females: 170.4-206 g
- Fasting period before study: no
- Housing: individually in polysulfonate cages (motor activity measurements were conducted in polycarbonate cages)
- Use of restrainers for preventing ingestion (if dermal): yes, covered for at least 6 hours after application using a semiocclusive dressing, consisting of 4 layers of porous gauze dressing
- Diet: ad libitum; ground Kliba maintenance diet mouse/rat “GLP”, meal, supplied by Provimi Kliba SA, Kaiseraugst, Switzerland
- Water: ad libitum, water bottles
- Acclimation period: 6 days

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

IN-LIFE DATES: From: 27 January 2014 To: 30 April 2014
Route of administration:
dermal
Vehicle:
corn oil
Details on exposure:
TEST SITE
- Area of exposure: 10% of the body surface
- Type of wrap if used: The skin was covered for at least 6 hours after application using a semiocclusive dressing, consisting of 4 layers of porous gauze dressing (Absorbent gauze EP supplied by Lohmann GmbH & Co. KG, Neuwied, Germany) and a stretch bandage (Fixomull® stretch [adhesive fleece] supplied by Beiersdorf AG, Hamburg, Germany).
- Time intervals for shavings or clipplings: The animals were reclipped at least once a week (depending on hair growth).

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the treated skin was washed with lukewarm water
- Time after start of exposure: After removal of the dressing.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): The application volume was 4 mL/kg bw, based upon the latest individual body weight determination.
- Concentration (if solution):

VEHICLE
- Justification for use and choice of vehicle (if other than water): no information

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes, semiocclusive dressing.
Details on mating procedure:
No data on mating. Reproductive parameters investigated in this repeated dose toxicity study are considered for the endpoint reproduction toxicity.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The stability of the test substance in corn oil at room temperature for a period of 8 days was demonstrated during the application period.
The test substance was completely miscible with corn oil and thus a solution. Therefore, the test-substance preparation was considered to be homogenous. Consequently further homogeneity analyses were not carried out.
Concentration control analyses of the test-substance preparations were performed in samples of all concentrations at the start of the application period.
Duration of treatment / exposure:
3 months
Frequency of treatment:
5 days per week
Remarks:
Doses / Concentrations:
100, 300 and 1000 mg/kg bw/day
Basis:
other: dermal application
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: at the request of the sponsor.
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily (working days), once daily (Satudays, Sundays and public holidays)


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Day 0 and subsequently once a week.

BODY WEIGHT: Yes
- Time schedule for examinations: Day 0 and thereafter at weekly intervals.

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
Food consumption was determined weekly as representative value over a period of 1 day and calculated as mean food consumption in grams per rat and day.

WATER CONSUMPTION AND COMPOUND INTAKE: No
Drinking water consumption was monitored by daily visual inspection of the water bottles for any changes in volume.

OTHER:
FOB, Ophthalmoscopy, clinical chemistry, hematology, organ weights, histopathology.
Oestrous cyclicity (parental animals):
not examined
Sperm parameters (parental animals):
Parameters examined:
testis weight, histopathology (control and high dose groups) of testes, epididymides, prostate, seminal vesicles
Litter observations:
no
Postmortem examinations (parental animals):
SACRIFICE
-All animals at the end of the exposure period (3 months).

GROSS NECROPSY
- Gross necropsy according to guidelines.

HISTOPATHOLOGY / ORGAN WEIGHTS
-According to guidelines.
Postmortem examinations (offspring):
no
Statistics:
Food consumption, body weight, body weight change: A comparison of each group with the control group was performed using DUNNETT's test (twosided) for the hypothesis of equal means.
Weight parameters: Non-parametric one-way analysis using KRUSKAL WALLIS test (two-sided). If the resulting p-value was equal or less than 0.05, a pairwise comparison of each dose group with the control group was performed using WILCOXON test (two-sided) for the equal medians.
Reproductive indices:
-
Offspring viability indices:
-
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS):
No animal died prematurely in the present study. Clinical examinations did not reveal treatment-related, adverse effects up to and including a dose level of
1000 mg/kg bw/day. Although erythema, erosions and scales were most likely related to treatment they were assessed to be non-adverse as they occurred only temporarily for a few days in individual animals.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS):
No effects on body weight parameters which were of toxicological concern were observed in this study. Body weight change values were significantly increased in female animals of 1000 mg/kg bw/day on study day 14. The finding was assessed to be incidental and not related to treatment as no clear trend in body weight development occurred. No test substance-related effects on food consumption were obtained. All values were within the range typical for animals of this strain and age.

ORGAN WEIGHTS (PARENTAL ANIMALS):
All mean absolute and mean relative weight parameters did not show significant differences when compared to the control group.

GROSS PATHOLOGY (PARENTAL ANIMALS):
All findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment.

HISTOPATHOLOGY (PARENTAL ANIMALS):
All findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment.

OTHER FINDINGS (PARENTAL ANIMALS):
Concerning clinical pathology, no treatment-related, adverse effects were observed up to and including a dose of the compound of 1000 mg/kg bw/day.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no treatment-related adverse effects were observed
Description (incidence):
No animal died prematurely in the present study.
Body weight and weight changes:
not examined
Key result
Remarks on result:
other: not relevant
Key result
Reproductive effects observed:
no
Conclusions:
No adverse effects were observed on the reproductive organs of male and female rats in a 90-day dermal repeated dose toxicity study with the read-across substance Pyranol.
Executive summary:

Pyranol was applied by dermal application to groups of 10 male and 10 female Wistar rats at dose levels of 0 mg/kg bw/day (vehicle control), 100 mg/kg bw/day, 300 mg/kg bw/day and 1000 mg/kg bw/day over a period of 3 months (5 days per week) according to OECD 411. Observations relevant for this endpoint included organ weights testes, adrenal glands and thyroid glands, and histopatological examination (control and high dose animals) of testes, epididymides, prostate, seminal vesicles, uterus, vagina, cervix, ovaries, adrenal gland, pituitary gland and thyroid gland). No treatment-related adverse effects were observed up to and including 1000 mg/kg bw/day, the highest dose tested.

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The result is of sufficient quality and sufficiently adequate for this dossier.
Additional information

Analogue approach information, see also document Jasmal_Readacross_Florosa_Reproductivetoxicity_20151204 attached in section 13.

Pyranol was applied by dermal application to groups of 10 male and 10 female Wistar rats at dose levels of 0 mg/kg bw/day (vehicle control), 100 mg/kg bw/day, 300 mg/kg bw/day and 1000 mg/kg bw/day over a period of 3 months (5 days per week) according to OECD 411. Observations relevant for this endpoint included organ weights testes, adrenal glands and thyroid glands, and histopatological examination (control and high dose animals) of testes, epididymides, prostate, seminal vesicles, uterus, vagina, cervix, ovaries, adrenal gland, pituitary gland and thyroid gland). No treatment-related adverse effects were observed up to and including 1000 mg/kg bw/day, the highest dose tested.


Short description of key information:
For the read-across substance Florosa a dermal OECD 411 study (application 6 hours/day, 5 days/week): doses 100, 300 and 1000 mg/kg bw is available. There were no effects seen and the NOAEL derived is >=1000 mg/kg bw.

Justification for selection of Effect on fertility via dermal route:
For the read-across substance Florosa a dermal OECD 411 study (application 6 hours/day, 5 days/week): doses 100, 300 and 1000 mg/kg bw is available and this is sufficiently reliable and sufficiently adequate for covering this endpoint.
The read-across rationale can be found in the analogue approach document attached in Section 13.

Effects on developmental toxicity

Description of key information
For the read-across substance Florosa a dermal developmental toxicity study (OECD 414) is available. In the dermal developmental toxicity test no developmental (and maternal) effects were seen resulting in a NOAELs of >=1000 mg/kg bw/day.  
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June 2014 - February 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
2001
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Version / remarks:
1998
Deviations:
no
Principles of method if other than guideline:
Commission Regulation (EC) No 440/2008 of 30 May 2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), Part B: Methods for the determination of toxicity and other health effects: Prenatal Developmental Toxicity Study; Official Journal of the European Union, No. L 142.
GLP compliance:
yes (incl. QA statement)
Remarks:
2013
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Strain: Time-mated Wistar rats (CrIGIxBrIHan:WI)
- Source: Charles River Laboratories, Research Models and Services, Germany
- Animal identification: by ear tattoo
- Age at study initiation: 10-12 weeks
- Weight at study initiation: The body weight of the pregnant animals on day 0 varied between 143.8 – 189.4 g.
- Fasting period before study: no
- Housing: singly from day 0 - 20 p .c. in type DK III polycarbonate cages supplied by BECKER & CO., Castrop-Rauxel, Germany (floor area about 800 cm2). Dust-free wooden bedding was used in this study. For enrichment, wooden gnawing blocks were offered (Typ NGM E-022, supplied by Abedd® Lab. and Vet. Service GmbH, Vienna, Austria).
- Diet (e.g. ad libitum): ad libitum, ground Kliba maintenance diet mouse/rat meal (PROVIMI KLIBA SA, Kaiseraugst, Switzerland)
- Water (e.g. ad libitum): ad libitum, potable tap water in water bottles
- Acclimation period: 6 days

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

IN-LIFE DATES: From: 02 July 2014 To: 17 July 2014

ANALYSES
- Food: assayed for chemical as well as for microbiological contaminants
- Water: regularly assayed for chemical contaminants by the municipal authorities of Frankenthal and by Technical Services of BASF Aktiengesellschaft as well as for the presence of microorganisms by a contract laboratory
Route of administration:
dermal
Vehicle:
corn oil
Details on exposure:
TEST SITE
- Area of exposure: dorsal and dorso-lateral parts of the trunk
- % coverage: not less than 10% of the body surface
- Type of wrap if used: semi-occlusive dressing
- Time intervals for shavings or clipplings: The rats were shaved on the application area at least 18 hours before the first treatment and if it was necessary additional times during the treatment period.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): After the daily 6-hour treatment period, the dressing was removed and the application site was washed off with lukewarm water and dried.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2 mL/kg bw/day, based on the most recent individual body weight.
- Constant volume or concentration used: yes

VEHICLE
- Justification for use and choice of vehicle (if other than water): corn oil, no justification
- Amount(s) applied (volume or weight with unit): 2 mL/kg bw/day

USE OF RESTRAINERS FOR PREVENTING INGESTION: no
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 corn oil at room temperature over a period of 8 days had been verified prior to the start of the study (Project No.: 01Y0639/09Y087). Concentrations were verified at the beginning of the application period.
Given that the test substance was completely miscible with corn oil, solutions were considered to be homogenous without further analysis.
Details on mating procedure:
- Impregnation procedure: purchased timed pregnant:
The animals were mated by the breeder ("time-mated") and supplied on day 0 post coitum (GD 0) (= detection of vaginal plug / sperm). The animals arrived  on the same day (GD 0) at the experimental laboratory. The  following day was designed "day 1"  (GD 1). Animals were assigned to the test groups by taken random selection. The animals were acclimated to the laboratory conditions between start of the study (beginning of the experimental phase) and first application (GD 6).
Duration of treatment / exposure:
day 6 through day 19 post coitum (p.c.) (GD 6 to GD 19)
Frequency of treatment:
once daily for at least 6 hours
Duration of test:
On day 20 p.c. (GD 20) all surviving females were sacrificed
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: at request of the sponsor
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes, check for mortality
- Time schedule: twice a day on working days or once a day (Saturday, Sunday or on public holidays) (days 0-20 p.c.)

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

BODY WEIGHT: Yes
- Time schedule for examinations: on days 0, 1, 3, 6, 8, 10, 13, 15, 17, 19 and 20 p.c.
The body weight change of the animals was calculated from these results

CORRECTED BODY WEIGHT GAIN (net maternal body weight change): Yes
- Time schedule: calculated after terminal sacrifice (terminal body weight on day 20 p.c. minus weight of the  unopened uterus minus body weight on day 6 p.c.)

FOOD CONSUMPTION: 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 ovaries (weight of the unopened uterus, number of corpora lutea, number and distribution of implantation sites classified as live fetuses or dead implantations (early resorptions, late resorptions, dead fetuses)

SKIN EXAMINATION: Yes
The application site was examined twice (before and after the 6-hour exposure). Possible skin reactions were classified following OECD Guideline for Testing of Chemicals No. 404: Acute Dermal Irritation/Corrosion (adopted 24 Apr 2002). Classification was documented for each animal.
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
- Number of dead fetuses: Yes
- Calculations of conception rate and pre- and postimplantation losses
Fetal examinations:
At necropsy each fetus was weighed, sexed, and external tissues and all orifices were examined macroscopically. The sex was determined by observing the distance between the anus and the base of the genitalia. 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.
- External examinations: Yes, all per litter
- Soft tissue examinations: Yes, half per litter
- Skeletal examinations: Yes, half per litter
- Head examinations: Yes, half per litter
Statistics:
Simultaneous comparison of all dose groups with the control group using the DUNNETT-test (twosided) for the hypothesis of equal means was performed for: 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, proportions of resorptions, proportion of live fetuses in each litter, litter mean fetal body weight, litter mean placental weight.

Pairwise comparison of each dose group with the control group using FISHER'S EXACT test (one-sided) for the hypothesis of equal proportions was performed for: female mortality, females pregnant at terminal sacrifice, number of litters with fetal findings.

Pairwise comparison of each dose group with the control group using the WILCOXON- test (one-sided) for the hypothesis of equal medians was performed for: proportions of fetuses with malformations, variations and/or unclassified observations in each litter.
Indices:
The conception rate (in %): (number of pregnant animals/ number of fertilized animals) x 100

The preimplantation loss (in %): ((number of corpora lutea – number of implantations)/ number of corpora lutea) x 100

The postimplantation loss (in %): ((number of implantations – number of live fetuses)/ number of implantations) x 100
Historical control data:
included in report.
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 study. Therefore, the following females were excluded:
- Test group 0 (0 mg/kg bw/day): one female – not pregnant
- Test group 3 (1000 mg/kg bw/day): one female – not pregnant

Mortality:
There were no substance-related or spontaneous mortalities in any females of all test groups.

Clinical symptoms:
No clinical signs or changes of general behavior, which may be attributed to the test sub-stance, were detected in any female at dose levels of 100, 300 or 1000 mg/kg bw/day during the entire study period.
One low-dose (100 mg/kg bw/day), three mid-dose (300 mg/kg bw/day) as well as one high-dose animal (1000 mg/kg bw/day) occasionally showed vaginal hemorrhage either before daily dermal application or after the daily 6-hour exposure time. This finding was observed in these individuals on GD 15-17 only, and is most likely related to handling and semiocclusive dressing, but not to the test substance itself. The assessment was also supported by the fact that no impairment of reproduction parameters became obvious.

Skin examination:
The treated skin of all female animals of all test groups was free from any notable findings during the entire study period.

Food consumption:
The mean food consumption of the dams in all test groups was comparable to the concurrent control throughout the entire study period.

Body weight data:
The mean body weights and the average body weight gains of all test substance-treated dams in test groups 1-3 were comparable to the controls throughout the entire study period. However, on GD 6-8, the mean body weight gain value of the high-dose dams (1000 mg/kg bw/day) was significantly lower (-37%), but recovered afterwards and was comparable throughout the remaining treatment period.

Corrected (net) body weight gain:
The corrected body weight gain of animals in all test groups was not influenced by treatment. The differences between these groups and the control group revealed no dose-dependency and were assessed to be without biological relevance.

Uterus weight:
The mean gravid uterus weights of the animals of the test groups 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.

Reproduction data:
The conception rate was 96% in controls and in 1000 mg/kg bw/day animals, and 100% in test groups 100 and 300 mg/kg bw/day.
No test substance-related and/or biologically relevant differences between controls and the test groups were observed with regard to conception rate, mean number of corpora lutea and implantation sites or values calculated for the pre- and the postimplantation losses, the number of resorptions as well as viable fetuses. All observed differences were considered to reflect the normal range of fluctuations for animals of this strain and age. This includes the apparently lower mean number of viable female fetuses at 300 mg/kg bw/day.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: not determinable due to absence of adverse toxic effects
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 the test groups was comparable to the control fetuses. The significantly lower mean number of viable female fetuses at 300 mg/kg bw/d was considered to be incidental and without any toxicological relevance.

Weight of the placentae:
The mean placental weights of the test groups were comparable to the corresponding control group.

Weight of the fetuses:
The mean fetal weights were comparable between the control and the test groups. Biologically relevant differences were not observed. The significantly lower mean weight of female fetuses in test group 100 mg/kg bw/d did not show a dose-response relationship and was clearly within the historical control data.

Fetal external malformations:
No external malformations were recorded.

Fetal external variations:
One external variation, i.e. limb hyperextension, was detected for one high-dose fetus (1000 mg/kg bw/d). This single finding was considered to be spontaneous in nature.

Fetal external unclassified observations:
No unclassified external observations were recorded.

Fetal soft tissue malformations:
No soft tissue malformations were recorded.

Fetal soft tissue variations:
Two soft tissue variations were detected, i.e. large liver lobe and dilated renal pelvis. The incidences of these variations were neither significantly nor dose-dependently increased. Therefore, all differences were not considered biologically relevant.

Fetal soft tissue unclassified observations:
No unclassified soft tissue observations were recorded.

Fetal skeletal malformations:
One skeletal malformation was detected in the high dose group (1000 mg/kg bw/day) affecting the fore-limb. This single finding can be found in the historical control data in a comparable frequency. An association to the treatment was not assumed.

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 appeared without a relation to dosing. The overall incidences of skeletal variations were comparable to the historical control data.
The increased incidence of the skeletal variation “wavy rib” was only marginally above the historical control data. Therefore, the finding was regarded to be incidental and not related to treatment.

Fetal skeletal unclassified cartilage observations
Some isolated cartilage findings without impact on the respective bony structures, which were designated as unclassified cartilage observations, occurred in all test groups. The observed unclassified cartilage findings were related to the skull, the sternum and ribs. They did not show any relation to treatment.
Key result
Dose descriptor:
other:
Remarks on result:
not determinable due to absence of adverse toxic effects
Abnormalities:
not specified
Developmental effects observed:
not specified

Based on the analytical results it is concluded, that Pyranol is stable in corn oil over a period of 8 days at ambient temperature. The determined concentrations were in the range of 90 % - 110 % of the nominal concentration: between 98.7 and 100.5%.

 

The values of Pyranol in corn oil were found to be in the range of 90 % – 110 % of the nominal concentration (96.8-103.0%)

No test substance could be detected in the vehicle control sample with a concentration of ≥ 30 % of the lowest calibration solution.

These results demonstrated the correctness of the concentrations of Pyranol in corn oil.

Conclusions:
Dermal application of Pyranol to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at a dose level of 1000 mg/kg bw/day did not cause any evidence of maternal toxicity or prenatal developmental toxicity.
Based on the absence of substance- related adverse effects, the no observed adverse effect level (NOAEL) for maternal toxicity and for prenatal developmental toxicity was 1000 mg/kg bw/day, the highest tested dose.
In addition, as no local effects were observed , the NOAEL for local dermal effects in this study is 1000 mg/kg bw/day, the highest dose tested.
Executive summary:

In a prenatal developmental toxicity study the test substance Pyranol was applied dermally (6 hours/day) to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) for the evaluation of its potential maternal and prenatal developmental toxicity (according to OECD 414). With regard to clinical examinations, no signs of general systemic toxicity including food consumption and body weight gain were observed. No toxicologically relevant differences between the animals receiving the test substance and control animals were observed. No differences of toxicological relevance between the control and the treated groups (100, 300 or 1000 mg/kg bw/day) 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. Similarly, no influence of the test substance on fetal weight and sex distribution of the fetuses was noted at any dose level. Overall, there was no evidence for toxicologically relevant, adverse effects of the test substance on fetal morphology at any dose level.

Based on the absence of substance- related adverse effects, the no observed adverse effect level (NOAEL) for maternal toxicity and for prenatal developmental toxicity was 1000 mg/kg bw/day, the highest tested dose.

In addition, as no local effects were observed , the NOAEL for local dermal effects in this study is 1000 mg/kg bw/day, the highest dose tested.

Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The result is of sufficient quality and sufficiently adequate for this dossier.
Additional information

The reproductive toxicity of Jasmal (18871-14-2) using read across from Florosa (63500-71-0).

 1. Introduction and hypothesis for the analogue approach

Jasmal is a 4-hydroxypyran with an acetate group on the C1 position l and at C2 a linear pentane group. For this substance no repeated dose toxicity data are available. In accordance with Article 13 of REACH,lacking information should be generated whenever possible by means other than vertebrate animal tests, i.e. applying alternative methods such as in vitro tests, QSARs, grouping and read-across. For assessing the repeated dose toxicity of Jasmal the analogue approach is selected because for one closely related analogue repeated dose toxicity information is available which can be used for read across.

Hypothesis:Jasmalhas similar reproductive toxicity compared to Florosa resulting in a similar NOAEL.This hypothesis is based on similarity in structure, physico-chemical parameters and assumed similar metabolism and metabolites.

Available information:Forthe source substance Florosa a 90-day dermal toxicity study is available (according to OECD TG 411) and a dermal developmental toxicity test. No fertility effects were seen in this 90-day dermal toxicity test and the derived NOAEL for fertility are therefore >=1000 mg/kg bw. In the dermal developmental toxicity test no developmental (and maternal) effects were seen resulting in a NOAELs of >=1000 mg/kg bw/day. At the ECHA dissemination site a 28-day oral gavage toxicity test is reported without an indication of fertility effect. Also in the OECD TG 421reported at the ECHA dissemination no effects on fertility and/or developmental toxicity were seen. reported The resulting NOAEL for fertility and developmental toxicity of >=625 mg/kg bw and >=1000 mg/kg bw, respectively.

2. Target chemical and source chemical(s)Chemical structures of the target chemical and the source chemicals are shown in the data matrix below, including available physico-chemical properties and toxicological information, thought relevant for repeated dose toxicity, of Jasmal and Florosa.

3. Purity / ImpuritiesJasmal is a multi-constituent containing 2 diasteromers and some impurities being very similar to these two diastereomers. Therefore its constituents and impurities indicate similar repeated dose toxicity potential. Florosa is also a multi-constituent and contains similar stereo-isomers as Jasmal which support the read across from Florosa to Jasmal.

4. Analogue approach justification

According to Annex XI 1.5 read across can be used to replace testing when the similarity can be based on a common backbone and a common functional group. It can also be used when the analogues used will have the same or similar metabolites. When using read across the result derived should be applicable for C&L and/or risk assessment and it should be presented with adequate and reliable documentation.

Structural similarities and differences:Jasmal and Florosa both have the pyran-ring structure and a butane group attached to this ring. On the C1 ring position Jasmal has an acetate group attached to it while Florosa has an alcohol functional group. Jasmal does not have a methyl group at this C1 while Florosa has. Jasmal has the butane group on the C2 atom of the ring while Florosa has it on the C3 position.

Toxico-kinetic:In the data matrix the characteristics of Jasmal and Florosa are summarised. Both substances are expected to be absorbed via the oral route based on their molecular weight water solubility and log Kow. Also dermal absorption is expected to a significant extent. Florosa may present somewhat higher dermal absorption based on its lower molecular weight (172 versus 214). The dermal absorption of Florosa was measured in an in vitro dermal absorption study (OECD TG 428) resulting in 18 and 44% dermal absorption at the high (9000 ug/cm2) and low dose 1000 ug/cm2, respectively.

In the gut and in the liver the ester bond of Jasmal will be metabolised into its alcohol. In the liver both Jasmal and Florosa structures will open at the oxygen atom in the ring and O-alkylation is anticipated.

Fig. 1 Metabolic pathway of Jasmal. Firstly the ester cleavage is presented and thereafter the anticipated O-alkylation of the Jasmal-ring

 

 

Fig. 2 The anticipated O-dealkylation of Florosa based on EFSA (2011).

The ester bond of Jasma will be readily cleaved by carboxylesterases in the gut and liver (and other organs) into its respective alcohol (Toxicological handbooks).

 

EFSA (2011) has evaluated the metabolism of ethers, including cyclic ethers like Jasmal and Florosa. Their evaluation is copied here: “Several metabolic options are available to aliphatic and aromatic ethers. One pathway for aliphatic and aromatic ethers is O-dealkylation to form the corresponding aldehydes and alcohols if a suitable alkyl substituent (methyl or ethyl) is attached to the ether oxygen. The resulting alcohols may be further oxidised followed by conjugation and excretion, while the aldehydes (i.e. acetaldehyde and formaldehyde) are oxidised to carboxylic acids, which participate in fundamental biochemical pathways, including the fatty acid pathway and tricarboxylic acid cycle, resulting in CO2 aromatic moiety may undergo cytochrome P450-catalysed C-oxidation (ring-hydroxylation or side-chain oxidation), followed by conjugation with sulphate or glucuronic acid and then excretion, mainly via the urinary route”. In Fig. 2 the O-dealkylation of the pyran group in Florosa is presented and thought to be similar to the O-dealkylation of Jasmal. The alkyl chains of Jasmal and Florosa are likely prone to beta oxidation similar to fatty acid metabolisation

 

As presented by EFSA (2011) also all substances are likely to be oxidised on their CH3-methyl groups becoming alcohols, aldehydes and/or carboxylic acids. Such oxidation is expected to increase the water solubility and therefore its excretion. No reactive metabolites are anticipated here for Jasmal or Florosa or their metabolites.

 

Experimental data to support the read across of Jasmal and Florosa. Jasmal and Florosa do not show acute oral and dermal toxicity. Both are not skin irritants or skin sensitisers indicating limited reactivity. They are both negative in the genotoxicity assays. Jasmal is not classified for eye irritation, while Florosa is classified, which may be due to its somewhat lower MW (172 versus 214) and/or different test method (in vivo OECD TG 405 and in vitro OECD TG 438, respectively). Despite the eye irritation of Florosa which may not be that relevant for reproductive toxic endpoints, generally the experimental information further supports the absence of reactivity of both substances. 

 

5. Data matrix

The relevant information on physico-chemical properties and toxicological characteristics are presented in the Data Matrix in Table 1.

6. Conclusions per endpoint for C&L, PBT/vPvB and dose descriptor

When using read across the result derived should be applicable for C&L and/or risk assessment, cover an exposure period duration comparable or longer than the corresponding method and be presented with adequate and reliable documentation.

Fertility:For Florosa a dermal 90-day repeated dose toxicity test is available with a NOAEL of >=1000 mg/kg bw/day which does not lead to classification and labelling for fertility. Jasmal is expected to metabolise in a metabolite similar to Florosa. Therefore the Florosa NOAEL of >=1000 mg/kg bw/day in the 90-day dermal repeated doses toxicity for fertility can be used for read-across to Jasmal.

Final conclusion on hazard, C&L, DNEL and risk characterization:Jasmal has a NOAEL of >=1000 mg/kg bw. Classification and labelling is not needed for this endpoint in view of the absence of adverse effects on fertility and developmental toxicity, according to CLP Regulation (EC) No. 1272/2008 and amendments.A DNEL derivation is not needed because for fertility and developmental toxicity for all routes ‘no adverse effects are observed’ can be concluded, which subsequently results in ‘no hazard is identified’.  

 

Data matrix for the read across to Jasmal from Florosa

Common names

Jasmal

Florosa

Chemical structures

CAS no

18871-14-2

63500-71-0

 

Target

Source

REACH registration

Annex IX in 2016

Annex X (2010)

Physico-chemical data

 

 

Molecular weight

214.31

172

Physical state

liquid

Liquid

Melting point,oC

-20

< -20

Vapour pressure, Pa

0.49

1

Water solubility, mg/l

215

24000

Log Kow

3.2

1.64

Human health endpoints

 

 

Acute oral tox in mg/kg bw

LD 50 > 5000 (OECD TG 401)

LD 50 > 5000 (OECD TG 401)

Acute dermal tox in mg/kg bw

LD 50 >2000 (OECD TG 402)

LD 50 >2000 (OECD TG 402)

Skin irritation

Not irritant (No irritation in acute dermal toxicity study OECD TG 402))

Not irritant (OECD TG 404)

Eye irritation

Not-eye irritant (OECD TG 438)

Eye irritant (OECD TG 405)

Skin sensitisation

Not skin sensitiser (OECD TG 406)

Not sensitising (OECD TG 406)

Genotoxicity – Ames test, CAB and Gene mutations

Negative

Negative

Repeated dose toxicity mg/kg bw

Read across

90-day NOAELs >=1000 (OECD TG 411)

Fertility effects in repeated dose toxicity in mg/kg bw

Read across

90-day dermal NOAEL >= 1000 (OECD TG 411)

Developmental toxicity in mg/kg bw

Read across

Dermal NOAEL >=1000 (OECD TG 414)

 

References

ECHA, 2013, Pyranol registration:http://apps.echa.europa.eu/registered/data/dossiers/DISS-975e89e3-d8af-0759-e044-00144f67d031/DISS-975e89e3-d8af-0759-e044-00144f67d031_DISS-975e89e3-d8af-0759-e044-00144f67d031.html

Site visited September, 2015. 

 

EFSA, 2011, http://www.efsa.europa.eu/en/efsajournal/doc/1848.pdf

   

 

Justification for classification or non-classification

Based on the absence of fertility and developmental toxicity effects in the OECD 414 and OECD TG 411 studies with the read-across substance Florosa an analogue of Jasmal, Jasmal does not need to be classified for reproductive toxicity (fertility and developmental) when considering the criteria outlined in Annex I of 1272/2008/EC (CLP).

Additional information