N,N'-bis(5,5-dimethyl-1,3,2-dioxaphosphinane-2-oxide-2-yl)ethane-1,2-diamine

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

January 24, 2017 to March 28, 2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Objective of study:

toxicokinetics

other: The aim of this study is to summarize the hazardous information obtained so far as a safety evaluation of DAIGUARD-850 (SH-0850) and to gain its toxicokinetics-related information.

Qualifier:

no guideline followed

Principles of method if other than guideline:

After peer-reviewing individual study reports and summarizing the toxicity information of the substance, its toxicokinetics-related information was extracted. All studies were conducted under GLP in accordance with OECD guidelines.

GLP compliance:

not specified

Specific details on test material used for the study:

No further details specified in the study report.

Radiolabelling:

no

Species:

other: Various

Details on species / strain selection:

Information collected from several studies involoving different species and strains.

Route of administration:

other: Various

Details on absorption:

In the results of single oral, inhalation and dermal administration studies as well as repeated oral dose toxicity studies using rats, systemic toxic effects were not recognized in any of those studies, and thus the absorption of the substance was considered to be generally low. However, since the ratio of polychromatic erythrocytes to total erythrocyte counts (PCE/TE) in bone marrow revealed a dose response relationship in the mice micronucleus test, indicating that this substance was absorbed to some or a lesser extent in the oral route. In this regard, DAIGUARD-850 (SH-0850) did not show any toxic effects as shown from the results of the preliminary test for a micronucleus test using mice although the substance was absorbed orally.

Details on distribution in tissues:

Since the substance had a very low level of toxicity and did not have any specific target organ(s), it was considered that the substance would not occur in an extreme distribution and accumulation toward any specific organ(s).

Details on excretion:

No information available.

Details on metabolites:

No information available.

Bioaccessibility (or Bioavailability) testing results:

No information available.

Summarization of toxicity information

As for DAIGUARD-850 (SH-0850), no mortality occurred in acute oral and dermal toxicity studies in rats given up to the limit dose, and there were no clinical signs as well as no abnormalities in macroscopic observation. In an acute inhalation toxicity study, slightly laboured respiration during an exposure period and decreased body weights in the early days of post-exposure were found at the limit dose, which were slight and reversible transient changes. Here, laboured respiration observed in an acute inhalation toxicity study was considered to be a non-specific symptom brought by inhalable dusts.

In both a dermal irritation study and a skin sensitization study, neither local irritating effects nor systemic clinical signs were observed. While, in an eye irritation study, slight irritating effects on the conjunctiva were found, but disappeared within 48 hours, thus the effect was only transient.

In a 7-day repeated oral dose toxicity study with rats, there were no abnormalities in clinical signs, body weight changes or necropsy findings up to 1,000 mg/kg/day, the limit dose. Similarly, no toxic signs were revealed with no abnormalities in clinical chemistry as well as pathological examinations in 28-day and 90-day repeated oral dose toxicity studies with rats, and NOAEL of the studies were determined over 1,000 mg/kg/day. Moreover, no effects on parental systemic toxicity and on reproductive/developmental performance were noted in a reproductive/developmental screening test with rats. In addition, a dose-range finding preliminary test of a micronucleus test using mice revealed no abnormalities in clinical signs and body weight changes when they were given 2,000 mg/kg/day for two straight days.

Thus, the level of acute oral toxicity in mice was also considered to be very low. In the main test of a micronucleus test, no significant change was seen in a ratio of polychromatic erythrocytes having micronucleus (MNPCE/PCE) up to the dose of 2,000 mg/kg, indicating that DAIGUARD-850 (SH-0850) was negative for micronucleus inducing activity in mice bone marrow. However, since the ratio of polychromatic erythrocytes per total erythrocytes (PCE/TE ratio) increased in a dose-dependent manner, this was considered to be a treatment-related effect of the substance.

 

Outline of results of toxicity study reports for DAIGUARD-850 (SH-0850)

No.	Study type	Route	Species, strain, sex	Dose	No. of dose	Results
1	Acute toxicity	Oral	Rat, Wistar, Female	2,000 mg/kg Suspension solution in distilled water	Single	No abnormalities in clinical signs, body weights and necropsy findings.
2	Acute toxicity	Inhalation	Rat, Wistar, Male/Female	5.07 mg/L (dust, inhalable fraction: 61.4%)	Single	Clinical signs: Laboured respiration (during exposure), No abnormality (post-exposure), Body weight: Transiently decrease, necropsy: No abnormality
3	Acute toxicity	Dermal	Rat, Wistar, Male/Female	2,000 mg/kg, 24-hr occlusive application (gauze-patch moistened with water)	Single	No abnormality in clinical signs, local effects, body weights, necropsy findings.
4	Skin irritation	Dermal	Rabbit, NZW, Male	5,000 mg/animal, 4-hr occlusive application (gauze-patch moistened with water)	Single	No local irritative effects up to 72 hours after removal of patch. No abnormalities in systemic signs or body weights.
5	Eye irritation	Eye application	Rabbit, NZW, Male	100 mg/animal, placed into conjunctival sac	Single	Eye irritation (Conjunctival redness, chemosis, discharge), disappeared at 48 hr. No abnormalities in systemic signs or body weights.
6	Skin sensitization (LLNA)	Ear application	Mouse, CBA/J Rj, Female	10, 20, 50% solution (25 µl/animal)	3 days	SI = 0.7-1.1 vs. 15.2 (positive control, HCA), concluded as negative. No abnormalities in systemic signs and local irritating effects.
7	Repeated dose toxicity	Oral	Rat, SD, Male/Female	30-1,000 mg/kg/day suspension solution in distilled water	7 days	No abnormalities in clinical signs, body weights, organ weights and necropsy findings.
8	Repeated dose toxicity (OECD TG 407)	Oral	Rat, SD, Male/Female	100, 300, 1,000 mg/kg/day suspension solution in olive oil	28 days	No treatment-related effects in clinical signs, body weights, hematology, blood clinical chemistry, organ weights, necropsy findings, histopathological findings. NOAEL=1,000 mg/kg/day
9	Repeated dose toxicity (OECD TG 408)	Oral	Rat, SD, Male/Female	100, 300, 1,000 mg/kg/day suspension solution in olive oil	90 days	No treatment-related effects in clinical signs, body weights, ophthalmogical findings, hematology blood clinical chemistry, orgam weights, necropsy findings, histopathological findings. NOAEL = 1,000 mg/kg/day
10	Reproductive/ developmental screening (OECD TG 421)	Oral	Rat, SD, Male/Female	100, 300. 1,000 mg/kg/day suspension solution in olive oil	Males: from 14 days before mating until the day before necropsy through the mating period (35 days in total) Females: from 14 days before mating until day 12 of lactation	Parental animals: No treatment-related effect in estrous cycle, copulation index, fertility index, gestation index, number of implantation sites, delivery index, or delivery and maternal behaviour. Offspring: No treatment-related effects in sex ratio, birth index, viability index on post-natal Day 4 (PND4), or viability index on PND13, external examinations, ano-genital distance (AGD), nipple development, plasma T4 concentration on PND13 and body weight. NOAEL (parental systemic effects) = 1,000 mg/kg/day NOAL (reproductive/developmental effects) = 1,000 mg/kg/day
11	Micronucleus (preliminary test)	Oral	Mouse, CD-1, Male/Female	62.5-2,000 mg/kg/day suspension solution in olive oil	2 days	No abnormalities in clinical signs and body weights.
	Micronucleus (main test)	Oral	Mouse, CD-1, Male/Female	500, 1,000, 2,000 mg/kg/day suspension solution in olive oil	2 days	Micronucleus induction: negative. Ratio of polychromatic erythrocytes in total erythrocytes (PCE/TE): increase in dose-dependent manner. No abnormalities in clinical signs and body weights.

 

 

Extraction and summarization of toxicokinetics-related information

From the above toxicity results, the toxicokinetics information of DAIGUARD-850 (SH-0850) on absorption, distribution, metabolism, and excretion were extracted and summarized as described below.

a. Absorption:

In the results of single oral, inhalation and dermal administration studies as well as repeated oral dose toxicity studies using rats, systemic toxic effects were not recognized in any of those studies, and thus the absorption of the substance was considered to be generally low. However, since the ratio of polychromatic erythrocytes to total erythrocyte counts (PCE/TE) in bone marrow revealed a dose response relationship in the mice micronucleus test, indicating that this substance was absorbed to some or a lesser extent in the oral route. In this regard, DAIGUARD-850 (SH-0850) did not show any toxic effects as shown from the results of the preliminary test for a micronucleus test using mice although the substance was absorbed orally.

 

b. Distribution:

Since the substance had a very low level of toxicity and did not have any specific target organ(s), it was considered that the substance would not occur in an extreme distribution and accumulation toward any specific organ(s).

 

c. Metabolism:

No information available.

 

d. Excretion

No information available.

Conclusions:

With reference to toxicokinetics information, the absorption of the substance was likely to be low in any of the oral, dermal or inhalation routes, but evidence of absorption of DAIGUARD-850 (SH-0850) directly in an oral route in mice was obtained from a dose-dependent increase in the ratio of polychromatic erythrocytes to total erythrocyte counts (PCE/TE ratio) in bone marrow in a mice micronucleus test. However, no toxic signs occurred in a mice micronucleus test including the preliminary one, thus there was no species difference between mice and rats from an aspect of toxicity, and it was considered that no large difference existed in the degree of oral absorption rate between the two species. Moreover, since the substance did not reveal the specific target organ toxicity in repeated dose toxicity studies with rats, it was considered that the substance would not occur in an extreme distribution and accumulation on any specific organ(s). In addition, no information was available with regard to metabolism and excretion of the substance.

Executive summary:

DAIGUARD-850 (SH-0850) has a very low level of toxicity in acute toxicity studies in oral, inhalation and dermal routes with rats, and repeated oral dose toxicity studies up to 90 days and reproduction/developmental toxicity screening test with rats. No target organ(s) was specified in repeated dose toxicity studies.

The absorption rate ofDAIGUARD-850 (SH-0850) was likely to be poor in any oral, dermal or inhalation route. However, a dose-dependent increase in the ratio of polychromatic erythrocytes occupied in total erythrocyte counts of bone marrow was found in a mouse micronucleus test, which gave direct evidence as a toxicokinetics finding indicating that DAIGUARD-850 (SH-0850) was absorbed in an oral route in mice. But there were no toxic signs in a mouse micronucleus test including the preliminary one. It was considered, therefore, that no species difference existed between rats and mice from the aspect of toxicity, and that the degree of oral absorption appeared to be almost the same level. Further, since this substance did not show specific target organ toxicity in repeated dose toxicity studies in rats, it was considered that the substance would not occur in an extreme distribution and accumulation on any specific organ(s). In addition, no information was available with regard to metabolism and excretion of the substance.

Description of key information

The absorption rate of DAIGUARD-850 (SH-0850) was likely to be poor in any oral, dermal or inhalation route. Further, since this substance did not show specific target organ toxicity in repeated dose toxicity studies in rats, it was considered that the substance would not occur in an extreme distribution and accumulation on any specific organ(s). In addition, no information was available with regard to metabolism and excretion of the substance.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

DAIGUARD-850 (SH-0850) has a very low level of toxicity in acute toxicity studies in oral, inhalation and dermal routes with rats, and repeated oral dose toxicity studies up to 90 days and reproduction/developmental toxicity screening test with rats. No target organ(s) was specified in repeated dose toxicity studies.

The absorption rate of DAIGUARD-850 (SH-0850) was likely to be poor in any oral, dermal or inhalation route. However, a dose-dependent increase in the ratio of polychromatic erythrocytes occupied in total erythrocyte counts of bone marrow was found in a mouse micronucleus test, which gave direct evidence as a toxicokinetics finding indicating that DAIGUARD-850 (SH-0850) was absorbed in an oral route in mice. But there were no toxic signs in a mouse micronucleus test including the preliminary one. It was considered, therefore, that no species difference existed between rats and mice from the aspect of toxicity, and that the degree of oral absorption appeared to be almost the same level. Further, since this substance did not show specific target organ toxicity in repeated dose toxicity studies in rats, it was considered that the substance would not occur in an extreme distribution and accumulation on any specific organ(s). In addition, no information was available with regard to metabolism and excretion of the substance.