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Description of key information

Oral OECD 422 in rats
14, 28 and 90 day inhalation studies in rats

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
20 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
acceptable

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LOAEC
20 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
acceptable

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
subchronic
Species:
rat
Quality of whole database:
acceptable

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
limited

Additional information

Inhalation studies:

In the 14 day inhalation study (10 exposure days), the highest dose level tested (83 mg/m3) was considered to be the NOAEC. At this dose, there was a small drop in terminal body weight (5%), but it was not significant. There were no clinical signs of toxicity nor any gross or microscopic signs of toxicity. Some small fluctuations in organ weights occurred in the high dose group, but these were considered related to the small drop in body weight and not an adverse effect. There was no assessment of clinical chemistry or hematology in this study.

In the 1 month inhalation study (exposure 6h/d, 5d/wk), the findings were largely consistent with those observed in the 14 day inhalation study. The highest dose in this study was approximately 500 mg/m3 and this dose produced a number of clinical signs of toxicity (alopecia, red staining around the eyes and nose, behavioural changes) as well as effects on body weight and organ weights. Body weights were depressed in the high dose group (males and females) and there were some associated increases in organ weights, for example the liver (absolute and relative weight). This affect on liver weight was considered to be treatment related and may be an adaptive response to treatment rather than an adverse effect since there were no related histopathological findings that accompanied the change in liver weight. Other changes in organ weights were attributed to the decrease in body weight in the high dose animals. Hematology and clinical chemistry did not produce any consistent findings (some significant increases and decreases observed, but no clear dose response), with the exception of female plasma cholinesterase. This was depressed (significantly) in all female dose groups, with the level in the high dose group being approximately 1/3 that of the control. Plasma cholinesterase has been associated with liver damage, and in the high dose females there were also indications of liver damage based on clinical chemistry parameters such as SGPT, creatinine and globulin levels which were all significantly increased compared to control. However, there were no such changes in these parameters at the lower dose levels, nor was there any pathology, or organ weight data to indicate liver toxicity at the middle and lower doses. Therefore, the significance of this finding is unclear. It is limited only to the females and does not appear to be associated with any other changes and whilst liver damage can cause changes in plasma cholinesterase, it is understood (at least in humans) that a number of other causes exist, for example such as stress and injuries such as bone breakage. Based on the lack of other findings in the mid and low doses and the unclear significance of the plasma cholinesterase changes, it can be argued that the NOAEC for this study is actually the mid dose of approximately 95 mg/m3.

In the 3 month inhalation study (exposure 6h/d, 5d/wk), the findings were very consistent with those identified in the previous studies, but the decreases in body weight and organ weight changes occurred to some extent at all doses in at least one sex. Body weights were decreased in the males at the high dose only (400 mg/m3), but in the females at all doses (20, 100 and 400 mg/m3). It is of note that in the mid dose (100 mg/m3), the decrease in body weight only became significant during the 4th week, which is somewhat consistent with the lack of effects on body weight at a similar dose in the 1 month study. In the high dose group in both males and females, there were various increases in clinical chemistry parameters that are consistent with the liver being a target organ for toxicity (increased SGPT, creatinine, globulin). There were no gross or microscopic pathological changes indicative of liver toxicity, although there was again an increase in the males (all doses) and females (high dose only) in the absolute and relative liver weights. Kidney weights (absolute) in the high dose males and relative kidney weights in the high dose males and all female dose groups were increased relative to control. This, however, could be an artifact of effects on body weight since there was no pathology associated with the changes in organ weight. Female plasma cholinesterase was significantly decreased in a dose related manner in the mid and high dose groups, and a non significant decrease in the low group. Again, the significance of this finding is unclear, particularly since there was no effect on the erythrocyte cholinesterase levels. In the high dose males and females, there also appeared to be evidence of a mild anemia; however, the etiology of this is unclear since there was no supporting pathology, or evidence of increased red blood cell destruction. Taking all the findings together, it appears that the liver is a target organ, but effects observed may be adaptive rather than adverse (at least at the mid and low doses). The remaining effects on body weight effects could be related to stress (respiratory and sensory irritancy was observed in all studies following exposure, but generally limited to the highest dose) and decreased food consumption/efficiency, although unfortunately there was no recording of food consumption to confirm this. Thus, whilst there appears to be evidence of systemic toxicity it does not appear to be 'specific' and the effects observed at the lowest dose in this study (20 mg/m3) (female body weight decrease, and increased absolute and relative liver weights) could thus be considered as 'general signs of toxicity'.

An important consideration to be taken into account when assessing the inhalation studies is that they were all performed using whole body exposure. The test atmospheres were generated using an aerosol to give the required doses. However, the vapour pressure of this substance is so low that this material will have a tendency to settle out of the air and deposit on the surfaces of the cage and the animals fur. This will result in a combination of oral and inhalation exposure since the test material would be consumed during preening, the end result being potentially higher systemic exposures than if one were to simply convert the air concentration to a systemic dose.

Also of note in both these inhalation studies are the clinical observations in the high dose groups (510 mg/m3 and 400 mg/m3 in the 1 and 3 month studies, respectively). These clinical signs indicate some irritancy (allopecia, irritation of the eyes etc.), but also indicate that the animals were somewhat distressed by the exposure, and may have had some evidence of a central nervous depression (lack of cleaning of the fur, some behavioural changes, general malaise). This information might suggest that this substance is also producing some acute CNS depression such as seen with other hydrocarbon solvents like diethyl benzene, ethyl benzene, etc. It appears that these effects do not persist after exposure and recovery occurs. Thus, the effects appear to be transient in nature.

Oral toxicity studies:

In the OECD 422 study, doses of 80 and 320 mg/kg bw produced evidence of systemic toxicity presenting as body weight and organ weight changes. There were no significant findings in the FOB, clinical chemistry or hematology (with the exception of a decrease in eosinophil levels in the high and mid dose group). There were no test article-related macroscopic findings at the scheduled necropsies. Mean absolute and relative kidney weights in the 80 and 320 mg/kg/day group males and mean absolute and relative liver weights in the 320 mg/kg/day group males and females were increased. Also in the 320 mg/kg/day group, mean absolute and relative thyroid gland weights were increased in the females, and mean absolute and relative thymus weights were decreased in males and females. No test article- related effects on organ weights were observed in the 20 mg/kg/day group males or females. Test article- related increased incidences and severity of mineralization, multifocal deposits or irregular basophilic material were noted in the kidneys in the 320 mg/kg/day group males, correlating to increased kidney weights. Hepatocellular hypertrophy was observed in the livers of these males, corresponding to increased liver weights. Follicular cell hypertrophy was observed in the thyroid gland in the 320 mg/kg/day group males and females. This finding correlated to increased thyroid gland weights in these animals and is possibly linked to the increase in liver size at this dose. Atrophy of the thymus was observed in three females in the 320 mg/kg/day group, corresponding to decreased thymus weight in these females. No test article- related microscopic findings were observed in the 20 or 80 mg/kg/day group males and females.The NOAEL for systemic toxicity was considered to 20 mg/kg/day based on decrements in body weight gains and/or food consumption and changes in organ weights in the 80 and 320 mg/kg/day groups and microscopic findings in the 320 mg/kg/day group.

Considering the consistency between the main findings of the inhalation and oral studies, it appears that there are minimal differences in dosing via the two routes and bioavailability can be considered to be similar.

Justification for classification or non-classification

No classification for chronic toxicity or target organ toxicity is proposed.