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Administrative data

Description of key information

There is a 28-day repeated dose inhalation study in rats available for n-propyl propionate and there are no repeated dose oral or dermal studies available. In addition, there are several repeated dose inhalation studies ranging from 9 days to 90 days in duration for the other substances in the category, n-pentyl propionate and n-butyl propionate refer to the justification for read across attached to section 13 of the dataset).  The only common finding across all the studies has been histopathologic changes in the nasal tissues (olfactory epithelium damage) and this can be considered to be a local effect, while again across all the studies there have been no major indications of any systemic toxicity up to the highest doses tested.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
238 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
good

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

Additional information

The table below summarizes the key repeated dose toxicity information for the group of substances –

Compound tested

Duration of exposure

GLP

Doses tested

Guideline

NOEC (ppm)

Effects seen/ observed

Local effects (organs affected)

Pentyl propionate

28 days (20 exposures)

Yes

0, 116, 350, 1375 ppm

OECD TG 412

NOEC – 116 ppm (683.1567 mg/m3)

No effects seen up to 1375 ppm

Nasal tissues – olfactory epithelium damage

Butyl propionate

11 days (9 exposures)

Yes

0, 800, 1600, 3200 ppm

OECD TG 412

NOEC < 800 ppm

Reduced body weight and gains across all groups, reduced food and water consump. at 1600 and 3200 ppm and transient changes in clinical pathology related to reduced body weight

Nasal tissues – olfactory epithelium damage

Butyl propionate

2 weeks (10 exposures)

Yes

0, 250, 500, 2000, 4000 ppm

OECD TG 412

NOEC - 500 ppm

Reduced body weight gain, food consump. noted in 2000 and 4000 ppm groups

Nasal tissues – olfactory epithelium damage in the 2000 and 4000 ppm groups

Butyl propionate

13 weeks (5 days/week)

Yes

0, 250, 750,1500 ppm

EPA OTS 798.2450

NOEC (systemic toxicity) – 747 ppm; NOEC (local effects) – 247 ppm

Reduced body weight gains and food consump. observed at 1500 ppm

Nasal tissues – olfactory epithelium damage

Propyl propionate

2 weeks (9 exposures)

Yes

0, 50, 250, 2000 ppm

OECD TG 412

NOAEC - > 50 < 250 ppm

Reduced body weight at 2000 ppm, reversible during recovery, no other effects

Nasal tissues – olfactory epithelium damage

Propyl propionate

Approx. 30 days

Yes

0, 50, 250, 500 ppm

OECD TG 422

LOAEC – 50 ppm

Slight reductions in body weight and food consump. at 250 and 500 ppm

Nasal tissues – olfactory epithelium damage

Data on n-propyl propionate:

In a GLP study conducted according to OECD TG 412 (Repeated Dose Inhalation Toxicity: 28/14 -day), groups of male Crl:CD (SD) IGS BR rats were exposed (whole body) to vapours of H-24826 (propyl propionate) at levels of 50, 250 and 2000 ppm (nominal concentrations) for 6 hours/day, 9 exposures over a 2 -week period. Inhalation exposure of male rats to H-24286 at concentrations of 250 or 2000 ppm produced degeneration and necrosis of the olfactory epithelium. Evidence of reversibility, though not complete, was present following the 3-week recovery period. Under the conditions of this study and based upon changes in the olfactory epithelium, the NOAEL for pathology was 50 ppm. The actual NOAEL is between 50 and 250 ppm and is expected to lie near the upper bound of that range, as effects at the low-effect level of 250 ppm were limited to a single animal and were minimal and focal in nature.

In a GLP study conducted according to OECD TG 422 (Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test), groups of male and female Crl:CD(SD) rats were exposed (whole body) to vapours of propyl propionate at levels of 50, 250 and 500 ppm (nominal concentrations) for 6 hours/day, 7 days/week. Exposure to n-propyl propionate resulted in slight reductions in food consumption and body weight throughout the study in females exposed to 250 and 500 ppm. Treatment related histopathologic effects were also evident in the nasal tissues of males and females exposed to all test concentrations. The nasal tissue effects consisted of very slight degeneration of the olfactory epithelium. In addition males exposed to 500 ppm and females exposed to 50 ppm had a higher incidence of adipose tissue atrophy than the controls. This was interpreted to have questionable significance. No treatment-related effects were seen in reproductive performance, pup survival and growth, neurologic function, clinical chemistry, or hematology. Therefore, the no-observed-effect concentration (NOEC) for general toxicity was considered to be greater than 500 ppm (the highest tested dose in this study).

Due to the lack of a 90-day study on n-propyl propionate, data on other members of the category and analogues are included to assess the potential sub-chronic repeated dose toxicity of n-propyl propionate.

Data on n-pentyl propionate:

In a GLP study conducted according to OECD TG 412 (Repeated Dose Inhalation Toxicity 28/14-day), five male and five female Crl:CD(SD) rats per group were whole-body exposed to 0, 116, 350, or 1375 ppm (parts per million) (0, 686, 2065, or 8111 mg/m3, respectively) of n-pentyl propionate (6 hours/day, 5 days/week, 4 consecutive weeks) for 20 exposures to evaluate the potential for respiratory tract and systemic toxicity. Exposures occurred under dynamic airflow conditions. In-life observations, feed consumption, body weights, hematology, clinical chemistry, coagulation, and organ weights were evaluated. In addition, a gross necropsy was conducted followed by an extensive histopathological examination of tissues.

There were no treatment-related clinical observations, nor effects in hematology, prothrombin time, or clinical chemistry parameters. There were no treatment related gross pathologic observations. Although no time-sex-dose interaction was identified, when the data for male and female rats were combined (time-dose interaction), rats exposed to 1375 ppm had body weights that were statistically identified as lower than their respective controls. Statistically identified lower mean feed consumption values were observed on test days 1-5 in male rats exposed to 350 and 1375 ppm when compared to their respective controls. This decrease in feed consumption was transient resolving by the second week of the study and correlated with lower body weight gains seen in these groups. As such these effects are not considered to be evidence of adverse systemic effects.

Histopathologic changes attributed to repeated inhalation exposure to n-pentyl propionate were present in the nasal passage. The treatment-related lesions were slight, bilateral, multifocal olfactory epithelial degeneration of the dorsal and dorso-medial meatus of all males and females exposed to 1375 ppm. The degeneration was characterized by thinning, disarray and atrophy of the olfactory epithelial cells. Individual necrotic and sloughed epithelial cells accompanied the degenerative change. Similar changes were also present in three females exposed to 350 ppm. Very slight, unilateral, focal olfactory epithelial degeneration occurred in one male and one female, exposed to 350 ppm.

 

Based on the presence of treatment-related histopathologic alterations in the nasal airways of male and female rats exposed to 350 and 1375 ppm n-pentyl propionate, the no-observed-effect concentration (NOEC) for local effects in both male and female Crl:CD(SD) rats repeatedly exposed to n-pentyl propionate for four weeks (20 exposures) was 116 ppm (683.1567 mg/m3). The NOAEC for systemic toxicity is considered to be the top dose of 1375 ppm (8111 mg/m3).

Data on n-butyl propionate:

In a GLP study conducted according to OECD TG 412 (Repeated Dose Inhalation Toxicity 28/14 -day), groups of male and female Fischer 344 rats were exposed (whole body) to vapours of butyl propionate at levels of 800, 1600 and 3200 ppm (nominal concentration) for 6hours/day, 9 exposures over a period of 11 days. In conclusion, exposure of rats to n-butyl propionate vapor for 9 days of exposure over an 11-day period produced effects upon body weight, food and water consumption, and microscopic changes in the nasal cavities at exposure concentrations of 1600 and 3200 ppm. Decreases in body weight, body weight gain, and microscopic changes in the anterior olfactory mucosa were observed even at the lowest concentration. Thus, a no-observed-effect level (NOEL) was not determined for exposure to n-butyl propionate vapor.

In a range-finding GLP study conducted according to OECD TG 412 (Repeated Dose Inhalation Toxicity 28/14 -day), groups of male and female Sprague Dawley rats were exposed (whole body) to vapours of butyl propionate at levels of 0, 250, 500, 2000 and 4000 ppm (nominal concentration) for 6 hours/day, 10 exposures over a 2-week period.In conclusion, exposure to vapours of n-butyl propionate had no adverse effect at any exposure level on survival and organ weights data. Test article-related clinical signs were noted in the 2500 and 4000 ppm groups and consisted primarily of drooping eyelids and salivation during exposure, and red or brown material or staining around the nose and/or mouth one hour following exposure. Body weight gain and food consumption were inhibited in the 2500 and 4000 ppm groups generally throughout the treatment period. Exposure-related lesions were noted at the microscopic examination of nasal tissues which consisted of cytoplasmic vacuolation, necrosis and/or atrophy of the olfactory epithelium (with or without dilatation of Bowman's glands) in nasal sections III, IV, V and VI of the 2500 and 4000 ppm groups. Based on the exposure related lesions observed in the nasal tissues, the no-observable effect level (NOEC) was considered to be 500 ppm.

In a GLP study conducted according to EPA OTS 798.2450 (90 -day Inhalation Toxicity), groups of male and female Sprague Dawley rats were exposed (whole body) to vapours of butyl propionate over a period of 13 weeks at levels of 250, 750 and 1500 ppm for 6 hours/day, 5 days/week. In conclusion, exposure of rats to n-butyl propionate for 13 weeks resulted in reduced body weight gains and food consumption in the 1500 ppm group males essentially throughout the exposure period, slight and transient reductions in body weight gain in the 1500 ppm group females and histopathologic lesions of the nasal tissues in the 750 and 1500 ppm group animals. Similar findings in the olfactory epithelium lining were also noted in animals of the dose range finding study and this was also substantiated by an independent Pathology Advisory Group. Based on the data obtained during the 8-week recovery (nonexposure) period, the effects on body weight gain and food consumption were completely reversible. The histopathological lesions showed substantial to complete reversibility at the end of the 8-week recovery period. Based on the exposure related lesions observed in the nasal tissues at the study week 13 primary necropsy, the no-observable effect level (NOEL) for olfactory epithelium damage was considered to be 247 ppm. The NOEL for systemic toxicity, based on decreased body weight gain was considered to be 747 ppm.

Conclusions:

A common finding across all the propionates (n-pentyl propionate, n-butyl propionate, n-propyl propionate) was histopathologic changes in the nasal tissues (olfactory epithelium damage) and this can be considered to be a local effect, while again across all the studies there have been no major indications of any systemic toxicity up to the highest doses tested. The major effects across all the propionates have been reductions in body weights and weight gain with reduced food and water (in some instances) consumption and transient changes in clinical pathology secondary to weight loss or reduction. To conclude, it is unlikely that a 90-day study (if conducted) will lead to a reduction in NOEC, supporting this is the fact that significant decreases in NOEC values are not noted with increase in the study duration or length of the study, across all the propionates.

The key (local) effect i.e. histopathologic changes in the nasal tissues (olfactory epithelium damage) will be considered more as an irritant effect secondary to the release of propionic acid after hydrolysis by the carboxylesterases (widely distributed in the body of mammalian species and this can hydrolyse esters in various compounds).Specifically, the carboxylesterases metabolise propionates releasing these acids which can then cause local irritation of the respiratory tract epithelia.

The NOEC value of 50 ppm (238 mg/m3) from the 28-day on n-propyl propionate will be used for DNEL derivation (local effects) and DNEL’s for systemic toxicity will not be derived as they would be far less sensitive than the values used for calculation of local effects.

Justification for classification or non-classification

Based on the results noted in the repeated dose toxicity studies and based on the Guidance to Regulation (EC) No. 1272/2008 on Classification, Labelling and Packaging of substances and mixtures, n-propyl propionate will not be classified for Single Target Organ Toxicity - Repeated Exposure (STOT-RE).