Registration Dossier

Administrative data

Description of key information

In a key OECD 422 study, read-across substance butanedioic acid, sulfo-, 1-C12-18-alkyl esters, disodium salts (CAS 90268 -36 -3) was administered orally to rats at dose levels of 60, 120 or 300 mg test item/kg bw/day (Hansen, 2013). One of 10 male and one of 10 female animals of the high dose group died prematurely on test day 33 or on gestation day 9. Slight to moderate salivation was noted in a few male and female animals of the medium dose group, whereas in the (medium and) high dose group, effects comprised of piloerection and a slight to extreme salivation, reduced body weight, clinical chemistry changes, organ weights changes (thymus, liver), macroscopic changes (stomach) and histopathological changes in the liver (hepatocellular hypertrophy and macrovesicular vacuolation evoked by fatty change) and the non-glandular stomach (squamous cell hyperplasia) of male and female animals. These latter changes are considered to be related to a local activity of the test item. As humans lack a forestomach, the relevance of these changes for humans is questionable. A NOAEL of 60 mg/kg bw/day for maternal and paternal toxicity was concluded, which can also be accepted for the target substance (based upon read-across justification).

Supporting dose range finding studies were available for the read across substances disodium isodecyl sulfosuccinate (CAS 37294 -29 -8) and butanedioic acid, sulfo-, 1-C12-18-alkyl esters, disodium salts(CAS 90268 -36 -3), both applied by oral gavage to Wistar rats for 14 days, and both leading to a NOAEL of 300 mg/kg bw.

Subchronic (90 -day) dietary toxicity studies were available for the target substance both in rats and dogs, however the studies were disregarded due to limitations compared to OECD 408 guideline.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Remarks:
read-across
Justification for type of information:
See attached read-across justification
Reason / purpose:
read-across source
Reason / purpose:
reference to same study
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
1male and 1 female of the high dose group died on day 33 and day 26 respectively; slight signs of systemic toxicity were noted predominantly in form of pilo-erection and increased salivation in males and females dosed at 120 & 300 mg/kg bw
Mortality:
mortality observed, treatment-related
Description (incidence):
1male and 1 female of the high dose group died on day 33 and day 26 respectively; slight signs of systemic toxicity were noted predominantly in form of pilo-erection and increased salivation in males and females dosed at 120 & 300 mg/kg bw
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
decreased at 120 and 300 mg/kg bw in male rats and at 300 mg/kg bw in female rats prmating, mating, during gestationa and during lactation
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
decreased at 120 and 300 mg/kg bw in male rats and at 300 mg/kg bw in female rats prmating, mating, during gestationa and during lactation
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
increased MCHC in males at 120 mg/kg bw; increased haemoglobin, red blood cells, haematocrit and MCHC value in males dosed 300 mg/kg bw; decrease aPTT time in females dosed 300 mg/kg bw
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
increased ALAT in males dosed at 120 mg/kg bw; increased ALAT, aP and ASAT and decreased cholesterol in males dosed at 300 mg/kg bw; increased ALAT and ASAT and decreased globulin, cholesterol, chloride, potassium in females dosed 300 mg/kg bw
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
decr. epididymis weights in M at 120 mg/kg; incr. liver and decreased thymus/testes weights in M at 300 mg/kg; incr. liver/adrenal and decr. heart weights in F at 120 mg/kg; incr. kidney/adrenal weights and decr. heart/ovary weight in F at 300 mg/kg
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
detachment of stomach mucosa, whitish thickenings and ulcers in males dosed 300 mg/kg bw; detachment of stomach mucosa in famels dosed at 120 and 300 mg/kg bw
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
hepatocellular hypertrophy and macrovesicular vacuolation in liver and squamous cell hyperplasia in the non-glandular stomach in males and females at 300 mg/kg bw; changes in the mammary glands, the uterus and vagina in females at 300 mg/kg bw
Histopathological findings: neoplastic:
no effects observed
Details on results:
MORTALITY:
One of 10 male animals (no. 64) of the high dose group (300 mg test item/kg bw/day) died on test day 33, showing piloerection and reduced motility before death.
One of 10 female animals (no. 71) of the high dose group (300 mg test item/kg b.w./day) died on gestation day 9, showing piloerection and salivation on a few days during the premating, mating and gestation period.

CLINICAL SIGNS:
Male animals
Slight salivation was noted in 2 animals of the intermediate dose group (120 mg test item/kg b.w./day) on one day each.
In the high dose group (300 mg test item/kg bw/day) piloerection and slight to moderate salivation was noted for several animals during the whole study for 1 up to 13 test days. Breathing sounds were noted in animal no. 61 for 1 day.
Female animals
In the intermediate dose group (120 mg test item/kg bw/day) piloerection was noted for 1 animal on 1 day during the mating period. During the gestation period moderate salivation was noted in 3 animals on one day each.
In the high dose group (300 mg test item/kg bw/day) piloerection was noted for several animals on 3 up to 10 test days and slight to extreme salivation in all female animals (2 up to 11 test days) during the pre-mating, mating and gestation period. A haemorrhagic vagina or nose was noted for animal no. 72 on gestation days 11 and 16. During the lactation period piloerection, reduced motility and changes in the status of faeces were noted for the emaciated female animal no. 75.

BODY WEIGHT AND WEIGHT GAIN
Male animals
A reduction in body weight was noted in the intermediate dose group (120 mg test item/kg bw/day) from test day 8 by 6.7% until the end of the study by 6.2%, statistically significant (p≤0.05) on test days 8, 22, 29 and 42.
In the high dose group (300 mg test item/kg bw/day) the reduction in body weight was more pronounced, with 9.0% on test day 8 and 13.3% at the end of the study, statistically significant (p≤0.01) from test day 8 to the end of the study.
Accordingly, statistically significant (p≤0.05 or p≤0.01) reductions in body weight gain were noted in the intermediate and the high dose group (120 and 300 mg test item/kg bw/day).
Female animals
A decrease in body weight (300 mg test item/kg bw/day) was noted in the high dose group, starting at the end of the pre-mating period by 5.4%. Statistically significant (p≤0.01) reductions were noted during the gestation period from gestation day 7 (by 9.6%) to 20 (by 23.9%) and on lactation day 1 (by 22.0%) and 4 (by 23.8%).
Statistically significant reductions in body weight gain were noted on gestation day 14 (p≤0.01) and 20 (p≤0.05) in the intermediate dose group (120 mg test item/kg bw/day).
In the high dose group (300 mg test item/kg bw/day) statistically significant reductions in body weight gain were noted on test day 8 (p≤0.01) and during the gestation period from gestation day 7 (p≤0.05) to gestation day 20 (p≤0.01).

FOOD CONSUMPTION:
Male animals
A statistically significant (p≤0.01) reduction in food consumption by 14.1% was noted in the interme-diate dose group (120 mg test item/kg bw/day) during the first test week.
In the high dose group (300 mg test item/kg bw/day) the food consumption was statistically significantly (p≤0.01) reduced by 20.7% during the first and by 15.3% during the second test week.
Female animals
At the intermediate dose group (120 mg test item/kg bw/day) a statistically significant reduction in food consumption was noted during the first week of gestation by 7.3% (p≤0.05) and during the second week of gestation by 13.8% (p≤0.01).
In the high dose group (300 mg test item/kg bw/day) a statistically significant (p≤0.01) reduction in food consumption was noted from the first test week (by 26.3%) until the end of the gestation period (by 6.8%).

HAEMATOLOGY
Male animals
At 120 mg test item/kg bw/day the MCHC value was slightly but statistically significantly (p≤0.01) increased by 2.6%.
In the high dose group (300 mg test item/kg bw/day) a statistically significant (p≤0.01) increase was noted for the concentration of haemoglobin (+11.8%), the number of red blood cells (+11.1%), the haematocrit value (+9.1%) and the MCHC value (+2.6%).
Female animals
A statistically significant (p≤0.01) decrease in the aPTT time by 8.4% was noted in the high dose group (300 mg test item/kg bw/day).

CLINICAL CHEMISTRY
Male animals
In the intermediate dose group (120 mg test item/kg bw/day) statistically significant (p≤0.01) increases were noted for the enzyme activity of ALAT (+158%) and aP (+175%).
In the high dose group (300 mg test item/kg bw/day) statistically significant (p≤0.01) increases were noted for the activity of ALAT (+688.3%), aP (+306%), ASAT (91%).
A statistically significant (p≤0.05) decrease by 33% was noted in the high dose group for the cholesterol concentration.
Female animals
In the high dose group (300 mg test item/kg bw/day) statistically significant (p≤0.01) increases were noted in the activity of ALAT (+674%) and ASAT (+104%).
The concentrations of globulin (by 8.8%), cholesterol (by 62%), chloride (by 3.1%) and potassium (by18%) were statistically significantly (p≤0.01) decreased in the high dose group (300 mg test item/kg bw/day).

NEUROBEHAVIOUR
No test item-related influence was noted for observational and functional screening and for spontaneous motility.

ORGAN WEIGHTS
Male animals
In the high dose group (300 mg test item/kg bw/day) the body weight at autopsy was statistically significantly (p≤0.01) decreased by 13.5%.
Starting at the intermediate dose group (120 mg test item/kg bw/day) a statistically significant (p≤0.05, right only) dose related decrease by 18.3% at maximum was noted for the absolute organ weight of the left + right epididymis.
In the high dose group (300 mg test item/kg) the following statistically significant changes were noted:
An increase by 34.0% (p≤0.01) of the relative liver weight and by 19.6% (non-significant) of the abso-lute liver weight.
The relative and absolute organ weight of the thymus was decreased by 42.5% (p≤0.05) and by 49.0% (p≤0.01).
The relative organ weights of the left and right gonads were reduced by 14.9% (p≤0.01) and by 13.7% (p≤0.05).
Female animals
A statistically significant (p≤0.01) reduction in the body weight at autopsy by 22.2% was noted in the high dose group (300 mg test item/kg bw/day).
In the intermediate dose group (120 mg test item/kg) a statistically significant (p≤0.01) increase was noted in the relative liver weight by 23%.
The absolute heart weight was statistically significantly decreased by 16.7%.
The relative organ weights of the left and right adrenal glands were statistically significantly (p≤0.01) increased by 26.2% and 24.4%.
In the high dose group (300 mg test item/kg) the relative organ weights of the left and right kidneys were statistically significantly increased by 17.2% (p≤0.05) and by 20.9% (p≤0.01).
The absolute organ weight of the heart was statistically significantly (p≤0.05) decreased by 33.1%.
The absolute organ weight of the right gonad was statistically significantly (p≤0.05) decreased by 37.5% and the absolute organ weight of the left gonad non-significantly by 25.5%.
Similar but not statistically significant increases as in the intermediate dose groups were noted for the relative liver weight and the left and right adrenal glands.

GROSS PATHOLOGY
Male animals
Macroscopic changes were noted in the stomach of 3 animals of the high dose group (300 mg test item/kg bw/day) in form of a detachment of the mucosa, whitish thickenings and ulcers. The find-ings were considered to be test item-related.
Female animals
A test item-related detachment of the mucosa was noted in the stomach of one animal of the inter-mediate dose group (120 mg test item/kg bw/day)
In the high dose group (300 mg test item/kg bw/day) a test item-related detachment of the mucosa was noted in 2 animals.

HISTOPATHOLOGY: NON-NEOPLASTIC (restricted to the control group and the high dose group):
Male and female animals
Test item related changes were noted in the liver (hepatocellular hypertrophy and macrovesicular vacuolation evoked by fatty change) and in the non-glandular stomach (squamous cell hyperplasia) in the animals of the high dose group (300 mg test item/kg).
Female animals
Test item related changes were noted in the mammary glands, the uterus and vagina in form of a decreased acinar development, stromal hyperplasia in the endometrium and metestrus in only 1 of 5 animals of the high dose group (300 mg test item/kg bw/day).

No microscopic changes were noted for the reproductive organs of the male and female rats of the high dose group (300 mg test item/kg bw/day) and no changes were noted on the stages of spermatogenesis.



Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: paternal/maternal effects
Dose descriptor:
NOAEL
Effect level:
120 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: reproductive/developmental effects
Critical effects observed:
not specified

Table 1. Mean body weight male rats

Sex: Male

Day(s) Relative to Start Date

1

8vv

15v

22vv

29vv

36vv

42vv

Group 1: control

351.76

382.89

384.38

417.44

438.70

452.95

466.48

Group2: 60mg/kg

347.77

376.01

378.72

416.27

438.79

453.18

454.34

Group3:

120 mg/kg

347.15

357.20*

360.33

392.72*

407.73*

427.61

437.78*

Group 4:

300 mg/kg

347.69

348.30**

344.28**

366.48**

366.91**

389.61**

404.56**

v Group Factor Dunnett’s Test Anova: Statistical Test: Analysis of Variance p<0.05

vv Group Factor Dunnett’s Test Anova Statistical Test: Analysis of Variance p<0.01

*Statistical Test Dunnett 2 Sided: p < 0.05

**Statistical Test Dunnett 2 Sided: p < 0.01

 

 Table 2. Mean body weight female rats

Sex: Female

Day(s) Relative
 to Start Date

Day(s) Relative
 to Mating (L)

Day(s) Relative to Littering (A)

1

8

15

0

7v

14vv

20vv

1vv

4vv

Group 1: control

233.93

246.30

234.90

254.51

287.30

320.92

393.10

307.38

323.92

Group2: 60mg/kg

233.89

240.31

233.37

247.96

278.33

300.66

361.13

287.00

301.92

Group3:

120 mg/kg

234.95

246.07

238.78

253.23

275.22

296.82

364.65

281.60

301.66

Group 4:

300 mg/kg

237.37

231.22

222.11

242.82

289.58**

265.88**

277.20**

239.68**

246.93**

Statistical Test Dunnett’s Test (Anova)

Group Factor Dunnett’s Test (Anova): v –Statistical Test: Analysis of Variance p<0.05

                                                                vv- Statistical Test: Analysis of Variance p<0.01

**-Statistical Test: Dunnett 2 Sided p<0.01

 

 

Table 3. Mean haematological parameters male and female rats

Day 15 Relative to Start Date

Sex: Male

HGB

(mmol/L)

RBC

(x10E6/µL)

HCT

(%)

MCHC

(g/L)

Sex: Female

aPTT

(seconds)

Group 1: control

9.64

8.032

47.64

326.228

Group 1:

control

15.06

Group2: 60mg/kg

10.10

8.408

49.08

331.157

Group2:

60mg/kg

14.22

Group3:

120 mg/kg

10.20

8.676

49.04

334.830**

Group3:

120 mg/kg

14.18

Group 4:

300 mg/kg

10.78**

8.924*

51.96**

334.605**

Group 4:

300 mg/kg

13.80*

Dunnett:

* 5% significance level

** 1% significance level

 

Table 4. Mean biochemical parameters male rats with changes

Day 15 Relative to Start Date

Sex: Male

Cholesterol (total)

(mmol/L)

ALAT

(U/L)

aP

(U/L)

ASAT

(U/L)

Group 1: control

1.054

35.8

157.4

81.4

Group2: 60mg/kg

0.862

38.4

245.0

81.6

Group3:

120 mg/kg

0.730

92.4**

433.2**

93.2

Group 4:

300 mg/kg

0.702*

282.2**

639.4**

155.4**

Dunnett:

* 5% significance level

** 1% significance level

 

Table 5. Mean biochemical parameters female rats with changes

Day 15 Relative to Start Date

Sex: Female

Globulin

(g/L)

Cholesterol (total)

(mmol/L)

Chloride

(mmol/L)

Potassium

(mmol/L)

ALAT

(U/L)

ASAT

(U/L)

Group 1: control

28.86

1.760

102.2

3.542

34.4

77.2

Group2: 60mg/kg

27.58

1.266**

 

101.2

3.430

38.6

77.0

Group3:

120 mg/kg

27.24

1.400

101.2

3.230

60.4

93.4

Group 4:

300 mg/kg

26.32*

0.672**

99.0**

2.916**

266.4**

157.8**

Dunnett:

* 5% significance level

** 1% significance level

 

Table 6. Absolute organ weights in male and female rats (g) with changes

 

Gonads

Epididymis

Kidney

Heart

Thymus

Males

left

right

left

right

left

right

Group 1

1.804

1.824

0.722

0.767

1.586

1.560

1.382

0.486

Group 2

1.793

1.784

0.717

0.706

1.598

1.648

1.374

0.406

Group 3

1.750

1.751

0.679

0.676*

1.344*

1.336*

1.296

0.362

Group 4

7.789

1.789

0.651

0.627**

1.500

1.464

1.158

0.248**

Females

 

 

 

 

 

 

 

 

Group 1

0.055

0.064

 

 

0.942

0.964

1.080

0.296

Group 2

0.048

0.056

 

 

0.996

1.016

0.990

0.220

Group 3

0.056

0.061

 

 

0.982

0.982

0.900*

0.208

Group 4

0.041

0.040*

 

 

0.813

0.853

0.723*

0.168*

**( p≤0.01),

*(p≤ 0.05), Dunett test or Student’s t-test

 

Table 7. Relative organ weights in male and female rats (g) wiht changes

 

Adrenals

Gonads

Kidney

Liver

Thymus

Males

left

right

left

right

left

right

Group 1

0.078

0.077

4.086

4.130

3.658

3.600

31.48

1.114

Group 2

0.075

0.076

4.158

4.135

3.708

3.824

34.02

0.948

Group 3

0.082

0.083

4.230

4.233

3.268

3.254

33.80

0.880

Group 4

0.090

0.093

4.693**

4.696*

3.872

3.782

42.18**

0.640*

Females

 

 

 

 

 

 

 

 

Group 1

0.122

0.127

0.186

0.219

3.230

3.308

41.44

1.022

Group 2

0.138

0.126

0.170

0.201

3.508

3.578

45.16*

0.780

Group 3

0.154**

0.158**

0.204

0.220

3.526

3.534

50.98**

0.748

Group 4

0.199

0.178

0.193

0.193

3.785*

3.998**

50.13

0.735

**( p≤0.01),

*(p≤ 0.05), Dunett test or Student’s t-test

 

Table 8. Histopathology males and females

Sex

Male

Female

Group

Gr.1

Gr.2

Gr.3

Gr.4

Gr.1

Gr.2

Gr.3

Gr.4

No. animals

10

10 

 10

10

10

 10

 10

10

Examinded

5

 

 

5

5

 

 

5

Liver

Fatty change

0

 

 

3

0

 

 

4*

Hypertrophy, hepatocellular

0

 

 

5**

0

 

 

4*

Mammary gland

Marked acinar development

 

 

 

 

5

 

 

1*

Stomach

Marginal non-glandular; squamous cell hyperplasia

 

 

0

 

 

 

 

3

 

 

0

 

 

 

 

4*

Uterus (incl. cervix and oviducts)

Endometrium; stromal hyperplasia

 

 

 

 

5

 

 

1*

Vagina

Metestrus

 

 

 

 

4

 

 

1

Fisher’s Two-Tailed Exact Test Performed:

*= 5% Significance

**= 1% Significance

Conclusions:
The following no-observed adverse-effect (NOAEL) levels were established:
Paternal/ Maternal toxicity: NOAEL= 60 mg/kg bw/day, p.o.
Reproductive/Development toxicity: NOAEL=120 mg/kg bw/day, p.o.

Executive summary:

In a key OECD guideline 422, read across substance butanedioic acid, sulfo-, 1-C12-18-alkyl esters, disodium salts (CAS 90268 -36 -3) was administered orally to rats at dose levels of 60, 120 or 300 mg test item/kg bw/day. The application started two weeks before mating on test day one and ended on the day or one day before sacrifice. Day of sacrifice was on test day 43 for the male rats and on lactation day 4 or shortly thereafter for the female rats).

Effects on the parental generation (general toxicity)

One of 10 male and one of 10 female animals of the high dose group (300 mg test item/kg bw/day) died prematurely on test day 33 or on gestation day 9 (TD 26).

Slight to moderate salivation was noted in a few male and female animals of the inter-mediate dose group (120 mg test item/kg bw/day) on 1 day each, which was regarded as test item-related.

In the high dose group (300 mg test item/kg bw/day) piloerection and a slight to extreme salivation was noted for several to all male and female animals on several days and regarded as test item-related.

A statistically significant reduction in body weight was noted for the male animals of the intermediate dose group (120 mg test item/kg bw/day) and for both sexes at the high dose group (300 mg test item/kg bw/day).

Statistically significant increases in the activity of ALAT and/or aP and ASAT and decreases in the globulin, cholesterol, chloride and potassium concentrations were noted for the male and/or female animals of the intermediate and/or the high dose group (120 and/or 300 mg test item/kg bw/day).

Statistically significant changes were noted for several organ weights of the male and female animals of the intermediate and the high dose group (120 and 300 mg test item/kg bw/day), most remarkable for the thymus and liver weights of the animals of the high dose group.

Macroscopic inspection at autopsy revealed test item-related changes in the stomach of male animals at the high dose group (300 mg itest item/kg b.w./day and and female animals of the intermediate and high dose group (120 and 300 mg test item/kg bw/day).

Histopathological examination of the organs from animals of the high dose group (300 mg test item/kg bw/day) revealed test item-related changes in the liver (hepatocellular hypertrophy and macrovesicular vacuolation evoked by fatty change) and the non-glandular stomach (squamous cell hyperplasia) of male and female animals. These latter changes are considered to be related to a local activity of the test item. As humans lack a forestomach, the relevance of these changes for humans is questionable.

Reproductive toxicity

The high number of 5 pregnant dams with a total loss of implantation sites in the high dose group (300 mg test item/kg bw/day) led to a statistically significant reduction in the gestation index, in the mean number of implantation sites per dam, in the mean number of born pups per dam and in the birth index. Accordingly, the implantation loss index was statistically significantly increased in the high dose group.

The high percentage of stillbirths led to a statistically significantly reduced live birth index in the high dose group (300 mg test item/kg bw/day).

Test item related effects were also noted on the pups from the 3 remaining dams of the high dose group (300 mg test item/kg bw/day), expressed by a statistically significantly reduced survival rate during the lactation period, a statistically significant reduction in the mean litter weight and in the total litter weight per dam on lactation day 1 and 4.

Effects on the development of the F1offsprings (pups)

In the high dose group (300 mgtest item/kg b.w./day)the total litter weight per dam of the 3 dams with live born pups was reduced on lactation day 1 and on lactation day 4 by 42 and 56%, respectively.

The external examinations of the pups revealed no testitem-related external visible changes in any of the treatment groups, except for ‘no milk in the stomach’ in pups which were found dead during the lactation period.

The following no-observed adverse-effect levels were established:

Paternal and maternal toxicity: NOAEL= 60 mg/kg b.w./day, p.o.; Reproductive/developmental toxicity: NOAEL=120 mg/kg b.w./day, p.o.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
60 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
reliable
Organ:
liver
stomach

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In a key OECD guideline 422, read across substance butanedioic acid, sulfo-, 1-C12-18-alkyl esters, disodium salts (CAS 90268 -36 -3) was administered orally to rats at dose levels of 60, 120 or 300 mg test item/kg bw/day. The application started two weeks before mating on test day one and ended on the day or one day before sacrifice. Day of sacrifice was on test day 43 for the male rats and on lactation day 4 or shortly thereafter for the female rats. One of 10 male and one of 10 female animals of the high dose group (300 mg test item/kg bw/day) died prematurely on test day 33 or on gestation day 9 (TD 26). Slight to moderate salivation was noted in a few male and female animals of the inter-mediate dose group (120 mg test item/kg bw/day) on 1 day each, which was regarded as test item-related. In the high dose group (300 mg test item/kg bw/day) piloerection and a slight to extreme salivation was noted for several to all male and female animals on several days and regarded as test item-related. A statistically significant reduction in body weight was noted for the male animals of the intermediate dose group (120 mg test item/kg bw/day) and for both sexes at the high dose group (300 mg test item/kg bw/day). Statistically significant increases in the activity of ALAT and/or aP and ASAT and decreases in the globulin, cholesterol, chloride and potassium concentrations were noted for the male and/or female animals of the intermediate and/or the high dose group (120 and/or 300 mg test item/kg bw/day).Statistically significant changes were noted for several organ weights of the male and female animals of the intermediate and the high dose group (120 and 300 mg test item/kg bw/day), most remarkable for the thymus and liver weights of the animals of the high dose group. Macroscopic inspection at autopsy revealed test item-related changes in the stomach of male animals at the high dose group (300 mg test item/kg bw/day and female animals of the intermediate and high dose group (120 and 300 mg test item/kg bw/day). Histopathological examination of the organs from animals of the high dose group (300 mg test item/kg bw/day) revealed test item-related changes in the liver (hepatocellular hypertrophy and macrovesicular vacuolation evoked by fatty change) and the non-glandular stomach (squamous cell hyperplasia) of male and female animals. These latter changes are considered to be related to a local activity of the test item. As humans lack a forestomach, the relevance of these changes for humans is questionable. A NOAEL of 60 mg/kg bw/day was concluded for maternal and paternal toxicity.

 

Supporting dose range finding studies were available for the read across substances disodium isodecyl sulfosuccinate (CAS 37294 -29 -8) and butanedioic acid, sulfo-, 1-C12-18-alkyl esters, disodium salts(CAS 90268 -36 -3), both applied by oral gavage to Wistar rats for 14 days, and both leading to a NOAEL of 300 mg/kg bw.

 

Subchronic (90 -day) dietary toxicity studies were available for the registered substance both in rats and dogs, however the studies were disregarded due to limitations compared to OECD 408 guideline.

Justification for classification or non-classification

Based on the absence of severe toxicity at low dose levels, the Registered substance does not have to be classified for systemic target organ toxicity according to CLP Regulation (EC) No. 1272/2008.