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Description of key information

- 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
980 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
50 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

The repeat-dose toxicity of dibasic esters, a structurally similar substance, was tested in rats using all conventional routes of exposures: oral (for 14 days), dermal (for 14 days) and inhalation (for up to 90 days). Dimethyl glutarate was tested individually in a 90-day inhalation study.

 

Oral route:

One oral study is available and was selected as a supporting study based on an assigned Klimisch score of 4 (due to limited documentation). In this sub-acute study, dibasic ester blend was administered in feed at 10000, 20000 or 50000 ppm (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 50000 ppm. At the end of a 2-week recovery period, body weight had returned to normal, except at 50000 ppm 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 (20000 ppm equivalent to 1841 mg/kg) 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 there was not a full recovery of body weight after 14 days so it is not possible to rule out some systemic toxicity not otherwise apparent from the other parameters assessed in the study. Due to the drop in body weight the overall No Observed Effect Level is the lowest dose of 10000 ppm (equivalent to 980 mg/kg bw).

 

Dermal route:

One dermal study (Dashiell, 1981) is available and was selected as a key study based on a Klimisch score of 1. In this sub-acute study, dibasic ester blend was administered daily 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, urinalysis, ophthalmology or anatomic pathology. The NOEL for systemic toxicity was therefore 1000 mg/kg over 14 days of dermal application to rats.

 

Inhalation route:

Three 90-day inhalation studies and one 14-day inhalation study are available. A 90-day study (Bamberger, 2000) on dimethyl glutarate at 10, 50 or 400 mg/m3 was selected as the key study based on a Klimisch score of 1. 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. Statistically significant 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. The hormone level changes occurred together with statistically significantly increased epididymal sperm counts in males exposed to 50 or 400 mg/m3 dimethyl glutarate. The NOEC for systemic toxicity was therefore set at 10 mg/m3 based on decreases in hormone levels and increased epididymal sperm counts at 50 mg/m3 and above. The toxicological significance of these statistically significant changes was unclear, as a decrease in male sex hormones should have resulted in a reduction of epididymal sperm counts, and yet the opposite was observed. In addition, none of these effects were observed in the dedicated fertility study using the dibasic ester blend, nor were any histopathological findings noted in the reproductive organs and tissues in 2 additional 90-day studies using the dibasic ester blend. These hormonal variations can therefore be considered of no toxicological significance. See further discussion in IUCLID Section 7.12 - Additional Toxicological Information.The NOEC can be set at 50 mg/m3 based on respiratory local changes.

 

In a similar 90-day study (Kelly, 1987), 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 S.à r.l., 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.

 

In a third inhalation study (Kelley, 1987a), selected as a supporting study and assigned a Klimisch score of 2, degeneration of the olfactory epithelium was observed in male and female rats that were exposed to 160, 400 or 1000 mg/m3 of DBE for 14 weeks. Other than the nasal lesions, histopathology examination showed no deleterious effects in the DBE-exposed rats at any tested concentration. However, dose dependent decreased absolute and relative liver weights in female rats in all DBE-exposed groups and decreased absolute and relative male liver weights in the 1000 mg/m3 were reported. In the absence of a recovery period, and corroborative liver histopathology findings, the biological significance of liver weight effects is not known. Slightly depressed body weights and slightly decreased blood sodium concentrations were also reported, in males and females, in the 1000 mg/m3 group; and a slight increase in blood calcium concentration was observed in female rats exposed to 400 and 1000 mg/m3 DBE for 14 weeks. However, these changes were considered of minimal biological significance. A NOEC was not demonstrated in this study for the olfactory epithelial degeneration observed in rats after exposure to DBE

 

In a fourth inhalation study (Ferenz, 1981), selected as a supporting study and assigned a Klimisch score of 4, male rats were exposed (whole-body exposure) to 0, 100, 300 or 900 mg/m3 for 14 days (6 hours/day, 5 days/week). Changes in relative weights of lungs and liver at the end of the exposure period were noted at 900 mg/m3 with no histopathological correlates, and therefore with no clear toxicological significance. A tentative NOEC of 300 mg/m3 over 14 days can be set.

  

As demonstrated by the various inhalation studies, 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. This has also been supported by results in primate nasal tissues using ethyl acrylate (Ref. Frederick CB, 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 over predictive in the rat model as compared to humans, because of the morphological and physiological differences.

 

Hormone levels and sperm findings are further discussed in the relevant section (See Discussion of the "7.8 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 EU Regulation 1272/2008 (CLP), no STOT- single exposure Cat. 3' classification is 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.