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Administrative data

Description of key information

No data available for the diisobutyl esters, however read-across data available for the dimethyl esters:

- Oral route (14 days, rat): NOEL = 10000 ppm (equivalent to 980 mg/kg bw)

- Dermal route (14 days, rat): NOEL (systemic toxicity) = 1000 mg/kg bw

- Inhalation (90 days, rat):       NOEC (respiratory local toxicity) = 50 mg/m3

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
2 500 mg/kg bw/day
Study duration:
chronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
400 mg/m³
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat

Additional information

There are no data available for the diisobutyl esters of succinic acid and glutaric acid.

There is a Klimisch reliability 4 study available for the diisobutyl adipate however. This study looked at repeated dose toxicity via the oral route in rats (wistar, male and female) over the period of 24 months with interim sacrifices at 3, 6, and 12 months. Three dose levels were used, 0.1, 0.5 and 2.5% in the diet (approx equivalent to 100, 500 and 2500 mg/kg bw). IN this study there were no treatment related effects observed at any dose up to 12 months dosing. Unfortunately due to high mortality across all groups including control, information for the 24 month sacrifice was limited to 8 animals in the mid dose group and 2 in the control group. As such it was not considered in the oveall judgement. It should be noted that the mortality observed was not attributed to test material and that in the animals surviving at 24 months in the mid dose group there were no signs of test material related adverse effects. Observations in this study were limited to bodyweight, organ weight and pathology of a limited selection of organs. Despite the limited reporting/scope of the study it appears that under the conditions of the study, diisobutyl adipate was of very low toxicity. This is consistent with data comng from the methyl esters of these acids.

In order to support the hazard assessment of the diisobutyl esters, additional read across to the methyl esters of the same acids is used to fill this endpoint. The justification for this is as follows. In the toxicokinetic section it is indicated that once these esters enter the body they are rapidly broken down to the constituent acids and alcohols. As such, the toxicity of both dimethyl and diisobutyl esters will be driven by the toxicity of the acids and alcohols released rather than the parent compound.

 

The repeat dose toxicity of methanol from an oral 90 day gavage study gives a no effect level of 500 mg/kg and a low effect level of 2500 mg/kg bw in rats. A 90 day oral toxicity study in rats using isobutanol gave a no effect level of 1450 mg/kg bw. Considering the amount of methanol in dimethyl esters and Isobutanol in diisobutanol esters, both alcohols would be present at levels far below their NOELs in a limit dose of 1000 mg/kg of the esters. Therefore the alcohols would not be expected to contribute to the oral toxicity of either the dimethyl or diisobutyl esters.

 

Due to the higher molecular weight of isobutanol, a dose of isobutyl esters will contain less of the acids compared to the same dose of methyl esters. As such if the acids are driving the toxicity, the isobutyl esters would be expected to be less toxic. Therefore it is considered acceptable to use repeat dose data generated on methyl esters to support the hazard assessment for isobutyl esters.

Repeated dose toxicity data for the methyl esters is available for all three routes of exposure: oral (for 14 days), dermal (for 14 days) and inhalation (for up to 90 days).

 

Oral route:

One study of reliability 4 according to Klimisch criteria (due to limited documentation) is available and was selected as a supporting study. In this sub-acute study, dibasic ester blend was administered in feed at 10000, 20000 or 50000ppm (equivalent to 980, 1841 or 3958 mg/kg bw/day, respectively, based on average food consumption and body weight changes over the dosing period). Initial and sporadic decreases in body weight and body weight gain were observed at 20000 and 50000ppm. At the end of a 2-week recovery period, body weight had returned to normal, except at 50000ppm where it was still 7% lower than in controls. The lower bodyweight in the mid and high dose animals appears to be related more to the palatability of the feed rather than a general toxic effect. This is demonstrated by the decreased food consumption in the mid and high dose groups. As such it is likely that the mid dose tested did not produce systemic toxicity and can be considered as a NOAEL (since bodyweight recovered after cessation of test material administration). In the highest dose tested the bodyweight increased in a consistent manner after exposure was terminated, but the animals did not acheive a weight similar to the mid, low and control dose groups. This is not necessarily evidence of systemic toxicity and could still be attributed to the decreased food consumption during the 14 day study period.

 

Dermal route:

One study of reliability 1 according to Klimisch criteria is available and was selected as a key study. In this subacute study, dibasic ester blend was administered dayly at 0, 100, 300 or 1000 mg/kg bw. There was a low incidence of local findings illustrative of minimal to mild dermal irritation as erythema and/or edema (graded as very slight) and an increased incidence of focal eschar formation (scabbing) or desquamation in all groups applied the dibasic ester blend, starting around the end of the first week of dosing. No test article-related findings were seen in clinical observations, food consumption, clinical pathology, urinalyis, ophthalmology or anatomic pathology. The NOEL for systemic toxicity was therefore 1000 mg/kg over 14 days of dermal application to rats.

Considering the effects observed on the skin in this study (local irritation) it might be considered appropriate to calculate a Dermal DNEL for local effects. However this has not been done for the following reasons:

1) the substance is a solvent and so repeated exposure might be expected to be irritating to the skin under the occlusive conditions of the study due to the drying and de-fatting of the skin by the solvent.

2) the study protocol used a 6 hour occlusive exposure to the skin for 14 days. Such an exposure condition is designed to ensure the best take up of the compound through the skin, however it does not represent realistic exposure conditions for a worker or consumer.

Taking these into account it is argued that the LOEL for irritation from this study is not relevant to a human exposure scenario and therefore cannot be used as the basis for the calculation of a local DNEL.

 

Inhalation route:

TWO studies are available. A 90-day study on the individual components of dibasic ester blend (dimethyl glutarateat 10,50 or 400 mg/m3, dimethyl succinate at 400 mg/m3 and dimethyl adipate at 400 mg/m3) of reliability 1 according to Klimisch cotation criteria was selected as the key study. In this study, the main findings consisted of degeneration/atrophy of the olfactory mucosa of the dorsal meatus or dorsomedial aspect of the dorsal endoturbinate, and focal respiratory metaplasia of the olfactory mucosa of the dorsal meatus at 400 mg/m3 of all three esters. Decreases in serum testosterone concentrations were also noted in males exposed to 50 or 400 mg/m3 dimethyl glutarate. Decreases in serum luteinizing hormone (LH) concentrations were observed in males exposed to 400 mg/m3 dimethyl glutarate. Serum estradiol concentrations were also decreased in females exposed to 400 mg/m3 dimethyl succinate. The hormone level changes occurred together with significantly increased epididymal sperm counts in males exposed to 50 or 400 mg/m3 dimethyl glutarate or 400 mg/m3 dimethyl succinate. The NOEC for systemic toxicity was therefore set at 10mg/m3 based on decreases in hormone levels and increased epididymal sperm counts at 50 mg/m3 and above. However, those hormonal changes and sperm counts may be considered irrelevant as they were not observed in a similar study using the dibasic ester blend (see also section "7.8. Toxicity to reproduction" for further details). As such it is considered appropriate to take the highest dose (400 mg/m3) as a systemic NOAEC, and the 50 mg/m3 DMG dose level as the NOEC for local effects in the respiratory tract.

 

In a similar 90-day study, of reliability 1 according to Klimisch cotation criteria and selected as a supporting study, the concentrations tested were 20, 76 and 390 mg/m3 of dibasic ester blend. Olfactory epithelial lesions similar to those seen in the key study were observed at 76 and 390 mg/m3 in both genders, but also in females exposed to 20 mg/m3 and control females. A peer-review of nasal tissues by certified pathologists was performed (Ref. Pathology peer review of nasal tissue slides from two 90-day studies on behalf of Invista SARL, Experimental Pathology Laboratories, Inc., EPL Report No.: 851-001,18 September 2009). The peer review showed that olfactory epithelial lesions in the control females were seen with a roughly similar incidence and severity than in the females exposed to 20 mg/m3. This similarity between 20 mg/m3 and control females casts doubt on whether these lesions at this level of exposure are clearly related to the test substance. Furthermore, several male and female rats showed squamous metaplasia of the respiratory epithelium. This change which was clearly unrelated to the test substance may be a confounding factor in evaluating low-dose effects. Therefore, the study is regarded as inconclusive as to the respiratory local changes and 20 mg/m3 is likely a NOEC in this study, and 76 mg/m3 likely a LOAEC, which is consistent with the NOEC of 50 mg/m3 determined in the key study. The NOAEC for systemic toxicity from this study appears to be the highest dose tested (390 mg/m3) due to the minimal and non-adverse findings observed in the study at this dose level. This is consistent with the NOAEC for systemic effects observed in the key study.

 

Overall, the top dose tested in both studies appears to be the NOAEL for systemic effects. In the absence of any adverse treatment related systemic toxicity it is not considered appropriate to derive systemic DNELs. This is consistent with data from the diisobutyl adipate.

Irritating effects on the respiratory epithelium, and atrophy/degeneration of the nasal and olfactory epithelium are critical effects consistently observed with various ester derivatives (butyl acrylate, methyl acrylate, methylmethacrylate, methyl acetate, ethyl acrylate, lactate esters) These effects are thought to be related to a mechanism common between esters (including dibasic esters) which involves hydrolysis by unspecific carboxylesterases located in the nasal/olfactory epithelium to release corresponding acids and alcohols. However, there are well-known differences in the anatomy and physiology of the nasal and olfactory epithelia between rats and humans. Although some variability in the experimental results of carboxylesterase activity exists, depending on the methodology and the substrate used, there is a general trend supporting lower nasal esterase activity towards esters from human tissues compared to those from rat tissues.(Ref. Frederick C.B. et al. Use of a hybrid computational fluid dynamics and physiologically based inhalation model for interspecies dosimetry comparisons of ester vapours. Toxicol Appl Pharmacol. 183(1): 23-40, 2002). The respiratory local effects should therefore be of a lower concern in the human situation.These effects are thought to be overpredictive in the rat model as compared to humans, because of the morphological and physiological differences.

Even though these local effects are considered to be of lower reference to humans, it is considered appropriate to derive a DNEL for local effects (inhalation). When extrapolating from the methyl esters to the isobutyl esters in calculating a local effects DNEL, a factor of 2 will be taken into consideration to account for the difference in irritancy between isobutanol and methanol (isobutanol is more irritating to the respiratory tract than methanol).

 

Hormone levels and sperm findings are further discussed in the relevant section (See Discussion of the Toxicity to Reproduction section).

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: other

Justification for classification or non-classification

Based on the classification criteria of Annex VI Directive 67/548/EEC, no R37 classification is warranted because no signs of immediate or massive upper respiratory tract irritation are observed following inhalation of dibasic ester blend in rats or humans.

 

Based on the classification criteria of UN/EU GHS, 'STOT – single exposure Cat. 3' classification is NOT warranted because nasal lesions appear to be subchronic effects in rats. No 'STOT – repeated exposure' classification is warranted because the toxicological relevance of rat findings to humans is limited based on interspecies differences.

 

No classification is warranted based on repeat-dose experimental data on dibasic esters.