Registration Dossier

Administrative data

Description of key information

Based on substance specific data and/or read-across from a structurally similar substance:
Oral: LD50 (rat, m/f) > 2000 mg/kg bw
Inhalation: LC50 (rat, m/f) > 2.3 mg/L air (based on read-across)
Dermal: LD50 (rat/rabbit, m/f) > 2000 mg/kg bw (based on weight of evidence and read-across)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
13 May - 27 May 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study.
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
Ministerium für Umwelt Baden-Württemberg, Stuttgart, Germany
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Interfauna, Süddeutsche Versuchstierfarm, Tuttlingen, Germany
- Weight at study initiation: 182-198 g (males), 168-186 g (females)
- Housing: individually in Macrolon cages (area 800 cm², height 17 cm)
- Diet: Haltungsdiät "ALMA 0801 H 1003", twice 8 g daily
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
other: not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: animals were observed daily for mortality and clinical signs. Body weights were determined prior to study initiation, on the day of oral administration (Day 0), and daily thereafter, except on Days 4, 11 and 12 post-administration.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross necropsy
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during the study period.
Clinical signs:
Two rats (one male and one female) were slightly apathetic on the day of application (Day 0) and on Day 1 post-application. The anal region of two other male rats was slightly covered with light brown and pasty excrements on Day 1 post-application. On Day 2 post-application, both symptoms were not noted any more. Other acute toxicological symptoms were not observed during the 14-day observation period.
Body weight:
No effect on body weight was noted.
Gross pathology:
No macroscopical organ changes were observed in any animal.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
CLP: not classified
DSD: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 1-2) and consistent studies, and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5.1, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1981/08/27
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This non-GLP study is similar to current guideline, but deviates significantly enough to warrant restriction.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
Minimal detail provided. No histopathology conducted to determine cause of gross pathology findings.
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Animals weighing approximately 135 g were supplied by King Animal Labs. Upon arrival, the animals were quarantined to the laboratory for 1 week. Apparently healthy rats were selected for the study. Animals were housed 3/sex/cage and then individually after the exposure period in suspended stainless steel cages. Animal rooms were maintained at 22 °C, 40% humidity, and 12 h light cycles. Purina Rodent Chow 5001 and water were available ad libitum except during the exposure period.

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
A generating system was used to generate concentrated vapour of the test article. An air-vapour mixture was produced by bubbling dry air at 5 L/min through 1 L of test article heated to 66 °C. This vapour mixture passed into the exposure chamber with no dilution air added.
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
4 h
Concentrations:
2.3 mg/L nominal concentration
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Rats were exposed for 4 h to vapours generated from a single batch of the test article. The projected exposure concentration was not to exceed 15 mg/L. The concentration of the test article in the atmosphere was determined by dividing the quantity for the test article consumed by the volume of air passed through the chamber during the exposure period (nominal concentration). All rats were observed for 14 days following exposure.

Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 2.3 mg/L air (nominal)
Exp. duration:
4 h
Mortality:
No animals died following exposure to the test article.

Clinical signs:
other: Diarrhoea was noted in one rat following exposure. All remaining rats appeared normal.
Body weight:
All test rats were weighed immediately prior to exposure. Body weights were not recorded following the observation period for comparison.

Gross pathology:
Gross necropsy findings for nine rats were within normal limits. The remaining rat had red foci throughout the liver.
Other findings:
Tan livers and kidneys were observed at necropsy, however, these were not deemed to be treatment-related.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
CLP: not classified
DSD: not classified
Executive summary:

In an acute inhalation toxicity study, male and female Wistar rats were exposed to test substance at a nominal concentration of 2.3 mg/l under continuous air flow conditions for 4 h. The LC50 is >2.3 mg/L. Diarrhea was noted in one animal, all other animals appeared normal. Based on the results of this study, the test substance would be not classifiable in accordance with the classification system of GHS. This toxicity study is classified as acceptable and satisfies the guideline requirement for acute inhalation toxicity in rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 2) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common functional group(s) and similarities in physicochemical and/or (eco)toxicological properties (refer to endpoint discussion for further details).
The selected study is thus sufficient to fulfil thestandard information requirements set out in Annex VII, 8.5.2, in accordance with Annex XI,1.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises studies which each alone are regarded insufficient for assessment (Klimisch score 2). However, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006.
Furthermore, The available information comprises adequate, reliable studies (Klimisch score 2) ansd consistent studies from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common functional group(s) and similarities in physicochemical and/or (eco)toxicological properties (refer to endpoint discussion for further details).
Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VII, 8.5.3, of Regulation (EC) No 1907/2006.

Additional information

Justification for grouping of substances and read-across

There are no data available on the acute toxicity by inhalation of zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate). In order to fulfil the standard information requirements set out in Annex VIII, Section 8.5.2, in accordance with Annex XI, Section 1.5 of Regulation (EC) No 1907/2006, read-across from a structurally similar substance is conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having considered the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, whereby physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity, the substance Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts (CAS 84605-29-8) is selected as reference substances for assessment of the acute toxicity by inhalation.

The read-across is based on structural similarity as both chemicals belong to the substance class of Zinc alkyldithiophosphates (ZDDP) which are produced by a chemical reaction of Phosphorous pentasulfide with low molecular weight alcohols followed by a subseuqent reaction with zinc oxide. A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Overview of acute toxicity

 

Target substance (a)

Source substance (b)

CAS No.

6990-43-8

84605-29-8

Chemical name

zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate)

Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts

Acute toxicity: oral

Experimental result:
LD50 (rat, m/f) > 2000 mg/kg bw

--

Acute toxicity: inhalation

RA: CAS 84605-29-8

Experimental result:
LC50 (rat, m/f) > 2.3 mg/L air

Acute toxicity: dermal

WoE:

Experimental result:
Minimum lethal dose(rabbit, m/f) = 5010 mg/kg bw

 

RA: CAS 84605-29-8

Experimental result:
LD50 (rat/rabbit, m/f) > 2000 mg/kg bw

(a) The substance subject to the REACh Phase-in registration deadline of 31 May 2013 is indicated in bold font. Only for this substance a full set of experimental results and/or read-across is given.

(b) Reference (read-across) substance(s) are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

 

Acute toxicity: oral

CAS 6990-43-8

Zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) was tested for acute oral toxicity in rats in a GLP-compliant study conducted according to OECD guideline 401 (Ebert, 1992). A group of 5 male and 5 female Sprague-Dawley rats was given a single oral dose of the test material at 2000 mg/kg bw by gavage. No mortalities occurred and no effect on body weight was noted. Two rats (one male and one female) were slightly apathetic on the day of application (Day 0) and on Day 1 post-application. The anal region of two other male rats was slightly covered with light brown and pasty excrements on Day 1 post-application. On Day 2 post-application, both symptoms were not noted any more. Other acute toxicological symptoms were not observed during the 14-day observation period. No macroscopical organ changes were observed in any animal.

Based on the results of these studies, the oral LD50 in male and female rats was estimated to be greater than 2000 mg/kg bw.

Zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) had been tested for acute oral toxicity in earlier studies.

In Sprague-Dawley rats given the test material at 1580, 2000, 2510 and 3160 mg/kg bw by oral gavage, the LD50 value in males and females was determined to be 2320 (1970-2775) mg/kg bw (Younger, 1965). During the study period, severe diarrhoea, tremors, increasing weakness, dyspnoea and collapse were observed. No changes in body weight were reported in any animal. Necropsy revealed gastroenteritis, liver discolouration and haemorrhagic areas in the lungs.

In two studies conducted by Birch (1973), groups of male and female Sprague-Dawley rats were orally exposed to the test material at 1260, 1580, 2000 and 2510 mg/kg bw in one study, and at 3160, 3980, 5010 and 6310 mg/kg bw in the other study.

In the first study, the oral LD50 was calculated to be 1800 (1710-1890) mg/kg bw. Survivors showed reduced appetite and activity after two to three days. In not surviving animals increasing weakness, collapse and death were observed. In the animals found dead, necropsy revealed haemorrhagic areas of the lungs, slight liver discolouration and acute gastrointestinal inflammation. No changes were noted in animals sacrificed at termination.

In the second study, the calculated oral LD50 value was 4500 (4270-4730) mg/kg bw. Survivors showed reduced appetite and activity after two to three days. In not surviving animals increasing weakness, collapse and death were observed. Lung and liver hyperaemia and acute gastrointestinal inflammation were seen in animals found dead, while no effects were observed at necropsy of animals sacrificed at termination.

Acute toxicity: inhalation

CAS 84605-29-8

An acute inhalation toxicity study was conducted with Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts following a method similar to OECD guideline 403 (Findlay, 1981). Sprague-Dawley rats (5 per sex) were whole body exposed to vapours of the test material at a nominal concentration of 2.3 mg/L air for 4 h. No mortalities occurred. Diarrhoea was noted in one rat following exposure. All remaining rats appeared normal. Gross necropsy findings were within normal limits, except for one animal showing red foci throughout the liver. Tan livers and kidneys were observed at necropsy, however, these effects were deemed to be not treatment-related.

The LC50 in male and female rats was thus estimated to be > 2.3 mg/L.

Acute toxicity: dermal

CAS 6990-43-8

Three early studies (prior to GLP) are available in which the acute dermal toxicity of zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) has been investigated, by determination of the minimum lethal dose in male and female New Zealand White rabbits.

In a study by Younger (1965), animals (one per dose) were dermally exposed to the test substance (50% v/v in corn oil) at 794, 1260, 2000, 3160, 5010 and 7940 mg/kg bw under occlusive conditions (no data on exposure duration). Between Days 3 and 5 (end of the post-exposure observation period), the female exposed to 5010 and the male exposed to 7940 mg/kg bw had died. Clinical signs of toxicity included increasing weakness and were followed after two days by tremors, dyspnoea and squealing. The body weight gains were within the normal ranges in surviving animals during the study period. Necropsy of the not surviving animals revealed pulmonary hyperaemia. The liver and kidneys of the animals were of normal size and colour. The minimum lethal dermal dose was 5010 mg/kg bw/day in this study.

Birch (1975) conducted two studies in which animals were dermally exposed for 24 h to the undiluted test substance at 5010 (one male) and 7940 (one male and one female) mg/kg bw, or 40% (w/v) test substance in corn oil at 3160 (one male), 5010 (one female) and 7940 (one male and one female) mg/kg bw, respectively. The type of coverage was not reported.

Taken together, exposure to 7940 mg/kg bw resulted in mortality in two males and one female between Days 3 and 6 of the 14-day post-exposure period. No mortalities occurred at the lower dose levels. In both studies, survivors showed reduced appetite and activity after three to five days. In the not surviving animals increasing weakness and collapse were observed. Necropsy findings of the animals found dead included lung hyperaemia, liver and kidney discolouration, enlarged gall bladder and gastrointestinal inflammation. The organs of animals sacrificed at termination appeared normal. The minimum lethal dermal dose in both studies was thus 7940 mg/kg bw.

The available studies indicate that dermal exposure results in mortality only at high dose levels from 5010 to 7940 mg/kg bw. As described above, in contemporary acute oral toxicity studies mortality occurred at lower dose levels. Taken all information into account, it appears unlikely that the dermal LD50 could be lower than the oral LD50, which in the most reliable study available was estimated to be > 2000 mg/kg bw. Therefore, based on expert judgement, the dermal LD50 of Zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) is considered to be also greater than 2000 mg/kg bw.

In support of this notion, the available data on the structurally related substance Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts were considered in the weight of evidence assessment by mean of read-across.

CAS 84605-29-8

The acute dermal toxicity of Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts was assessed in Sprague-Dawley rats in a GLP study following a method similar to OECD guideline 402 (Guillot, 1985). The test substance was applied as a 50.04% (w/v) solution in 10% aqueous dispersion of gum Arabic. A group of 10 animals (5 per sex) were exposed to the test material at 2002 mg/kg bw for 25 h under semiocclusive conditions. No mortalities occurred up to the end of the 14-day observation period. Prostration was noted in one animal. No other behavioural anomalies were observed. Desquamation of the skin was noted on Day 11.

As no animals died, the dermal LD50 in male and female rats was estimated to be > 2002 mg/kg bw.

In another study in New Zealand White rabbits, the undiluted test substance was applied to the abraded skin of a group of 4 animals (2 per sex) at 2000 mg/kg bw (Bruce and Bernard, 1980). The skin was exposed for 24 h under semiocclusive conditions. No mortality was observed during the study period. Erythema was observed in one animal on Days 2 and 3 post-application. All animals exhibited peeling of the skin at the dose site on the last three days of the study. At necropsy, one animal showed pale kidneys, the remaining animals being without notable changes.

The dermal LD50 in male and female rabbits was thus greater than 2000 mg/kg bw.

Conclusions for acute toxicity

The substance zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) has been tested for acute oral toxicity in several studies. All studies consistently show that the substance is of low toxicity after acute oral exposure. The most adequate and reliable study indicates that the oral LD50 in male and female rats is > 2000 mg/kg bw.

There is no information available on acute toxicity by inhalation. Therefore, in order to fulfil the standard information requirements set out in Annex VII, Section 8.5.2, in accordance with Annex XI, Section 1.5 of Regulation (EC) No 1907/2006, read-across from a structurally similar substance is conducted.

An acute inhalation toxicity study with Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts (CAS 84605-29-8) resulted in an LC50 value > 2.3 mg/L air in male and female rats.

The acute dermal toxicity of zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) has been investigated in several studies in rabbits. The available data indicate that mortality occurs at high dose levels, with reported minimum lethal dermal doses of 5010 and 7940 mg/kg bw. Together with the available information on acute oral toxicity, the dermal LD50 is likely to be higher than 2000 mg/kg bw.

Available information on the structurally similar substance Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts supports this assumption. The acute dermal toxicity of the substance has been assessed in rats and rabbits, resulting in dermal LD50 values > 2000 mg/kg bw.

Based on the available data, the substance zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) is considered to be not toxic by the oral, inhalation and dermal routes.


Justification for selection of acute toxicity – oral endpoint
The selected study is the most adequate and reliable study based on overall quality assessment (refer to the endpoint discussion for further details).

Justification for selection of acute toxicity – inhalation endpoint
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall quality assessment (refer to the endpoint discussion for further details).

Justification for selection of acute toxicity – dermal endpoint
Hazard assessment is based on the weight of evidence from all available studies.
Hazard assessment is also conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall quality assessment (refer to the endpoint discussion for further details).

Justification for classification or non-classification

Based on substance specific data and read-across from a structurally similar substance following an analogue approach, the available data on the acute toxicity of the substance do not meet the classification criteria according to Regulation (EC) No 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.