Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Acute oral toxicity: read-across from Jasmal: OECD TG 401: LD50 >5000 mg/kg bw

Acute dermal toxicity: read-across from Jasmal: OECD TG 402: LD50 >2000 mg/kg bw

Acute inhalation (route to route extrapolation): > 13000 mg/m3

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2018
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read-across information.
Justification for type of information:
The read-across justification is presented in the Endpoint summary Acute toxicity. The accompanying files are also attached there.
Reason / purpose for cross-reference:
read-across source
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Remarks on result:
other: read-across from Jasmal
Interpretation of results:
other: Not acutely orally toxic
Remarks:
according to EU CLP (EC No. 1272/2008 and its amendments)
Conclusions:
The acute oral toxicity test showed an LD50 of >5000 mg/kg bw
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
October 22, 1979 - November 5, 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Justification for type of information:
This information is used for read-across to Jessemal.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
No details on test material, no purity, no details on environmental conditions.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Wistar-strain albino
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Suitable licensed dealer
- Age at study initiation: approx. 6 to 8 weeks
- Weight at study initiation: 200 - 238 g
- Fasting period before study: approx. 18 hours
- Housing: Animals were housed in galvanized cages with indirect bedding
- Diet: Free access to diet consisted of a growth and maintenance ration from a commercial producer
- Water: Free access to water
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): temperature controlled
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Individual doses, calculated on the basis of bodyweight, were administered using a stainless steel intragastric feeding needle.
Doses:
5000 mg/kg bodyweight
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: The animals were observed for signs of pharmacologic activity and drug toxicity at 1, 3, 6 and 24 hours after application and thereafter daily.
- Necropsy of survivors performed: yes, at the end of the observation period the animals were killed, necropsied and subjected to complete gross necropsy, with all findings noted.
- Body weights: Individual body weights were recorded immediately before treatment and then on the 14th day of the observation period.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred.
Clinical signs:
Slight depression was oberserved among all animals at 3, 6 and 24 hours after application of the substance.
Body weight:
Normal bodyweight increases were observed on the 14th day of the observation period.
Gross pathology:
No gross changes were observed.
Interpretation of results:
other: Not acutely orally toxic
Remarks:
according to EU CLP(EC No. 1272/2008 and its amendments)
Conclusions:
The acute oral toxicity test showed an LD50 of >5000 mg/kg bw
Executive summary:

In this study performed equivalent to OECD TG 401 guideline and GLP principles, 10 rats (5 males and 5 females) were administered to the substance at a dose level of 5000 mg/kg bw. No deaths occurred. Slight depression was oberserved among all animals at 3, 6 and 24 hours after application of the substance. Normal bodyweight increases were observed on the 14th day of the observation period. No gross changes were observed. The acute oral LD50 for the substance in male and female rats was determined to be >5000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The acute oral toxicity result is of sufficient quality and adequate for this dossier.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read-across information.
Justification for type of information:
The read-across justification is presented in the Endpoint summary Acute toxicity. The accompanying files are also attached there.
Reason / purpose for cross-reference:
read-across source
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Remarks on result:
other: read-across from Jasmal
Interpretation of results:
other: Not acute dermally toxic
Remarks:
according to EU CLP (EC No. 1272/2008 and its amendments)
Conclusions:
The acute dermal toxicity of the substance was >2000 mg/kg bw.
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
27 February, 2001 - 13 March, 2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
This information is used for read-across to Jessemal.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
(1987)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Sprague-Dawley CD (Crl: CD® ( SD) IGS BR)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent, UK
- Age at study initiation: approximately 8 weeks
- Weight at study initiation: males: 288 - 309 g; females: 233 - 259 g
- Housing: The animals were housed in suspended polypropylene cages furnished with woodflakes. The animals were housed individually during the 24-hour exposure period and in groups of five, by sex, for the remainder of the study.
- Diet: Free access to food (Rat and Mouse SQC Expanded Diet No. 1, Special Diets Services Limited, Witham, Essex, UK)
- Water: Free access to drinking water
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): set to maintain 19 - 25
- Humidity (%): set to maintain 30 - 70
- Air changes (per hr): At least 15
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: area of shorn skin
- % coverage: approximately 10% of the total body surface area
- Type of wrap if used: A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of selfadhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing: The treated skin and surrounding hair was wiped with cotton wool moistened with distilled water to remove any residual test material.
- Time after start of exposure: 24 hours
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations:
Mortality and clinical signs: The animals were observed for deaths or overt signs of toxicity 0.5, 1, 2 and 4 hours after dosing and subsequently once daily for 14 days. After removal of the dressings and subsequently once daily for 14 days, the test sites were examined for evidence of primary irritation and scored for skin reactions.
Bodyweights: Individual bodyweights were recorded prior to application of the test material on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: At the end of the study the animals were killed by cervical dislocation and subjected to gross pathological examination. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded.
Statistics:
Not performed.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred.
Clinical signs:
There were no signs of systemic toxicity.
Body weight:
All animals showed expected gains in bodyweight over the study period.
Gross pathology:
No abnorrnalities were noted at necropsy.
Other findings:
There were no signs of dermal irritation.
Interpretation of results:
other: Not acute dermally toxic
Remarks:
according to EU CLP (EC No.1272/2008 and its amendments)
Conclusions:
The acute dermal toxicity of the substance was >2000 mg/kg bw.
Executive summary:

In this study performed to OECD TG 402 guideline and GLP principles, 10 rats (5 males and 5 females) were administered to the substance at a dose level of 2000 mg/kg bw. No deaths occurred and there were no signs of systemic toxicity. All animals showed expected gains in bodyweight over the study period. There were no signs of dermal irritation and no abnorrnalities were noted at necropsy. The acute dermal LD50 for the substance in male and female rats was determined to be >2000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The acute dermal toxicity result is of sufficient quality and adequate for this dossier.

Additional information

Acute oral and dermal toxicity is assessed based on read-across from Jasmal to Jessemal. The executive summaries of the source information on the substance is presented below, followed by the read-across rationale.

Jasmal and its acute oral toxicity

In a study equivalent to OECD TG 401 guideline and GLP principles, 10 rats (5 males and 5 females) were administered to the substance at a dose level of 5000 mg/kg bw. No deaths occurred. Slight depression was oberserved among all animals at 3, 6 and 24 hours after application of the substance. Normal bodyweight increases were observed on the 14th day of the observation period. No gross changes were observed.The acute oral LD50 for the substance in male and female rats was determined to be >5000 mg/kg bw.

Jessemal and its Acute inhalation toxicity derived from Jasmal's acute oral toxicity

Acute inhalation is predicted based on the acute oral toxicity in accordance with the ECHA CLP guidance document (2015, 3.1.3.3.4: 1 mg/kg bw = 0.0052 mg/l (5.2 mg/m3). The acute inhalation is predicted to be: LC50=5000 x 5.2 x 50/100 = 13000 mg/m3 (using 100% inhalation and 50% oral absorption). The calculated saturated vapour concentration 34.7 mg/m3 (MW*VP/ 8.3 (gas constant)*298K). This means that the acute inhalation concentration cannot be reached and therefore no acute inhalation is anticipated.

Jasmal and its Acute dermal toxicity

In a study performed according to OECD TG 402 guideline and GLP principles, 10 rats (5 males and 5 females) were administered to the substance at a dose level of 2000 mg/kg bw. No deaths occurred and there were no signs of systemic toxicity. All animals showed expected gains in bodyweight over the study period. There were no signs of dermal irritation and no abnorrnalities were noted at necropsy. The acute dermal LD50 for the substance in male and female rats was determined to be >2000 mg/kg bw.

The acute toxicity of Jessemal based on read across from data available for Jasmal (CAS #18871-14-2)

 

Introduction and hypothesis for the analogue approach

For the multi-constituent substance Jessemal all constituents > 1% are identified. The substance consists mainly of two sub-groups of constituents, Tetrahydropyran acetate -like constituents, and Branched alkyl diacetates-type.For Jessemal no experimentalacute oral 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 acute oral and acute dermal toxicity of Jessemal, the analogue approach is selected because for one of the constituents, Jasmal, acute oral and acute dermal toxicity data is available which can be used for read-across.

Hypothesis: Jessemal has the same acute oral and dermaltoxicity as Jasmal.

Available information:For Jasmal acute oral and dermal studies are available, equivalent to OECD TG 401, Rel. 2 and OECD TG 402, Rel. 1, showing LD50 > 5000 and 2000 mg/kg bw, respectively.

Target chemical and source chemical(s)

Chemical structures of the target chemical and the source chemical(s) are shown in the data matrix, including physico-chemical properties.

Purity / Impurities

The major and minor constituents of Jessemal are presented in the Data matrix. The impurities < 10% are grouped depending their resemblance with Tetrahydropyran acetate -like constituents, and Branched alkyl diacetates-type.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. 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, which is presented below.

Analogue selection:For Jessemal the substance Jasmal was selected as source chemical for read-across becauseJessemal‘sconstituents arethe same and/orvery similar to Jasmal’sand for Jasmal experimental acute toxicity information is available.

Structural similarities and differences: Jessemal andJasmal are both reaction masses containing similar Tetrahydropyran acetate-like constituents with molecular weight of 214. Jessemal also contains constituent of Branched alkyl diacetates with molecular weights of 244. These diacetates have one additional acetic ester and have an open ring structure not present in Jasmal. Jessemal hastwo minor impurities just exceeding the 1% level, one being the alcohol derivative of the Tetrahydropyran acetates and the other one of the Branched alkyl diacetates, which will not be addressed further being only very minor constituents.

Toxico-kinetics, absorption: Jessemal and Jasmalare expected to have similar absorption via all routes based on the similarity in chemical structure and physico-chemical properties. Jessemal and Jasmal both have molecular weights, water solubility and log Kow values favourable for uptake. All constituents are acetic esters, which will be cleaved by carboxyl esterases and the corresponding alcohols and acetic esters will be the key metabolites (Toxicological handbooks; Belsito et al., 2008).The Branched diacetates will be present twice as much acetic acid than Jasmal.

Toxico-dynamics: The similar constituents present in Jessemal and Jasmal will present similar reactivity and therefore similar acute toxicity.

Uncertainty of the prediction: There are no uncertainties other than those already addressed above.

Data matrix

The relevant information on physico-chemical properties and toxicological characteristics are presented in the data matrix below.

Conclusions on acute oral toxicity for hazard and risk assessment

For Jessemal no acute toxicity data is available. Jasmal information can be used for read-across is used to fill this data gap. 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.This documentation is presented in the current text. For the analogue Jasmal,a well conducted acute oral toxicity test with a LD50 of > 5000 mg/kg bw, and a well conducted acute dermal toxicity test with a LD50 >2000 mg/kg bw are available. This information can be directly used for read across to Jessemal.

Final conclusion:For Jessemal the oral LD50 is >5000 mg/kg bw, and the dermal LD50 is >2000 mg/kg bw.

 

Data matrix for supporting the read across to Jessemal from Jasmal for acute toxicity.

Names

Jessemal

Tetrahydropyran acetates

Jasmal + 3 other similarimpurities

Branched alkyl diacetates

Other branched alkyl diacetates (4 impurities)

Read-across

Target

Target

Major constituent

Source

(and impurities)

Target

Minorconstituent

Target

Impurities

Chemical structures

Not applicable

Typical conc. (%)

Not applicable

20-40

<23

10-20

<22

CAS #

Not applicable

38285-49-3

18871-14-2

67634-09-7

--

Einecs

945-946-3

 

242-640-5

 

 

REACH registration

2018

 

Registered

 

 

MW

Not applicable

214

214

244

244

Phys-chem*

 

 

 

 

 

Log Kow

3.5 (exp.)*

3.2 (est.)

3.2 - 3.7 (exp.)

3.7 (est.)

3.7 (est.)

Ws (mg/L)

714.1 (exp.)

67.8 (est.)

214.9 (exp.)

17.8 (est.)

17.8 (est.)

Human health

 

 

 

 

 

Acute oral toxicity in mg/kg bw

>5000

(Read across)

>5000

(Read across)

>5000

(Read across)

>5000

(Read across)

>5000

(Read across)

Acute dermal toxicity in mg/kg bw

>2000

(Read across)

>2000

(Read across)

>2000

(Read across)

>2000

(Read across)

>2000

(Read across)

*Log Kow is based on the major constituent, the log Kow range is 3.5 to 4.2.

 

References:

- Belsito, D., Bickers, D., Bruze, M., Calow, P., Greim, H., Hanifin, J.M., Rogers, A.E., Saurat, J.H., Sipes, I.G., Tagami, H., 2008, A toxicologic and dermatologic assessment of cyclic acetates when used as fragrance ingredients, Food and Chemical Toxicology 46, Suppl 12:S1-27.

 

 

Justification for classification or non-classification

The substance does not have to be classified for acute toxicity by the oral, inhalation and dermal route according to EU CLP (EC No. 1272/2008, and its amendments).