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Description of key information

The effects observed can be attributed to the irritating properties of allyl glycidyl ether (AGE), which were local effects on the nasal mucosa instead of systemic effects. The 14 days NOAEC (local effects) for inhalation toxicity in rat and mice was below 117 mg/m3. The 90 days NOAEC (local effects) for inhalation toxicity in rat and mice was lower than 19 and 4.7 mg/m3, respectively.

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
LOAEC
19 mg/m³
Study duration:
subchronic
Species:
rat

Additional information

Inhalation route:

In a subchronic study (NTP 1990), rats (10/sex/group) were exposed to AGE vapors at 0, 19, 47, 140, 467 and 934 mg/m3 during 90 days (6h/day, 5 days/week). All rats survived. The body weight gain of male and female rats exposed to 140, 467 and 934 mg/m3 were decreased. In addition, body weight gain of male rats exposed to 47 mg/m3 was also decreased. Absolute (dose-related; 120-132% of control) and relative (110-116%; not clear dose-related) liver weight was increased in females at 47 mg/m3 and above. During necropsy, inflammation, epithelial hyperplasia and/or squamous metaplasia of the nasal passage were observed in rats at 19 mg/m3 and above in a dose-related manner. Hyperostosis and focal fibrosis of the nasal passage were observed in a dose-related manner in most rats at 140 mg/m3 and above. In addition, metaplasia of the larynx, trachea and bronchi were seen in rats exposed to 47 mg/m3 and above. Focal inflammatory changes of the lungs were also seen, but were not treatment related as it was also seen in control animals. The NOAEC for local effects was established to be below 19 mg/m3 based on histopathological findings in the nasal passage. No adverse systemic toxicity effects were observed up to the highest dose tested.

In a subacute study (NTP 1990), rats (5/sex/group) were exposed to AGE vapors at 0, 117, 233, 467, 933 and 2333 mg/m3 during 14 days (6h/day, 5 days/week). All rats exposed to 2333 mg/m3 died after two to five days exposure and one male rat died on day 11 after exposure to 467 mg/m3. Rats exposed to 933 and 2333 mg/m3 had signs of respiratory distress and initially, all exposed rats had excessive lacrimation and rhinorrhea. Although not dose-related, a decrease in body weight gain in male rats was observed. No treatment-related effect on body weight was seen in female rats. Rhinitis was observed in all exposed rats in a dose-related manner. Moderate to marked laryngitis and tracheitis, marked destruction of the entire upper respiratory tract epithelium and evidence of widespread lymphoid depletion/necrosis were seen at 2333 mg/m3. Mild squamous metaplasia of the nasal turbinate epithelium was observed in animals at 933 mg/m3. The NOAEC for local effects was established to be below 117 mg/m3 based on the rhinitis observed.

Similar observation were observed in a subchronic study in mice exposed to AGE vapor at concentrations of 0, 4.7, 19, 47 and 140 mg/m3 for 90 days and in a subacute study at concentrations of at 0, 117, 233 and 467 mg/m3 for 14 days. The NOAEC for local effects was established to be below 4.7 and 117 mg/m3 in the subchronic and subacute studies, respectively, based on histopathology in the nasal passage.

In another study, respiratory tract injury was investigated by histological examination in the nasal cavity including lungs in groups of 10 mice subject to whole body inhalation exposure for 4, 9 and 14 days, 6 h/day to 0, 11.7 and 33.1 mg/m3 of AGE. Based on the histological changes, it can be concluded that AGE caused only nasal lesions as no lung injury were observed after exposure for 4, 9 and 14 days at 33.1 mg/m3 dose level.

Take all data into consideration, effects on body weight gain as well as the nasal passage can be attributed to the irritating properties of AGE. The effects on body weight gain could be due to refusal to eat but food consumption was not recorded. Although some standard parameters for assessing systemic toxicity were not investigated (hematology, biochemistry and urinalysis), histopathology examination of the organs did not reveal any pathologic alteration indicating absence of systemic effect. Therefore, classification is not justified.

 

Dermal route:

In a scarcely documented summary report (Reliability 4), 0.2 ml of AGE (equivalent to 194 mg/rat) was applied undiluted daily 

(except weekends) until the degree of eschar formation made further applications undesirable or the animals showed signs of systemic 

toxicity. The exposure was under occlusive conditions and the test patch was removed 1 h after each application. 3 of the 6 animals died after the 7th application and further applications were discontinued. Signs of systemic toxicity appeared 48 hours before death and the  surviving animals were below normal in appearance. None of the animals gained weight and the weight of those that died decreased significantly prior to death.

 

Other routes:

In a scarcely documented summary report (Reliability 4), male rats received intramuscular injections of 400 mg/kg bw AGE for 3 consecutive days. 2 out of 3 rats showed atrophy or loss of lymphoid tissue and decreased leucocytes count. In the same report, male rats were exposed to AGE via intramuscular injections (400 mg/kg bw) on days 1, 2, 8 and 9. Focal testicular necrosis was observed in 1 of 2 of the 3 surviving rats sacrificed on day 12.


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

Justification for classification or non-classification

EU classification according to Annex VI of Directive 67/548/EEC: no classification required

GHS classification ( EC No 1272/2008):

- Specific Target Organ Toxicity: Repeated Exposure: no classification required