Registration Dossier

Diss Factsheets

Administrative data

Description of key information

A NOAEL for systemic toxicity of 1000 mg/kg bw/day was established for Phosphoric acid, C12-18-alkyl esters, potassium salts based on read-across information from an OECD 422 guideline study with Phosphoric acid, dodecyl ester, sodium salt.

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Refer to attached document
Reason / purpose for cross-reference:
read-across source
Key result
Dose descriptor:
NOAEL
Remarks:
systemic effects
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: No substance related systemic effects
Key result
Dose descriptor:
LOEL
Remarks:
local effects
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: at 250 mg/kg bw/day: intendation of the anterior stomach, at 500 and 1000 mg/kg bw/day: rough mucosa and/or white foci in the anterior stomach, histologically: erosion/ulcers, thickening of the anterior stomach mucosa, edema in submucosal tissue
Key result
Dose descriptor:
NOEL
Remarks:
local effects
Effect level:
125 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male
Basis for effect level:
other: edema in the submucosal tissue of the anterior stomach
Key result
Dose descriptor:
NOEL
Remarks:
local effects
Effect level:
62.5 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
female
Basis for effect level:
other: edema in the submucosal tissue of the anterior stomach
Critical effects observed:
not specified
Conclusions:
A NOAEL for systemic toxicity of 1000 mg/kg bw/day was established for Phosphoric acid, C12-18-alkyl esters, potassium salts based on read-across information from an OECD 422 guideline study with Phosphoric acid, dodecyl ester, sodium salt.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Read-across from a study according to OECD 4422 Guideline with GLP

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

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Forestomach findings related to an irritant activity of the test item are common findings in rat gavage studies. The stomach of rats is anatomically different from the human stomach. The rat stomach consists of two anatomically distinct parts of approximately equal size: a non-glandular forestomach and a glandular stomach. The forestomach is connected to the oesophagus at the gastro-oesophageal junction, and is clearly separated from the glandular stomach by a distinct border called the limiting ridge. The forestomach is not present in humans. The main function of the rat forestomach is storage and trituration of ingested food prior to digestion in the glandular stomach. The forestomach is a holding compartment and due to this function a long exposure time to orally - especially by gavage as bolus dose - administered doses in this organ occurs. Thus, an irritant test item can easily take effect at the forestomach squamous epithel.

 

Additional information

Available data from Phosphoric acid, dodecyl ester, sodium salt were used to evaluate effects after repeated exposure of Phosphoric acid, C12-18-alkyl esters, potassium salts.

In a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test according to OECD guideline 422 Phosphoric acid, dodecyl ester, sodium salt was administered 12 Sprague-Dawley rats/sex/dose daily by oral gavage at dose levels of 0 (control), 250, 500, 1000 mg/kg bw/day.

The males were exposed 14 days before mating, through the mating period, up to 1 day before termination (42 days in total). The females were exposed 14 days before mating, through the mating and gestation period, up to day 4 of lactation (42 to 45 days in total). Additional 5 males and 5 females were added to the control group and 1000 mg/kg group as a recovery group to examine the reversibility of the effects. Those animals were observed for another 14 days.

Administration of Phosphoric acid, dodecyl ester, sodium salt had no effect on any of the following: general condition, results of function tests, grip strength, spontaneous motor activity, body weight, food consumption, or the results of urinalysis (including water intake), or haematological tests.

 

A mild but significant increase of the serum ALT in males of the highest dose group at the end of the administration period was not accompanied by histopathological findings and was within the range of physiological variations in historical controls. Therefore it was judged, that these findings were not of toxicological relevance.

 

In the pathological examination performed at the end of the administration period, gross observation showed indentation of the forestomach in the animals of the 250 mg/kg and higher dose groups, and rough mucosa and/or white foci in the anterior stomach in the animals of the 500 mg/kg and higher dose groups. Histological observation showed erosions/ulcers of the forestomach, thickening of the forestomach mucosa, and edema in the submucosal tissue. In the pathological examination performed at the end of the recovery period, only one male animal of the highest dose group showed moderate thickening of the anterior stomach mucosa.

 

A functional equivalent to the rat forestomach is missing in humans. A histological similar in humans is the oesophagus, because the epithelium of the human oesophagus is morphologically of the same type as the forestomach epithelium of rats. However, tissue exposure in the human oesophagus is likely to be minimal compared to tissue exposure in the rat forestomach since the epithelial contact is much shorter in the human oesophagus compared to the rat forestomach and it seems very unlikely that exposure to concentrations far below those having an irritating potential is hazardous to man. Further on, a constantly repeated oral bolus ingestion of substances like the PAEs, is very unlikely. When test items are administered with the feed or the drinking water – exposure procedures more realistic to the exposure situation of humans –, forestomach effects do not occur.

 

The NOAEL for systemic toxicity is 1000 mg/kg bw/day

 

Justification for read-across

Evaluation of structure-activity relationship is based on data from structural similar substances with the same basic structure, salts of phosphoric acid alkyl ester, varying mainly in the chain length of fatty acid moiety. 

A detailed justification document for the read-across is attached in the respective target records of IUCID.

Justification for classification or non-classification

Repeated dose toxicity of Phosphoric acid, C12-18-alkyl esters, potassium salts was assessed based on data from a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening study with the read-across substance Phosphoric acid, dodecyl ester, sodium salt.

 

The no-observed-adverse-effect-level (NOAEL) for systemic toxicity was considered to be 1000 mg/kg/day, the highest tested dose.

Evaluating information from the sub-acute toxicity study a classification with STOT-RE according to GHS Regulation EC No 1272/2008 for Phosphoric acid, C12-18-alkyl esters, potassium salts is considered not warrant.