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Administrative data

Description of key information

28 d NOAEL = 150 mg/kg bw/d (rat, OECD TG 407, RL1: 0, 15, 150 or 1000 mg/kg bw/d)

91 d NOAEL = 500 mg/kg bw/d (rat, combined repeated dose/1 generation reproduction study, no guideline; RL2: 0, 500, 1000, 2000 mg/kg bw/d) (read-across from 2,4,7,9-Tetramethyl-5-decyne-4,7-diol )

91 d NOAEL = 250 mg/kg bw/d (beagle dog, no guideline, RL2: 0, 200, 250 and 300 mg/kg/day) (read-across from 2,4,7,9-Tetramethyl-5-decyne-4,7-diol)

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: oral
Remarks:
other: one generation reproduction study preceeds OECD Guidelines
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: 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
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Duration of treatment / exposure:
91 days
Dose / conc.:
500 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Dose / conc.:
2 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10 male
20 female
Control animals:
yes
Details on study design:
Ten male and twenty female sexually mature rats were randomly assigned to each group.  Males were sacrificed following the 20th day of breeding and females were sacrificed when their litters were weaned at 21 days of age.  Animals were fed their respective diets from the start of cohabitation until their scheduled sacrifice.  
The weanlings were randomized within their respective groups and carried on the same dose levels as their parents for 91 days.  Test diets were prepared weekly. Analytical monitoring of the test diets was performed.  Statistical analysis of the body weight, food consumption, clinical chemistry, and hematology data was performed using the Student’s t-test.
Observations and examinations performed and frequency:
Males were sacrificed following the 20th day of breeding and females were sacrificed when their litters were weaned at 21 days of age.  Animals were fed their respective diets from the start of cohabitation until their scheduled sacrifice.  
The weanlings were randomized within their respective groups and carried on the same dose levels as their parents for 91 days.  Test diets were prepared weekly. Analytical monitoring of the test diets was performed.  Statistical analysis of the body weight, food consumption, clinical chemistry, and hematology data was performed using the Student’s t-test.
Clinical signs:
no effects observed
Description (incidence and severity):
No rats expired in this phase of the experiment
Mortality:
no mortality observed
Description (incidence):
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):
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.
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Description (incidence and severity):
No gross abnormalties were observed in any of the F0 parents, either male or female.
Histopathological findings: non-neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): All rats survived for the duration of the study. No abnormal clinical signs were observed in any of the rats, either test or control, during the entire study period.

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.

Hematological Values 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: All total WBC counts, mean as well as individual, were
within our normal range.
WBC Diff: All rats exanined displayed normal differential counts.
Plat. Est : The platelets of all rats examined were deemed to have
been adequate.

Hematological Values at 92 Days:

RBC: All total RBC counts, mean 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 #I122 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 platele testimate of all rats examined were
deemed to have been adequate.

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

Clinical Chemistry:

FBS: Low dose female rat #I1070 had an FBS of 260 mg/dl;
histopathologically this ra t 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 both high dose 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 rat #1117 had an SGPT wake of 105. Histopathologically this
rat exhibited mild pulmonary Iyphocytosis.
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 #1082 had
a Total Protein value of 8.52 g/dl. Histopathologically this rat
exhibited pulmonary lymphocytosis.
Alk. Phos/ase: The low and high dose mean values were
statistically less than the correspondirig control values. This is
of no biological significance, however, since all values, mean as
well as individual, were normal.


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

OTHER FINDINGS (PARENTAL ANIMALS): None
Dose descriptor:
NOAEL
Effect level:
ca. 500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Critical effects observed:
no
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The key study is GLP compliant and is of high quality, Klimisch score = 1

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

For the assessment of toxicity after repeated administration of 2,4,7,9-tetramethyldecane-4,7-diol a 28 d study is available. In addition, a subacute (28 d) toxicity study in rat and a subchronic (90 d) toxicity study in beagle dogs and in rats are available for the source substance 2,4,7,9-Tetramethyl-5-decyne-4,7-diol. A detailed justification for read-across is attached to iuclid section 13.

 

Subacute toxicity

The purpose of this study was to determine the toxicity of the test article, 2,4,7,9-tetramethyldecane-4,7-diol, following oral (gavage) administration to the rat for at least 28 days.

Male and female HsdBrlHan:WIST rats were assigned to four groups (five animals/sex/group). Each group received dose preparations at dose levels of 0, 15, 150 or 1000 mg/kg of body weight at a dose volume of 5 mL/kg.

A pilot study run before the start of the study confirmed that in three male and three female rats dosed at 1000 mg/kg for five days no severe toxicity was seen.

Assessment of toxicity was based on mortality, clinical observations, clinical and anatomic pathology evaluations, clinical pathology and functional observational battery and locomotor activity.

There were no decedents during the study.

Total cholesterol was seen to increase in a dose-related manner in both males and females. Animals dosed at 1000 mg/kg/day recorded increases in total cholesterol compared to control of 71% for males (p<0.001) and 63% for females (p<0.01).

Animals dosed at 150 mg/kg/day also showed increases in both sexes (males 29% and females 25%).

A dose-related increase in globulin was seen in males dosed at 150 mg/kg/day (8%) and 1000 mg/kg/day (25%, p<0.01). Group mean globulin was also increased in a dose-related manner in females. This was reflected in an increase in total protein values in these animals.

Group mean liver weights adjusted to overall mean body weight increased in males and females dosed at 150 mg/kg/day and at a greater magnitude in animals dosed at 1000 mg/kg/day.

Macroscopically, there was large or mottled liver, and pale or mottled kidney in some treated animals.

Microscopically, in high dose animals, there was hepatocyte hypertrophy in the liver; increased follicular cell hypertrophy in the thyroid; increased hyaline droplets (males only) and focal nephropathy in the kidney; and minor squamous cell hyperplasia in the forestomach, due to effects of the test article. Liver hepatocyte hypertrophy and increased hyaline droplets in the male kidney were also seen in intermediate dose animals.

Microscopic findings in the liver, thyroid, male kidney and stomach of low dose animals were similar to controls and therefore this dose was considered to be the overall no observable effect level (NOEL).

In conclusion, the test item was orally administered at dose levels of 0, 15, 150 and 1000 mg/kg/day for at least 28 days and was well tolerated. There were no significant clinical observations, and only minor increases in bodyweight and food consumption at 1000 mg/kg/day. Increases in total cholesterol, globulin and total protein were of unknown toxicological significance. Microscopic changes in the liver, thyroid, male kidney and stomach were due to effects of the test article, but only those in the liver and thyroid were of toxicological significance. Microscopic findings in the liver, thyroid, male kidney and stomach of animals dosed at 15 mg/kg/day were similar to controls.

The increases in total cholesterol in animals dosed at 150 and 1000 mg/kg/day could be associated with changes in the liver which is the site of cholesterol synthesis. High liver weights in animals dosed at 150 and 1000 mg/kg/day correlated with the large or mottled liver seen macroscopically and those changes seen microscopically. The most notable microscopic changes were the increase in hepatocyte hypertrophy, and the associated thyroid follicular cell hypertrophy. In the rat, follicular cell hypertrophy is generally considered to be an adaptive change due to increased thyroid hormone

metabolism in the liver and is commonly associated with liver cell hypertrophy. The hyaline droplets and associated tubular degeneration are common background findings in the male rat, and whilst the incidence appeared to be treatment-related they are considered to be of no toxicological significance.

The liver weight changes and the severity of the microscopic changes in the liver, thyroid and kidney can be associated with the increased metabolism of the test item, and therefore, 150 mg/kg/day was considered to be the No-Adverse-Effect Level (NOAEL).

  

2,4,7,9-Tetramethyl-5-decyne-4,7-diol was administered to Long-Evans rats (6/sex/dose level) at dose levels of 625, 1250, 2500 and 5000 ppm in the diet for a period of 28 days. Evaluation of mortality, physical observations, body weight, and food consumption data, as well as gross necropsy observations did not reveal any adverse effects considered to be attributable to the administration of 2,4,7,9-Tetramethyl-5-decyne-4,7-diol at any of the dose levels. However, histopathology was not performed in this study.

 

Subchronic toxicity

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 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.

 

2,4,7,9-Tetramethyl-5-decyne-4,7-diol was administered orally to beagle dogs in gelatin capsules at dose levels of 0, 200, 250 and 300 mg/kg/day for 91 days. Because the dogs had to be gradually acclimated from 50 mg/kg/day to higher dose levels of the test item to avoid vomiting, the total test period was 130 days. The control animals received capsules of granulated table sugar. Capsule administration followed feeding by approximately one hour. All dogs survived for the duration of this study with few clinical signs. Occasional dogs in the mid- and high-dose groups exhibited sporadic, compound-related, neurological disturbances (convulsions, tremors, incoordination and/or paralysis) during the study. All other observations, including feed consumption, body weight gains, organ weights (except liver), clinical chemistries, hematology, urinalysis, gross pathology, and histology were judged to reflect no compound-related/ biologically significant changes. This study did not establish a no-observed-effect-level (NOEL) of test item in dogs, since mean liver weights and liver-to-body weight ratios in all test item-treated groups were higher than in corresponding control groups. However, since no histological abnormalities were observed in these livers, the liver enlargement was judged to be due to hyperplasia of the hepatic endoplasmic reticulum, where xenobiotic/drug metabolizing enzymes are located. These common adaptive liver changes are generally reversible, after test compound exposure is discontinued. The NOAEL was established at 200 mg/kg bw/d based on neurological disturbances at 250 and 300 mg/kg bw/d. 

 

Both, the target and the source substance induced liver weight changes and microscopic changes in the liver which are in general associated with increased xenobiotic metabolism and thus, are considered to be adaptive rather than adverse effects.

 

Based on the available data, the overall dose descriptor for repeated dose toxicity of 2,4,7,9-tetramethyldecane-4,7-diol is the subchronic NOAEL of 500 mg/kg bw/d obtained in the 90 d study in rats conducted with the source substance 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, since this NOAEL lead to the most conservative DNEL (see iuclid section 7 – Toxicological information).

 

There are no data gaps for the endpoint repeated dose toxicity. 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.

Justification for classification or non-classification

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