Phosphorodithioic acid, O,O-di-C1-14-alkyl esters, zinc salts

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL was estimated to be 781 mg/kg bw when rat were exposed with Phosphorodithioic acid, O,O-di-C1-14-alkyl esters, zinc salts. 

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

Data is predicted using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: as below

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

- Name of test material (IUPAC name): Dialkyl(C1-C14)dithiophosphoric acid, zinc salt
- Common name: Phosphorodithioic acid, O,O–di–C1–14–alkyl esters, zinc salts
- Molecular formula: C28H60O4P2S4Zn
- Molecular weight: 716.38 g/mol
- Smiles notation: [Zn+2].CCCCCCCOP(=S)([S-])OCCCCCCC.CCCCCCCOP(=S)([S-])OCCCCCCC
- InChl: 1S/2C14H31O2PS2.Zn/c2*1-3-5-7-9-11-13-15-17(18,19)16-14-12-10-8-6-4-2;/h2*3-14H2,1-2H3,(H,18,19);/q;;+2/p-2
- Substance type: Organic
- Physical state: liquid

Species:

rat

Strain:

Wistar

Details on species / strain selection:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Remarks on MMAD:

not specified

Vehicle:

water

Details on exposure:

not specified

Details on mating procedure:

not specified

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

The duration of treatment covered a 2-week premating and a mating period in both sexes, approximately 1 week post-mating in males,and the entire gestation period as well as 4 days of lactation and 2 weeks thereafter in females.

Frequency of treatment:

daily

Details on study schedule:

not specified

Dose / conc.:

781 mg/kg bw/day

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

not specified

Positive control:

not specified

Parental animals: Observations and examinations:

not specified

Oestrous cyclicity (parental animals):

not specified

Sperm parameters (parental animals):

not specified

Litter observations:

not specified

Postmortem examinations (parental animals):

not specified

Postmortem examinations (offspring):

not specified

Statistics:

not specified

Reproductive indices:

not specified

Offspring viability indices:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Dose descriptor:

NOAEL

Effect level:

781 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

other: No effect observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality / viability:

no mortality observed

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

781 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

gross pathology

other: No effect observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Reproductive effects observed:

not specified

Treatment related:

not specified

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

(((((((("a" or "b" or "c" or "d" or "e" or "f" )  and ("g" and ( not "h") )  )  and ("i" and ( not "j") )  )  and ("k" and ( not "l") )  )  and "m" )  and ("n" and ( not "o") )  )  and ("p" and ( not "q") )  )  and ("r" and "s" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Zinc metal and salts by OECD HPV Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Soluble complexes of Zinc by US-EPA New Chemical Categories

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Alkoxy AND Thiophosphate by Organic Functional groups

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Alkoxy AND Overlapping groups AND Thiophosphate by Organic Functional groups (nested)

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Miscellaneous sulfide (=S) or oxide (=O) AND Phosphite, aliphatic attach [-O-P] AND Sulfur, phosphorus attach [-S-] AND Thio-phosphorus [S=P] AND Zinc [Zn] by Organic functional groups (US EPA)

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Anion AND Cation by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Non binder, MW>500 by Estrogen Receptor Binding

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group OR Non binder, non cyclic structure OR Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules (GSH) by Protein binding potency

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Slightly reactive (GSH) OR Slightly reactive (GSH) >> 2-Alkenyl carbonitriles (MA) OR Slightly reactive (GSH) >> Alkyl cinnamates (MA) by Protein binding potency

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Stable form by Tautomers unstable

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Hydroxyazo form - 1,5-H shift by Tautomers unstable

Domain logical expression index: "m"

Similarity boundary:Target: CCCCCCCOP(=S)(OCCCCCCC)S{-}.[Zn]{2+}.S{-}P(=S)(OCCCCCCC)OCCCCCCC
Threshold=40%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Alkoxy AND Overlapping groups AND Thiophosphate by Organic Functional groups (nested)

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Dihydroxyl group by Organic Functional groups (nested)

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Alkoxy AND Overlapping groups AND Thiophosphate by Organic Functional groups (nested)

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Cycloalkene by Organic Functional groups (nested)

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.58

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is <= 18.9

Conclusions:

NOAEL was estimated to be 781 mg/kg bw when rat were exposed with Phosphorodithioic acid, O,O-di-C1-14-alkyl esters, zinc salts.

Executive summary:

In an prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for Phosphorodithioic acid, O,O-di-C1-14-alkyl esters, zinc salts. The NOAEL was estimated to be 781 mg/kg bw when rat were exposed with Phosphorodithioic acid, O,O-di-C1-14-alkyl esters, zinc salts. 

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

781 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimisch 2 and from OECD QSAR toolbox

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproductive toxicity: Oral

In different studies, Phosphorodithioic acid, O,O-di-C1-14-alkyl esters, zinc salts has been investigated for reproductive toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats along with the study available on structurally similar read across substanceQuat-Silsesquioxane (CAS no 27668-52-6)and Calcium distearate (CAS no 1592-23-0). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies.

In an prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for Phosphorodithioic acid, O,O-di-C1-14-alkyl esters, zinc salts. The NOAEL was estimated to be 781 mg/kg bw when rat were exposed with Phosphorodithioic acid, O,O-di-C1-14-alkyl esters, zinc salts.

 

In another experimental study conducted by Siddiquiet al(Fundamental And Applied Toxicology 21, 6 6 - 7 0 (1993)) on structurally similar read across substanceQuat-Silsesquioxane (CAS no 27668-52-6),Sprague-Dawley female rats by using Quat-Silsesquioxane in the concentration of 0, 100, 300, or 1000 mg/kg/day orally by gavage in corn oil.No maternal mortality and clinical signs or behavioral changes were observed in treated female rats as compared to control. No effect on body weight and feed consumption changes were observed in treated female rats as compared to control. Similarly, no effect on reproductive parameters such as number of corpora lutea, number of live fetuses per litter, litter size, mean fetal body weight, or mean crown-rump length was observed in treated rats. Ratio of male and female pups at the 1000 mg/ kg/day dose level was significantly different from the control group but was not considered treatment related. Slight but significant increase in relative liver weight of treated female rats was observed as compared to control. In addition, No effect on viability, fetal body weight and external malformations were observed in treated fetuses as compared to control. One fetus with bent limb bones, two fetuses from different mothers with microphthalmia and two other fetuses with omphalocele were observed at 1000 mg/kg/day and single fetus with multiple malformations were observed at 300 mg/kg/day in treated fetuses as compared to control. The incidence of developmental variations in the treated litters was not significantly increased over the control incidence. They occurred in low frequency and were distributed randomly across the Quat-Silsesquioxanetreated and control groups. Therefore,NOAEL was considered to be 300 mg/kg bw for P generation and 1000 mg/kg for F1 generation when Sprague-Dawley female rats were treated withQuat-Silsesquioxane orally by gavage from day 6 to 15 of gestation.

Further supported by experimental study conducted byDupont Chem Co (NTRL,OT50546181, 09/01/92, National Technical Information Service, 1992) on structurally similar read across substanceQuat-Silsesquioxane (CAS no 27668-52-6), Albinofemale rats by using Dow Corninc @Q9-5700 in the concentration of 0, 100, 300 and 1000 mg/kg orally. 1 nongravid rats died at 1000 mg/kg and 1 pregnant rats died at 100 mg/kg as compared to control. No untoward behavioral reactions were observed in treated female rats as compared to control.Similarly,Noeffect on gestation andgross pathological changes were observed in treated female rat as compared to control. In addition, No effect on fetuses Body weight were observed as compared to control. No external abnormalities and skeletal and internal developmental effect were observed in treated fetuses as compared to control. Therefore, NOAEL was considered to be 1000 mg/kg for P and F1 generation when  Albinofemale rats were treated with Dow Corninc @Q9-5700 orally from gestation days 6 through 15.

This further supported by experimental study conducted by Organization for Economic Cooperation and Development (CoCAM 2, 17-19 April 2012)on structurally similar read across substance Calcium distearate (CAS no 1592-23-0), Sprague-Dawley male and female rats were treated with Calcium distearate in the concentration of 0, 250, 500 and 1000 mg/kg bw orally by gavage. Alopecia was observed in the control and treatment groups of both sexes. No mortality and change in body weight were observed in treated male and female rats we compared to control. A decrease of statistically significant change in food consumption was observed at 2 weeks in 1000 mg/kg bw/day group. No statistically significant change in organ weights among the groups. Splenomegaly and testicular atrophy were observed in 1 and 1 males of the 0 and 1000 mg/kg bw/day groups, respectively. Discoloration of adrenal gland was observed in 1 female of the 250 mg/kg bw/day group. However, there was no toxic effect of the test article on these organs in histopathology; therefore, this was considered to be a sporadically occurring sign In all reproductive organs in control and high dose groups, the lesion related with the test article was not observed. Adrenocortical necrosis was observed in 1 female of the 250 mg/kg bw/day group. In addition, No statistically significant differences were observed in the following parameters examined: gestation period, the number of corpora lutea and implantation, delivery index, the number of live and dead pups, the percentage of live and dead pups to implantations, pre-implantation loss, post-implantation loss, sex ratio, viability ratio, number of neonates with external anomalies, and body weights of pups on post-natal day 0 and day 4. Therefore, NOAEL was considered to be 1000 mg/kg bw/day for P and F1 generation when Sprague-Dawley male and female rats were treated with Calcium distearate orally by gavage.

Thus, based on the above studies and predictions on Phosphorodithioic acid, O,O-di-C1-14-alkyl esters, zinc salts and its read across substances, it can be concluded that NOAEL value is 781 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, Phosphorodithioic acid, O,O-di-C1-14-alkyl esters, zinc salts can be Not classified as reproductive toxicant.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the above studies and predictions on Phosphorodithioic acid, O,O-di-C1-14-alkyl esters, zinc salts and its read across substances, it can be concluded that NOAEL value is 781 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, Phosphorodithioic acid, O,O-di-C1-14-alkyl esters, zinc salts can be Not classified as reproductive toxicant.