Sodium O,O-di-sec-butyl dithiophosphate

Endpoint summary

Description of key information

Read-across (IBP1-Na)

OECD 422:

Effects on the F0-generation NOAEL (no-observed-adverse-effect level): 200 mg IBP1-Na/kg b.w./day, p.o.
Effects on reproduction NOAEL (no-observed-adverse-effect level): 600 mg IBP1-Na/kg b.w./day, p.o.

OECD 408:

The no-observed-adverse effect level (NOAEL) was established at 600 mg/kg bw/day in males and female rats.

 

Read-across (EP1-Na)

OECD 422: Based on these observations the NOAEL for systemic toxicity of male/female rats was 1000 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

Combined repeated toxicity study with reproduction/developmental toxicity screening test

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

Please refer to Read Across Statement attached in Section 13

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Mortality:

mortality observed, non-treatment-related

Description (incidence):

There was no test item related mortality at any dose level.
One dam at 450 mg/kg bw/day (1/12), was found dead on post-partum (lactation) day 5. There were no preceding clinical signs for this animal. Based on findings at necropsy and histological evaluation, the cause of death was judged to be individual disease and not related to the treatment as no death occurred at the higher (1000 mg/kg bw/day) dose level.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Slightly reduced mean body weight gain in male and female animals at 1000 mg/kg bw/day resulted in minor changes in the mean body weight (≥ - 7 % relative to control) therefore was considered to have little or no toxicological relevance.

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Behaviour (functional findings):

no effects observed

Immunological findings:

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Gross necropsy revealed slight damage of mucous membrane of the stomach in some female animals at 450 and 1000 mg/kg bw/day due to the local effect of the test item (thickened mucous membrane, erosion).

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Squamous cell hyperplasia in the non-grandular part of the stomach was observed in some female animals at 450 and 1000 mg/kg bw/day (4/4 and 6/6 respectively)

Dose descriptor:

other: NOAEC

Effect level:

30 other: mg/mL (administered to animals of 150 mg/kg bw/day group)

Based on:

act. ingr.

Sex:

female

Basis for effect level:

gross pathology

histopathology: non-neoplastic

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: Systemic toxicity

Critical effects observed:

not specified

Conclusions:

There were no signs of systemic toxicity in male or female animals at 150, 450 or 1000 mg/kg bw/day. In the female animals at 450 and 1000 mg/kg bw/day, squamous cell hyperplasia in the non-glandular part of the stomach referred to the local effect of the test item. Besides of this local tissue irritation no other histological findings were noted.

Based on these observations the No Observed Adverse Effect Levels (NOAEL) were determined as follows:
NOAEL for systemic toxicity of male/ female rats: 1000 mg/kg bw/day
NOAEC (stomach irritation, female rats): 30 mg/mL (administered to animals of 150 mg/kg bw/day group)

Remark: The test substance as produced and marketet contains NaOH due to the production method.

Executive summary:

The toxicity of the substance was assessed in a Combined Dose Toxicity Study with the Reproductive/Developmental Screening Test according to OECD 422 (adopted 29 July 2016). Doses of 0 (control), 150, 450 and 1000 mg/kg bw/day was administered by gavage to 12 Wistar rats/sex/dose. Male rats were dosed daily for 44 days, female rats were dosed daily for 51 or 56 days.

 

No test item related mortality or clinical signs of systemic toxicity were observed in male or female animals during the study. Slightly reduced mean body weight gain in male and female animals at 1000 mg/kg bw/day resulted in minor changes in the mean body weight (≥ - 7% relative to control) therefore was considered to have little or no toxicological relevance. No changes in haematological or clinical biochemistry parameters were observed in either sex. The gross pathology showed no changes in organ weights compared to control group. Slight damage of mucous membrane of the stomach in some female animals at 450 and 1000 mg/kg bw/day were observed due to the local effect of the test item (thickened mucous membrane, erosion). In female animals at 450 and 1000 mg/kg bw/day, squamous cell hyperplasia in the non-glandular part of the stomach referred to the local effect of the test item. Besides of this local tissue irritation no other histological findings were noted.

 

Based on these observations the NOAEL for systemic toxicity of male/female rats was 1000 mg/kg bw/day.

 

Reference 2

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

Please refer to Read Across Statement attached in Section 13

Reason / purpose for cross-reference:

read-across source

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

There were no treatment-related adverse observations in either sex.
The following clinical findings were recorded during the study:
Salivation and moving the bedding were observed in MD and HD animals, immediately after administration with a roughly similar incidence among those groups. These clinical findings, closely related to the administration procedure, indicate a local effect of the test item formulation and are not considered as signs of adverse systemic effects. Similar findings were not observed in males and females of the LD and C groups.
In addition, on one single day in one female and on two occasions in another female, both from the HD group, abnormal breathing was recorded after dosing. Alopecia was also observed in 2 females of LD group for 6 days. As these effects were observed only on few days and/or with no dose response, they are considered not to be toxicologically relevant.
With the exception of moribund condition of animal no 32 (male HD,) no other clinical observations were recorded during the daily observations.
During the course of the study, the following parameters of the weekly detailed clinical observations were statistically different to the control in males: salivation higher in HD in week 6 (HD 4.7, control 4.0), in week 7 (HD 4.9, control 4.0), in week 8 (HD 6.0, control 4.0), in week 9 (HD 4.9, control 3.7), in week 10 (HD 4.9, control 4.0) and in week 11 (HD 5.1, control 4.0), spontaneous activity lower in HD in week 7 (HD 3.6, control 4.0), in week 8 (MD 3.2, HD 2.6, control 3.9) and in week 9 (HD 3.6, control 4.0). Furthermore, in week 3, lower animal sleeps score in MD and HD (MD 0.0, HD 0.0, control 0.5) and higher animal moving in the cage score in MD and HD (MD 1.0, HD 1.0, control 0.5) was observed.
The following parameters of the weekly detailed clinical observations were statistically different to the control in females: salivation higher in HD in week 4 and 5 (HD 4.6, control 4.0), in week 7 (HD 5.0, control 4.0), in week 8 (HD 5.2, control 4.0), in week 9 (HD 6.0, control 4.0) and in week 10 (HD 5.4, control 4.0), spontaneous activity lower in MD and HD in week 9 (MD 3.4, HD 3.2, control 4.0) and in week 10 (HD 3.5, control 4.0). Furthermore, in week 8, lower animal sleeps score in LD, MD and HD (LD 0.0, MD 0.0, HD 0.0, control 0.3) and higher animal moving in the cage score in LD, MD and HD (LD 1.0, MD 1.0, HD 1.0, control 0.7) was observed.
All other detailed clinical observation parameters were within the normal range of variation of historical control data for this strain. Any statistically significant differences between dose and control groups are not assumed to be biologically relevant.
There were no ophthalmoscopic findings in any of the animals of this study.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

There was no treatment-related mortality in either sex.
Animals no. 31 (male HD) was found dead on day 84 and male no. 32 (male HD) was euthanized for ethical reasons on day 35.
Animal no. 70 (female MD) was found dead on day 12 but was almost completely cannibalised by the cage mates and therefore no tissues were available for histopathology.
Animal no. 32 was euthanized in a moribund condition. Until this condition occurred clinical signs like abnormal breathing, salivation, piloerection and hunched posture had been observed for a week. Although the gross lesions recorded in animals nos. 31 and 32 (affections of the thoracic cavity) were indicating a gavage error, the histological evaluation of the organs and tissues did not reveal the cause of morbidity/death of these animals.
The cause of death of the animal no. 70 could not be established as no tissues were available for histopathology.
Apart from that no mortality occurred in the control or any of the dose groups during the treatment and recovery period of this study.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

In both males and females, the mean body weight increased with the progress of the study in all groups.
In males, the mean body weight was 10-11 % higher in the HD group from day 36-90 without achieving statistical significance. On day 90 the difference in body weight of the HD males to controls reached 11.02 %. This body weight increase is considered to be a test item related. Moreover increase in MD male body weight was also observed but this increase was marginal (0-4.68 %).
In females, the mean body weight was 5-8 % higher in the HD group from day 36-90 and statistical significance was achieved on day 50 and 64 when compared with the controls. This mean body weight was within the expected historical range of variation with no considerable differences between dose groups and control group during the treatment period.
In HD males the overall body weight change from day 1 to 90 was higher without achieving statistical significance compared to the controls. However, statistically significantly higher body weight change was observed during day 85-90 in MD and HD groups when compared with the controls.
In accordance with body weight development, in females, the weight gain was within the expected historical range of variation. However, overall body weight change from day 1 to 90 was marginally but statistically significantly higher in MD and HD group when compared with the controls.
Therefore these finding in HD males but not females represent test item relation. However, toxicological significance of this increase in body weight gain in males was not clear.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

In correlation to body weight gain, the food consumption in males and females was higher at the beginning of the study and then constantly decreased with the progress of the study in all groups, which is considered to be a normal development as food demand is usually highest at a young age and then constantly decreases. During the whole treatment period, food consumption of the male and female HD group was higher compared to the corresponding control group, which correlates to the higher mean body weight and body weight gain of the male and females in these groups.

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

In female, statistically significantly higher WBC (MD 3.436, HD 3.750 and control 2.065) and PLT (MD 851.8, HD 855.6 and control 697.5) counts were observed in MD and HD group when compared with the controls. These statistically significant differences between dose and control groups in females are not assumed to be biologically relevant as no such effect was observed on differential WBC count and values for both WBC and PLT were within the normal range of variation of historical control data.
All other haematology parameters in males and females were within the normal range of variation of historical control data for this strain.
Blood coagulation was not affected by IBP1-Na. The observed values were within the normal range of variation of historical control data.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

In the female, statistically significantly lower ALAT (17.97 % of control) and ASAT (20.31 of control) were observed in HD group when compared with the controls. These statistically significant differences between dose and control groups in females are not assumed to be biologically relevant as decrease in these liver enzymes have no biological significance and values for both ALAT and ASAT were within the normal range of variation of historical control data.
Besides, all parameters of clinical chemistry in males and females were within the normal range of variation of historical control data for this strain and are not assumed to be toxicologically relevant.

Urinalysis findings:

no effects observed

Description (incidence and severity):

Slightly high protein and erythrocytes levels were found in the urine of few male and females of all groups including controls. As this effect was observed in animals of all groups including control, it was considered to be isolated findings with no toxicological relevance.
All other parameters of urinalysis in test item treated males and females at the end of the treatment period were not considerably different to the corresponding control and were within the normal range of variation of historical data for this strain.

Behaviour (functional findings):

no effects observed

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

At the end of the treatment period in HD group of both, males and females, a moderate statistically significantly higher mean absolute and relative (to body weight) weight of liver was recorded, compared to the corresponding control (mean absolute/relative +29%/+18% in males and +13%/+9% in females). In histology, this effect was associated with centrilobular hepatocellular hypothrophy in both genders. There were no further indicators for toxicity in any of the organs and tissues examined. Therefore, this finding is not considered to be of adverse nature, but related to increase in liver metabolism.
The kidney of HD males but not females was statistically significantly higher with mean absolute organ weight value of 21% above the C group. Histopathologically, there were minor changes characterized by minimal tubular dilation associated with a swelling (vacuolation) of the epitehlia and such lesions are in general reversible. There were no findings indicating a morphological injury (see also histopathology phase report) and therefore this effect on male kidney weight was not considered to be adverse.
In HD males, a statistically significantly higher absolute mean weight of prostate with seminal vesicles and coagulation glands (3.38 g in HD vs 2.80 g in C) was recorded. In the light of the absence of histopathological effect, this effect on prostate with seminal vesicles and coagulation glands weight was not considered to be adverse.
Besides, all male and female organ weights were within the normal range of variation of historical control data for this strain and differences between dose and control groups are not assumed to be biologically relevant.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Pathological changes were observed in the following animals. Abnormal red color and fluid filled thoracic cavity was observed in male no. 31 (HD). The thymus showed abnormal dark color in male no. 32 (HD). There was also black focus on lung and gas filled stomach and gastrointestinal tract was observed in male no. 32. Histopathologically, lung finding was due to congestion and for stomach finding, no histopathological correlate was observed.
The spleen of female no. 66 (MD) was reported to be enlarged. In histology, this finding correlates with congestion. There was also a cyst on ovary found in female no. 55 of LD group for which no histopathological correlate was observed.
Fluid filled uterus with cervix was recorded in 2/10 LD females (no. 51 and 54), 2/10 MD females (no. 63 and 65) and 2/10 HD females (no. 71 and 80). In histology, this finding correlates with female cyclic change and represents a normal background finding for this strain.
Female no. 70 could not be observed for macropscopic findings as the animal was completely cannibalised by the cage mates.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Under the conditions of this study, there were three decedents at 600 mg/kg. The cause of morbidity/death could not be established.
Gross lesions were not remarkable, however, histopathology revealed lesions in the liver and kidneys 8 males only) at a minor severity. Secondary lesions were noted in the adrenal glands and thymus.
In the liver, there was hepatocellular hypertrophy (mainly centrilobular) at minor severity degrees at 600 mg/kg in both sexes. There were no further indicators for toxicity in any of the organs and tissues examined. Therefore, this finding is not considered to be of adverse nature, but related to increase liver metabolism.
In male kidneys at 600 mg/kg, there were minor changes characterized by minimal tubular dilation associated with a swelling (vacuolation) of the epitehlia, mainly in the rectal and distal tubules. The nature of this lesion is unknown but is likely related to storage in tubular cells and subsequent water uptake/disturbed release. Such lesions are in general reversible. There were no findings indicating a morphological injury.
Secondary findings, deemed to be stress-related consisted of diffuse cortical hypertrophy (zona fasciculata) at a minor severity in both sexes at 600 mg/kg, and a minimally increased thymic atrophy in males only.

In general, these findings are minor in severity and not considered to be adverse. Therefore, the NOAEL may be established at 600 mg/kg/day.

Histopathological findings: neoplastic:

not specified

Other effects:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

600 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

behaviour (functional findings)

body weight and weight gain

clinical biochemistry

clinical signs

food consumption and compound intake

gross pathology

haematology

histopathology: non-neoplastic

mortality

ophthalmological examination

organ weights and organ / body weight ratios

urinalysis

Critical effects observed:

not specified

Conclusions:

Based on the study findings, the overall NOAEL of test item for systemic toxicity in this study is considered to be at 600 mg/kg bw/day.

Executive summary:

The test was performed according to the OECD guideline 408 under GLP compliance. On the basis of the present study, the 90-Day Repeated Dose Oral Toxicity study with test item in male and female Wistar rats, with dose levels of 30, 150, and 600 mg/kg body weight day the following conclusions can be made: No effect of toxicological relevance was observed on male and female body weight, food consumption, haematology, clinical biochemistry, urine parameters, clinical signs, gross pathology and organ weight up to 600 mg/kg bw/day. The histomorphological no-observed-adverse effect level (NOAEL) was established at 600 mg/kg bw/day in males and female rats. Based on the study findings, the overall NOAEL of the test item for systemic toxicity in this study is considered to be at 600 mg/kg bw/day.

Reference 3

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

Please refer to Read Across Statement attached in Section 13

Reason / purpose for cross-reference:

read-across source

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

No test item-related premature death was noted

Mortality:

mortality observed, treatment-related

Description (incidence):

No test item-related premature death was noted

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

A slight reduction in body weight was noted until the end of the study on test day 38 for the male rats of the high dose group (600 mg IBP1-Na/kg b.w./day). Body weight at autopsy was reduced accordingly.

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Examination of the haematological and biochemical parameters revealed statistically significant changes in the male and female animals of the high dose group (600 mg IBP1-Na/kg b.w./day), which were considered as to be test item-related.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Males: A statistically significant increase in the plasma activity of ALAT and ASAT, a decrease of the chloride concentration and a decrease in the globulin concentration leading to an increase in the albumin/globulin ratio were noted in the high dose gr.

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

The neurological screening revealed a reduction for the hindlimb grip strength of the male and female animals of the high dose group (600 mg IBP1-Na/kg b.w./day).

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Examination of the organ weights revealed a slightly statistically significant increase in the relative liver weight of the male rats of the high dose group (600 mg IBP1-Na/kg b.w./day).

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

The histopathological examination revealed test item related changes in the forestomach from male and female rats of the intermediate and the high dose group (200 and 600 mg IBP1-Na/kg b.w./day) in form of hyperplasia and hyperkeratosis of the squamous cell epithelium, infiltration with neutrophilic granulocytes, granulation tissue and ulcerations.
Additionally, test item-related changes were noted in the liver in the form of a centrilobullar hepatocellular hypertrophy at 600 mg/kg bw/day.

Key result

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: systemic effects

Critical effects observed:

not specified

Conclusions:

Effects on the F0-generation
NOAEL (no-observed-adverse-effect level): 200 mg IBP1-Na/kg b.w./day, p.o.
Effects on reproduction
NOAEL (no-observed-adverse-effect level): 200 mg IBP1-Na/kg b.w./day, p.o.
Remark: the test solution contains NaOH due to the production method.

Due to the similarity of the target substance, SBP1-Na, and the source substance, IBP1-Na, the result of this study is assessed to be adequate in order to fulfil the requirements of REACH. The read-across approach is further described in the document “Justification of read across from CAS No 53378-51-1, IBP1-Na (source) to CAS No 33619-92-0, SBP1-Na (target)” attached in “Point 13 Assessment reports”.

Executive summary:

The test was performed according to the OECD guideline 422 under GLP compliance. Crl:CD(SD) strain rat was tested with sample. NOAEL values were determined as follow:

Effects on the F0-generation

NOAEL (no-observed-adverse-effect level): 200 mg IBP1-Na/kg b.w./day, p.o.

Effects on reproduction

NOAEL (no-observed-adverse-effect level): 200 mg IBP1-Na/kg b.w./day, p.o.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

high quality

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

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:


Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; digestive: stomach

Justification for classification or non-classification

NOAEL is well above classification criterion according to Regulation (EC) No 1272/2008.