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Diss Factsheets

Administrative data

Description of key information

Acute oral toxicity:
Numerous studies are present in public literature that describe the effects after a single oral exposure. However most of these studies use sublethal dosages to assess the antifertility effects and the underlying mechanisms. A few studies are conducted to assess the LD50 value: Kennelly et al. (1970) and Hine et al. (1956).
Acute inhalation toxicity:
Three studies are available, one GLP guideline study (TNO, 1992), the Carpenter et al. publication (1949) and the Hine et al. publication (1956).
Acute dermal toxicity: no information available.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Dose descriptor:
150 mg/kg bw

Additional information

Acute toxicity: oral

The most extensive study that determines the oral LD50 is the one of Kennelly et al. (1970). Laboratory rats (Long Evans strain) and wild-caught rats are exposed to levels up to 300 mg/kg bw. The LD50 for all rats ranges from 150 mg/kg to >300 mg/kg. For the purpose of this dossier, only the value for the Long-Evans rat is taken into account (LD50 = 150 -200 mg/kg). The same strain of rats was used in the study of Hine et al. (1956), where an LD50 of 150 mg/kg (95% CI = 130 -180 mg/kg) was found. This value is used as the acute oral LD50.

Other studies which were mentioned in the ESIS IUCLID4 file contain LD50 values but no information was given on the methods, the route of exposure or other relevant information. The values are however in the same classification range, as prescribed by both CLP and DSD. In Paul et al. (1974) a male rat LD50 of 55 mg/kg bw was mentioned. In Ericsson and Baker (1970) an acute oral rat LD50 of 152 mg/kg was mentioned. And in Dorobantu et al. (1970) a rat LD50 of 127 mg/kg (CI = 114 -141 mg/kg) was mentioned.

Effects on the kidneys have been observed in Hine et al. (1956), Morris and Williams (1980) and Dorobantu et al. (1970).

At an intragastric dose of 150 mg/kg in Long-Evans rats, unusual kidney changes were observed. The lesions described were acute inflammation in the perirenal fat, early necrosis of the tubular epithelium with precipitated protein in the tubules, and stages of regeneration of epithelium with dilation of tubules and presence of casts. Other gross findings included hyperemia of the adrenal gland and adhesions of the stomach to adjacent tissues. No other microscopic lesions were noted (Hine et al., 1956).

Group-housed Sprague-Dawley rats exposed orally to 80 mg/kg had the kidney weight significantly increased (compared to control) 24 hours after treatment and this remained so for at least 7 days after administration. The kidneys were of normal coloration, but were tense and in some cases lobulated. Forty-two days after treatment, kidney weight and appearance were comparable with the control values. No mortality was observed. When singly-housed rats were given the same dose, the 3/8 rats that died became anuric and the kidneys were whitish and furry. In transverse section, the white region extended 1-2 mm in from the surface, where after normal coloration was observed (Morris and Williams, 1980). In the same study, Wistar rats were exposed by single i.p. to doses of 80, 100 and 120 mg/kg. Mortality occurred only at 120 mg/kg, where 4/9 rats died between day 3 and 6 with intermittent oliguria (decreased urine production) and anuria (non-passage of urine). Kidney enlargement, anuria, polyuria, proteinuria and glucosuria were recorded after 100 and 120 mg/kg, suggesting kidney failure at these doses.

In the Dorobantu study (1970), rats of both sexes were injected with a dose of 135 mg/kg. Histopathological examination showed that the worst damage is found in the kidneys, which present variable alterations, ranging from simple lipidoproteical dystrophia to extensive cortical necrosis, followed by intense phenomena of typical regenerations. These observations were confirmed by enzymatic modifications. In other organs no severe and wide destructive/degenerative lesions were found.

Acute toxicity: inhalation

Three studies are available assessing the acute inhalation toxicity. TNO (1991) exposed male and female Wistar rats for 6h (whole body exposure) to an actual vapour concentration of 16.7 ppm and did not find mortality or any other effects (LC50 > 16.7 ppm, i.e. > 0.08 mg/L). Carpenter et al. (1949) exposed Sherman rats for 4h and observed the rats for 14 days thereafter. The LC50 that could be derived from this study lies between 0.28 and 1.13 mg/L (62 and 250 ppm). Hine et al. (1956) exposed Long-Evans rats for 8h (whole body exposure) to a highest attainable vapour concentration of 90 ppm and did not find mortality (LC50 > 90 ppm, i.e. > 0.44 mg/L). This study was used as supporting evidence. The TNO study (Klimisch 1) and the Carpenter study (Klimisch 3) are used in a weight of evidence approach to conclude on classification.

Justification for classification or non-classification

Acute oral toxicity: the oral LD50 values found in literature roughly range from 55 up to 300 mg/kg. According to the DSD, the substance should be classified as toxic (R25), when the LD50 lies between 25 and 200 mg/kg. According to CLP, the substance should be classified as Acute tox category 3 (H301), when the LD50 lies between 50 and 300 mg/kg.

As the substance causes kidney damage after single exposure, even at sublethal dosages, the substance should also be classified as R39/25 according to DSD and as STOT single exposure category 1 (H370) according to CLP. The antifertility effects in male animals after single exposure are taken into account in the classification for toxicity for reproduction.

Acute inhalation toxicity: the inhalatory LC50 lies between 90 and 250 ppm, or 0.44 mg/L and 1.13 mg/L. According to the DSD, the substance should be classified as toxic (R23), as the LC50 lies for the greatest part between 0.5 and 2 mg/L. According to CLP, the substance should be classified as Acute tox category 2 (H330), as the LC50 lies for the greatest part between 0.5 and 2 mg/L