Registration Dossier

Toxicological information

Endpoint summary

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Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

The test item, when fed to rats under the conditions of this experiment, showed no effect at 500 mg/kg/day.

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
Study period:
1979
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: both substances start with an acetylene group as core structure, however, in the target substance this acetylene group has been fully hydrogenated during the manufacturing process; geminal hydroxyl groups on the alpha carbon atoms; distal to the geminal hydroxyl groups is an isobutyl group (methyl isopropyl)
- 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

Since the central acetylene group in the source substance is sterically shielded by the neighbouring functional groups, this structural difference does not lead to major differences in reactivity and/or toxicity, which is demonstrated based on the available toxicological data.

Therefore, read-across from the existing toxicity studies on the source substance 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: 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
Remarks:
Doses / Concentrations:
500 mg/kg/d
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
1000 mg/kg/d
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
2000 mg/kg/d
Basis:
nominal in diet
No. of animals per sex per dose:
10 male
20 female
Control animals:
yes
Clinical signs:
no effects observed
Description (incidence and severity):
No rats expired in this phase of the experiment.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Only one pertinent finding: The mean body weight of the high dose female group after weaning its young was significantly lower than the corresponding control.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Only one pertinent finding: The mean body weight of the high dose female group after weaning its young was significantly lower than the corresponding control.
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Description (incidence and severity):
No gross abnormalities were observed in any of the Fo parents, either male or female.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
Histopathology examination of the reproductive organs from all Fo parents revealed no abnormalities.
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Test substance intake: The feed consumption of the high dose female group after weaning its young was significantly lower than the control. There was no other pertinent findings.
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): All rats survived for the duration of the study.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): Only one pertinent finding: The mean body weight of the high dose female group after weaning its young was significantly lower than the corresponding control.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS): The feed consumption of the high dose female group after weaning its young was significantly lower than the control. There was no other pertinent findings.


GROSS PATHOLOGY (PARENTAL ANIMALS): No gross abnormalities were observed in any of the Fo parents, either male or female.

HISTOPATHOLOGY (PARENTAL ANIMALS): Histopathology examination of the reproductive organs from all Fo parents revealed no abnormalities.

OTHER FINDINGS (PARENTAL ANIMALS): None
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
Clinical signs:
no effects observed
Description (incidence and severity):
No abnormal clinical sign were observed in any of the rats, either test or control, during the entire study period.
Mortality / viability:
no mortality observed
Description (incidence and severity):
No rats expired in this phase of the experiment.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There was persistent statistically significant decrease in the rate of mean weekly body weight gain in the high dose rats, goth male and female, througout the experiment, for most weeks in the mid dose rats, both male and female, and for ...
Gross pathological findings:
no effects observed
Description (incidence and severity):
No pertinent gross pathology findings were observed in any of the Fla rats at terminal sacrifice.
Histopathological findings:
effects observed, treatment-related
Description (incidence and severity):
The most frequent finding was lymphocytosis of the lungs, either peribronchial or perivascular. This condition, endemic in this strain of rat, was seen in the control as well as in the test animals. The most significant finding, however, ...
VIABILITY (OFFSPRING): No rats expired in this phase of the experiment.

CLINICAL SIGNS (OFFSPRING): No abnormal clinical sign were observed in any of the rats, either test or control, during the entire study period.

BODY WEIGHT (OFFSPRING): There was persistent statistically significant decrease in the rate of mean weekly body weight gain in the high dose rats, goth male and female, througout the experiment, for most weeks in the mid dose rats, both male and female, and for a few weeks in the low dose male rats. The body weight in all the test groups was significantly lower from the corresponding control groups even during zero week due to the fact that these animals came from dams already on various levels of the compound. The rats in the various groups at zero week had widely variable initial body weights because the corresponding Fo dams conceived - and gave birth - at different times.The difference between either the low dose groups and the control groups or the mid dose groups and the control groups is less than 10 % of the corresponding control weight during the last six weeks on test while both high dose groups differed by mor than 10 % from the beginning. Because of this factor we do not consider the low dose and the mid dose difference to be biologically significant.

SEXUAL MATURATION (OFFSPRING)

ORGAN WEIGHTS (OFFSPRING):
Heart: The mean cardiac weight of the high dose male rats was significantly lower than the control. However, there was no morphologic abnormalities observerd microscopically.
Liver: The mean liver weight of the mid and high dose male rats, as well as of all test female rats was significantly higher than the corresponding control rats.
Kidneys: The mean renal weights were not remarkable.
Gonads: The mean testicular weights were not remarkable, while the ovarian weight of the mid dose female group was significantly less than the control group. There was no accompanying histopathology, however, of the ovaries of the mid dose rats.
Brain: The mean brain weight of all the male test groups and of the high dose female group was significantly lower than the corresponding control weight. We do not consider this, hoever, to be of any biological significance since there was no accompanying histopathology of the brain.

GROSS PATHOLOGY (OFFSPRING): No pertinent gross pathology findings were observed in any of the Fla rats at terminal sacrifice.

HISTOPATHOLOGY (OFFSPRING): The most frequent finding was lymphocytosis of the lungs, either peribronchial or perivascular. This condition, endemic in this strain of rat, was seen in the control as well as in the test animals. The most significant finding, however, was the cloudy swelling of the liver seen in a dose dependent way in the mid dose and high dose rats, both male and female. This most likely implies an adaptive hyperplasia of the sub-cellular endoplasmic reticulum of the hepatic cells of the affected test groups.

OTHER FINDINGS (OFFSPRING):

Organ-to-body weight ratios:
Heart-to-body weight ratios: These were not remarkable.
Liver-to-body weight ratios: The ratios for both male and female test groups were considerably higher than the corresponding control values with a dose dependent pattern. The female ratios were slightly higher the the male ones.
Kidneys-to-body weight ratios: These were not remarkable.
Gonads-to-body weight ratios: These were not remarkable.
Brain-to-body weight ratios: These were not remarkable.

Clinical Chemistry:
FBS: Low dose female rat #1070 had an FBS of 260 mg/dl; histopathologically this rat was not remarkable.
BUN: All values, individual as well as mean, were normal.
SGOT: All values, individual as well as mean, were normal.
SGPT: The mean mid dose female and doth high dose male and female values were significantly higher than control. These differences are of no biological significance, however, since all mean as well as individual values except one were normal; high dose male rate #1117 had an SGPT value of 105. Histopathologically this rat exhibited mild pulmonary lymphocytosis.
GGTP: All values, individual as well as mean, were normal.
Total Protein: The mean value for the mid dose groups, male and female, as well as for the high dose groups, both male and female, was significantly higher than control. All mean as well as individual values except one were normal; mid dose female rat #1028 had a Total Protein value of 8.52 g/dl. Histopathologically this rat exhibited pulmonary lymphocytosis.

Hematology:
Hematological Value at 45 Days:
RBC: The mean total RBC counts in the mid dose and the high dose male test groups were significantly lower than the control. All values, however, mean as well as individual, were within our normal range.
HGB: The mean hemoglobin values of the mid dose and high dose male rats were significantly lower than the control, while the same value was higher than the control in the high dose female rats. All values, however, mean as well as individual, were within our established normal range.
HMCT: The mean HMCT values for the low and high dose group of male rats were statistically lower than the control, while the mean HMCT value for the high dose female group was statistically higher than the control. All values, however, mean as well as individual, were within normal range.
WBC Diff: All rats examined displayed normal differential counts.
Plat. Est.: The platelets of all rats examined were deemed to have been adequate.

Hematological Values at 91 Days:
RBC: All total RBC counts, as well as individual, were within normal range.
HGB: All HGB values, mean as well as individual, except one were within normal range; high dose female rat #1122 had a HGB of 11.6 g/dl; histologically this rat exhibited mild pulmonary lymphocytosis.
HMCT: All HMCT values, mean as well as individual, were within normal range.
WBC: The mean total WBC counts of the low and high dose groups were significantly higher than the control groups. All total WBC counts, however, mean as well as individual, were within normal range.
WBC Diff: All rats examined displayed a normal differential counts.
Plat. Est.: The platelet estimate of all rats examined were deemed to have been adequate.

Urinalysis:
Urinalysis at 45 days: There were no significant differences between the test and control groups, male or female, in any urinalysis parameters.
Urinalysis at 91 days: There were no significant differences between the test and control groups, male or female, in any urinalysis parameters.



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:
not specified

The only pertinent findings observed in the Fo parents were: a slight decrease in the mean weaning weight of both male and female pups of the high-dose group, a slight decrease in lactation indices of the high-dose group, decreased body weight and feed consumption of the high-dose female group and normal histology of the reproductive organs in the Fo
parents.  Fertility, viability and gestation indices were not affected.  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: Summary of F0/F1a Reproduction Data

Dose Group         Number of Dams                  Total Number of Pups
(mg/kg/day)        Mated        Conceived        Live-         Still   Day 4        Culled  
Day 21                     
                                        born    born        
   Day 4*
0                 20          20                 235          4        226          43          180
500                 20          20                 252          2        247          51          195
1000                 20          20                 229          0        220          37          173
2000                 20          19                 225          4        214          27          164
* Litters with more than 10 pups were culled to 10

2,4,7,9-Tetramethyl-5-decyne-4,7-diol: Summary of F0/F1a Reproduction Data
(continued)
Dose Group    Avg. # of Pups/Litter          Avg. Pup
Weaning Weight (g)
(mg/kg/day)   Day 4           Weaned 
              M      F            M      F              Male        Female
0             6.0    5.4            4.6          4.5              45.7        44.2
500             6.6    5.8            5.0          4.8              42.0        40.9
1000             5.8    5.3            4.6          4.1              36.6        35.8
2000             5.5    5.8            4.1          4.6              28.8        25.7
The following pertinent findings were observed in the F1a rats: slight decrease in the mean rate of body weight gain in both sexes at the mid- and high-dose (there was also a
significant decrease in this parameter in the low-dose male group during the first eight weeks), normal mean hematological findings, clinical chemistry findings, and
urinalysis findings after 91 days on test, significant increase in the absolute and relative liver weights of both sexes at the mid- and high-dose, corresponding
histopathology of the liver showing mild to moderate centrilobular cloudy swelling of hepatocytes of the mid- and high-dose rats.  The test item, when fed to rats under the
conditions of this experiment, showed no effect at 500mg/kg/day but did have a toxic effect in the Fla generation at >1,000 mg/kg/day.

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 OECD 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 are available for the target substance 2,4,7,9-tetramethyldecane-4,7-diol. However, a single generation reproduction study was conducted with the structurally related substance 2,4,7,9-Tetramethyl-5-decyne-4,7-diol. A justification for read-across is attached to iuclid section 13.

The purpose of this study was to evaluate the possible toxicity of 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, when 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 lactation 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. 


Effects on developmental toxicity

Description of key information

A testing proposal for an OECD TG 414 study in rats is included in the dossier.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
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-tetramethyldecane-4,7-diol

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: No adequate data are available, neither for the target substance, nor for related substances, to cover this endpoint.
- 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.
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

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.

Evaluation will be reconsidered based on the outcome of the prenatal developmental toxicity study.