Butanedioic acid, 2-hydroxy-, 1,4-bis[5,7,7-trimethyl-2-(1,3,3-trimethylbutyl)octyl] ester

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: expert statement

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

other: expert statement

Title:

Unnamed

Year:

2008

Report date:

2008

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

expert statement

Test material

Test material information

Constituent 1

Reference substance name:

1,4-bis[2-(4,4-dimethylpentan-2-yl)-5,7,7-trimethyloctyl] 2-hydroxybutanedioate

EC Number:

807-422-1

Cas Number:

66918-01-2

Molecular formula:

C40H78O5

IUPAC Name:

1,4-bis[2-(4,4-dimethylpentan-2-yl)-5,7,7-trimethyloctyl] 2-hydroxybutanedioate

Applicant's summary and conclusion

Executive summary:

The data presented in the present dossier only allow for a qualitative assessment of the toxicokinetic behaviours of the test item.       

SALACOS 222 was tested for acute toxicity by oral and dermal application, for subacute oral toxicity and for irritant effects on skin as well as for skin sensitization in the Local Lymph node assay (LLNA) Test. Mutagenicity was assessed in an Ames test and in a chromosomal aberration assay.

In the test for acute oral toxicity, the substance was applied to three female HanRcc:WIST (SPF) rats at a concentration of 0.2 g/mL and administered at a dosinf volume of 10 mL/kg and 2000 mg/kg body weight. All animals survived until the end of the study period but a slight ruffled fur was observed in two females 2 to 3 hours post-dose.

Therefore, the median lethal dose of SALACOS 222 after single oral administration to female rats, observed over a period of 14 days is: LD50 (female rat): greater than 2000 mg/kg bw.

In the dermal toxicity study, SALACOS 222 was applied to five male and five female HanRCC:WIST (SPF) rats as delivered from the sponsor at a volume dosage of 2.18 mL/kg and 2000 mL/kg by dermal application. All animals were necropsied and examined macroscopically. No death occured during the study. No clinical signs were observed during the course of the study. The body weight of the animals was within the range of commonly recorded for this strain and age. The median lethal dose of SALACOS 222 after single dermal administration to both sexes, observed over a period of 14 days is: LD50 (rat): greater than 2000 mg/kg body weight.

In the skin irritation; the test item did not elicit any skin reactions at the application site of any animal at any of the observation times (all scores 0). The individual mean score for erythema/eschar and oedema for each of the three animals was therefore 0. SALACOS 222 is considered to be "not irritating" to rabbit skin.

In the eye irritation study; the instillation of SALACOS 222 into the eye resulted in mild, early-onset and transient ocular changes, such as slight reddening of the conjunctivae and sclera. These effects were reversible and were no longer evident 24 hours after treatment and no clinical signs were observed.

Thus, the test item did not induce significant or irreversible damage to the rabbit eye. SALACOS 222 is considered to be "not irritating" to the rabbit eye.

In the skin sensitisation assay, based on the standard sets, SALACOS 222 is regarded as a sensitizer in the LLNA if the exposure to one or more test concentration resulted in 3 -fold or greater increase in incorporation of 3HTdR compared with concurrent controls, as indicated by the Stimulation Index (S.I.). In this study Simulation Indices (S.I.) of 3.20, 4.23, and 6.75 were determined with the test item at concentrations of 25, 50, and 100 % in acetone: olive oil (4:1), respectively. The test item SALACOS 222 was found to be a skin sensitizer. Since the S.I. was increased above the threshold of 3 even at the lowest tested concentration an EC3 value could not be derived.

Based on the results of this five-day dose range-finding study, it is proposed that subacute toxicity study (28 days) SALACOS 222 was administered continously by gavage to rats at the nominal oral administration of SALACOS 222 to Wistas rats at doses of 50, 200, and 1000 mg/kg/day for 28 days resulted in no clinical signs of toxicological relevance were noted during daily observations, weekly detailed behavioral observations (week 1 -3) of during the functional observational battery (week 4). At 1000 mg/kg/day, two animals died before scheduled necropsy: male and female on day 7 and day 23 was found dead of treatment respectively. All other animals survived until scheduled necropsy. During the latter observations, no differences in grip strength or mean locomotor activity were noted at any dose level. Mean food consumption and body weight development were unaffected. Neither hematology nor clinical biochemistry parameters revealed any differences of toxicological relevance. Changes in the mean absolute and relative thymus weights were seen in males, but in the absence of histological correlation, the changes were considered to be incidental. Based on the results of this study, 1000 mg/mg bw/day of SALACOS 222 was considered to be the no-observed-adverse-effect-level (NOAEL). The 28 days subacute toxicity will be completed

The bacterial reverse mutagenic assay showed that the test item did not induce gene mutations by base pair changes of frameshifts in the genome of the strains used. Therefore, SALACOS 222 is considered to be non-mutagenic in this Salmonella typhimurium strains TA 1535, TA 1537, TA 98, and TA 100.

In the chromosome aberration test (in vitro), SALACOS 222, did not induce structural chromosome aberrations in V79 cells (Chinese hamster cell line). Therefore, it can be stated that under the experimental conditions reported, the test item SALACOS 222 did not induce structural chromosome aberrations in V79 cells (Chinese hamster cell line), when tested up to precipitating concentrations.

In the Ames study, there was also no tendency of higher mutation rates with increasing concentrations in the range below the generally acknowledged border of biological relevance. SALACOS 222 did not induce gene mutations by base pair or frame shifts in the genome of the strains used.

No other indications on the toxicological behaviour of SALACOS 222 could be derived from the results of the available studies.