Tetrahydro-3-pentyl-2H-pyran-4-yl acetate

Endpoint summary

Description of key information

For the read-across substance 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 this endpoint. 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 can be used for read-across to Jasmal. The result of the 90-day dermal toxicity study overrules the Florosa 28-oral gavage study with a NOAEL of 125 mg/kg bw. This is because when the NOAEL of the 90-dermal toxicity study is converted to the oral route using the experimental dermal absorption value of 18% the NOAEL is >=180 mg/kg bw on which bases it can be assumed that the effects seen in the 28-day oral gavage study do not have to be considered adverse.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

a short-term toxicity study does not need to be conducted because a reliable sub-chronic (90 days) or chronic toxicity study is available, conducted with an appropriate species, dosage, solvent and route of administration

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: dermal

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:

OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)

Version / remarks:

(1981)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.28 (Sub-Chronic Dermal Toxicity Test: 90-Day Repeated Dermal Dose Study Using Rodent Species)

Version / remarks:

(2008)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

BASF SE

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

Type of coverage:

semiocclusive

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.

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:

at least 6 hours daily

Frequency of treatment:

5 days per week (once daily)

Remarks:

Doses / Concentrations:
100, 300 and 1000 mg/kg bw/day
Basis:
nominal per unit body weight

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.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily (working days), once daily (Satudays, Sundays and public holidays)

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once before beginning of the applicationperiod (day 0) and subsequently once a week

DERMAL IRRITATION: Yes
- Time schedule for examinations: once each workday (immediately before application)

BODY WEIGHT: Yes
- Time schedule for examinations: before the start of application period, on day 0 and thereafter at weekly intervals

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: 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: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: before administration and toward the end of the application period
- Dose groups that were examined: control and high dose (other dose groups will be examined only if there is a striking discrepancy between the highest dose group and the control group)

HAEMATOLOGY: Yes
- Time schedule for collection of blood: day 92 (males) and day 93 (females)
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes (fasting peroid of about 16 to 20 hours)
- Blood was taken from the retro-bulbar venous plexus.
- Parameters examined: according to guideline

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: day 92 (males) and day 93 (females)
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes (fasting peroid of about 16 to 20 hours)
- Blood was taken from the retro-bulbar venous plexus
- Parameters examined: according to guideline

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: once towards the end of treatment
- Dose groups that were examined: all animals
- Battery of functions tested: (FOB) Home cage observation, open field observation, Sensory motor tests/ reflexes, Motor activity

Sacrifice and pathology:

All animals were sacrified by decapitation under isoflurane anesthesia.

GROSS PATHOLOGY: Yes
Anesthetized animals, adrenal glands, kidneys, liver, testes and thyroid glands were weighed.

HISTOPATHOLOGY: Yes
according to guidelines

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.

Clinical signs:

no effects observed

Dermal irritation:

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

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
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. Erythema, erosions and scales are considered related to treatment. Although these observations were not present untill the end of the study, the induction of skin erosion is considered adverse. The observation in the mid dose group (3 males) are questionable concerning substance-related adversity, as in this dose group erosion was observed in 3 males only (not in females), and in the control group 1 female showed erosion. In the high dose group erosion was observed in both males (5) and females (4), and considered as adverse effect.

BODY WEIGHT AND WEIGHT GAIN
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.

FOOD CONSUMPTION
No test substance-related effects on food consumption were obtained. All values were within the range typical for animals of this strain and age.

OPHTHALMOSCOPIC EXAMINATION
No test substance-related observations were noted. All findings were assessed as being incidental in nature since they occurred in individual animals only and did not show a dose-response relationship.

HAEMATOLOGY
No treatment-related changes among haematological parameters were observed.
In males of test group 300 mg/kg bw/day staticical significant decreases in the total values of white blood cells, neutrophiles, lymphocytes and monocytes were observed. These alterations were not dose-dependent and therefore they were regarded as incidental and not treatment-related.

CLINICAL CHEMISTRY
No treatment-related changes among clinical chemistry parameters were observed.
In females of the mid and high dose groups (300 mg/kg bw/day and 1000 mg/kg bw/day) glucose values were slightly but statistically significant decreased (4.99 and 4.72 mmol/L, respectively) compared to controls (5.36 mmol/L). Although the decreases in glucose were statistically significantly different to the control value and showed a dose-response relationship, these isolated findings were assessed as being fortuitous since similar increases were not observed in the males.

NEUROBEHAVIOUR
Deviations from "zero values" were obtained in several animals. However, as most findings were equally distributed between test-substance treated groups and controls, were without a dose-response relationship or occurred in single animals only, these observations were considered to have been incidental.

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

GROSS PATHOLOGY
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
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.

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

Critical effects observed:

not specified

Conclusions:

The administration of Pyranol by dermal application over a period of 3 months did not cause test substance-related adverse signs of systemic toxicity.
Therefore, under the conditions of the present study the no observed adverse effect level (NOAEL) was 1000 mg/kg bw/day in male and in female Wistar rats.
In addition, based on the observed skin erosion in high dose animals, the NOAEL for local dermal effects in this study is set at 300 mg/kg bw/day.

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).

Food consumption and body weights were determined weekly. The animals were examined for signs of toxicity or mortality at least once a day. In addition, the rats were daily examined for any clinically abnormal signs. The findings on the treated skin were obtained immediately before application once on each working day. Detailed clinical examinations in an open field were conducted prior to the start of the application period and weekly thereafter. Ophthalmological examinations were performed before the beginning and at the end of the application period. Beside this, a functional observational battery (FOB) as well as measurement of motor activity (MA) were carried out at the end of the application period. Clinicochemical and hematological examinations were performed towards the end of the application period. After the application period all rats were sacrificed and assessed by gross pathology. Organ weights were determined followed by histopathological examinations.

The administration of Pyranol by dermal application over a period of 3 months did not cause test substance-related adverse signs of systemic toxicity. Therefore, under the conditions of the present study the no observed adverse effect level (NOAEL) was 1000 mg/kg bw/day in male and in female Wistar rats.

In addition, based on the observed skin erosion in high dose animals, the NOAEL for local dermal effects in this study is set at 300 mg/kg bw/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The result is of sufficient quality and sufficiently adequate for this dossier.

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000

Study duration:

subchronic

Species:

rat

Quality of whole database:

The result is of sufficient quality and sufficiently adequate for this dossier.

Additional information

The repeated dose toxicity of Jasmal (18871-14-2) using read across from Florosa/Pyranol (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 repeated dose 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 (OECD TG 414). Both dermal toxicity tests have NOAELs of >=1000 mg/kg bw/day for systemic (and reproductive effects). On the ECHA dissemination site also data on a 28-day oral gavage toxicity test are presented with a NOAEL of 125 mg/kg bw (LOAEL of 625 mg/kg bw). Also a dermal reproscreen study (OECD TG 421) is available showing an overall NOAEL of >=1000 mg/kg bw.

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 / Impurities

Jasmal 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 Jasmal will be readily cleaved by carboxylesterases in the gut and liver (and other organs) into its respective alcohol (Toxicological handbooks, Yamada et al.).

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 of Jasmal and Florosa supporting the read across. Both substances do not show acute oral or 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 versus in vitro, OECD TG 438). Despite the eye irritation of Florosa, generally the experimental information presented further supports the absence of reactivity for 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.

For Florosa a dermal 90-day repeated dose toxicity test is available with a systemic NOAEL of >=1000 mg/kg bw/day which does not lead to classification and labelling for this endpoint. 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 can be used for read-across to Jasmal. The result of the 90-day dermal toxicity study overrules the Florosa 28-oral gavage study with a NOAEL of 125 mg/kg bw. This is because when the NOAEL of the 90-dermal toxicity study is converted to the oral route using the experimental dermal absorption value of 18% the NOAEL is >=360 mg/kg bw on which bases it can be assumed that the effects seen in the 28-day oral gavage study do not have to be considered adverse.

For Florosa also a dermal local long-term NOAEL is derived. This local NOAEL is not applicable for Jasmal as for the local endpoints the read across cannot be applied in view of the differences in functional groups: alcohol versus ester, respectively

Final conclusion on hazard, C&L, DNEL and risk characterization: Jasmal has a NOAEL of >=1000 mg/kg bw/day. Classification and labelling is not needed for this endpoint in view of the absence of adverse effects, according to CLP Regulation (EC) No. 1272/2008). A DNEL derivation is not needed because for repeated dose 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 (OECD TG 404)	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		90-day dermal NOAEL >= 1000 OECD TG 411
		28-day oral gavage NOAEL = 125 mg/kg bw (REACH dissimination)
Developmental toxicity systemic toxicity in mg/kg bw		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 NOAEL of >=1000 mg/kg bw/day observed in a dermal 90 -day study of read-across substance Florosa, Jasmal does not need to be classified for (dermal) repeated dose toxicity when considering the criteria in the CLP 1272/2008/EC and its amendments.