Registration Dossier
Registration Dossier
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EC number: 433-470-4 | CAS number: -
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
Vanillin was considered to have no teratogen effects
In a valid OECD 421 study no indication of toxic effect on reproductive function or developmental toxicity were observed with 1,6-hexanediol.
Information on the two source substances will represent a similar or worse case than the target substance.
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- 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:
- test procedure in accordance with national standard methods with acceptable restrictions
- Justification for type of information:
- 1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This report addresses the use of a combination of data for hexane-1,6-diol (CAS No. 629-11-8) and for vanillin (CAS No. 121-33-5) to address the reproductive/developmental toxicity screening data requirement for 1,6-bis(methoxybenzoyloxy)hexane (CAS No. 390359-18-9) in an analogue read-across approach. The basis for this read-across approach is that, upon oral administration, the target substance is expected to hydrolyse prior to absorption into hexane-1,6-diol and p-anisic acid (CAS No. 100-09-4). The reproductive/developmental toxicity of the hexane-1,6-diol metabolite will be assessed using information on hexane-1,6-diol, and the reproductive/developmental toxicity of the p-anisic acid metabolite will be assessed using information on vanillin, to which it is structurally very similar.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See attached justification for full details
PURITY/IMPURITIES
The target substance is known to be of high purity (typically 96.8 % w/w), and to contain two known impurities. The first known impurity, typically present at 1.72 % w/w, is the mono-ester analogue of the target substance, which is an intermediate hydrolysis product of the target substance, and which is itself expected also to hydrolyse to the same products as the target substance. The second known impurity, typically present at 0.52 % w/w, is one of the final hydrolysis products of the target substance. On this basis, the source substances effectively represent typically >99 % w/w of the target substance. The purities of the samples of source material that were tested are not specifically known, but it is assumed that they would not have been sufficiently impure as to substantially affect the study results. On this basis, the applicability of the data on the source substance to the target substance is not expected to be compromised by the presence of impurities in either substance.
The p-anisic acid metabolite and vanillin source substance are both oxygenated benzene compounds, carrying both carbonyl and methoxy substituent groups, and are identified as possessing 50.2% structural similarity in the ChemIDplus advanced database, which is one of ECHA’s recommended data sources for analogue identification. They differ only in that, in p-anisic acid the carbonyl group is the carboxylic acid, and is positioned para to the methoxy group, whereas in vanillin the carbonyl group is the aldehyde and is positioned meta to the methoxy group and para to a hydroxy group.
3. ANALOGUE APPROACH JUSTIFICATION
See attached justification for full details
The basis for this read-across approach is that the target substance is a bis carboxylic ester that, upon oral administration, is expected to metabolise, hydrolytically and prior to absorption, into hexane-1,6-diol and p-anisic acid.
4. DATA MATRIX
See attached justification for full details - Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- read-across: supporting information
- Specific details on test material used for the study:
- 1,6-Bis(methoxybenzoyloxy)hexane value is read-across from supporting 1,6-hexanediol and vanillin
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 316 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Remarks:
- Vanillin
- Sex:
- female
- Basis for effect level:
- clinical signs
- Remarks on result:
- other: based on the experimental data for vanillin (NOAEL = 250 mg/kg bw) and the amount of p-anisic acid metabolite produced during metabolism.
- Dose descriptor:
- NOEL
- Generation:
- F1
- Effect level:
- ca. 633 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Remarks:
- Vanillin
- Basis for effect level:
- other: teratogenicity
- Remarks on result:
- other: based on the experimental data for vanillin (NOEL = 500 mg/kg bw) and the amount of p-anisic acid metabolite produced during metabolism.
- Reproductive effects observed:
- no
- Conclusions:
- Vanillin was considered to have no teratogen effects
In a valid OECD 421 study no indication of toxic effect on reproductive function or developmental toxicity were observed with 1,6-hexanediol.
Information on the two source substances will represent a similar or worse case than the target substance.
Reference
The 1,6-hexanediol metabolite is clearly identical to the first source substance, and the amount produced will be equivalent to 31% w/w of the dose of target substance.
The p-anisic acid metabolite is structurally very similar to the second source substance, and the amount produced will be equivalent to 79% w/w of the dose of target substance.
The sum of the above values exceeds 100% due to the mass added by the incorporation of water of hydrolysis.
As such, based on the experimental data for vanillin (NOEL = 500 mg/kg bw), the NOEL of the target substance for developmental toxicity can be predicted to be approximately 633 mg/kg bw. The toxicity data on the vanillin source substance will represent a very similar or slightly worse case than, and provide a sound basis for a slightly conservative assessment of, the toxicity of the target substance.
Effect on fertility: via oral route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 633 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
HYPOTHESIS FOR THE ANALOGUE APPROACH
This report addresses the use of a combination of data for hexane-1,6-diol (CAS No. 629-11-8) and for vanillin (CAS No. 121-33-5) to address the reproductive/developmental toxicity screening data requirement for 1,6-bis(methoxybenzoyloxy)hexane (CAS No. 390359-18-9) in an analogue read-across approach. The basis for this read-across approach is that, upon oral administration, the target substance is expected to hydrolyse prior to absorption into hexane-1,6-diol and p-anisic acid (CAS No. 100-09-4). The reproductive/developmental toxicity of the hexane-1,6-diol metabolite will be assessed using information on hexane-1,6-diol, and the reproductive/developmental toxicity of the p-anisic acid metabolite will be assessed using information on vanillin, to which it is structurally very similar.
10 female rats per group were exposed one week before mating until 4 days post partum to 0, 125, 250, 500 mg/kg bw/day of Vanillin. Maternal toxicity had been reported with only few details: death, clinical signs and change in body weight and feed consumption. The NOAEL maternal was considered to be 250 mg/kg bw. No effect on pups were reported and the NOEL for teratogenicity was the highest dose tested 500 mg/kg bw.
In a valid OECD 421 study no indication of 1,6-hexanediol toxic effect on reproductive function or developmental toxicity were observed.
The 1,6-hexanediol metabolite is clearly identical to the first source substance, and the amount produced will be equivalent to 31% w/w of the dose of target substance.
The p-anisic acid metabolite is structurally very similar to the second source substance, and the amount produced will be equivalent to 79% w/w of the dose of target substance.
The sum of the above values exceeds 100% due to the mass added by the incorporation of water of hydrolysis.
As such, based on the experimental data for vanillin (NOEL = 500 mg/kg bw), the NOEL of the target substance for developmental toxicity can be predicted to be approximately 633 mg/kg bw. The toxicity data on the vanillin source substance will represent a very similar or slightly worse case than, and provide a sound basis for a slightly conservative assessment of, the toxicity of the target substance.
Effects on developmental toxicity
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
Vanillin was considered to have no teratogen effects
In a valid OECD 421 study no indication of toxic effect on reproductive function or developmental toxicity were observed with 1,6-hexanediol.
Information on the two source substances will represent a similar or worse case than the target substance.
Additional information
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
