Registration Dossier

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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

No Reproduction / Developmental Toxicity Screening Test is available for PETMP.


Based on the categroy approach, it is beeing evaluated, if GDMP can be used as worst-case substance for the category of GDMP, PETMP, TMPMP and Di-PETMP (for details see category approach attached in 13.1). If GDMP can be used as worst-case substance for the categroy, a combined repeated dose toxicity test and reproduction/ developmental toxicity screening test will be performed with GDMP to be used as source for the reproductive toxicity enpoint. Depending on the outcome of the study, performance of an reproduction/developmental toxicity screening assay with PETMP may be necessary.


The worst-case approach will be reevaluated as soon as new data with GDMP has been generated.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
other justification
Justification for data waiving:
other:
Justification for type of information:
Currently, no data on toxicokinetics/metabolism is available for this category. Based on structural features (e.g. sterical hindrance) it is however assumed, that ester cleavage would not be fast and complete, especially since the substances contain up to 6 ester functions, which are in addition sterically shielded. Therefore, it seems more reasonable to base the category hypothesis on structural similarity.
In addition, it is not clear yet, whether the strength of the effects vary in a predictable manner, or if no relevant variations occur. However, there are variations in structure (number of ester bonds and consequently number of free -SH groups) and physicochemical properties (especially water solubility and log Kow). It is assumed that these variations will also be reflected by variations in effect levels. Therefore, scenario 4 is the working hypothesis for the time being.
More data points within the category are needed to further strengthen the category hypothesis . The scenario selection will be re-evaluated after the studies are finished.
This currently selected scenario covers the category approach for which the read-across hypothesis is based on structural similarity. For the REACH information requirement under consideration, the property investigated in studies conducted with different source substances is used to predict the property that would be observed in a study with the target substance if it were to be conducted. Similar properties are observed for the different source substances; this may include absence of effects for every member of the category.
There are expected to be differences in strength of the effects forming a regular pattern. The prediction will be based on a worst-case approach. The read-across is a category approach based on the hypothesis that the substances in this category share structural similarities with common functional groups. This approach serves to use existing data on skin/eye irritation, skin sensitisation, genetic toxicity, acute toxicity, repeated-dose toxicity and reproductive toxicity endpoints for substances in this category.
The hypothesis corresponds to Scenario 4 of the RAAF. The substances GDMP, TMPMP, PETMP, and Di-PETMP are esters of a common acid, 3-mercaptopropionic acid (3-MPA). The key functionality of the substances within this category is the presence of free SH-groups. It is hypothesised that the strength of effects correlates with the number of SH-groups. In addition, differences in bioavailability are expected to influence the strength of effects.
For detailed information, refer to section 13.2
Reason / purpose for cross-reference:
read-across: supporting information
Effect on fertility: via oral route
Endpoint conclusion:
no study available (further information necessary)
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

The oral administration of PETMP to pregnant rats by oral gavage during gestation at dose levels of 50, 120 and 300/200 mg/kg bw/day (incorporating a correction factor for 97.4 % purity), resulted in treatment-related effects for females treated with 300/200 mg a.i./kg bw/day with an associated effect on fetal growth.
The No Observed Effect Level (NOEL) for the pregnant females and the survival, growth and embryofetal development of the offspring was considered to be 120 mg a.i./kg bw/day.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2014-06-19 - 2015-01-07
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: guideline study, GLP
Qualifier:
according to guideline
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Version / remarks:
30 May 2008
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
22 January 2001
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
other: Crl:CD(SD) IGS BR
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: young adult
- Weight at study initiation: 190 to 264 g (on arrival)
- Fasting period before study: no
- Housing: ndividually in solid-floor polypropylene cages with stainless steel mesh lids furnished with softwood flakes (Datesand Ltd., Cheshire, UK), containign environmental enrichment
- Diet (e.g. ad libitum): pelleted diet (Rodent 2018C Teklad Global Certified Diet, Harlan UK, Oxon, UK), ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 1 - 2 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

Animals were delivered in two batches containing time mated females prior to Day 3 (Day 0 or Day 1) of gestation.
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
emulsion in Corn Oil

VEHICLE
- Concentration in vehicle: 12.5, 30, 75/50 mg a.i./L
- Amount of vehicle (if gavage): dose volume 4 mL/kg bw/d
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test item concentrations were determined by HPLC with UV detection (215 nm) using an external standard.
Samples were extracted with acetonitrile (ultra-sonicated for 15 min and then centrifuged at 4500 rpm for 10 min).

Details on mating procedure:
- Impregnation procedure: purchased timed pregnant
Duration of treatment / exposure:
Day 3 to Day 19 of gestation
Frequency of treatment:
daily
Duration of test:
animals were killed on Day 20 of gestation
No. of animals per sex per dose:
24
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on dose range finding study
Maternal examinations:
Morbidity/Mortality Inspection
Twice daily, early and late during the working period.

CAGE SIDE OBSERVATIONS: No

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once daily during the gestation period; immediately before and soon after dosing, half an hour post dosing, one hour post dosing and approximately four hours post dosing

BODY WEIGHT: Yes
- Time schedule for examinations: Day 3 (before start of treatment), and on Days 4, 5, 8, 11, 14 and 17 of gestation. Body weights were also recorded for surviving animals at terminal kill (Day 20)

FOOD CONSUMPTION: Yes
-Day 3, 5, 8, 11, 14, 17 and 20 of gestation

WATER CONSUMPTION: Yes
Monitored daily by visual inspection of water bottles

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
- Organs examined: Full external and internal macroscopic examination of adult females. Any macroscopic abnormalities were recorded.
As macroscopic changes were noted in the stomach of the decedent females; the stomach from all females surviving to termination were retained at necropsy. The ovaries and uteri of pregnant females were removed, examined and the following data recorded.



Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- fetal weight
- placental weight
- fetal sex

Statistics:
Group mean values were calculated to include data from all females with live fetuses on Day 20 of gestation.
The following parameters were analyzed statistically, where appropriate, using the test methods outlined below:
Female body weight change, food consumption and gravid uterus weight: Shapiro Wilk normality test and Bartlett’s test for homogeneity of variance and one way analysis of variance, followed by Dunnett’s multiple comparison test or, if unequal variances were observed, on alternative multiple comparison test.
All caesarean necropsy parameters and fetal parameters: Kruskal-Wallis non-parametric analysis of variance; and a subsequent pairwise analysis of control values against treated values using the Mann-Whitney ‘U’ test, where significance was seen.
Fetal evaluation parameters, including skeletal or visceral findings: Kruskal-Wallis nonparametric analysis of variance and Mann-Whitney ‘U’ test.
Indices:
Pre and Post Implantation Loss
Sex Ratio
Historical control data:
Historical control data for Sprague-Dawley Crl:CD® (SD) IGS BR Rat are provided in the study report for the following parameters: Gestation Body Weights, Gestation Food Consumption, Litter Data, External Fetal Observations, Visceral Fetal Findings, Skeletal Fetal Findings
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Mortality
One female treated with 300/200 mg a.i./kg bw/day was killed in extremis on Day 8 due to the persistence of clinical observations of clonic convulsions, splayed gait, occasional body tremors and ataxia. Multiple raised areas were apparent in the non-glandular region of the stomach at necropsy.
One female treated with 120 mg a.i./kg bw/day was found dead on Day 13 following observations of clonic convulsions, decreased respiratory rate, laboured respiration, gasping respiration, staining of the fur and increased salivation immediately post dose. This animal was found to have an oily red fluid in the thoracic cavity at necropsy, and sloughing of the glandular region of the stomach was also apparent. The death of this animal was considered to have been caused by a dosing trauma or aspiration of the test item when dosed.

Clinical Observations
A number of females treated with 300/200 mg a.i./kg bw/day had transient episodes of occasional body tremors, tonic and clonic convulsions, hunched posture, ataxia, lethargy, piloerection, splayed gait and, laboured respiration and decreased respiratory rate up to Day 11. Thereafter no such observations were apparent.
The majority of animals at this dose level also had episodes of increased salivation post-dose from Day 8 onwards. Observations of this nature are commonly experienced following the oral administration of an unpalatable or slightly irritant test item formulation and in isolation are considered not to be of toxicological importance. No such effects were detected in females surviving to necropsy at 50 or 120 mg a.i./kg bw/day.

Body Weight
Females treated with 300/200 mg a.i./kg bw/day showed group mean body weight losses between Day 3 and Day 4 with differences from control attaining statistical significance. Recovery was evident thereafter although group mean body weight gains were slightly lower than control from Day 14 onwards. Consequently, cumulative body weight gains to Day 5 were statistically significantly lower than controls and thereafter remained lower than control throughout the treatment period.
Gravid uterus weight for females treated with 300/200 mg a.i./kg bw/day was slightly lower than controls however statistical significance was not achieved. Body weight gain when adjusted for the contribution of the gravid uterus was also slightly lower than controls. No such effects were detected in females treated with at 50 or 120 mg a.i./kg bw/day

Food Consumption
Food consumption for females treated with 300/200 mg a.i./kg bw/day was statistically significantly lower than controls to Day 8 of the study and generally remained lower than controls throughout the remainder of the treatment period. No such effects were detected in females treated with 50 or 120 mg a.i./kg bw/day.

Water Consumption
Daily visual inspection of water bottles did not reveal any overt intergroup differences.

Post Mortem Studies
No macroscopic abnormalities were detected in any female surviving to termination.
Dose descriptor:
NOEL
Effect level:
120 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOEL
Effect level:
120 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Litter Data and Litter Placental and Fetal Weights
The mean male fetal weight for fetuses from females treated with 300/200 mg a.i./kg bw/day was statistically significantly lower than controls. The mean female fetal weight and mean fetal weight for both sexes were also slightly lower than controls, however, statistical significance was not achieved.
There were no obvious adverse effects of maternal treatment on litter data as assessed by the number of implantations, early and late embryonic/fetal deaths and live fetuses or sex ratio, as assessed by percentage male.

Fetal Examination
Increased incidence of fetuses showing incomplete ossification of the thoracic centrum or less than four ossified caudal vertebrae achieved statistical significance in comparison to controls for females treated with 300/200 mg a.i./kg bw/day. Increased incidence of incomplete ossification of the interparietal and occiptal (supra-occiptal), dumb-bell shaped thoracic centrum and unossified metacarpals were also apparent when compared to controls although the magnitude of these differences did not achieve statistical significance.
A lower incidence of the number of fetuses showing ossification of the 1st metatarsal attained statistical significance for females treated with 300/200 or 120 mg a.i./kg bw/day Visceral examination of the fetuses from females treated with 200 mg a.i./kg bw/day also revealed increased incidence of absent renal papilla with differences from control attaining statistical significance. Increased incidence of increased cavitation of the renal pelvis was also apparent, however, statistical significance was not achieved.
Remarks on result:
not measured/tested
Abnormalities:
not specified
Developmental effects observed:
not specified

Stability of the test item formulations

Measured concentrations of the test item formulations were within 100-107% of nominal. Formulations were stable when kept for 12 d at 4°C.

Group Mean Body Weight Values

Dose Level

(mg a.i./kg bw/day)

 

Body Weight (g) at Day of Gestation

 

3

4

5

8

11

14

17

20

0 (Control)

mean

244.8

249.4

255.0

270.2

289.9

309.1

342.8

386.2

sd

22.9

23.5

24.1

24.5

27.2

28.9

33.7

39.2

n

24

24

24

24

24

24

24

24

50

mean

242.4

247.1

253.2

268.4

286.5

305.2

338.4

382.5

sd

12.4

12.1

12.3

13.5

16.2

16.0

18.2

17.8

n

24

24

24

24

24

24

24

24

120

mean

243.3

247.0

253.5

268.5

289.9

306.3

337.8

381.4

sd

12.6

12.5

13.0

15.3

16.5

20.5

23.4

27.4

n

23

23

23

23

23

23

23

23

300/200

mean

242.5

242.2

248.0

263.5

283.7

300.7

330.3

370.3

sd

18.2

21.2

22.7

22.4

22.2

24.7

28.5

34.2

n

23

23

23

23

23

23

23

23

 

Group Mean Body Weight Change

Dose Level

(mg a.i./kg bw/day)

 

Cumulative Body Weight Change (g) from Day 3 of Gestation

 

4

5

8

11

14

17

20

0 (Control)

mean

4.7

10.3

25.4

45.2

64.4

98.0

141.5

sd

3.6

3.9

5.5

8.0

9.6

14.6

21.8

n

24

24

24

24

24

24

24

50

mean

4.7

10.8

26.0

44.0

62.8

96.0

140.1

sd

2.5

3.3

4.1

8.2

8.3

11.0

12.4

n

24

24

24

24

24

24

24

120

mean

3.7

10.1

25.1

46.5

63.0

94.5

138.0

sd

2.7

2.7

5.0

7.1

11.9

15.2

21.1

n

23

23

23

23

23

23

23

300/200

mean

-0.3**

5.5*

21.0

41.2

58.1

87.8

127.8

sd

6.2

7.5

7.1

8.1

10.2

14.9

24.6

n

23

23

23

23

23

23

23

 

Group Mean Gravid Uterus Weight and Adjusted Body Weight and Body Weight Change Values

Dose Level

(mg a.i./kg bw/day)

 

Body Weight (g)

on Days of

Gestation

Body Weight

Change (g)

during Days of

Gestation

3 – 20

Gravid

Uterus

Weight

(g)

Adjusted to

Body

Weight (g)

Day 20

Adjusted to

Body Weight

(g)

Change

3 - 20

3

20

0 (Control)

mean

244.8

386.2

141.5

83.115

303.1

58.3

sd

22.9

39.2

21.8

15.272

26.6

10.5

n

24

24

24

24

24

24

50

mean

242.4

382.5

140.1

82.959

299.6

57.2

sd

12.4

17.8

12.4

7.565

18.1

12.9

n

24

24

24

24

24

24

120

mean

243.3

381.4

138.0

81.329

300.1

56.8

sd

12.6

27.4

21.1

11.972

21.6

15.0

n

23

23

23

23

23

23

300/200

mean

242.5

370.3

127.8

74.138

296.2

53.7

sd

18.2

34.2

24.6

23.279

26.5

12.8

n

23

23

23

23

23

23

 

* Significantly different from control group p<0.05

** Significantly different from control group p<0.01

Conclusions:
The oral administration of PETMP to pregnant rats by oral gavage during gestation at dose levels of 50, 120 and 300/200 mg/kg bw/day (incorporating a correction factor for 97.4 % purity), resulted in treatment-related effects for females treated with 300/200 mg a.i./kg bw/day with an associated effect on fetal growth.
The No Observed Effect Level (NOEL) for the pregnant females and the survival, growth and embryofetal development of the offspring was considered to be 120 mg a.i./kg bw/day.
Executive summary:

In a developmental toxicity study according to OECD Guideline 414 (22 January 2001) and EU method B.31 (30 May 2008) PETMP (97.4% a.i.) was administered was administered to 24 time mated femaleSprague-Dawley Crl:CD® (SD) IGS BR strain rats/dose in corn oilby gavageat dose levels of 0,50, 120, and 300/200 mg a.i./kg bw/day (incorporating a correction factor for 97.4% purity)from days 3 through 20 of gestation.


Adverse clinical signs were apparent in two animals treated with 300 mg a.i./kg bw/day following one dose therefore the dose level was reduced to 200 mg a.i./kg bw/day. Therefore, the first twelve animals of the high dose received the test item at 300 mg a.i./kg bw/day for one or two days prior to the reduction of the dose level; the remaining twelve animals were treated with 200 mg a.i./kg bw/day throughout dosing. Clinical signs, body weight change, food and water consumptions were monitored during the study.


All females were terminated on Day 20 of gestation and subjected to gross necropsy including examination of the uterine contents. The number of corpora lutea, number, position and type of implantation, placental weights, fetal weight, sex and external and internal macroscopic appearance were recorded. Half of each litter were examined for detailed skeletal development and the remaining half were subjected to detailed visceral examination.


One female treated with 300/200 mg a.i./kg bw/day was killedin extremison Day 8 due to the persistence and severity of clinical observations. One female treated with 120 mg a.i./kg bw/day was found dead on Day 13. The death of this animal was considered to have been caused by a dosing trauma or aspiration of the test item when dosed.


Clinical observations of occasional body tremors, clonic convulsions, hunched posture, ataxia, lethargy, pilo-erection, splayed gait and, labored respiration and decreased respiratory rate were apparent transiently up to Day 11 in females treated with 300/200 mg a.i./kg bw/day.  No such effects were detected in females surviving to necropsy at 50 or 120 mg a.i./kg bw/day.


At 300/200 mg a.i./kg bw/day group mean body weight losses were apparent on Day 4 with an associated reduction in cumulative body weight gain being seen to Day 5 of treatment. Initial recovery of body weight gain was apparent thereafter, however, body weight performance from Day 14 onwards appeared to be lower than controls. Gravid uterus weight and body weight gain, when adjusted for the contribution of the gravid uterus were also slightly lower than controls. No such effects were detected in females treated with 50 or 120 mg a.i./kg bw/day.


Food consumption for females treated with 300/200 mg a.i./kg bw/day was generally lower than controls throughout the treatment period with differences from control attaining statistical significance to Day 8. No such effects were detected in females treated with 50 or 120 mg a.i./kg bw/day.


Daily visual inspection of water bottles did not reveal any overt intergroup differences.


No macroscopic abnormalities were detected in any female surviving to termination.


 


The maternal LOAEL is 200 mg a.i./kg bw/day, based on clinical signs, reduced body weight, reduced body weight gain, reduced food consumption and slightly lower gravid uterus weight (though not statistically significant). The maternal NOEL is 120 mg a.i./kg bw/day. 


 


The mean male fetal weight for fetuses from females treated with 200 mg a.i./kg bw/day was statistically significantly lower than controls. The mean female fetal weight and mean fetal weight for both sexes were also slightly lower than controls, however, statistical significance was not achieved.


Increased incidence of fetuses showing incomplete ossification of the thoracic centrum or less than four ossified caudal vertebrae achieved statistical significance in comparison to controls for females treated with 300/200 mg/kg bw/day. Increased incidence of incomplete ossification of the nasal, frontal, interparietal and occiptal (supra-occiptal), dumb-bell shaped thoracic centrum and unossified metacarpals were also apparent when compared to controls although the magnitude of these differences did not achieve statistical significance.


A lower incidence of the number of fetuses showing ossification of the 1st metatarsal attained statistical significance for females treated with 200 or 120 mg/kg bw/day A.I. In isolation and in the absence of any differences in a number of variants or a syndrome of variance, the intergroup difference at 120 mg a.i./kg bw/day was considered not to be toxicologically significant. Visceral examination of the fetuses from females treated with 200 mg a.i./kg bw/day also revealed increased incidence of absent renal papilla with differences from control attaining statistical significance. Increased incidence of increased cavitation of the renal pelvis was also apparent, however, statistical significance was not achieved.


 


The developmental LOAEL is 200 mg a.i./kg bw/day, based on lower mean male fetal weight, increased incidence of fetuses showing incomplete ossification of the thoracic centrum or less than four ossified caudal vertebrae, increased incidence of absent renal papilla.  The developmental NOEL is 120 mg/kg bw/day.


 


Based on Classification and Labelling guidance it can be postulated that classification as a developmental toxicant at either Category 1B or 2 may not be warranted because of the effects seen in adults with consequential effects on offspring development.


 


The developmental toxicity study in the rat is classified acceptable and satisfies the guideline requirement for a developmental toxicity study (OECD 414) in rat.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
Species:
rat
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

Based on Classification and Labelling guidance it can be postulated that classification as a developmental toxicant at either Category 1B or 2 may not be warranted because of the effects seen in the prenatal developmental toxicity study were observed in  adults with consequential effects on offspring development. Classification will be reevaluated when data from reproduction/developmental screening assay are generated.

Additional information