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Description of key information

oral repeated dose, short term:

source substance Zinc bis(O,O-diisobutyl dithiophosphate) (CAS 68457 -79 -4): GLP, according to OECD Guideline 422, Klimisch 1, rat, oral (gavage), NOEL (portal-of-entry) = 40 mg/kg bw/day (localised injury to the nonglandular portion of the stomach), NOAEL (systemic effects) = 160 mg/kg bw

source substance Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate) (CAS 4259 -15 -8): GLP, similar to OECD Guideline 407, Klimisch 1, rat, oral (gavage), NOEL (portal-of-entry) = 10 mg/kg bw/day, NOAEL = 125 mg/kg bw/day (systemic effects).

Based on the available data and based on the performed studies for CSA as key value the value at which no adverse effect was observed was choosen. This value is a bit higher than the NOEL. Unfortunately the provided data is different, because one study shows the NOEL and the other one shows the NOAEL, but nevertheless the results are in range, because the observed NOAEL of the one substance is higher than the NOEL of the other substance.

sub-chronic toxicity: oral

experimental study planned (based on read-across)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
125 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Good due to high quality guideline studies

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

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

Repeated dose toxicity: via oral route - systemic effects


source substance Zinc bis(O,O-diisobutyl dithiophosphate) (CAS 68457 -79 -4)


In a guideline combined repeated dose and reproduction / developmental screening study (OECD 422) conducted according to GLP, WIL Research Labs (2010) evaluated the potential toxic effects of the test substance when administered to rats. This study was designed to evaluate the toxic effects, including neurobehavioral effects, of the test material to parental animals and to evaluate the potential to effect male and female reproductive performance such as gonadal function, mating behavior, conception, parturition, and early postnatal development. The test material was administered orally by gavage once daily to 3 groups of Crl:CD(SD) rats at levels of 10, 40 or 160 mg/kg/day. The low- and mid-dose groups each consisted of 10 rats/sex and the high-dose group consisted of 15 rats/sex. A concurrent control group of 15 rats/sex received the vehicle, mineral oil USP, on a comparable regimen. Ten males/group selected for pairing were dosed for 14 days prior to mating through 1 day prior to euthanasia for a total of 28 doses. Ten females/group selected for pairing were dosed for 14 days prior to mating through lactation day 3 for a total of 40-52 doses; females that failed to deliver were dosed through the day prior to euthanasia (post-mating day 25) for a total of 40 doses. The extra 5 males and 5 females in the control and high-dose groups were not used for mating and were treated beginning on study day 0; following 28 doses for the males and 40 doses for the females, these animals were assigned to the post‑treatment period and remained on study for a 14-day non-dosing period.


Test item-related moribundity, clinical findings, and microscopic findings in the non glandular portion of the stomach, characterized by epithelial hyperplasia, hyperkeratosis, and inflammation, were observed in the 160 mg/kg/day group. The injury to the nonglandular portion of the stomach was localized and considered to be irritation from test item portal-of-entry effects. Based on these results, the NOEL for portal-of-entry effects was considered to be 40 mg/kg/day, and excluding the histologic injury to the nonglandular stomach, the no-observed-adverse-effect level (NOAEL) for systemic toxicity was considered to be 160 mg/kg/day.


 


source substance Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate) (CAS 4259 -15 -8)


The toxicity potential of the test article, was evaluated in this 28-day study in rats. This study was also conducted to aid in dose level selection for an OECD reproduction/developmental toxicity screening study. The test article in Mazola® Corn Oil was administered orally by gavage to five groups, each consisting of five male and five female Sprague- Dawley Crl:CD® BR rats, for a period of 28 consecutive days. Dosage levels were 10, 50, 125, 250 and 500 mg/kg/day. All animals were dosed at a volume of 5 mL/kg. A concurrent control group of identical design received the vehicle, Mazola® Corn Oil, on a comparable regimen at a dose volume of 5 mL/kg. The animals were observed for clinical signs and effects on body weight, food consumption and organ weights. Necropsies were performed on all animals that died or were euthanized at study termination. A microscopic examination was conducted on selected tissues from the control, 250 and 500 mg/kg/day dose groups.


Three males and one female dosed at 500 mg/kg/day died between study days 6 and 16. These deaths were attributed to treatment. One female dosed at 125 mg/kg/day died on study day 7. The cause of death for this female was unknown. No deaths were observed at the higher dose level of 250 mg/kg/day, and the death of this female was not attributed to oral administration of the test article.


All other animals survived to the scheduled necropsy. Test article related clinical signs included changes in fecal consistency, discoloration of the feces, tan, yellow or brown staining on various body surfaces, rales, salivation and aggression in the 125, 250 and 500 mg/kg/day group males and females. Rales and salivation were also observed in the 50 mg/kg/day group males. Body weight gain was inhibited in the 250 mg/kg/day group males and the 500 mg/kg/day group males and females during the first two days of dosing. Inhibition of body weight gain continued in the high dose group males through study day 12. Food consumption was slightly reduced in the 500 mg/kg/day group males and females during the first week of dosing.


At the scheduled necropsy, thickened mucosa in the nonglandular portion of the stomach was observed in one 500 mg/kg/day group male and in one and two females in the 250 and 500 mg/kg/day groups, respectively. At the microscopic examination, one 250 mg/kg/day group male and all 500 mg/kg/day group females had submucosal edema in the glandular andlor non-glandular portions of the stomach. Three of the high dose group females also had suppurative inflammation, primarily in the non- glandular portion of the stomach. These findings are consistent with a response to a gastric irritant. Mean absolute and relative adrenal gland weights in the 250 and 500 mg/kg/day group males and females were increased when compared to the control group values. No test article related histopathological lesions were observed in the adrenal glands to account for the increases.


Based on the data obtained, a dose level of 500 mg/kg/day would exceed a maximum tolerated dose for a subsequent reproduction/developmental toxicity study in rats. Treatment-related increases in mean absolute and relative adrenal gland weights occurred at the 250 and 500 mg/kg/day dose levels. However, no test article-related histopathological lesions were observed in the adrenal glands to account for the increases. Based on these findings, the No Adverse Effect Level NOAEL was determined to be 125 mg/kg/day. A dose level of 10 mg/kg/day was considered to be the NOAEL (no observable adverse effect level) for local effects.


 


sub-chronic toxicity: oral


This requirement will be fullfiled by using data within the Category as soon as this data is available

Justification for classification or non-classification

In accordance to Regulation (EC) No 1272/2008 classification of this substance is not required for prolonged exposure.