Name: COMPLETE / SUBSTANCE : 1,3-propanediol, 2-butyl-2-ethyl- / 115-84-4 Tue, 5 Sep
2023, 13:07:05+0900 /Legal entity owner: National Institute of Health Sciences / Kawasaki / Japan
Printing date: 2023-09-05T13:07:05.977+09:00

iTable of Contents
0/0 ............................................................................................................................. 1
National Institute of Health Sciences .................................................................... 2
1,3-propanediol, 2-butyl-2-ethyl- ............................................................................ 4
OECD .......................................................................................................... 4
D Health Effects .................................................................................. 4
67 Repeated dose toxicity: oral .................................................... 4
RepeatedDoseToxicityOral. 001 ............................................ 470 Genetic toxicity in vitro ......................................................... 14
Genetic toxicity in vitro.001 ................................................ 14
Genetic toxicity in vitro.002 ................................................ 20
73 Toxicity to reproduction ........................................................ 24
ToxicityReproduction. ........................................................ 24
DOMAIN .................................................................................................... 35
1,3-propanediol, 2-butyl-2-ethyl- .......................................................... 35
References ................................................................................................................ 36
Reference Substances ...................................................................................... 36
1,3-propanediol, 2-butyl-2-ethyl- .................................................................. 36
Test Materials .................................................................................................. 37
1,3-propanediol, 2-butyl-2-ethyl- .................................................................. 37
Literatures ....................................................................................................... 38
Combined repeat dose and reproductive/developmental toxicity screening
test of 1,3-propanediol, 2-butyl-2-ethyl by oral administration in rats .............. 38
In Vitro Chromosomal Aberration Test of 1,3-Propanediol, 2-butyl-2-ethyl
on Cultured Chinese Hamster Cells. ........................................................... 39
Reverse Mutation Test of 1,3-Propanediol, 2-butyl-2-ethyl on Bacteria. ........... 40ii

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Dossier subject
Dossier subject
1,3-propanediol, 2-butyl-2-ethyl- / 115-84-4
Public nameSubmitting legal entity
National Institute of Health Sciences / Kawasaki / Japan
Dossier creation date/time
Tue, 5 Sep 2023, 13:07:05+0900
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LEGAL_ENTITY: National Institute of Health
Sciences
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General information
Legal entity nameNational Institute of Health Sciences
Remarks
Disclaimer: The contents in this document were created based on the MHLW (Ministry of Health,Labour and Welfare) peer reviewed study reports (in Japanese) in JECDB (Japan Existing Chemical
Database) at http://dra4.nihs.go.jp/mhlw_data/jsp/SearchPageENG.jsp. Authorship is in the Divisionof Risk Assessment, the National Institute of Health Sciences, and the contents do not reflect any official MHLW opinions or any other regulatory policies.

Address
Address 1
Tonomachi 3-25-26
Address 2
Kawasaki-ku
Postal code
210-9501
Town
KawasakiRegion / State
Kanagawa
CountryJapan
JP

Identifiers
Other IT system identifiers
IT system
LEO
ID
10767
IT systemIUCLID42

ID
16558402024DIV750

3

1,3-propanediol, 2-butyl-2-ethylOECD
Health Effects
Repeated dose toxicity: oral
ENDPOINT_STUDY_RECORD: RepeatedDoseToxicityOral. 001

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Administrative data
Endpoint
short-term repeated dose toxicity: oral
Type of information
experimental study
Adequacy of study
key study
Robust study summary
false
Used for classification
false
Used for SDS
false
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
guideline study OECD Test Guideline study under GLP condition
Reliability 1
Cross-reference
Reason / purpose for cross-reference
reference to same study
Related information
OECD / Toxicity to reproduction / ToxicityReproduction. / 1,3-propanediol, 2-butyl-2-ethyl- / 115-84-4

Data source
Reference
Combined repeat dose and reproductive/developmental toxicity screening test of 1,3-propanediol, 2bu / Ministry of Health, Labour and Welfare (MHLW), Japan / study report4Data accessdata published https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF115-84-4d.pdf

Materials and methods
Test guideline
Qualifieraccording to guideline
Guideline
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction /Developmental Toxicity Screening Test)
Deviationsno
GLP compliance
yes
Limit test
no

Test material
Test material information
1,3-propanediol, 2-butyl-2-ethylSpecific details on test material used for the study- Name of test material (as cited in study report): 1,3-propanediol, 2-butyl-2-ethyl- Analytical purity: 99.8%- Storage condition of test material: Cold and dark place (2-8°C)- Stability under test conditions: The stability of test material was identified by analysis of the remainder.

Test animals
Speciesratcommon rodent species
Strainother: Crl: CD (SD)Sexmale/female
Details on test animals or test system and environmental conditions
TEST ANIMALS- Source: Charles River Japan, Inc., Atsugi Breeding Center.
- Age at study initiation: 10 weeks old- Weight at study initiation: Male: 378 g (353-416 g), Female: 233 g (209-265 g)- Housing: Animals were individually housed in bracket-type metallic wire-mesh cages (254W × 350D
× 170H mm), from gestation day 17 to lactation day 4, Dams were bred individually or with individual
littermates in plastic cages (340W x 400D x 185H mm) and bedding.
- Diet: Solid feed (NMF: Oriental Yeast Co., ltd.) was given ad libitum.
- Water: Tap water was given ad libitum.
- Acclimation period: 16 days
5

ENVIRONMENTAL CONDITIONS- Temperature (°C): 23±3 (actual temperature: 22-24°C)- Humidity (%): 50±20% (actual humidity: 40-60%)- Air changes (per hr): 10-15- Photoperiod (hrs dark / hrs light): 12 hr dark/12 hr light (light: 7:00-19:00)

Administration / exposure
Route of administration
oral: gavage
Vehiclemethylcellulose 0.5w/v%
Details on oral exposure- Amount of vehicle (if gavage): 5 mL/kg- Dosing volume: 5 mL/kg
Analytical verification of doses or concentrations
yes
Details on analytical verification of doses or concentrations
The concentration of test suspensions was analyzed by GC on the dosages used in groups of males
at weeks 1 and 6 of administration. Results showed that the concentration of test suspensions ineach concentration was 94.5 to 107.0% of the nominal concentration and both values were within theacceptable range (concentration: percentage of nominal concentration, 100±10%)Duration of treatment / exposure(P) Males: 42 days including 14 days pre-mating(P)Females: 41-46 days including 14 days pre-mating, mating and gestation periods and the days until
day 4 of lactation
Female (no mating, satellite group): 42 days
Frequency of treatment
Once/day, 7 days/week
Doses / concentrations
Dose / conc.
20

mg/kg bw/day (actual dose received)

Dose / conc.
100

mg/kg bw/day (actual dose received)

Dose / conc.
500

mg/kg bw/day (actual dose received)

No. of animals per sex per dose
Mating group: 12 animals/sex/dose (0, 20, 100, and 500 mg/kg bw/day)
Non-mating group: 10 females/dose (0 and 500 mg/kg bw/day)Recovery group: 5 males/dose in the mating group and 5 females/dose in the non-mating groups (0and 500 mg/kg bw/day)6

Control animals
yes, concurrent vehicle
Details on study design- Dose selection rationale: Based on the results of a 14-day preliminary study, the highest dose of 500
mg/kg bw/day was selected as an expected obvious toxic dose, and the lowest dose of 20 mg/kg
bw/day was selected as an expected no toxic dose. The middle dose levels of 100 mg/kg bw/day
were selected.
[14-day preliminary study]
A 14-day repeated dose oral toxicity test (Crl:CD(SD) rats, doses: 0, 250, 500 or 1000 mg/kg bw/day).
At 1,000 mg/kg bw/day, ataxia and prone/lateral position in males and females, increased platelet,
decreased AST and glucose in males, increased liver weight in males and females, decreased thymu
s weight in males, increased kidney weight in females, elevated region of forestomach in males andfemales, large kidney in males were observed. At 500 mg/kg bw/day, ataxia in females, decreased
thymus weight in males were observed. At 250 mg/kg bw/day, decreased thymus weight in males
were observed.
- Rationale for animal assignment (if not random): Body weight-balanced randomization

Examinations
Observations and examinations performed and frequency
CAGE SIDE OBSERVATIONS: Yes- Time schedule: 4 times/day (before administration, immediately after administration, 30 minutes
after administration and 1-3 hours after administration) during the administration period. Once a day
during the recovery period.
DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule:
Males in the main groups and females in the non-mating groups: once before the start of administrati
on, once every weekly during the administration.
Females in the mating groups: once before the start of administration, days specified during mating,gestation, and lactation (mated animals: gestation days 1, 7, 14 and 20, unmated animals: 6 and 13 days after the start of mating, parturient animals: lactation day 4)
Males and females in the recovery groups: once before the start of administration, once every weekly
during the administration and recovery periods.
BODY WEIGHT: Yes- Time schedule for examinations:
Males in the main groups and females in the non-mating groups: days 1, 8, 15, 22, 29, 36 and 42 of ad
ministration and on the day of necropsy
Males and females in the recovery groups: days 1, 8, 15, 22, 29, 36 and 42 of administration, and days
1, 8 and 14 of recovery and on the day of necropsy.
Females in the mating groups: days 1, 8 and 15 of administration (uncopulated animals: day 22 ofadministration), days 0, 7, 14, and 20 of gestation, days 0, 4 of lactation, and on the day of necropsy
Food consumption: Yes
Measurement of food consumption was conducted on all animals at the following frequencies:
Males in the main groups and females in the non-mating groups: days 1, 8, 15, 30 and 42 of administr
ation
Males and females in the recovery groups: days 1, 8, 15, 30 and 42 of administration, and days 1, 8
and 14 of recovery
Females in the mating groups: days 1, 8 and 15 of administration, days 0, 7, 14, and 20 of gestation,days 2 and 4 of lactation
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
7

- Time schedule for collection of blood: At the end of administration period, or at the end of recovery
period in both sexes- Anaesthetic used for blood collection: Isoflurane- Animals fasted: Yes- How many animals:
5 animals/sex/group- Parameters examined: red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mea
n corpuscular hemoglobin, mean corpuscular hemoglobin concentration, reticulocyte percentage,platelet count, white blood cell count, differential white blood cell count, absolute number of each
white blood cell, prothrombin time, activated partial thromboplastin time, fibrinogen.
CLINICAL CHEMISTRY: Yes- Time schedule for collection of blood: At the end of administration period, or at the end of recovery
period in both sexes- Animals fasted: Yes- How many animals:
5 animals/sex/group- Parameters checked: ALP, total cholesterol, triglyceride, phospholipids, total bilirubin, glucose, blood urea nitrogen, creatinine, sodium, potassium, chloride, calcium, inorganic phosphorus, total protein,
albumin, A/G ratio, AST (GOT), ALT (GPT), LDH, γ-GTP
URINALYSIS OF MALES: Yes- Time schedule for collection of urine: final week of administration (days 36 to 37 of administration)and in the final week of recovery (days 8 to 9 of recovery)- Metabolism cages used for collection of urine: Yes
A urine collector to collect four-hour urine samples under fasting but ad libitum drinking conditions,followed by collection of 20-hour urine samples under ad libitum feeding and drinking conditions.
- How many animals: 5 animals/group- Parameters checked: pH, protein, ketones, glucose, occult blood, bilirubin, urobilinogen, color, sediment, urine volume (4-hour volume), osmotic pressure, sodium, potassium, chloride, urine volume (20hour volume), water intake (24-hour volume)
BLOOD HORMONE: No
NEUROBEHAVIOURAL EXAMINATION: Yes- Time schedule for examinations:
Males in the main groups and females in the non-mating groups: final week of administration (day 38
of administration)
Females in the mating groups: lactation day 4 (day 41 to day 43 of administration) after necropsy of
F1 pupsMales and females in the recovery groups: final week of administration (day 38 of administration) andin the final week of recovery (day 10 of recovery).
- Dose groups that were examined: All dose groups (5 animals/sex/group)- Battery of functions tested:
1) Manipulative Test. Auditory response, approach response, touch response, tail pinch response,
pupillary reflex, aerial righting reflex, landing foot splay
2) Measurement of Grip Strength. Following manipulative test, grip strength of forelimb and hind limb
were measured by CPU gauge MODEL-RX-5 (AIKOH Engineering Co., Ltd.).
3) Measurement of Motor Activity. Following measurement of grip strength, motor activity wasmeasured by a motor activity sensor for experimental animals NS-AS01 (Neuro Science, Inc.). The
measurement was conducted for 1 hour, and measured values at 10-minute intervals and from 0 to
60 minutes were collected.
Sacrifice and pathology
GROSS PATHOLOGY: Yes
ORGAN WEIGHT: Yes [brain, pituitary, thyroids (including parathyroids), adrenal gland, thymus, spleen,
heart, liver, kidney, testis, epididymis, prostate, seminal vesicles, ovary, uterus]
8HISTOPATHOLOGY: Yes, [cerebrum, cerebellum (including pons), sciatic nerve, spinal cord (thoracic),eye ball, optic nerve, Harderian gland, pituitary, thyroid, parathyroid, adrenal glands, thymus, spleen,submandibular lymph nodes, mesenteric lymph nodes, heart, thoracic aorta, trachea, lung (including
bronchial), tongue, larynx, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum,
submandibular gland, liver, pancreas, kidney, bladder, testis, ovary, epididymis, uterus, vagina, prostate, seminal vesicles, skin (inguinal), mammary gland (inguinal), sternum and femur (including bonemarrows), skeletal muscle of femur, and individual identification site (pinna with ear tag)]
Statistics
For quantitative data, homogeneity of variance was tested using Bartlett method first. If the variance
was homogenous, statistical difference between each treatment group and the control group was
analyzed using Dunnett method. If not homogenous, statistical difference between each treatmentgroup and the control group was tested using Steel method. For comparison of quantitative data be
tween two groups in the recovery test, homogeneity of variance was analyzed by F-test. Then, if homo
genous, student's t-test was applied. If not homogenous, Aspin-Welch's t-test was used.
Regarding clinical observation (except for frequency of urination, defecation, rearing and grooming)and sensory reactivity, Steel test was applied. Regarding auditory response, approach response, touch
response, tail pinch response, pupillary reflex, aerial righting reflex, Fisher's test was applied.

Results and discussion
Results of examinations
Clinical signs
effects observed, treatment-related
Mortality
no mortality observed
Body weight and weight changes
no effects observed
Food consumption and compound intake (if feeding study)no effects observed
Food efficiency
not examined
Water consumption and compound intake (if drinking water study)
not examined
Ophthalmological findings
not examined
Haematological findings
no effects observed
Clinical biochemistry findings
no effects observed
Urinalysis findings
effects observed, treatment-related
Behaviour (functional findings)
effects observed, treatment-related
Immunological findings
not examined
9Organ weight findings including organ / body weight ratios
effects observed, treatment-related
Gross pathological findings
effects observed, treatment-related
Neuropathological findings
not examined
Histopathological findings: non-neoplastic
effects observed, treatment-related
Histopathological findings: neoplastic
not examined
Details on results
CLINICAL SIGNS AND MORTALITY:
Mortality: There was no death.
Clinical signs:[At the dosing period]: Ataxia was observed in males and females at 500 mg/kg bw/day, and prone/
lateral position was observed in mating females at 500 mg/kg bw/day.
[At the recovery period]: There were no changes related to the test substance in any groups.
DETAILED CLINICAL OBSERVATIONS:
There were no changes related to the test substance in any groups at the dosing and recovery perio
ds.
BODY WEIGHT:
There were no changes related to the test substance in any groups at the dosing and recovery
periods.
FOOD CONSUMPTION:
There were no changes related to the test substance in any groups at the dosing and recovery periods.
URINALYSIS:[At the dosing period]: A decrease tendency in urine pH was observed in males and non-mating
females at 500 mg/kg bw/day.
[At the recovery period]: There were no changes related to the test substance in any groups.
HAEMATOLOGY:[At the end of dosing period]: An increase in lymphocyte (%) and a decrease in neutrophil (%) wereobserved in males at 500 mg/kg bw/day and in mating females at 20 mg/kg bw/day and above. These changes were considered of little toxicological significance because there were no abnormalities inrelated parameters such as white blood cell count.
[At the end of recovery period]: There were no changes related to the test substance in any groups.
CLINICAL CHEMISTRY:[At the end of dosing period]: Decreases in glucose was observed in non-mating females at 500 mg/
kg bw/day. This change was considered of little toxicological significance because it was a minorchange and there were no histopathological changes in the pituitary, thyroid, adrenal, or liver asso
ciated with glycemic regulation.
[At the end of recovery period]: There were no changes related to the test substance in any groups.
NEUROBEHAVIOURAL EXAMINATION:
1) MANIPULATIVE TEST:
There were no changes related to the test substance in any groups at the dosing and recovery
periods.
2) GRIP STRENGTH TEST:
10

There were no changes related to the test substance in any groups at the dosing and recovery periods.
3) LOCOMOTOR ACTIVITY MEASUREMENT:[At the dosing period]: A decrease in locomotor activity was observed in mating females at 500 mg/kg
bw/day.
[At the recovery period]: There were no changes related to the test substance in any groups.
ORGAN WEIGHTS:[At the end of dosing period]:
An increase in relative liver weight was observed in males and females at 500 mg/kg bw/day. An inc
rease in relative kidney weight was observed in males at 100 mg/kg bw/day. Increases in absoluteand relative kidney weights were observed in males at 500 mg/kg bw/day.
[At the end of recovery period]: An increase in relative liver weight was observed in non-mating fema
les at 500 mg/kg bw/day.
GROSS PATHOLOGY:[At the end of dosing period]:
Thickening in limiting ridge of stomach was observed in males at 500 mg/kg bw/day.
[At the end of recovery period]:
There were no changes related to the test substance in any groups.
HISTOPATHOLOGY: NON-NEOPLASTIC:[At the end of dosing period]:
Kidney: Granular cast, regenerated tubule, eosinophilic body in tubular cell were observed in males at
100 mg/kg bw/day and above. Dilatated tubule, necrosis or desquamation in tubular cell were obs
erved in males at 500 mg/kg bw/day.
Stomach: Hyperplasia of squamous in limiting ridge was observed in males and non-mating females
at 500 mg/kg bw/day.
[At the end of recovery period]:
Kidney: Granular cast, regenerated tubule, eosinophilic body in tubular cell were observed in males at
500 mg/kg bw/day.

Effect levels
Key result
false
Dose descriptor
NOAEL
Effect level20

mg/kg bw/day (actual dose received)

Based ontest mat.
Sex
male
Basis for effect level
histopathology: non-neoplastic
Kidney: Granular cast, regenerated tubule, eosinophilic body in tubular cell were observed in males
at 100 mg/kg bw/day.
organ weights and organ / body weight ratios
An increase in relative kidney weight was observed in males at 100 mg/kg bw/day.

11

Key result
false
Dose descriptor
NOAEL
Effect level100

mg/kg bw/day (actual dose received)

Based ontest mat.
Sex
femaleBasis for effect level
behaviour (functional findings)
Decrease in locomotor activity was observed in mating females at 500 mg/kg bw/day.
clinical signs
Ataxia and prone/lateral position were observed in females at 500 mg/kg bw/day.
histopathology: non-neoplastic
Stomach: Hyperplasia of squamous in limiting ridge was observed in non-mating females at 500
mg/kg bw/day.
organ weights and organ / body weight ratios
An increase in relative liver weight was observed in females at 500 mg/kg bw/day.
urinalysis
A decrease tendency in urine pH was observed in non-mating females at 500 mg/kg bw/day.

Any other information on results incl. tables
Figures and Tables (in English) are available in the following full report of the study.
https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF115-84-4d.pdf

Applicant's summary and conclusion
Conclusions
The NOAEL for repeated dose toxicity in this study was determined to be 20 and 100 mg/kg bw/day
for males and females, respectively.
Executive summary
In the combined repeated dose and reproductive/developmental screening test (OECD TG422), SD rats
were treated orally with 1,3-propanediol, 2-butyl-2-ethyl at the doses of 0, 20, 100 and 500 mg/kg bw/day.
Males (12 males/dose: 5 males were treated as a recovery group) were dosed for 42 days including a
14 day pre-mating period and mating periods. Mating females (12 females/dose) were dosed for 41-46
days including 14 day premating, mating, and gestation periods and days until day 4 of lactation. Nonmating female (10 females/dose: 5 females were treated as a recovery group) were dosed for 42 days.
The following findings were observed in examination at the administration period or end ofadministration period. In the clinical signs, ataxia was observed in males and females at 500 mg/kg bw/
day, and prone/lateral position was observed in mating females at 500 mg/kg bw/day. In the locomotor
activity measurement, decrease in locomotor activity was observed in mating females at 500 mg/kg
bw/day. In the urinalysis, decrease tendency in urine pH was observed in males and non-mating females12

at 500 mg/kg bw/day. In the organ weights, an increase in relative liver weight was observed in males
and females at 500 mg/kg bw/day. An increase in relative kidney weight was observed in males at 100
mg/kg bw/day. Increases in absolute and relative kidney weights were observed in males at 500 mg/kg
bw/day. In the gross pathology, thickening in limiting ridge of the stomach was observed in males at 500
mg/kg bw/day. In the histopathology, granular cast, regenerated tubule and eosinophilic body in tubularcell of kidney in males at 100 mg/kg bw/day and above, dilatated tubule, necrosis or desquamation in
tubular cell of kidney in males at 500 mg/kg bw/day, hyperplasia of squamous in limiting ridge of thestomach in males and non-mating females at 500 mg/kg bw/day were observed. Based on the above
results, NOAEL for the repeated dose toxicity of 1,3-propanediol, 2-butyl-2-ethyl was determined to be 20
and 100 mg/kg bw/day for males and female rats, respectively.

13Genetic toxicity in vitro
ENDPOINT_STUDY_RECORD: Genetic toxicity in vitro.001

UUID: 3f4e2678-9bb9-4de6-b363-985bb60a6c8c
Dossier UUID:
Author:Date: 2022-03-25T10:46:38.000+09:00
Remarks:

Administrative data
Endpoint
in vitro gene mutation study in bacteria
Type of information
experimental study
Adequacy of study
key study
Robust study summary
false
Used for classification
false
Used for SDS
false
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
other: OECD Test Guideline study under GLP condition

Data source
Reference
Reverse Mutation Test of 1,3-Propanediol, 2-butyl-2-ethyl on Bacteria. / Ministry of Health, Labour andWelfare (MHLW), Japan / study report
Data accessdata published

Materials and methods
Test guideline
Qualifieraccording to guideline
Guideline
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
14

in vitro gene mutation study in bacteria
Deviations
no
Qualifieraccording to guideline
Guideline
JAPAN: Guidelines for Screening Mutagenicity Testing Of Chemicals
genetic toxicity in vitro, otherDeviationsno
GLP compliance
yesType of assay
bacterial reverse mutation assay
in vitro gene mutation study in bacteria

Test material
Test material information
1,3-propanediol, 2-butyl-2-ethylSpecific details on test material used for the study- Name of test material (as cited in study report): 1,3-Propanediol, 2-butyl-2-ethyl- Analytical purity: 99.8%

MethodSpecies / strain
Species / strain / cell typeS. typhimurium TA 1535, TA 1537, TA 98 and TA 100
bacteria
Species / strain / cell type
E. coli WP2 uvr A
bacteria
Metabolic activation
with and without
Metabolic activation system
S9 mix; SD male rat liver, induced by phenobarbital and 5,6-benzoflavone
Justification for deviation from the high dose level-S9 mix:
39.1, 78.1, 156, 313, 625, 1250 μg/plate (TA100 strain)
9.77, 19.5, 39.1, 78.1, 156, 313 μg/plate (TA1535, TA1537 strains)
156, 313, 625, 1250, 2500, 5000 μg/plate (WP2uvrA, TA98 strains)+S9 mix:
15

39.1, 78.1, 156, 313, 625, 1250 μg/plate (TA100, TA1535, TA1537 strains)
156, 313, 625, 1250, 2500, 5000 μg/plate (WP2uvrA, TA98 strains)
Maximum concentration was established based on the result of the preliminary test at concentration
up to 5000 ug/plate. In this test, the growth inhibition was observed at 313 μg/plate and above forS. typhimurium TA 1535 and TA1537 strains without S9 mix, at 1250 μg/plate and above for S.
typhimurium TA100 strain with or without S9 mix, for S. typhimurium TA1535 and TA1537 stains with
S9 mix, at 5000 μg/plate for S. typhimurium TA98 and E. coli WP2uvrA with or without S9 mix.
Vehicle / solvent- Vehicle(s)/solvent(s) used: DMSO
Controls
Untreated negative controlsnoNegative solvent / vehicle controls
yes
True negative controlsnoPositive controls
yes
Positive control substanceother: -S9 mix: 2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide (AF-2), sodium azide (SAZ) and 2-methoxy-6chloro-9-[3-(2-chloroethyl)-aminopropylamino]acridine 2HCl (ICR-191) ;+S9 mix: 2-aminoanthracene (2AA), benzo[a]pyrene (B[a]P)
Details on test system and experimental conditions
METHOD OF APPLICATION: Preincubation
DURATION- Preincubation period: 20 min at 37°C
- Exposure duration:48 or 50 hrs
NUMBER OF PLATES: 3
NUMBER OF REPLICATIONS: 2
DETERMINATION OF CYTOTOXICITY- Method: other: growth inhibition
Evaluation criteria
A chemical was judged to be mutagenic when the mean number of revertant colonies per plateincreased more than twice that of the negative control and when the dose-related and reproducible increase was observed.
StatisticsnoResults and discussion
Test results
Key result
trueSpecies / strain
S. typhimurium TA 1535
16

bacteria
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity -S9 mix: 313 μg/plate;+S9 mix: 625 μg/plate and above
Vehicle controls validity
valid
Positive controls validity
valid
Key result
trueSpecies / strain
S. typhimurium TA 1537
bacteria
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity -S9 mix: 313 μg/plate;+S9 mix: 1250 μg/plate
Vehicle controls validity
valid
Positive controls validity
valid
Key result
trueSpecies / strain
S. typhimurium TA 98
bacteria
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity -S9 mix: 2500 μg/plate and above;+S9 mix: 2500 μg/plate and above
Vehicle controls validity
valid
17

Positive controls validity
valid
Key result
trueSpecies / strain
S. typhimurium TA 100
bacteria
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity -S9 mix: 1250 μg/plate;+S9 mix: 1250 μg/plate
Vehicle controls validity
valid
Positive controls validity
valid
Key result
trueSpecies / strain
E. coli WP2 uvr A
bacteria
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity -S9 mix: 2500 μg/plate and above;+S9 mix: 2500 μg/plate and above
Vehicle controls validity
valid
Untreated negative controls validity
not examined
Positive controls validityvalid

Any other information on results incl. tables
Figures and Tables (in Japanese) are available in the following full report of the study.
https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF115-84-4e.pdf
Please also see the attached files (Tables in English)
18Applicant's summary and conclusion
Conclusions
Interpretation of results (migrated information): negative
In a bacterial reverse mutation assay using Salmonella typhimurium TA100, TA1535, TA98, and TA
1537, and Escherichia coli WP2uvrA (OECD TG 471), 1,3-propanediol, 2-butyl-2-ethyl was negativewith or without metabolic activation.

19

ENDPOINT_STUDY_RECORD: Genetic toxicity in vitro.002

UUID: 54d54bfa-7d24-4257-869d-9e2a9a092627
Dossier UUID:
Author:Date: 2022-03-25T10:47:51.000+09:00
Remarks:

Administrative data
Endpoint
in vitro chromosome aberration study in mammalian cells
Type of information
experimental study
Adequacy of study
key study
Robust study summary
false
Used for classification
false
Used for SDS
false
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
other: OECD Test Guideline study under GLP condition

Data source
Reference
In Vitro Chromosomal Aberration Test of 1,3-Propanediol, 2-butyl-2-ethyl on Cultured Chinese Hamster /Ministry of Health, Labour and Welfare (MHLW), Japan / study report
Data accessdata published

Materials and methods
Test guideline
Qualifieraccording to guideline
Guideline
OECD Guideline 473 (In Vitro Mammalian Chromosome Aberration Test)in vitro cytogenicity / chromosome aberration study in mammalian cells
Deviations
no20

Qualifieraccording to guideline
Guideline
JAPAN: Guidelines for Screening Mutagenicity Testing Of Chemicals
genetic toxicity in vitro, otherDeviationsno
GLP compliance
yesType of assay
other: in vitro mammalian chromosome aberration test

Test material
Test material information
1,3-propanediol, 2-butyl-2-ethylSpecific details on test material used for the study- Name of test material (as cited in study report): 1,3-Propanediol, 2-butyl-2-ethyl- Analytical purity: 99.8%

MethodSpecies / strain
Species / strain / cell typeother: Chinese hamster lung(CHL/IU) cells
Metabolic activation
with and without
Metabolic activation system
S9 mix; SD male rat liver, induced by phenobarbital and 5,6-benzoflavone
Justification for deviation from the high dose level
Cell growth inhibition study-S9 mix (short-term treatment): 3.22, 6.45, 12.9, 25.8, 51.6, 103, 206, 413, 825, 1650 ug/mL+S9 mix (short-term treatment): 3.22, 6.45, 12.9, 25.8, 51.6, 103, 206, 413, 825, 1650 ug/mL-S9 mix (continuous treatment, 24hr): 3.22, 6.45, 12.9, 25.8, 51.6, 103, 206, 413, 825, 1650 ug/mL-S9 mix (continuous treatment, 48hr): 3.22, 6.45, 12.9, 25.8, 51.6, 103, 206, 413, 825, 1650 ug/mL
Main study-S9 (short-term treatment): 386, 463, 556, 667, 800 ug/mL+S9 (short-term treatment): 386, 463, 556, 667, 800 ug/mL-S9 (continuous treatment, 24hr): 98.8, 148, 222, 333, 500 ug/mL-S9 (continuous treatment, 48hr): 98.8, 148, 222, 333, 500 ug/mL
Vehicle / solvent- Vehicle(s)/solvent(s) used: DMSO
Controls
Untreated negative controlsno21

Negative solvent / vehicle controls
yes
True negative controlsnoPositive controls
yes
Positive control substanceother: [-S9]: mitomycin C; [+S9]: cyclophosphamide
Details on test system and experimental conditions
METHOD OF APPLICATION:
Exposure duration:- [short-term treatment]: 6 hrs + 18 hrs- [continuous treatment]: 24, 48 hrs
SPINDLE INHIBITOR: Colcemid
STAIN: Giemsa stain (2 v/v%) for 15 min.
NUMBER OF REPLICATIONS: 2
NUMBER OF CELLS EVALUATED: 100 + 100 cells /concentration
DETERMINATION OF CYTOTOXICITY- Method: relative total growth
Evaluation criteria
For the evaluation of the frequencies of structural aberrations and of polyploidy induced, the following
criteria were employed. Appearance incidence of cell with chromosomal aberrations: Negative (-):
less than 5%, Equivocal(±): more than 5% and less than 10%, Positive(+): 10% and above
StatisticsnoResults and discussion
Test results
Key result
trueSpecies / strainother: Chinese hamster lung (CHL/IU) cells
Metabolic activation
with and without
Genotoxicity
negative
Cytotoxicity / choice of top concentrations
cytotoxicity
Vehicle controls validity
valid
Positive controls validity
valid
Additional information on results
RANGE-FINDING/SCREENING STUDIES (if applicable):22

50% cell growth inhibition (IC50): 719 ug/mL (short-term treatment, +S9 mix), 732 ug/mL (short-term treatment, -S9 mix), 340 ug/mL (continuous treatment, 24hr), 332 ug/mL (continuous treatment, 48hr)

Any other information on results incl. tables
Figures and Tables (in English) are available in the following full report of the study.
https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF115-84-4f.pdf

Applicant's summary and conclusion
Conclusions
Interpretation of results (migrated information): negative with or without metabolic activation
In an in vitro chromosomal aberration test using CHL/IU cells (OECD TG 473), 1,3-propanediol, 2butyl-2-ethyl was negative with or without metabolic activation.

23

Toxicity to reproduction
ENDPOINT_STUDY_RECORD: ToxicityReproduction.

UUID: 11f098b8-901d-40b9-b056-78658d53a2bb
Dossier UUID:
Author:Date: 2022-03-25T14:28:55.000+09:00
Remarks:

Administrative data
Endpoint
reproductive toxicity, other A combined repeated dose/reproductive developmental toxicity study
Type of information
experimental study
Adequacy of study
key study
Robust study summary
false
Used for classification
false
Used for SDS
false
Reliability
1 (reliable without restriction)
Rationale for reliability incl. deficiencies
guideline study OECD Test Guideline study under GLP condition
Reliability 1
Cross-reference
Reason / purpose for cross-reference
reference to same study
Related information
OECD / Repeated dose toxicity: oral / RepeatedDoseToxicityOral. 001 / 1,3-propanediol, 2-butyl-2ethyl- / 115-84-4

Data source
Reference
Combined repeat dose and reproductive/developmental toxicity screening test of 1,3-propanediol, 2bu / Ministry of Health, Labour and Welfare (MHLW), Japan / study report
Data accessdata published https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF115-84-4d.pdf

Materials and methods
24Test guideline
Qualifieraccording to guideline
Guideline
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction /Developmental Toxicity Screening Test)
Deviationsno
GLP compliance
yes
Limit test
no

Test material
Test material information
1,3-propanediol, 2-butyl-2-ethylSpecific details on test material used for the study- Name of test material (as cited in study report): 1,3-propanediol, 2-butyl-2-ethyl- Analytical purity: 99.8%- Storage condition of test material: Cold and dark place (2-8°C)- Stability under test conditions: The stability of test material was identified by analysis of the remainder.

Test animals
Speciesrat
Strainother: Crl: CD (SD)Sexmale/female
Details on test animals or test system and environmental conditions
TEST ANIMALS- Source: Charles River Japan, Inc., Atsugi Breeding Center.
- Age at study initiation: 10 weeks old- Weight at study initiation: Male: 378 g (353-416 g), Female: 233 g (209-265 g)- Housing: Animals were individually housed in bracket-type metallic wire-mesh cages (254W × 350D
× 170H mm), from gestation day 17 to lactation day 4, Dams were bred individually or with individual
littermates in plastic cages (340W x 400D x 185H mm) and bedding.
- Diet: Solid feed (NMF: Oriental Yeast Co., ltd.) was given ad libitum.
- Water: Tap water was given ad libitum.
- Acclimation period: 16 days
ENVIRONMENTAL CONDITIONS- Temperature (°C): 23±3 (actual temperature: 22-24°C)- Humidity (%): 50±20% (actual humidity: 40-60%)- Air changes (per hr): 10-15- Photoperiod (hrs dark / hrs light): 12 hr dark/12 hr light (light: 7:00-19:00)

25

Administration / exposure
Route of administration
oral: gavage
Vehicleother: 0.5w/v% methylcellulose
Details on exposure- Amount of vehicle (if gavage): 5 mL/kg- Dosing volume: 5 mL/kg
Details on mating procedure- M/F ratio per cage:1/1- Length of cohabitation: up to 5 days
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
Analytical verification of doses or concentrations
yes
Details on analytical verification of doses or concentrations
The concentration of test suspensions was analyzed by GC on the dosages used in groups of males
at weeks 1 and 6 of administration. Results showed that the concentration of test suspensions ineach concentration was 94.5 to 107.0% of the nominal concentration and both values were within theacceptable range (concentration: percentage of nominal concentration, 100±10%)Duration of treatment / exposure(P) Males: 42 days including 14 days pre-mating(P)Females: 41-46 days including 14 days pre-mating, mating and gestation periods and the days
until day 4 of lactation
Female (no mating, satellite group): 42 days
Frequency of treatment
Once/day, 7 days/week
Doses / concentrations
Dose / conc.
0mg/kg bw/day (actual dose received)

Dose / conc.
20

mg/kg bw/day (actual dose received)

Dose / conc.
100

mg/kg bw/day (actual dose received)

Dose / conc.
500

mg/kg bw/day (actual dose received)

No. of animals per sex per dose
Mating group: 12 animals/sex/dose (0, 20, 100, and 500 mg/kg bw/day)
Non-mating group: 10 females/dose (0 and 500 mg/kg bw/day)26

Recovery group: 5 males/dose in the mating group and 5 females/dose in the non-mating groups (0and 500 mg/kg bw/day)Control animals
yes, concurrent vehicle
Details on study design- Dose selection rationale: Based on the results of a 14-day preliminary study, the highest dose of 500
mg/kg bw/day was selected as an expected obvious toxic dose, and the lowest dose of 20 mg/kg
bw/day was selected as an expected no toxic dose. The middle dose levels of 100 mg/kg bw/day
were selected.
[14-day preliminary study]
A 14-day repeated dose oral toxicity test (Crl:CD(SD) rats, doses: 0, 250, 500 or 1000 mg/kg bw/day).
At 1,000 mg/kg bw/day, ataxia and prone/lateral position in males and females, increased platelet,
decreased AST and glucose in males, increased liver weight in males and females, decreased thymu
s weight in males, increased kidney weight in females, elevated region of forestomach in males andfemales, large kidney in males were observed. At 500 mg/kg bw/day, ataxia in females, decreased
thymus weight in males were observed. At 250 mg/kg bw/day, decreased thymus weight in males
were observed.
- Rationale for animal assignment (if not random): Body weight-balanced randomization

Examinations
Parental animals: Observations and examinations
CAGE SIDE OBSERVATIONS: Yes- Time schedule: 4 times/day (before administration, immediately after administration, 30 minutes aft
er administration and 1-3 hours after administration) during the administration period. Once a day during the recovery period.
DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule:
Males in the main groups and females in the non-mating groups: once before the start of administrat
ion, once every weekly during the administration.
Females in the mating groups: once before the start of administration, days specified during mating,gestation, and lactation (mated animals: gestation days 1, 7, 14 and 20, unmated animals: 6 and 13
days after the start of mating, parturient animals: lactation day 4)
Males and females in the recovery groups: once before the start of administration, once every weekly
during the administration and recovery periods.
BODY WEIGHT: Yes- Time schedule for examinations:
Males in the main groups and females in the non-mating groups: days 1, 8, 15, 22, 29, 36 and 42 of administration and on the day of necropsy
Males and females in the recovery groups: days 1, 8, 15, 22, 29, 36 and 42 of administration, and days
1, 8 and 14 of recovery and on the day of necropsy.
Females in the mating groups: days 1, 8 and 15 of administration (uncopulated animals: day 22 ofadministration), days 0, 7, 14, and 20 of gestation, days 0, 4 of lactation, and on the day of necropsy
Food consumption: Yes
Measurement of food consumption was conducted on all animals at the following frequencies:
Males in the main groups and females in the non-mating groups: days 1, 8, 15, 30 and 42 of administ
rationMales and females in the recovery groups: days 1, 8, 15, 30 and 42 of administration, and days 1, 8
and 14 of recovery
Females in the mating groups: days 1, 8 and 15 of administration, days 0, 7, 14, and 20 of gestation,days 2 and 4 of lactation
27

OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes- Time schedule for collection of blood: At the end of administration period, or at the end of recovery
period in both sexes- Anaesthetic used for blood collection: Isoflurane- Animals fasted: Yes- How many animals:
5 animals/sex/group- Parameters examined: red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, reticulocyte percentage,platelet count, white blood cell count, differential white blood cell count, absolute number of each
white blood cell, prothrombin time, activated partial thromboplastin time, fibrinogen.
CLINICAL CHEMISTRY: Yes- Time schedule for collection of blood: At the end of administration period, or at the end of recovery
period in both sexes- Animals fasted: Yes- How many animals:
5 animals/sex/group- Parameters checked: ALP, total cholesterol, triglyceride, phospholipids, total bilirubin, glucose, bloodurea nitrogen, creatinine, sodium, potassium, chloride, calcium, inorganic phosphorus, total protein,
albumin, A/G ratio, AST (GOT), ALT (GPT), LDH, γ-GTP
URINALYSIS OF MALES: Yes- Time schedule for collection of urine: final week of administration (days 36 to 37 of administration)and in the final week of recovery (days 8 to 9 of recovery)- Metabolism cages used for collection of urine: Yes
A urine collector to collect four-hour urine samples under fasting but ad libitum drinking conditions,followed by collection of 20-hour urine samples under ad libitum feeding and drinking conditions.
- How many animals: 5 animals/group- Parameters checked: pH, protein, ketones, glucose, occult blood, bilirubin, urobilinogen, color, sed
iment, urine volume (4-hour volume), osmotic pressure, sodium, potassium, chloride, urine volume (20-hour volume), water intake (24-hour volume)
BLOOD HORMONE: No
NEUROBEHAVIOURAL EXAMINATION: Yes- Time schedule for examinations:
Males in the main groups and females in the non-mating groups: final week of administration (day 38
of administration)
Females in the mating groups: lactation day 4 (day 41 to day 43 of administration) after necropsy of
F1 pupsMales and females in the recovery groups: final week of administration (day 38 of administration) andin the final week of recovery (day 10 of recovery).
- Dose groups that were examined: All dose groups (5 animals/sex/group)- Battery of functions tested:
1) Manipulative Test. Auditory response, approach response, touch response, tail pinch response, pupi
llary reflex, aerial righting reflex, landing foot splay
2) Measurement of Grip Strength. Following manipulative test, grip strength of forelimb and hind limb
were measured by CPU gauge MODEL-RX-5 (AIKOH Engineering Co., Ltd.).
3) Measurement of Motor Activity. Following measurement of grip strength, motor activity wasmeasured by a motor activity sensor for experimental animals NS-AS01 (Neuro Science, Inc.). The me
asurement was conducted for 1 hour, and measured values at 10-minute intervals and from 0 to 60
minutes were collected.

28

Oestrous cyclicity (parental animals)
Vaginal smears were collected from all females in the mating groups and microscopically examined
every day from the day after the start of administration until the day copulation was confirmed.
During the pre-mating administration period, vaginal smear pictures were classified as proestrus,
estrus, metestrus or diestrus and examined for the frequency of estrus and interval between estruses(estrous cycle). During the mating period, vaginal smears were examined for the presence of sperm.
Sperm parameters (parental animals)
Parameters examined in all P male parental generations: testis weight, epididymis weight, histopatho
logical examinations for testes, epididymides, seminal vesicle and ventral prostate.
Litter observations
PARAMETERS EXAMINED: The following parameters were examined in F1 offspring: Number and sexof pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, and weight gain.
GROSS EXAMINATION OF DEAD PUPS: Yes, for external and internal abnormalities.
Postmortem examinations (parental animals)
METHOD OF SACRIFICED: All animals were sacrificed by exsanguination under isoflurane anesthesia.
SACRIFICE: Males in main groups and females in non-mating groups: On next day after the last
administration (Day 43), Maternal animals: on Day 4 of lactation, and Male and females recovery anim
als: on Day 14 of recovery.
ORGAN WEIGHT: Yes [brain, pituitary, thyroids (including parathyroids), adrenal gland, thymus, spleen,
heart, liver, kidney, testis, epididymis, prostate, seminal vesicles, ovary, uterus]
HISTOPATHOLOGY: Yes, [cerebrum, cerebellum (including pons), sciatic nerve, spinal cord (thoracic),eye ball, optic nerve, Harderian gland, pituitary, thyroid, parathyroid, adrenal glands, thymus, spleen,submandibular lymph nodes, mesenteric lymph nodes, heart, thoracic aorta, trachea, lung (including
bronchial), tongue, larynx, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum,
submandibular gland, liver, pancreas, kidney, bladder, testis, ovary, epididymis, uterus, vagina, prost
ate, seminal vesicles, skin (inguinal), mammary gland (inguinal), sternum and femur (including bonemarrows), skeletal muscle of femur, and individual identification site (pinna with ear tag)]Postmortem examinations (offspring)
SACRIFICE- The F1 offsprings were euthanized on PND4 by exsanguination under isoflurane anesthesia.
GROSS NECROPSY：Yes- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, andabdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGTHS- Not examined.
Statistics
For quantitative data, homogeneity of variance was tested using Bartlett method first. If the variance
was homogenous, statistical difference between each treatment group and the control group was
analyzed using Dunnett method. If not homogenous, statistical difference between each treatmentgroup and the control group was tested using Steel method. For comparison of quantitative data be
tween two groups in the recovery test, homogeneity of variance was analyzed by F-test. Then, if homo
genous, student's t-test was applied. If not homogenous, Aspin-Welch's t-test was used.
Regarding clinical observation (except for frequency of urination, defecation, rearing and grooming)and sensory reactivity, Steel test was applied. Regarding implantation index, stillborn index, live birthindex, viability index and external abnormalities, Steel test was applied. Regarding copulation index,
insemination index, fertility index, and delivery index, auditory response, approach response, touch
response, tail pinch response, pupillary reflex, aerial righting reflex, Fisher's test was applied.
Reproductive indices
Each parameter was determined by the following equations:29

Copulation index (%) = (No. of copulated animals / No. of mated animals) × 100
Fertility index (%) = (No. of pregnant females / No. of copulated females) × 100
Insemination index (%) = (No. of males which impregnated females / No. of copulated males) × 100
Gestation length (days) = No. of days from pregnancy day 0 to parturition day
Delivery index (%) = (No. of females which delivered liveborns / No. of pregnant females) × 100
Implantation index (%) = (No. of implantation sites / No. of corpora lutea) × 100
Stillborn index (%) = (No. of stillborn / No of liveborns and stillborns) × 100
Live birth index (%) = (No. of liveborn / No. of implantation sites) × 100
External abnormalities (%) = (No. of pups with external abnormalities / No. of liveborns) × 100
Sex ratio = No. of liveborns males / No. of liveborns
Sex ratio of live pups on day 4= No. of live males on day 4/ No. of live pups on day 4
Offspring viability indices
Viability index on postnatal day 4 (%) = (No. of live pups on day 4 / No. of liveborns on day 0) × 100

Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
Clinical signs
effects observed, treatment-related
Description (incidence and severity)
See 7.5.1 Repeated dose toxicity.001
Mortality
no mortality observed
Body weight and weight changes
no effects observed
Food consumption and compound intake (if feeding study)no effects observed
Food efficiency
not examined
Water consumption and compound intake (if drinking water study)
not examined
Ophthalmological findings
not examined
Haematological findings
no effects observed
Clinical biochemistry findings
no effects observed
Urinalysis findings
effects observed, treatment-related
Description (incidence and severity)
See 7.5.1 Repeated dose toxicity.001
Behaviour (functional findings)
no effects observed30Immunological findings
not examined
Organ weight findings including organ / body weight ratios
effects observed, treatment-related
Description (incidence and severity)
See 7.5.1 Repeated dose toxicity.001
Gross pathological findings
effects observed, treatment-related
Description (incidence and severity)
See 7.5.1 Repeated dose toxicity.001
Neuropathological findings
not examined
Histopathological findings: non-neoplastic
effects observed, treatment-related
Description (incidence and severity)
See 7.5.1 Repeated dose toxicity.001
Histopathological findings: neoplastic
not examined

Reproductive function / performance (P0)
Reproductive function: oestrous cycle
no effects observed
Reproductive function: sperm measures
no effects observed
Reproductive performanceno effects observed

Details on results (P0)General toxicity: See 7.5.1 Repeated dose toxicity.001
Reproductive function / performance: no effects observed

Effect levels (P0)
Key result
false
Dose descriptor
NOAEL
Effect level20

mg/kg bw/day (actual dose received)

Based ontest mat.
31

Sex
male
Basis for effect level
organ weights and organ / body weight ratios
An increase in relative kidney weight was observed in males at 100 mg/kg bw/day.
histopathology: non-neoplastic
Kidney: Granular cast, regenerated tubule, eosinophilic body in tubular cell were observed in males
at 100 mg/kg bw/day.
Key result
false
Dose descriptor
NOAEL
Effect level100

mg/kg bw/day (actual dose received)

Based ontest mat.
Sex
femaleBasis for effect level
clinical signs
Ataxia and prone/lateral position were observed in females at 500 mg/kg bw/day.
urinalysis
A decrease tendency in urine pH was observed in non-mating females at 500 mg/kg bw/day.
organ weights and organ / body weight ratios
An increase in relative liver weight was observed in females at 500 mg/kg bw/day.
histopathology: non-neoplastic
Stomach: Hyperplasia of squamous in limiting ridge was observed in non-mating females at 500
mg/kg bw/day.
other: NEUROBEHAVIOURAL EXAMINATION:
A decrease in locomotor activity was observed in mating females at 500 mg/kg bw/day.
Key result
false
Dose descriptor
NOAEL
Effect level500

mg/kg bw/day (actual dose received)

Based ontest mat.
Sexmale/female
Basis for effect level
reproductive performance
No reproductive effects were observed in both males and females up to 500 mg/kg bw/day.

Results: F1 generation
32

General toxicity (F1)Clinical signs
no effects observed
Mortality / viability
no mortality observed
Body weight and weight changes
no effects observed
Gross pathological findings
no effects observed

Details on results (F1)
No effects observed.

Effect levels (F1)
Key result
false
Dose descriptor
NOAEL
Generation
F1
Effect level500

mg/kg bw/day (actual dose received)

Based ontest mat.
Sexmale/female
Basis for effect level
other:
There were no effects on developmental parameters up to 500 mg/kg bw/day.

Overall reproductive toxicity
Key result
false
Reproductive effects observednoAny other information on results incl. tables
Figures and Tables (in English) are available in the following full report of the study.
33

https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF115-84-4d.pdf

Applicant's summary and conclusion
Conclusions
In the combined repeated oral dose toxicity study with the reproduction/developmental toxicity
screening test (OECD TG 422) described above, there were no effects on the reproductive and dev
elopmental parameters up to 500 mg/kg bw/day. The NOAEL for the rat reproductive/developme
ntal toxicity of 1,3-propanediol, 2-butyl-2-ethyl was regarded as 500 mg/kg bw/day, the highest dosetested.

34

DOMAIN
SUBSTANCE: 1,3-propanediol, 2-butyl-2-ethylUUID: bcf517d6-06ec-49a8-9a07-a591bb369cd8
Dossier UUID:
Author:Date: 2023-09-05T13:06:53.767+09:00
Remarks:
Substance name
1,3-propanediol, 2-butyl-2-ethylLegal entity
National Institute of Health Sciences / Kawasaki / Japan

Identification of substance
Reference substance
1,3-propanediol, 2-butyl-2-ethyl- / 115-84-4
EC number

EC name

CAS number

CAS name

115-84-4
IUPAC nameRole in the supply chain
Manufacturer
false
Importer
false
Only representativefalse
Downstream user
false

35

References
Reference Substances
REFERENCE_SUBSTANCE: 1,3-propanediol, 2-butyl-2ethylUUID: 012d25fb-6126-44d7-964d-c433319ef9c9
Dossier UUID:
Author:Date: 2022-03-25T14:24:38.000+09:00
Remarks:
Reference substance name
1,3-propanediol, 2-butyl-2-ethyl-

Inventory
CAS number
115-84-4

Molecular and structural information
Molecular formula
C9H20O2
Molecular weight160.2536

Test Materials
TEST_MATERIAL_INFORMATION: 1,3-propanediol, 2butyl-2-ethylUUID: 89431b8c-07f6-4817-a83d-735088fd2923
Dossier UUID:
Author:Date: 2022-03-25T14:27:19.000+09:00
Remarks:
Name
1,3-propanediol, 2-butyl-2-ethyl-

37

Literatures
LITERATURE: Combined repeat dose and reproductive/
developmental toxicity screening test of 1,3-propanediol,
2-butyl-2-ethyl by oral administration in rats
UUID: 98144ba0-8cd8-4a07-b339-6be5e102b4b0
Dossier UUID:
Author:Date: 2021-10-22T15:37:28.000+09:00
Remarks:

General information
Reference Typestudy report
Title
Combined repeat dose and reproductive/developmental toxicity screening test of 1,3-propanediol, 2butyl-2-ethyl by oral administration in rats
Author
Ministry of Health, Labour and Welfare (MHLW), Japan
Year
2013
Bibliographic source
available in the web of Japan Existing Chemical Data Base (JECDB) at https://dra4.nihs.go.jp/
mhlw_data/home/pdf/PDF115-84-4d.pdf
Testing facility
BoZo Research Center
Report number
R-108838

LITERATURE: In Vitro Chromosomal Aberration Test of
1,3-Propanediol, 2-butyl-2-ethyl on Cultured Chinese
Hamster Cells.
UUID: 6182aba2-60ae-481c-a1b0-c18f9b4deb1b
Dossier UUID:
Author:Date: 2022-03-01T11:25:49.000+09:00
Remarks:

General information
Reference Typestudy report
Title
In Vitro Chromosomal Aberration Test of 1,3-Propanediol, 2-butyl-2-ethyl on Cultured Chinese Hamster
Cells.
Author
Ministry of Health, Labour and Welfare (MHLW), Japan
Year
2012
Bibliographic source
Japan Existing Chemical Data Base (JECDB) https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF11
5-84-4f.pdf
Testing facility
Bozo Research Center Inc.
Report date2012-03-23
Report number
T-G02339

LITERATURE: Reverse Mutation Test of 1,3-Propanediol,
2-butyl-2-ethyl on Bacteria.
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Author:Date: 2022-03-01T10:16:36.000+09:00
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General information
Reference Typestudy report
Title
Reverse Mutation Test of 1,3-Propanediol, 2-butyl-2-ethyl on Bacteria.
Author
Ministry of Health, Labour and Welfare (MHLW), Japan
Year
2012
Bibliographic source
Japan Existing Chemical Data Base (JECDB) https://dra4.nihs.go.jp/mhlw_data/home/pdf/PDF11
5-84-4e.pdf
Testing facility
Bozo Research Center Inc.
Report date2012-03-22
Report number
T-087940