Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

Not sensitising by structural similarity to acetyl tributyl citrate

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Remarks:
Predates Commission Regulation (EU) 2016/1688
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:
comparable to guideline study with acceptable restrictions
Justification for type of information:
An analogue approach is used for the hazard assessment of several human health endpoints. The hypothesis for the analogue approach is that data can be read-across from data-rich substances, namely acetyl tributyl citrate (ATBC, CAS 77-90-7), acetyl triethyl citrate (CAS 77-89-4) and triethyl citrate (TEC, CAS 77-93-0) to acetyl trihexyl citrate (ATHC, CAS 24817-92-3). The analogue approach is based on common breakdown products via physical and biological processes, and similar functional groups, according to Annex XI, Section 1.5, of Regulation EC No. 1907/2006. Read-across to ATHC is indicated in order to avoid unnecessary in vivo testing according to Article 25 of Regulation EC No. 1907/2006.
The analogue approach to evaluating the safety of triethyl citrate is adopted here, reflecting the approach used by various expert panels and authoritative bodies in their safety assessment of TEC, included JECFA, EFSA, U.S. FDA, EPA and CIR. The use of analogues for hazard evaluation is justified (Scenarios 1 and 2 of the RAAF, 2015) because the substances have common breakdown products via physical and biological processes, which reflects the similar functional groups in their chemical structure. The proposed analogues have similar functional groups, including: a citric acid (tricarboxylic acid) backbone, three short-chain alkyl esters, and an acetyl group (except for TEC). Other than the acetyl group, there are no other functional groups which may introduce additional toxicities. The substances display similar classification based on similar toxicities.
The target substance is expected to have essentially the same effect in the toxicity test/endpoint as does the source substance. Dose descriptors obtained for derivation of a DNEL are adequate and appropriate, and do not underestimate the hazards of the registered substance.
This information is adequate to fulfill the data requirements of Annex IX, to be the basis for classification and labelling decisions, and for risk assessment.
Reason / purpose for cross-reference:
read-across source
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Principles of method if other than guideline:
predates establishment of OECD 406 guideline
GLP compliance:
not specified
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The in vivo study was commissioned prior to the passage of Commission Regulation (EU) 2016/1688 amending Regulation (EC) No. 1907/2006 on these testing obligations.
Species:
guinea pig
Route:
intradermal and epicutaneous
Vehicle:
other: 0.01% Dobs/saline
Concentration / amount:
Induction: 2.5% in 0.01% Dobs/saline.
Induction-dermal: (occlusive patch application) with 100%.
Challenge (covered patch application) with 50% in absolute ethanol
Day(s)/duration:
21
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: ethanol
Concentration / amount:
Induction: 2.5% in 0.01% Dobs/saline.
Induction-dermal: (occlusive patch application) with 100%.
Challenge (covered patch application) with 50% in absolute ethanol
Day(s)/duration:
21
Adequacy of challenge:
highest non-irritant concentration
No.:
#2
Route:
epicutaneous, occlusive
Vehicle:
other: ethanol
Concentration / amount:
50%
Day(s)/duration:
7
Adequacy of challenge:
highest non-irritant concentration
No.:
#3
Route:
epicutaneous, occlusive
Vehicle:
other: ethanol
Concentration / amount:
50%
Day(s)/duration:
7
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
10 (one dose group)
Details on study design:
Ten guinea pigs according to the Magnusson-Kligman guinea pig maximization test method. Sensitization was induced by intradermal injections of both test substance and Freunds Adjuvant and the induction process supplemented seven days later by the test substance applied to the shoulder injection sites (2 in x 2 in) under occlusion (adhesive plaster, Poroplast, wound around trunk). The animals were challenged by occluded patch 14 days later. Second and third challenges were made in a weekly interval.
Challenge controls:
negative controls: 4 vehicle treated and 4 non-treated
Positive control substance(s):
no
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
50%
No. with + reactions:
2
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
50%
No. with + reactions:
3
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Remarks:
One animal killed in extremis
Key result
Reading:
rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
50% induction
No. with + reactions:
2
Total no. in group:
9
Remarks on result:
no indication of skin sensitisation
Remarks:
same results at 48 h
Key result
Reading:
other: Rechallenge #2
Hours after challenge:
24
Group:
test chemical
Dose level:
50%
No. with + reactions:
2
Total no. in group:
9
Remarks on result:
no indication of skin sensitisation
Remarks:
all resolved at 48 h

Animal 2 was killed in extremis due to an ulcerated neck application site. The positive reactions were mild and no more extreme than reactions in vehicle and/or untreated controls. Essentially none was considered a true positive.

Interpretation of results:
GHS criteria not met
Remarks:
GHS
Conclusions:
The test substance, ATBC, showed no evidence of sensitisation in guinea pigs, under the conditions of a guideline Magnusson Kligman Maximisation Test. Two rechallenges were undertaken on the test animals in order to verify the absence of sensitisation. This data is appropriate for read-across to the larger ester,acetyl trihexyl citrate, rather than data from smaller esters, TEC or ATEC.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

ATBC was non-sensitising in a GPMT. In the same experiment under the same conditions, smaller esters were postitive (triethyl citrate, acetyl triethyl citrate). It is likely that larger esters are likely less bioavailable, resulting in less risk for sensitisation.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

A thorough in vivo study on dermal sensitisation was performed on a series of alkyl citrate esters. The smaller chain esters were sensitisers, but the larger acetyl tributyl citrate was clearly not sensitising in three dermal challenges of the substance. The most appropriate read-across analogue for ATHC is the larger ester, ATBC, which is less likely bioavailable via the dermal route. It is considered non-sensitising and is not classified according to Regulation EC No. 1272/2008.

.