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EC number: 201-932-2 | CAS number: 89-71-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Description of key information
Acute oral toxicity of Ylanganate based on read across from methyl p-methyl benzoate (similar to OECD TG 401): LD50 3300 mg/kg bw
Key value for chemical safety assessment
Acute toxicity: via oral route
Link to relevant study records
- Endpoint:
- acute toxicity: oral
- Type of information:
- experimental study
- Remarks:
- Methyl p-Methylbenzoate
- Adequacy of study:
- key study
- Study period:
- 1972
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: The study is similar to OECD TG 401 study with 4-methyl benzoate predates GLP.
- Justification for type of information:
- Information is used for read across to Ylanganate
- Reason / purpose for cross-reference:
- read-across source
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 401 (Acute Oral Toxicity)
- GLP compliance:
- no
- Test type:
- standard acute method
- Limit test:
- no
- Species:
- rat
- Strain:
- not specified
- Sex:
- not specified
- Details on test animals or test system and environmental conditions:
- Standard conditions
- Route of administration:
- oral: unspecified
- Vehicle:
- not specified
- Details on oral exposure:
- Gavage application
- Doses:
- 1220, 1730, 2470, and 5000 mg/kg
- No. of animals per sex per dose:
- 10 animals per dose
- Control animals:
- no
- Details on study design:
- - Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes, lungs, liver, kidneys, intestines, stomach and spleen were studied.
- Other examinations performed: clinical signs - Key result
- Sex:
- not specified
- Dose descriptor:
- LD50
- Effect level:
- 3 300 mg/kg bw
- Based on:
- test mat.
- 95% CL:
- >= 2 200 - <= 5 000
- Mortality:
- 1220 mg/kg: no mortality was observed
1730 mg/kg: 1/10 animals died on day 14
2470 mg/kg: 2/10 animals died on day 1
5000 mg/kg: 10/10 animals died on day 1 - Clinical signs:
- 1220 mg/kg: no clinical signs were observed
1730 mg/kg: slight lethargy was observed
2470 mg/kg: ataxia, piloerection, ptosis, and lethargy were observed
5000 mg/kg: flaccid, lethargy, and coma were observed - Gross pathology:
- Necropsy observations:
1220 mg/kg: Lungs, dark areas (3/10); kidneys dark, mottled (2/10); stomach, areas red (5/10); spleen, large (1/10); spleen, dark (1/10)
1730 mg/kg: Lungs, dark areas (1/10); liver, dark (1/10); kidneys dark (1/10); kidneys dark, only 1 kidney, very large (1/10); intestine, areas red (1/10) stomach, areas red (1/10); spleen, dark (1/10).
2470 mg/kg: Lungs, dark areas (9/10); liver, dark (6/10); liver, mottled (2/10), kidneys dark (7/10); kidneys dark, mottled (1/10); intestine, areas yellow (1/10)
5000 mg/kg: Lungs, dark areas (1/10); liver, dark (8/10); intestine, areas red (6/10); spleen, large (1/10); spleen dark (7/10) - Interpretation of results:
- other: not classsified
- Remarks:
- according to the CLP Regulation EC 1272/2008 and its updates
- Conclusions:
- The oral acute LD50 in rats was determined to be 3300 mg/kg. For GHS the substance needs to be classified for xxx toxicity
- Executive summary:
In the study which predated GLP and OECD guidelines, a single oral administration of 1220, 1730, 2470, and 5000 mg/kg test substance to a group of 10 rats (sex and strain unspecified) was investigated for 14 days. Slight to more severe lethargy, ataxia, piloerection, ptosis, lethargy, flaccid, and coma were observed in the different dose groups. At necropsy effects on lungs, liver, kidneys, intestines, stomach, and spleen were observed in the different dose groups. In the 1730 mg/kg dose group one out of 10 animals died on observation day 14. Two out of 10 animals in the 2470 mg/kg dose group and 10 out of 10 animals in the 5000 mg/kg dose group died on day 1. Under the conditions of the test the oral acute LD50 in rats was determined to be 3300 mg/kg.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Quality of whole database:
- The result of the key study presented here The study is considered to be a reliability 2 since it predates GLP but is similar to OECD TG 401.
Additional information
The acute oral acute toxicity of Ylanganate is derived from methyl p-methylbenzoate (see read across justification). In the study on p-methyl benzoate , predating GLP and OECD guidelines but similar to the OECD TG 401 guideline, a single oral administration of 1220, 1730, 2470, and 5000 mg/kg test substance to a group of 10 rats (sex and strain unspecified) was investigated for 14 days. Slight to more severe lethargy, ataxia, piloerection, ptosis, lethargy, flaccid, and coma were observed in the different dose groups. At necropsy effects on lungs, liver, kidneys, intestines, stomach, and spleen were observed in the different dose groups. In the 1730 mg/kg dose group one out of 10 animals died on observation day 14. Two out of 10 animals in the 2470 mg/kg dose group and 10 out of 10 animals in the 5000 mg/kg dose group died on day 1. Under the conditions of the test the oral acute LD50 in rats was determined to be 3300 mg/kg.
In addition to this result information is added from benzyl acetate (Cas no 140 -11 -4) further supporting the LD50 value derived (NTP, 1986). An acute oral toxicity test was performed similar to the OECD 401 guidelines in five F344/N rats per sex and dose. A single dose of the test substance (250, 500, 1000, 2000, or 4000 mg/kg body weight) in corn oil was administered by gavage. All animals were examined twice daily for clinical signs and mortality during the 15-day observation period. All animals that received a dose of 4000 mg/kg body weight were inactive within 2 hours after dosing, and 4/5 males and 2/5 females in these groups died (all on day 2). Necropsies were not performed. The LD50 for Benzyl benzoate was found to be circa 4000 mg/kg bw. In another study with Benzyl acetate (Jenner et al., 1964) was also tested. Benzyl acetate was administered by oral gavage to 10 rats per sex and per dose. Animals were observed for 2 weeks. Clinical signs and mortality were recorded. Under the condition of the test the LD50 was determined to be 2490 mg/kg.
* NTP (National Toxicology Program) (1986) Toxicology and carcinogenesis studies of benzyl acetate (CAS No. 140-11-4) in F344/N rats and B6C3F1 mice (gavage studies). Technical Report Series No. 250.
* Food flavourings and compounds of related structure I. Acute oral toxicity. P.M. Jenner, E.C. Hagan, Jean M. Taylor, E.L. Cook, O.G. Fitzhugh. Food and Cosmetics Toxicology Volume 2, 1964, Pages 327-343
The acute oral toxicity of Ylanganate (CAS #89-71-4) using read across from Methyl p-methylbenzoate (CAS #99-75-2)
Introduction and hypothesis for the analogue approach
Ylanganate is a benzoic acid with a methyl ester group and a methyl group attached at the ortho position. For this substance no acute 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 toxicity of Ylanganate the analogue approach is selected because for a closely related analogue acute oral toxicity information is available which can be used for read across.
Hypothesis: p-Methyl benzoate has similar acute oral toxicity compared to Ylanganate resulting in a similar LD50 because the different position of the methyl group (para-position instead of ortho-position) is not affecting the acute oral LD50.
Available information: The source chemical Methyl p-methylbenzoate has been tested in a well-conducted acute oral toxicity test (similar to OECD TG 401) and the test receives a reliability of Klimisch 2. Under the conditions of the test, the oral acute LD50 in rats was determined to be 3300 mg/kg bw.
Target chemical and source chemical
Chemical structures of the target chemical and the source chemical are shown in the data matrix (Table 1), including physico-chemical properties and toxicological information, thought relevant for acute oral toxicity.
Purity / Impurities
It is not expected that the impurities of the source chemical affect the read-across justification. Ylanganate is a mono-constituent presenting a purity of => 100% and therefore impurities will not affect the acute oral toxicity. In view of Methyl p-methylbenzoate being a mono-constituent there will be no significant impurities relevant for read across (ECHA dissemination site, 2016)
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.
Structural similarities and differences:The Ylanganate (target) and Methyl-p-methyl benzoate (source) are structural isomers. Both substances have a similar backbone and functional groups as they are both benzoic acids with a methyl ester group and a methyl group attached to the benzene ring. The structural difference between Ylanganate and Methyl-p-methyl benzoate is the position of the methyl group; ortho versus para-position for Methyl p-methylbenzoate and Ylanganate, respectively. The difference in position of the methyl group on the benzoic acid is not expected to significantly influence the acute oral toxicity effects.
Toxico-kinetic similarities and differences:
Absorption:
Considering structural features on absorption the para-substitution of the methyl group of Methyl-p-methyl benzoate may be slightly higher compared to the ortho-substitution of Ylanganate because the para-position stabilizes the structure and makes it more planar. More planar structures can diffuse through membranes more easily. Therefore the LD50 of Methyl-p-methyl benzoate is considered conservative. Ylanganate and Methyl-p-methyl benzoate have similar molecular weight and physico-chemical properties indicating similar absorption characteristics (water solubility and log Kow). The slightly higher melting point of Methyl p-methylbenzoate (31 °C) will not influence the acute oral toxicity.
Metabolism:Ylanganate and Methyl p-methylbenzoate are esters which will be cleaved by carboxylesterases and possibly by hydrolysis (Fig. 1) (Wu et al., 2010, Yamada et al., 2013). Ylanganate will metabolise into to 2-Methylbenzoic acid (CAS # 118-90-1) and Methyl p-methylbenzoate will metabolise to 4-Methylbenzoic acid (CAS # 99-94-5). Methanol will be the minor product after cleavage of both substances and therefore the effect will be included in the oral LD50 of Methyl p-methylbenzoate. Thereafter glucuronation can be expected though at high doses benzoic acid could be excreted unchanged as the conjugated pathways may be saturated (EPA HPV, 2002).
Figure1The anticipated metabolic pathway of Ylanganate and Methyl p-methylbenzoate
Experimental data:Next to systemic effectsalso local effects can be relevant for acute oral toxicity. The similar skin and eye irritancy potential between both substances indicate similar gastro-intestinal tract irritation and therefore local effects are not affecting the read across for this acute oral toxicity endpoint.
Remaining uncertainty of the prediction:There is no remaining uncertainty, in view of similarities in structure, toxico-kinetic profile (absorption and metabolism) and reactivity profile between both substances the read across can be applied. The acute oral LD50 of Methyl p-methylbenzoate can be used for read across to Ylanganate.
Data matrix
The data matrix is presented at the end of this document: Table 1.
Conclusions per endpoint for Hazard assessment and C&L
For Methyl p-methylbenzoate a well conducted acute oral toxicity test is available (reliability 2) with a LD50 of 3300 mg/kg bw. In view of the similarity in structure, toxico-kinetics and reactivity this acute oral toxicity value of Methyl p-methylbenzoate can be used for read across to Ylanganate. This results in an LD50 for Ylanganate of 3300 mg/kg bw a dose descriptor is therefore not needed.
Final conclusion on hazard and C&L
Ylanganate does not need to be classified and labelled for acute oral toxicity because the LD50 value is > 2000 mg/kg bw in accordance with regulation EC No. 1272/2008 and its updates.
Data matrix
Table 1. Data matrix of Ylanganate and its source substance methyl p-methylbenzoate
Common names |
Ylanganate |
Methyl p-methylbenzoate |
Chemical structures |
||
CAS no |
89-71-4 |
99-75-2 |
Empirical formula |
C9H10O2 |
C9H10O2 |
Physico-chemical data |
||
Molecular weight |
150.2 |
150.2 |
Physical state |
liquid |
solid |
Melting point, °C |
< -20 |
31 |
Boiling point, °C |
216.3 |
224 |
Vapour pressure, Pa |
12.9 at 23°C |
8.2 at 20°C (calculated) |
Water solubility, mg/l |
2630 at 22°C |
398 at 20°C |
Log Kow |
3.0 |
2.7 |
Human health endpoints |
||
Acute oral tox in mg/kg bw LD50(OECD TG 401) |
Read across from |
3300 mg/kg bw (rat) (M.B. Research laboratories, Inc. 1977) |
Skin irritation |
A skin irritant (OECD TG 439) |
A skin irritant |
Eye irritation |
An eye irritant (OECD TG 438)
|
An eye irritant
|
References
Methyl-p-methyl benzoate, ECHA dissimination site,http://echa.europa.eu/registration-dossier/-/registered-dossier/5309/1, site visited, April 2016.
Wu, S., Blackburn, K., Amburgery, J., Jaworska, J., and Federle, T., 2010, A framework for using structural, reactivity, metabolic and physico-chemical similarity to evaluate the suitability of analogs for SAR-based toxicological assessments, Regul. Toxicol. Pharmacol., 56, 67-81.
Yamada, T., Tanaka, Y., Hasegawa, R., Sakuratani, Y., Yamada, J., Kamata, E., Ono, A., Hirose., A., Yamazoe, Y., Mekenyan, O., Hayashi, M., 2013, A category approach to predicting the repeated-dose hepatotoxicity of allyl esters, Reg. Toxicol. Pharmacol, 65, 189-195.
Justification for classification or non-classification
The acute oral toxicity of Ylanganate results in an LD50 of 3300 mg/kg bw and therefore the substance does not need to be classified for acute oral toxicity according to EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 an its updates.
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