Registration Dossier

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

NOAEL = 500 mg/kg bw/d (rat, 1 generation reproduction/90 d study; read-across: 2,4,7,9-Tetramethyl-5-decyne-4,7-diol and 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated(3.8).)

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar toxicological properties because
- they are manufactured from similar precursors under similar conditions
- they share structural similarities with common functional groups: the substances start with an acetylene group as core structure; geminal hydroxyl groups on the alpha carbon atoms; distal to the geminal hydroxyl groups is an isobutyl group (methyl isopropyl); the target substance 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (1.3) is further functionalised with ethylene oxide and has an ethoxylation degree of 1.3; the source substance 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (3.8) has an ethoxylation degree of 3.8
- they have similar physicochemical properties and thus, show a similar toxicokinetic behaviour
- they are expected to undergo similar metabolism: oxidation of the terminal methyl groups to result in alcohol, aldehyde and finally the corresponding acid

Therefore, read-across from the existing toxicity, ecotoxicity, environmental fate and physicochemical studies on the source substances is considered as an appropriate adaptation to the standard information requirements of REACH regulation.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see “Justification for read-across” attached to IUCLID section 13

3. ANALOGUE APPROACH JUSTIFICATION
see “Justification for read-across” attached to IUCLID section 13

4. DATA MATRIX
see “Justification for read-across” attached to IUCLID section 13
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Principles of method if other than guideline:
Design of Study I Single Generation Reproduction Study in the Rat (Flo->Fla):
Design of study II Ninety One Day Feeding Study (Fla Rats):

Ten male and twenty female sexually mature rats per groups were exposed to the following levels of the test item.

1. Low Dose: 500 mg/kg/d
2. Mid Dose: 1,000 mg/kg/d
3. High Dose: 2,000 mg/kg/d

The animals were mated and the newborn raised to weanling age.
The weanlings were randomized to their respective groups according to SOPs and carried on the same levels to the termination of the experiment.
Body weight and feed consumption data as well as several reproductive parameters were taken from the Fo rats.
Body weight and consumption data were taken weekly from the Fla rats.
Certain hematological and urine analytical parameters were performed on five male and five female Fla rats per group after 45 days and after 91 days.
Certain clinical chemistry parameters were performed on five male and five female rats per group after 91 days on test.
Gross necropsy was performed on all rats.
Organ weights and organ-to-body weight ratios were done on ten male and ten female Fla rats per group.
Complete histopathology was done on ten male and ten female rats from the high dose and control group while the major organs were examined histopathologically from all remaing survivors.


Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, Mass.
- Acclimation period: four weeks
- Housing: The animals were housed individually during quarantine in steel wire mesh suspended cages in a room by themselves with a constant temperature of 73° +/- 3° F (equal to 23° +/- 2° C), with a constant humidity of approximately 40 % to 70 % and with 100 % fresh air make-up, approximately eight to ten complete air changes per hour.
- Diet, Water: Feed and water were provided ad libitum.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23° +/- 2° C
- Humidity (%): 40 % to 70 %
- Air changes (per hr): 8 - 10
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
not specified
Frequency of treatment:
continuous via feed
Dose / conc.:
500 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
Dose / conc.:
2 000 mg/kg bw/day
Control animals:
yes
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
ca. 500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Reproductive effects observed:
no
Conclusions:
The test item showed no effect at 500 mg/kg/day but did have a toxic effect in the F1a generation at greater than or equal to 1,000 mg/kg/day while in the reproduction phase of this experiment there was a toxic effect at the 2,000 mg/kg/day level, a borderline effect at the 1,000 mg/kg/day level and no effect at 500 mg/kg/day.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Test done before GLP and Guidelines were established. Klimisch rating 2.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No experimental data on 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated(1.3) are available for the assessment of toxicity to reproduction. However, a single generation reproduction study was conducted with the structurally related source substances 2,4,7,9-Tetramethyl-5-decyne-4,7-diol and 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated(3.8). A detailed justification for read-across is attached to iuclid section 13.

 

2,4,7,9-Tetramethyl-5-decyne-4,7-diol was fed to the rat during a single generation reproduction study and for ninety one days to the F1a weanlings. The test material was mixed into the rats’ feed to provide dose levels of 0, 500, 1000, and 2000 mg/kg/day. Sexually mature Sprague-Dawley albino rats were divided into four groups, each consisting of ten male and twenty female rats. All Fo male rats, both test and control, were fed their respective diets until their litters reached the age of 21 days for weaning, when the Fo dams were sacrificed. The weanlings were randomized to their respective groups and carried on the same dose levels to the termination of the experiment.

The only pertinent findings observed in the Fo parents were:

1. Slight decrease in the mean weaning weight of both male and female pups of the high-dose group, 2. Slight decrease in fertility (95% vs. 100% in control) and lactation (88% vs 98% in control) indices of the high-dose group,

3. Decreased body weight and feed consumption of the high-dose female group,

4. Normal histology of the reproductive organs in the Fo parents.

The following pertinent findings were observed in the F1a rats:

1. Slight decrease in the mean rate of body weight gain in the mid- and high-dose male and female rats; there was also significant decrease in this parameter in the low-dose male group during the first eight weeks,

2. Normal mean hematological findings, clinical chemistry findings, and urinalysis findings after 91 days on test,

3. Significant increase in the liver weight of the mid- and high-dose male and female test groups with corresponding increase in the liver-to-body weight ratios,

4. Corresponding histopathology of the liver of the mid- and high-dose male and female rats, showing mild to moderate centrilobular cloudy swelling of hepatocytes.

2,4,7,9-Tetramethyl-5-decyne-4,7-diol, when fed to rats under the conditions of this experiment, showed no effect at 500 mg/kg/day but did have a toxic effect in the F1a generation at greater than or equal to 1,000 mg/kg/day while in the reproduction phase of this experiment there was a toxic effect at the 2,000 mg/kg/day level, a borderline effect at the 1,000 mg/kg/day level and no effect at 500 mg/kg/day.

 

2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated(3.8) was fed to the rat during a single generation reproduction study and for ninety one days to the F1a weanlings. The test material was mixed into the rats’ feed to provide dose levels of 0, 500, 1000, and 2000 mg/kg/day. Sexually mature Sprague-Dawley albino rats were divided into four groups, each consisting of ten male and twenty female rats. The animals were mated and the newborn raised to weanling age. The weanlings were randomized to their respective groups according to our Standard Operating Procedures and carried on the same levels to the termination of this 91 day feeding study. Body weight and feed consumption data as well as several reproductive parameters were taken from the F0 rats.

Certain hematological and urine analytical parameters were performed on five male and five female F1a rats per group after 45 days and 91 days. Clinical chemistry determinations were conducted on five male and five female F1a rats per group prior to sacrifice. Gross necropsy was performed on all rats. Organ weights and organ-to-body weight ratios were done on ten male and ten female F1a rats per group. Complete histopathology was done on ten male and ten female rats from the high dose and control groups while the major organs were examined histopathologically from all the remaining survivors.

The only pertinent findings observed in the F0 parents were the following:

1. Decrease in the weaning weight of the male and female high dose pups,

2.Decrease in the number of live born pups both male and female at the high dose level, Slight decrease in fertility (90% vs. 100% in control) index of the high-dose group,

3.Decreased body weight in all female test groups after weaning.

4.Normal histology of the reproductive organs.

The only pertinent findings observed in the F1a rats were as follows:

1. Only sporadic significant decrease in the feed consumption of the male test groups during the first: eight weeks on test.

2. Biologically significant decrease in the rate of body weight gain of the high dose male and female groups,

3. Normal clinical chemistry values after 91 days on test.

4. Normal hematology findings after 45 and 91 days on test.

5. Normal urinalysis results after 45 and 91 days on test,

6. Dose related increase in the liver to body weight ratios, particularly striking in the female test groups.

From the data it was concluded that, when the test item is fed to rats under the conditions of this experiment, it does not cause any toxic effect at levels of 500 mg/kg/d and 1,000 mg/kg/d, but it does

cause a toxic effect at 2,000 mg/kg/d.

 

 

Conclusion 

Both source substances induced a slight decrease in the mean weaning weight of both male and female pups of the high-dose group (2000 mg/kg bw/d). However, body weight and feed consumption of the high-dose dams was decreased.

In both studies conducted with the source substances there was a very slight decrease in fertility and lactation indices of the high-dose group, which is considered secondary to the lower body weight in the high dose dams. In the study conducted with 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated(3.8) there was in addition a slight decrease in the number of live born pups at the high dose level, which is also considered secondary to the lower body weight in the high dose dams.

 

The overall NOAEL used for chemical safety assessment is the value of 500 mg/kg/day obtained in the study with the source substance 2,4,7,9-Tetramethyl-5-decyne-4,7-diol.

 

There are no data gaps for the endpoint effects to fertility. No human data are available. However, there is no reason to believe that these results from rat and rabbits would not be applicable to humans.

Effects on developmental toxicity

Description of key information

No experimental data on developmental toxicity is available for 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (1.3). A testing proposal for an OECD TG 414 study in rats to be conducted with the source substance 2,4,7,9-Tetramethyl-5-decyne-4,7-diol is included in the dossier. A justification for read-across is attached to Iuclid section 13.

When the study data are available, a robust study summary will be prepared and submitted within an update of the dossier. Evaluation will be reconsidered based on the outcome of the prenatal developmental toxicity study.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study planned (based on read-across)
Study period:
As per timings provided in ECHA final decision
Justification for type of information:
TESTING PROPOSAL ON VERTEBRATE ANIMALS
According to REACH regulation Annex IX the conduct of a prenatal developmental toxicity study is required to cover the endpoint developmental toxicity.

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out: 2,4,7,9-Tetramethyl-5-decyne-4,7-diol (CAS no. 126-86-3)

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION [please address all points below]:
- Available GLP studies: no studies available
- Available non-GLP studies: no studies available
- Historical human data: no data available
- (Q)SAR: No adequate QSAR model is available to fulfill this information requirement.
- In vitro methods: Currently no validated and accepted in vitro methods are available to cover this
endpoint. It is currently not possible, with in-vitro models, to account for the influence of the complex processes of absorption, distribution in the body, metabolism and excretion that occur in the whole animal, which will affect the toxic properties of the test substance.
- Weight of evidence: No adequate data are available, neither for the target substance, nor for related substances, to cover this endpoint.
- Grouping and read-across: A justification for read-across is attached to Iuclid section 13.
- Substance-tailored exposure driven testing: Based on use conditions, exposure cannot be completely excluded.
- Approaches in addition to above [if applicable]: n.a.
- Other reasons [if applicable]: n.a.

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
Column 2 of Annex IX states that the reproductive toxicity studies do not need to be performed if:
- the substance is known to be a genotoxic carcinogen and appropriate risk management measures are implemented; or
- the substance is known to be a germ cell mutagen and appropriate risk management measures are implemented; or
- the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available) it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma/blood concentrations below detection limit using a sensitive method and absence of the substance and of metabolites of the substance in urine, bile or exhaled air) and there is no or no significant human exposure.
None of these conditions are met by the substance: The substance is not classified for carcinogenicity or mutagenicity. Furthermore, the substance was shown to be systemically available as demonstrated by findings reported in the available repeated dose toxicity studies. Therefore, the above listed column 2 adaptions cannot be applied.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Details on study design / methodology proposed:
The proposed study design is in accordance with the OECD 414 guideline (Prenatal Development Toxicity Study). The oral route of exposure is selected based on the physico-chemical properties of the substance. The rat is chosen as the initial species as detailed in ECHA's Endpoint specific guidance R.7a.
Reason / purpose:
read-across: supporting information
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Route of administration:
oral: gavage
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available (further information necessary)
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 substance has no structural alerts for developmental toxicity. Test done before GLP and Guidelines were established. This study contains data which are close to meet the criteria set forth in Regulation EC No. 440/2008 for filling REACH endpoints. The data is generated in a reliable laboratory using established protocols.


Justification for selection of Effect on developmental toxicity: via oral route:
Only one test available.

Toxicity to reproduction: other studies

Additional information

According to the UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS) Part 3 no classification required.

Justification for classification or non-classification

According to the UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS) Part 3 Chapter 3.7 this substance is not causing concern to be toxic to reproduction.