Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

parental and reproductive NOAEL = 3 mg a.i./kg bw/d; developmental NOAEL = 10 mg a.i./kg bw/d; OECD TG 416, rat; read across from DOPA-Glycinate

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

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar toxicological properties because
- they are manufactured from similar or identical precursors under similar conditions
- they share structural similarities with common functional groups (corresponding to scenario 2 of the read-across assessment framework): both, the target and source substance, are aliphatic amines with C8-18 alkyl chains and acetate functions
- Two thirds (w/w) of the target substance Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid (excluding the solvent water) are composed of the source substance DOPA-Glycinate. The remaining third of Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid consists of other aliphatic amines and derivatives which are considered as structural analogues to those constituting the source substance DOPA-Glycinate and may therefore be expected to elicit comparable (eco)toxicological effects.

The read-across hypothesis is based on structural similarity of target and source substances. Based on available experimental data, including key physicochemical properties and data from acute toxicity, repeated dose toxicity, genotoxicity and short term ecotoxicity studies, the read-across hypothesis is supported by a quite similar toxicological profile of both substances.

(Eco)toxicological, physicochemical and environmental fate data are summarised in the data matrix; robust study summaries are included in the Technical Dossier in the respective sections.

Therefore, read-across from the existing ecotoxicity, environmental fate and toxicity studies conducted with the source substances is considered as an appropriate adaptation to the standard information requirements of the REACH Regulation for the target substance, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.

Further details are attached to IUCLID section 13.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
For further details refer to IUCLID section 13.

3. ANALOGUE APPROACH JUSTIFICATION
For further details refer to IUCLID section 13.

4. DATA MATRIX
For further details refer to IUCLID section 13.

Reason / purpose:
read-across: supporting information
Reason / purpose:
read-across source
Species:
rat
Strain:
other: Wistar rats Crl: (WI) BR (outbred, SPF-Quality)
Sex:
male/female
Route of administration:
oral: gavage
Frequency of treatment:
daily
Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
not examined
Other effects:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, treatment-related
P-parents
No test item-related mortality was observed at any dose level.
Rales were observed at a low incidence and on few occasions among the high dosed animals; the high dosed females showed a slightly increased incidence of hunched posture. No nodules or masses were noted.
Body weights were decreased in:
- Males (100 mg/kg bw/d) from the 5th week of treatment onwards, which showed a statistical significant decrease during post mating.
- Females (100 mg/kg bw/d) showed a statistical significant decrease during pregnancy and lactation.
Body weight gain was statistically significantly decreased in:
- Males (100 mg/kg bw/d) during the last half of the pre-mating period.
- Females (100 mg/kg bw/d) during pregnancy.
Body weight and body weight gain for males of the 10 and 30 mg/kg dose group were unaffected.
Food consumption was statistically significantly decreased in:
- Females (100 mg/kg bw/d) during the pre-mating, pregnancy and lactation periods.
Relative food consumption was statistically significantly decreased in:
- Males (100 mg/kg bw/d) during weeks 1, 3 and 5 pre-mating.
- Females (100 mg/kg bw/d) during pre-mating and the first two weeks of pregnancy.
Minor statistically significant differences between controls and 10 or 30 mg/kg bw/d were considered to be of no toxicological relevance.
Details are presented in Table A6.8.2- 2
No test item related macroscopic findings were observed. Findings were considered to be within the range of biological variation of rats of this age and strain.
The number of implantation sites was statistically significant decreased in dams of the 100 mg/kg dose group.
The number of living pups at first litter check (day 1 of lactation) was statistically significantly decreased in the 100 mg/kg dose group.
Total postnatal loss between days 0 and 4 post partum was statistically significantly increased and the viability index was statistically significantly decreased in litters of the 10, 30 and 100 mg/kg dose groups when compared to the control group. However, these findings were considered to be of no toxicological significance.
Total breeding loss between days 5 and 25 post partum was statistically significantly increased in litters of the 30 mg/kg dose group when compared to the control group. This finding was considered to be of no toxicological significance.
Details are presented in Table A6.8.2- 4.


F1-parents
No test item-related mortality was observed at any tested dose level.
Clinical appearance was unaffected when treated up to 100 mg/kg bw/day. An increased incidence in piloerection was noted in animals of the 30 and 100 mg/kg dose groups during the first two weeks of treatment. A slightly increased incidence in hunched posture was noted in males of the 100 mg/kg dose group during the first two weeks of treatment. Because these findings were transient, they were not considered to be of any toxicological significance. One female of the 30 mg/kg bw/d group showed a palpable mass at the chest from week 15 onwards. This single observation was considered to be caused by chance and thus of no toxicological significance.
Body weights of males of the 100 mg/kg dose group were statistically significantly decreased during the pre-mating and mating period.
Females of the 100 mg/kg dose group showed statistically significantly decreased body weights during the first week of the pre-mating period. Because this was a transient effect, it was not considered to be of toxicological significance. Body weight gain was statistically significantly increased in females of the 10 mg/kg dose group during weeks 3–10 of the pre-mating period. Due to the absence of a dose response relationship, this finding was considered to be of no toxicological relevance.
Food consumption was statistically significantly decreased in males of the 100 mg/kg dose group during the pre-mating period and the relative food consumption was also slightly lower. During several weeks of the pre mating period, absolute and relative food consumption were statistically significantly decreased in females treated with 100 mg/kg.
Results are presented in Table A6.8.2- 2.
Macroscopic observations at necropsy did not reveal any alterations that were considered a result of treatment.
Reproduction parameters and breeding data were unaffected by treatment.
Results are presented in Table A6.8.2- 4.
Key result
Dose descriptor:
NOAEL
Remarks:
general parental toxicity
Effect level:
3 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: decreases in body weight, body weight gain and relative food consumption in male and female high dose animals (20 mg a.i./kg bw/day); absolute food consumption was significantly decreased in females only
Remarks on result:
other: Based on slightly higher toxicity of the target substance observed in the acute and repeated dose toxicity studies, a factor of 2 was applied to the NOAEL obtained in this study conducted with the source substance DOPA-Glycinate.
Key result
Dose descriptor:
NOAEL
Remarks:
reproduction
Effect level:
3 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: P-dams showed a reduced number of implantation sites at necropsy and living pups at day 1 of lactation. The number of implantations at birth was not significant in dams of the F1-generation.
Remarks on result:
other: Based on slightly higher toxicity of the target substance observed in the acute and repeated dose toxicity studies, a factor of 2 was applied to the NOAEL obtained in this study conducted with the source substance DOPA-Glycinate.
Critical effects observed:
no
Clinical signs:
no effects observed
Mortality / viability:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
F1-pups
Development of pups was similar for control and treated groups.
No test-item related macroscopic findings were observed upon necropsy of F1-weanlings.
Mean body weights of pups were similar for control and treated groups.


F2-pups
Development of pups was similar for control and treated groups.
No test-item related macroscopic findings were observed upon necropsy of F2-weanlings.
Mean body weights of pups were similar for control and treated groups.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Clinical signs, body weights and macroscopic examination were unaffected in F1- and F2-pups with maternal treatment up to 20 mg a.i./kg bw/d.
Remarks on result:
other: Based on slightly higher toxicity of the target substance observed in the acute and repeated dose toxicity studies, a factor of 2 was applied to the NOAEL obtained in this study conducted with the source substance DOPA-Glycinate.
Critical effects observed:
no
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Clinical signs, body weights and macroscopic examination were unaffected in F1- and F2-pups with maternal treatment up to 20 mg a.i./kg bw/d.
Remarks on result:
other: Based on slightly higher toxicity of the target substance observed in the acute and repeated dose toxicity studies, a factor of 2 was applied to the NOAEL obtained in this study conducted with the source substance DOPA-Glycinate.
Critical effects observed:
not specified
Reproductive effects observed:
yes
Lowest effective dose / conc.:
10 mg/kg bw/day (actual dose received)
Treatment related:
yes
Relation to other toxic effects:
reproductive effects as a secondary non-specific consequence of other toxic effects
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
The target substance Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid was slightly more toxic in the acute and repeated dose toxicity studies compared to the source substance DOPA-Glycinate, as demonstrated by the NOAEL obtained in the 90 d study and the LD50 obtained in the acute oral toxicity study, which were both lower by approx. a factor of 2 compared to the effect levels of the source substance. Thus, for precautionary reasons, a factor of 2 will be applied to the NOAEL obtained in this study conducted with the source substance DOPA-Glycinate.
The parental and reproductive NOAEL for the target substance Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid is therefore considered to be 3 mg a.i./kg bw/d, the developmental NOAEL is 10 mg a.i./kg bw/d.
As effects were only observed in the presence of marked general toxicity, the substance is not considered toxic to reproduction.
Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
3 mg/kg bw/day
Study duration:
chronic
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No experimental data on fertility effects are available for the target substance Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid. However, a two generation reproduction toxicity study is available for the closely related source substance DOPA-Glycinate. A justification for read-across is attached to IUCLID section 13.

 

DOPA-Glycinate (20% a.i., as manufactured) was administered to groups of male and female Wistar rats at 0 (control), 10, 30 or 100 mg/kg bw/day in water, corresponding to 2, 6 and 20 mg a.i./kg bw/day,by gavage during the pre-mating and mating period and to females also during gestation and lactation. The two generation reproduction study was carried out in compliance with OECD guideline 416 (1983) and also with the recent version OECD 416 (2001), except that the examination of oestrus cycle and sperm parameters were not conducted in the study.

 

Parental toxicity

Parental toxicity was assessed by observing mortality, clinical signs, body weights, food consumption, and macroscopic examination for both generations. Mortality and macroscopic examination were unaffected in parental animals (P) and F1-generation up to 100 mg/kg/day. At 100 mg/kg body weight/day, P-females showed a slightly increased incidence in hunched posture, while P-animals displayed rales at a low incidence and on few occasions. No treatment-related clinical signs were observed in animals of the F1-generation. P- and F1-animals of the 100 mg/kg dose group showed a reduced body weight, body weight gain, food consumption, and relative food consumption during their treatment period. 

Parental NOAEL= 30 mg/kg bw/day, corresponding to 6 mg a.i./kg bw/day based on decreases in body weight, body weight gain and relative food consumption in male and female high dose animals (100 mg/kg bw/day). Absolute food consumption was significantly decreased in females only.

 

Reproductive toxicity

Reproductive toxicity was assessed by observing the number of implantations at birth, mating performance, fertility indices, and breeding data. Mating performance, fertility indices, and breeding data were unaffected in animals of the P- and F1-generations when treated up to 100 mg/kg bw/day. P-dams of the 100 mg/kg bw/day dose group showed a reduced number of implantation sites at necropsy and living pups at day 1 of lactation. The number of implantations at birth was not significant in dams of the F1-generation. 

The increase in postnatal loss in the 10 mg/kg bw/day dose group was due to three litters in which an increased loss was observed. In one of those litters all fifteen pups died spontaneously or were killedin extremisbecause the dam died spontaneously due to delivery difficulties. The increase in postnatal loss in the 30 mg/kg bw/day dose group was mainly due to one litter in which all fourteen pups died on or before day 5post partum. This was probably due to bad health of the dam (hunched posture and body weight loss). The increase in postnatal loss in the 100 mg/kg bw/day dose group was mainly due to two litters in which an increased loss was observed. In one of those litters all nine pups died on or before day 5post partum. This was probably due to poor dam health (hunched posture, piloerection, and reduced body weight). These statistically significant differences were due to single observations, the number of affected litters was similar for control and treatment groups, and no true treatment related effect was observed. There was no dose response associated with these effects. As a consequence of these observations on postnatal loss, the viability index was statistically significantly decreased in litters from all dose groups. These findings are not considered to be toxicologically relevant, they do not display a dose response and as such are not taken into account for determining the reproductive NOAEL. 

Reproductive NOAEL= 30 mg/kg bw/day, corresponding to 6 mg a.i./kg bw/day based on a reduced number (-16% relative to controls) of implantation sites at necropsy of P females. Reduced numbers of living pups on day 1 of lactation for parental animals receiving 10, 30 and 100 mg/kg bw/day were statistically significant but did not follow a dose response and are not taken into account for determining the reproductive NOAEL.

 

Developmental toxicity

Developmental toxicity was assessed by observing clinical signs, body weights and macroscopic examination of the pups during their lactation period. Clinical signs, body weights and macroscopic examination were unaffected in F1- and F2-pups with maternal treatment up to 100 mg/kg body weight/day. 

Developmental NOAEL= 100 mg/kg bw/day, corresponding to 20 mg a.i./kg bw/day. No treatment-related macroscopic pathological effects were observed for any dose tested. 

No treatment-related mortality occurred during the study. Parental toxicity consisted of clinical signs (only P-animals), effects on body weights and food consumption for P- and F1-animals receiving 100 mg/kg bw/day. Reproductive toxicity consisted of a reduced number of implantation sites at necropsy and living pups on day 1 of lactation for P-animals receiving 100 mg/kg bw/day.

In conclusion, gavage treatment of male and female Wistar rats with DOPA-Glycinate (20% a.i.) at dose levels of 10, 30 or 100 mg/kg bw/day, corresponding to 2, 6 and 20 mg a.i./kg bw/day, over two generations revealed parental, and reproductive toxicity in animals receiving 100 mg/kg bw/day. Development of the pups was not affected up to the maximum dose of 100 mg/kg bw/day. 

Based on the results of this study, the parental and reproductive NOAEL was established at 30 mg/kg bw/day, corresponding to 6 mg a.i./kg bw/day. The developmental NOAEL was established at 100 mg/kg bw/day, corresponding to 20 mg a.i./kg bw/day.

 

Conclusion

The target substance Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid was slightly more toxic in the acute and repeated dose toxicity studies compared to the source substance DOPA-Glycinate, as demonstrated by the NOAEL obtained in the 90 d study and the LD50 obtained in the acute oral toxicity study, which were both lower by approx. a factor of 2 compared to the effect levels of the source substance. Thus, for precautionary reasons, a factor of 2 will be applied to the NOAEL obtained in this study conducted with the source substance DOPA-Glycinate.

The parental and reproductive NOAEL for the target substance Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid is therefore considered to be 3 mg a.i./kg bw/d, the developmental NOAEL is 10 mg a.i./kg bw/d.

As effects were only observed in the presence of marked general toxicity, the substance is not considered toxic to reproduction.

There are no data gaps for the endpoint toxicity to reproduction. No human information is available for this endpoint. However, there is no reason to believe that these results would not be applicable to humans.

Effects on developmental toxicity

Description of key information

not teratogenic; maternal NOAEL = 10 mg a.i./kg bw/d; NOAEL for survival, growth and development in utero = 4 mg a.i./kg bw/d; OECD TG 414, rat; read-across from DOPA-Glycinate

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

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar toxicological properties because
- they are manufactured from similar or identical precursors under similar conditions
- they share structural similarities with common functional groups (corresponding to scenario 2 of the read-across assessment framework): both, the target and source substance, are aliphatic amines with C8-18 alkyl chains and acetate functions
- Two thirds (w/w) of the target substance Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid (excluding the solvent water) are composed of the source substance DOPA-Glycinate. The remaining third of Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid consists of other aliphatic amines and derivatives which are considered as structural analogues to those constituting the source substance DOPA-Glycinate and may therefore be expected to elicit comparable (eco)toxicological effects.

The read-across hypothesis is based on structural similarity of target and source substances. Based on available experimental data, including key physicochemical properties and data from acute toxicity, repeated dose toxicity, genotoxicity and short term ecotoxicity studies, the read-across hypothesis is supported by a quite similar toxicological profile of both substances.

(Eco)toxicological, physicochemical and environmental fate data are summarised in the data matrix; robust study summaries are included in the Technical Dossier in the respective sections.

Therefore, read-across from the existing ecotoxicity, environmental fate and toxicity studies conducted with the source substances is considered as an appropriate adaptation to the standard information requirements of the REACH Regulation for the target substance, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.

Further details are attached to IUCLID section 13.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
For further details refer to IUCLID section 13.

3. ANALOGUE APPROACH JUSTIFICATION
For further details refer to IUCLID section 13.

4. DATA MATRIX
For further details refer to IUCLID section 13.

Reason / purpose:
read-across: supporting information
Reason / purpose:
read-across source
Species:
rat
Strain:
other: Wistar rats Crl: (WI) BR (outbred, SPF-Quality)
Route of administration:
oral: gavage
Vehicle:
water
Duration of treatment / exposure:
Day 6–16 of gestation
Frequency of treatment:
daily
Duration of test:
21 d
No. of animals per sex per dose:
24 females
Control animals:
yes, concurrent vehicle
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
No deaths occurred among treated and control females.
Four animals treated with 250 mg/kg bw/day showed incidental findings (hunched posture, laboured respiration, rales, brown discolouration of the snout, salivation and piloerection) which were however considered to be related to treatment. One animal treated with 40 mg/kg bw showed scabs on the nose and one which received 100 mg/kg bw showed piloerection. These effects were considered not to be treatment related. Alopecia was observed in all animals of all dose groups. Alopecia is commonly seen in animals of this strain used in this type of study and therefore no toxicological significance was attached to this finding.
Females receiving 250 mg/kg bw/day showed a decrease in body weight and body weight gain, which was statistically significant on gestation days 13 to 17 and 11 to 17, when compared to the control group. After correction of the uterus weight, a decrease in weight gain was noted in the 250 mg/kg bw dose group when compared to the control. However, this was not statistically significant due to the high standard deviation in this treated group.
Females treated with 250 mg/kg bw/day showed a statistically significant decrease in food consumption on gestation days 6 to 17. This finding was considered to be caused by the test substance. Females receiving 100 mg/kg bw/day showed a slight, statistically significant decrease in food consumption from gestation days 6–9 and 13–17 when compared to the control. However, this difference was considered to be unrelated to treatment because the mean of relative food consumption of females of this dose group were comparable with the control values.
No treatment-related macroscopic lesions were observed upon necropsy.
One female treated with 100 mg/kg bw/d did not become pregnant and was excluded from further calculations. The statistically significant differences seen in pre-implantation loss and implantation index of the 40 and 250 mg/kg bw/d dose group were considered to be unrelated to treatment, since treatment started on gestation day 6, which is after implantation. No treatment related effects were seen on post-implantation loss.
Results are presented in Table A6.8.1- 5 and Table A6.8.1- 6.
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity
Remarks on result:
other: Based on slightly higher toxicity of the target substance observed in the acute and repeated dose toxicity studies, a factor of 2 was applied to the NOAEL obtained in this study conducted with the source substance DOPA-Glycinate.
Abnormalities:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
The number of live foetuses observed in the treatment and control groups remained within biologically normal limits for rats of this age and strain and no treatment related differences were observed. In addition, no treatment-related effects on sex ratio were observed.
Foetal weights and of dams and placental weights of live foetuses of the 40 mg/kg bw/d group were significantly decreased when compared to the control group. Due to absence of a dose-relation, this change was considered to be unrelated to treatment.
External examination of the foetuses did not reveal any findings among foetuses of litters treated with the test substance that were considered to be an adverse effect of the test substance. There are minor morphological changes amongst all litters across all dose groups as well as the control. In general there were no indications of any consistent treatment or dose related effects on any of the parameters investigated, some of which are tabulated in A6.8.1-4 for illustrative purposes. However, in the 100 and 250 mg/kg bw/d dose groups there appeared to be a treatment related increase in the incidence of unilateral hydroureter compared with the concurrent controls in conjuction with interparietal and supraoccipital delayed ossification. There was also a slight increase in unilateral renal pelvic cavitation with treatment.
Dose descriptor:
NOAEL
Effect level:
4 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: increases in the incidence of unilateral hydroureter compared with the concurrent controls in conjuction with interparietal and supraoccipital delayed ossification; slight increase in unilateral renal pelvic cavitation at the two higher doses
Remarks on result:
other: Based on slightly higher toxicity of the target substance observed in the acute and repeated dose toxicity studies, a factor of 2 was applied to the NOAEL obtained in this study conducted with the source substance DOPA-Glycinate.
Abnormalities:
not specified
Developmental effects observed:
no

Table A6.8.1-3: Rat Maternal and Foetal Observations made at necropsy.

Parameter

Control

40 mg/kg/d

100 mg/kg/d

250 mg/kg/d

Number of dams examined

24

24

23a

24

Mortality of dams

0

0

0

0

Mean body weight [g] at day 0

262

267

256

261

Mean body weight [g] at day 17

364

377

352

341**

Mean body weight [g] at day 21

439

455

423

418

Mean body weight gain [%] day12

23

24

23

19**

Mean body weight gain [%] day 17

39

41

38

31**

Mean food consumption [g/rat/day], day 6–9

27

28

25*

23**

Mean food consumption [g/rat/day], day 9–13

28

28

26

22**

Mean food consumption [g/rat/day], day 13–17

29

30

26*

23**

Relative food consumption [g/kg bw/day], day 13–17

85

86

80

70**

Number of pregnant females

24/24

24/24

23/24

24/24

Abortions

0

0

0

0

 

 

 

 

 

No. of litters totally resorbed

0

0

0

0

No. of litters with viable foetuses

24

24

23

24

No. of corpora lutea/dam

18.6 ± 2.8

19.7 ± 2.9

17.9 ± 2.8

17.8 ± 2.1

No. of implantations/dam

15.5 ± 2.9

17.3 ± 2.4

15.0 ± 2.8

16.0 ± 2.6

Mean% pre-implantation loss

16.6

11.9#

16.5

10.1##

No. of resorptions/litter

0.5

0.5

0.6

0.9

Mean% post-implantation loss

3.5

2.9

4.1

5.5

Viable foetuses (total)

359

404

330

363

Viable foetuses/litter

15.0 ± 2.9

16.8 ± 2.3

14.3 ± 3.0

15.1 ± 3.2

Dead foetuses (total)

0

1

0

0

Foetal weight-males (g)

5.3 ± 0.5

5.3 ± 0.6

5.4 ± 0.4

5.4 ± 0.5

Foetal weight-females (g)

5.0 ± 0.5

4.9 ± 0.8

5.1 ± 0.4

5.1 ± 0.5

Foetal weight-sexes combined (g)

5.2 ± 0.5

5.1 ± 0.7

5.2 ± 0.4

5.2 ± 0.5

Sex ratio (M%:F%)

48:52

48:52

50:50

52:48

Mean placental weight (g)

0.51 ± 0.06

0.47 ± 0.06

0.53 ± 0.06

0.50 ± 0.06

 

 

 

 

 

a) one animal (female 51) did not become pregnant after mating.

* : Dunnett-test based on pooled variance significant at 5% level

** : Dunnett-test based on pooled variance significant at 1% level

#: Fisher’s Exact Test significant at level 5%

##: Fisher’s Exact Test significant at level 1%

 

Table A6.8.1-4: Incidence of Selected Rat Foetal Parameters*(Caesarean section data from day 21).

Parameter

Control

40 mg/kg/d

100 mg/kg/d

250 mg/kg/d

 

 

Number of foetuses (no. of litters) examined

visceral examination

182 (24)

201 (24)

162 (23)

180 (24)

 

skeletal examination

185 (24)

202 (24)

168 (23)

183 (24)

 

Visceral Examination - affected foetuses (no. of litters)

 

small additional vessel arising from aorta

1 (1)

0 (0)

0 (0)

0

 

small additional liver lobe

14 (12)

12 (9)

14 (7)

14 (11)

 

kidney and adrenal gland displaced

7 (6)

9(5)

4(4)

5(5)

 

↑ renal pelvic cavitation: unilateral

0 (0)

0 (0)

1 (1)

2 (2)

 

↑ renal pelvic cavitation: bilateral

1(1)

0 (0)

0 (0)

0 (0)

 

hydroureter: unilateral
           % of total foetuses:

4 (3)
2.2

5 (4)
2.5

12 (9)
7.1

17 (9)
9.3

 

hydroureter: bilateral

4 (2)

4 (3)

0 (0)

6 (5)

 

Skeletal Examination - affected foetuses (no. of litters)

 

delayed ossification interparietal
           % of total foetuses:

23 (13)
12.4

23 (13)
11.4

31 (10)
18.5

42 (13)
23.0

 

delayed ossification supraoccipital
           % of total foetuses:

4 (2)
2.2

7 (5)
3.5

12 (7)
7.1

19 (10)
10.4

 

delayed ossification hyoid

2 (2)

1 (1)

8 (6)

6 (3)

 

delayed ossification sternebrae (≥3)

2 (2)

3 (3)

1 (1)

6 (5)

 

anomalous sternabrae

9 (6)

7 (7)

7 (7)

14 (11)

 

Head Examination – affected foetuses (no. of litters)

 

bilateral slightly folded retina

1 (1)

0 (0)

0 (0)

1 (1)

 

 

 

 

 

 

 

*Some of the effects seen multiple times at any dose are recorded here. There was no consistent relationship between dose and any of the recorded effects noted in the original pathologist‘s report except for the incidence of hydroureter. Numbers in parenthesis indicate the number of litters in which that effect is found. 

 

 

Visceral Examination

A number of anomalies were recorded in all groups, the types, incidences and group distribution of which did not indicate any association with treatment.

In the intermediate and high dose groups (100 and 250 mg/kg body weight/day) there appeared to be a marginal increase in the incidence of unilateral hydroureter compared with the concurrent controls and the low dose group (40 mg/kg body weight/day), however, as no increases were recorded in the incidences of bilateral hydroureter or renal pelvic cavitation it was considered that this finding did not represent a toxicologically significant response to treatment.

In the high dose group (250 mg/kg body weight/day) one litter contained four fetuses with an accessory blood vessel associated with the superior pole of the kidney and a second litter contained one small foetus with cranial abnormalities and immature gonads. The isolated nature of these observations did not suggest any association with treatment.

 

Skeletal Examination

Compared with the concurrent controls and the low dose group (40 mg/kg body weight/day), there appeared to be indications of reduction in foetal ossification in the high dose group (250 mg/kg body weight/day) and, to a lesser extent, in the intermediate dose group (100 mg/kg body weight/day). Parameters affected included a number of cranial bones, viz. supraoccipital, interparietal, squamosal, jugal. maxilla(e) and hyoid, the caudal vertebral arches and humerus(i). Other ossification parameters were similar in all groups.

 

Morphological parameters

A number of foetuses in all groups showed minor morphological changes, but there were no indications of any consistent treatment or dose related associations or trends.

Conclusions:
The target substance Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid was slightly more toxic in the acute and repeated dose toxicity studies compared to the source substance DOPA-Glycinate, as demonstrated by the NOAEL obtained in the 90 d study and the LD50 obtained in the acute oral toxicity study, which were both lower by approx. a factor of 2 compared to the effect levels of the source substance. Thus, for precautionary reasons, a factor of 2 will be applied to the NOAEL obtained in this study conducted with the source substance DOPA-Glycinate.
The maternal NOAEL for the target substance is therefore considered to be 10 mg a.i./kg bw/d, the NOAEL for survival, growth and development in utero is 4 mg a.i./kg bw/d. The target substance Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid is not teratogenic.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
4 mg/kg bw/day
Study duration:
subacute
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
Additional information

No experimental data on developmental toxicity are available for the target substance Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid. However, a prenatal developmental toxicity study is available for the closely related source substance DOPA-Glycinate. A justification for read-across is attached to IUCLID section 13.

 

The potential of DOPA-Glycinate (20% a.i.) to induce embryotoxic effects in the rat (Wistar rats Crl: (WI) BR (outbred, SPF-Quality)) was investigated at 0 (control), 40, 100 and 250 mg/kg bw/day in water, administered from day 6 to day 16 post coitum, according to OECD guideline 414 (1981). Furthermore, the conduct of the study was consistent to the recent OECD guideline 414 (2001) in all important aspects, except that test substance was administered solely during the period of organogenesis.

 

Visceral Examination

A number of anomalies were recorded in all groups, the types, incidences and group distribution of which did not indicate any association with treatment.

In the intermediate and high dose groups (100 and 250 mg/kg body weight/day) there appeared to be an increase in the incidence of unilateral hydroureter compared with the concurrent controls and the low dose group (40 mg/kg body weight/day).

In the high dose group (250 mg/kg body weight/day) one litter contained four fetuses with an accessory blood vessel associated with the superior pole of the kidney and a second litter contained one small foetus with cranial abnormalities and immature gonads. The isolated nature of these observations did not suggest any association with treatment.

 

Skeletal Examination

Compared with the concurrent controls and the low dose group (40 mg/kg body weight/day), there appeared to be indications of a reduction in foetal ossification in the high dose group (250 mg/kg body weight/day) and, to a lesser extent, in the intermediate dose group (100 mg/kg body weight/day). Parameters affected included a number of cranial bones, viz. supraoccipital, interparietal, squamosal, jugal. maxilla(e) and hyoid, the caudal vertebral arches and humerus(i). Other ossification parameters were similar in all groups.

 

Morphological Examination

A number of foetuses in all groups showed minor morphological changes, but there were no indications of any consistent treatment or dose related associations or trends.

 

Dams treated with 250 mg/kg bw/d showed maternal toxicity comprising clinical signs, reduced body weight gain and food consumption during the treatment period. Based on the results of this study, DOPA-Glycinate (20% a.i.) is considered not to be teratogenic when orally administered to Wistar rats at levels up to and including 40 mg/kg bw/d.

The maternal no observed adverse effect level (NOAEL) was 100 mg/kg bw/d, corresponding to 20 mg a.i./kg bw/d.

The NOAEL for survival, growth and development in utero was 40 mg/kg bw/d, corresponding to 8 mg a.i./kg bw/d.

 

Conclusion

The target substance Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid was slightly more toxic in the acute and repeated dose toxicity studies compared to the source substance DOPA-Glycinate, as demonstrated by the NOAEL obtained in the 90 d study and the LD50 obtained in the acute oral toxicity study, which were both lower by approx. a factor of 2 compared to the effect levels of the source substance. Thus, for precautionary reasons, a factor of 2 will be applied to the NOAEL obtained in this study conducted with the source substance DOPA-Glycinate.

The maternal NOAEL for the target substance is therefore considered to be 10 mg a.i./kg bw/d, the NOAEL for survival, growth and development in utero is 4 mg a.i./kg bw/d. The target substance Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid is not teratogenic.

 

There are no data gaps for the endpoint developmental toxicity. No human information is available for this endpoint. However, there is no reason to believe that these results would not be applicable to humans.

Justification for classification or non-classification

In conclusion, the results of the available data on reproductive and developmental toxicity indicate that Reaction product of lauryl-PDA/lauryl-DETA with chloroacetic acid does not need to be classified for reproductive and developmental toxicity according to Regulation 1272/2008/EC and therefore labelling is not necessary.