Alkyl phosphites

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

150 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP study conducted in accordance to OECD 421 guideline. Klimisch rating 1. The available information comprises an adequate and reliable study (Klimish score 1).

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

In a study according to OECD test guideline 421, the test substance, in the vehicle (mineral oil) was administered orally by gavage once daily to 3 groups of Crl:CD(SD) rats, each group consisting of 12 males and 12 females. Dosage levels were 10, 50, and 150 mg/kg/day administered at a dosage volume of 5 mL/kg. A concurrent control group of 12 rats/sex received the vehicle on a comparable regimen. Males and females were approximately 10 weeks of age at the beginning of test substance administration. Males received 14 daily doses prior to pairing. Males were dosed throughout the mating period through 1 day prior to euthanasia for a total of 31-32 doses. Females received 14 daily doses prior to pairing and were dosed through lactation day 3 for a total of 39-52 doses; females with no evidence of mating were dosed through the day prior to euthanasia for a total of 52 doses. All animals were observed twice daily for mortality and moribundity. Clinical observations, body weights, and food consumption were recorded at appropriate intervals. All F0 females were allowed to deliver and rear their pups until lactation day 4. F1 clinical observations and body weights were recorded on PND 1 and 4. Pups were euthanized and discarded without macroscopic examination on PND 4. F0 males were euthanized following completion of the mating period and F0 females were euthanized on lactation day 4. Complete necropsies were conducted on all F0 animals, and selected organs were weighed. Selected tissues were examined microscopically from all F0 animals in the control and high-dose groups.

 

One female in the 10 mg/kg/day group was found dead on lactation day 0. This mortality was not considered test substance-related. All males and all other females survived to the scheduled euthanasia. Test substance-related clinical findings were observed for F0 males and females in the 150 mg/kg/day group and consisted of males, clear/red material around the mouth, and salivation prior to dosing. These findings were primarily observed at the time of dose administration or at approximately 1-2 hours following dose administration. Males were also observed at a low incidence for a limited number of F0 animals during the weekly detailed physical examinations. The aforementioned clinical findings were likely a result of taste aversion and/or the irritant properties of the test substance instead of a direct toxic effect. There were no test substance-related clinical findings observed for F0 males and females at 10 and 50 mg/kg/day during the weekly detailed physical examinations or at approximately 1-2 hours following dose administration throughout the study. There were no test substance-related effects on mean body weights, body weight gains, or food consumption for F0 males throughout the treatment period or for F0 females during the pre-mating, gestation, or lactation treatment periods at any dosage level. F0 male and female mating and fertility, male copulation and female conception indices, mean number of days between pairing and coitus, gestation length, and the process of parturition were unaffected by test substance administration at all dosage levels. There were no test substance-related macroscopic findings or effects on organ weights for F0 males and females at any dosage level. Test substance-related microscopic alterations were confined to the non-glandular stomach in the 150 mg/kg/day group F0 animals and consisted of minimal to moderate sub-mucosal edema and/or inflammation, and/or epithelial hyperplasia and/or ulceration of the mucosa. Alterations in the non-glandular stomach were attributed to the irritant effects of the test substance at the portal-of-entry. There were no test substance-related microscopic alterations for F0 males and females at 10 or 50 mg/kg/day. Mean F1 body weights and body weight gains were unaffected by parental test substance administration at all dosage levels. In addition, the mean number of pups born, live litter size, the percentage of males at birth, and postnatal survival were unaffected by parental test substance administration. None of the clinical findings for F1 pups or macroscopic findings for F1 pups that were found dead or euthanized due to death of the dam were attributed to the test substance.

 

Due to the absence of test substance-related effects on F0 reproductive endpoints, including F0 male and female mating and fertility, male copulation and female conception indices, mean number of days between pairing and coitus, gestation length, and the process of parturition, the no-observed-effect level (NOEL) for reproductive toxicity of the test substance when administered orally by gavage to Crl:CD(SD) rats was 150 mg/kg/day, the highest dosage level tested. In addition, due to the absence of test substance-related effects on the F1 offspring, the NOEL for neonatal toxicity was considered to be 150 mg/kg/day. Local toxicity (non-glandular stomach) was observed at a dosage level of 150 mg/kg/day. The most prominent clinical findings at this dosage level resulted from local toxicity and/or the irritant properties of the test substance. These findings included males, clear/red material around the mouth, and salivation. Test substance-related microscopic alterations were noted in the 150 mg/kg/day group and included minimal to moderate sub-mucosal edema and/or inflammation, and/or epithelial hyperplasia and/or ulceration of the mucosa. Alterations in the non-glandular stomach were attributed to the irritant effects of the test substance at the portal-of-entry and not systemic toxicity. Therefore, the NOEL for systemic toxicity was considered to be >/= 150 mg/kg/day.

 

 

Effects on developmental toxicity

Description of key information

Treatment with EC 424-820-7 by oral gavage in male and female Sprague-Dawley rats at dose levels of 0, 10, 50 and 150 mg/kg bw/day according to OECD 421 test guideline resulted in local irritating effects in high dose dams as shown by rales and clear/red material around the mouth following dose administration and minimal to moderate submucosal edema and/or inflammation and/or epthelial hyperplasia and/or ulceration of the nonglandular stomach mucosa. Based on these observations, The NOAEL for maternal local effects is 50 mg/kg bw/day. In the absence of systemic toxicity, the NOAEL for maternal systemic toxicity is at least 150 mg/kg bw/day, the highest dose tested. No reproduction and developmental toxicity was observed for treatment up to 150 mg/kg bw/day. A reproduction and developmental NOAEL of at least 150 mg/kg bw/day was derived.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

150 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

There was no evidence of effects on the pups in any of the three dose groups. The NOAEL = 150 mg/kg bw. This susbtance is corrosive, which limited the maximum dose in the study to 150 mg/kg bw.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

The following two repeated dose studies are available for the registration substance:

•       A 28-day repeated dose oral toxicity study in the rat with satellite recovery group (Freeman, 1995; OECD 407 with GLP; Klimisch 1)

•       An Oral (Gavage) Reproduction/Developmental Toxicity Screening Study of **EC 424-820-7** in Rats (Herbeth, 2012; OECD 421 with GLP; Klimisch 1)

 

In the oral gavage 28-day repeated dose toxicity study in rats, the registered substance did not show any adverse systemic effects up to the highest dose level tested (150 mg/kg bw/day), with the only significant effects being local irritation to the forestomach at 150 mg/kg bw/day. The dose level of 150 mg/kg bw/day was confirmed as the highest tolerable dose in a 7 day and 14-day range-finding study that is reported in the 28 day-day repeated dose toxicity endpoint study record. In these preliminary studies, administration of the registered substance up to 1000 mg/kg bw/day resulted in overt toxicity adverse clinical signs (dyspnea, staining, stool abnormalities, decreased food consumption, emaciation, rales, and/or poor condition etc.) and subsequently death prior to scheduled termination. At necropsy, there was evidence of stomach irritation in one in all doses tested, the gross stomach changes ranged from roughened mucosa in the 50 and 150 mg/kg bw/day dose groups to more severe changes in the 1000 mg/kg bw/day dose group such as sloughing and discoloration of the mucosa. A high dose level of 150 mg/kg bw/day was considered appropriate to avoid lethality and minimize excessive stomach irritation.

 

In a reproduction/developmental toxicity screening test in rats (Herbeth, 2012), gavage dosing of the registered substance up to 150 mg/kg bw/day in rats for up to 52 days resulted in no adverse effects in reproductive performance, offspring growth and development. There were no treatment-related adverse effects in the reproductive organs in the available studies. Again, the only significant effects being local irritation to the forestomach at 150 mg/kg bw/day.

 

Justification for selection of Effect on developmental toxicity: via oral route:
Key study for this endpoint. There is screening data available on developmental toxicity (OECD 421 study).

Justification for classification or non-classification

In an GLP study conducted in accordance with OECD guideline 421, the registration substance (EC 424-820-7) showed no evidence of reproductive or developmental toxicity. Therefore in accordance with Regulation (EC) No 1272/2008 (CLP) and based on the available data, the registration substance does not require classification for these endpoints.