Decan-1-ol, ethoxylated

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

OECD 416, rat, 2-generation, dermal: not teratogenic
Parental/F1: NOAELsystemic = 250 mg/kg bw/day; LOAELsystemic > 250 mg/kg bw/day
F1/2: NOAELdev = 250 mg/kg bw/day; LOAELdev > 250 mg/kg bw/day

Link to relevant study records

Reference

Endpoint:

two-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

14 JUN 1982 - 22 JUL 1983

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Deviations:

yes

Remarks:

Only 3 applications per week; no or only partial examination of oestrous cycle and sperm parameters, no analytical purity reported

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, Michigan, USA
- Age at study initiation: (P) 6 - 7 weeks; (F1) 4 - 7 weeks
- Weight at study initiation: (P) Males: 119.5 - 142.8 g; Females: 104.4 - 137.4 g; (F1) Males: 57.2 - 162.1 g; Females: 52.8 - 112.7 g
- Housing: animals were housed individually in wire-mesh bottom, polycarbonate cages
- Use of restrainers for preventing ingestion: no data
- Diet: Purina Formulab Chow (#5008), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 19 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1
- Humidity (%): 40 - 65
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 14 Jun 1982 To: 22 Jul 1983

Route of administration:

dermal

Vehicle:

water

Details on exposure:

TEST SITE
- Area of exposure: The test material was applied on the back of each animal.
- Time intervals for shavings or clippings: The back hair was shaved each week prior to initial weekly application and when necessary throughout the week to ensure adequate dermal exposure.

TEST MATERIAL
- Amount(s) applied: 1 mL/kg bw
- Concentration (if solution): 1, 10 and 25% (w/v)
- Constant volume or concentration used: yes

VEHICLE
- Amount(s) applied: 1 mL/kg bw

USE OF RESTRAINERS FOR PREVENTING INGESTION: no data

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: up to 3 weeks
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): individually in a polycarbonate cage with Absorb-dri (nestwood chips) as nesting material

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Since dosing solutions were analysed by a combination of high performance liquid chromatographic method and gas chromatographic method, and were stable for at least 7 weeks, separate batches of dosing solutions were prepared approximately every four weeks. Rats were treated with a new batch of the appropriate dosing solution within 7 weeks. Each dosing solution was analysed prior to its use for verification of the test material´s concentration. The maximum observed deviation from the nominal concentration was 10%.

Duration of treatment / exposure:

(P) Males: 102 days before mating.
(P) Females: 170 days from the initiation of the study until the F1 generation was weaned
(F1) Males: 123 days at weaning, during growth into adulthood, mating and production of an F2 generation
(F1) Females: 221 days at weaning, during growth into adulthood, mating and production of an F2 generation, 30 days after last litter was weaned

Frequency of treatment:

3 days/week (except during mating)

Details on study schedule:

- Selection of parents from F1 generation when pups were 4 - 7 weeks of age.
- P: mating after119 days of dosing
- F1: mating after 133 days of dosing

Dose / conc.:

10 mg/kg bw/day

Remarks:

nominal in water, corresponding to 1% (w/v)

Dose / conc.:

100 mg/kg bw/day

Remarks:

nominal in water, corresponding to 10% (w/v)

Dose / conc.:

250 mg/kg bw/day

Remarks:

nominal in water, corresponding to 25% (w/v)

No. of animals per sex per dose:

30 P males, 30 P females
20 F1 males, 40 F1 females
16 F1 males (reversibility test)

Control animals:

yes, concurrent vehicle

Positive control:

Not applicable

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Observations were made once daily during treatment and mating periods for morbidity, mortality, general physical appearance, and clinical signs of toxicity. During gestation and lactation periods rats were observed in the morning and afternoon.

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: Male and female body weights were taken weekly up the time of mating. Females were weighed on days 0, 7, 14, and 20 of gestation and on days 1, 4, 7, 21 and 28 of lactation. Pups were weighed as a litter on days 1, 4, 7, 21 and 28 of lactation, and were also weighed individually on day 28 of lactation.

FOOD CONSUMPTION AND COMPOUND INTAKE: No

WATER CONSUMPTION AND COMPOUND INTAKE: No

Oestrous cyclicity (parental animals):

Not examined.

Sperm parameters (parental animals):

Parameters examined in P/F1 male parental generations: testes weight, sperm count in testes, measurement of lactate dehydrogenase isozyme (LDH-X) activity from testicular homogenates

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 10 pups/litter (5/sex/litter as nearly as possible); excess pups were killed and discarded.

PARAMETERS EXAMINED
The following parameters were examined in F1 / F2 offspring: number and sex of pups, stillbirths, live births, postnatal mortality, weight gain (litter), presence of gross anomalies, physical abnormalities

GROSS EXAMINATION OF DEAD PUPS:
- yes, for external and internal abnormalities

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals, as soon as possible after the last litters in each generation were produced
- Maternal animals: All surviving animals, after the last litter of each generation was weaned

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera

HISTOPATHOLOGY
The following tissues were prepared for microscopic examination: prostate, seminal vesicles, epididymides, right testis, both ovaries with oviducts, uterus with cervix

ORGAN WEIGHTS
- The following organs were weighed: right testes, ovaries with oviducts, uterus with cervix

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at ~28 days of age
- These animals were subjected to postmortem examinations (macroscopic and microscopic examination as follows: 5 pups per sex per dose

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera (F1 parental animals / F2 pups)

HISTOPATHOLOGY
- The following tissues were prepared for microscopic examination: stomach, duodenum, jejunum, ileum, colon, cecum, pancreas, mesenteric lymph nodes, cervical lymph nodes, liver, spleen, kidneys, urinary bladder, adrenals, lung, tongue, thyroids, larynx, trachea, esophagus, submaxillary salivary gland, heart, aorta, thymus, cerebrum, cerebellum, brainstem, pituitary gland, spinal cord, sciatic nerve, eyes, psoas muscle, skin, nasal turbinates, costochondral junction, uterus, cervix, ovaries with oviducts, seminal vesicles prostate, testes, epididymis.
ORGAN WEIGHTS
- The following organs were weighed: liver, kidney, lung with trachea and larynx, brain (including entire brainstem), spleen, testes, heart, ovaries with oviducts, uterus with cervix

Statistics:

Organ weight, organ weight/body weight ratio, LDH-X enzyme activity and litter size, sex ratio, survival index and gestational length were analysed by analysis of variance. Treatment groups were compared to the control group by one-tailed Dunnett´s t-test at p=0.05. Body weights were analysed by analysis of covariance. Body weights in all dose groups were adjusted for body weight on the first day of dosing due to differences in initial weights among the treatment groups. Gestational weights were adjusted to the common body weight on gestational day 0, and lactational weights were adjusted to that on lactational day 1. Pup weights and number of live and dead pups were adjusted for the differences in litter size among all dose groups. The analysis of covariance was used to adjust the treatment means for the differences in the covariates among the treatment groups. Subsequent treatment comparisons against the control were then made on the adjusted treatment means. The adjusted treatment means represent the means of the treatment groups if they were to have the same mean value in the covariate. Fertility indices were analysed by one-tailed Fisher´s exact test. Mating indices were analysed by Chi-square with continuity correction. Sperm counts and survival indices were analysed by non-parametric method, Kruskal-Wallis test. Treatment groups were compared to the control by one tailed Dunnett´s t-test at p=0.05 on the ranked data.

Reproductive indices:

Mating Index (%) = (No. of females mated / No. of females housed with males) x 100
Fertility Index (%) = (No. of females pregnant / No. of females mated) x 100

Offspring viability indices:

Survival Index (%) = (pups alive at day 1 / total born pups) x 100
Lactation Index (%) = (pups alive at day 28 / pups alive day 4 after culling) x 100

Clinical signs:

no effects observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

F0 parental: 25% dose group: significantly decreased body weights; F1 males: 25% dose group: significantly decreased body weight at days 21, 28, 35 during dosing period (non-adverse)

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

F0 parental: 25% dose group: significantly decreased body weights; F1 males: 25% dose group: significantly decreased body weight at days 21, 28, 35 during dosing period (non-adverse)

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
Lacrimation, chromodacryorrhea, periocular swelling, ptosis, red nasal discharge, rhinorrhea, polyuria, soft stool, alopecia, odd-shaped pupil, and unkemptness were noted in the F0 and F1 parental rats in all dosage groups and the controls. In addition, the two highest dose groups, 10% and 25% of the test material, had a higher incidence of hunched posture. However, there were no pathological findings associated with these clinical signs. No mortality was observed in the F0 generation. However, five deaths were noted in the F1 generation. At necropsy, the posterior pharynx of each rat was filled with moist, finely ground and compacted food material that occluded the laryngeal opening of the rats. Similar material was also found in the esophagus of two rats and the trachea of one of these two rats. Death was apparently caused by asphyxiation and was not compound related because a similar finding was noted in the same strain of rats at another laboratory and a control rat was also affected.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
In the F0 adults, body weights of the 1% and 10% dose groups were not affected by the treatment. However, significantly lower (p<0.05) body weights of the 25% dose group were observed during certain intervals when compared to the control. There were statistically significantly lower body weights in the 25% dose group males between days 35-105 during the dosing period; in females, body weights were only significantly lower at day 49, but were slightly lower than the control during the rest of the dosing period. In the F1 adults, body weights of the 1% and 10% dose groups were not affected by the treatment when compared to the control group. However, body weights of the 25% dose group males were lower but only statistically significant (p<0.5) at days 21, 28 and 35 during the dosing period; body weights of the 25% dose group females were lower from days 14-119 during the dosing period when compared to the controls. There were no compound-related effects on maternal body weights of all dose groups during the gestational and lactational periods in the F0 and F1 generations when compared to the controls. On lactational day 14, maternal body weights of the 1%, 10% and 25% dose groups were statistically significantly higher than the control. These increases were of no toxicological significance.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
In the F0 parental males, testes weights in all dose groups were not affected by the treatment, whereas number of sperm per testes and per gram testes were significantly lower (p<0.05) in the 25% dose group when compared to the controls. Values of LDH-X enzyme activity in all dose groups were comparable to the control. However, in the F1 parental males, all the above mentioned parameters in all dose groups were comparable to the controls. The lower number of sperm in the testes of the 25% dose group F0 males was apparently due to a physiological variation as the values were within the normal range for this laboratory. Therefore, their difference is not considered to be a treatment-related effect. Since no effects were seen in F1 males, all rats prepared for the reversibility test were therefore killed and discarded.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Mating indices were 73.3, 83.3, 83.3 and 93.3/ in the F0 generation, and 65.0, 70.0, 82.1 and 83.8% in the F1 generation of the 0, 1, 10 and 25% dose groups, respectively. The incidences appeared to be higher in the test material dose groups than the control in both generations but not significantly different from the control group by Chi-square test with continuity correction. The lower mating performance data from the control rats is commonly observed in this particular strain of rats. There were no apparent morphological differences in all rats to explain the apparent infertility. There were no compound related effects on fertility index and mean gestational length of the F0 and F1 females. The fertility indices were 77.3, 64.0, 76.0 and 53.6 in the F0 generation and 88.5, 67.9, 87.5 and 77.4% in the F1 generation of the 0, 1, 10 and 25% dose groups, respectively. Mated females were those having a copulatory plug or sperm in the vaginal smear or giving birth without the presence of copulatory plug or sperm. Mean gestational length in all dose groups in the F0 and F1 generations was approximately 22 days. Few females without the presence of copulatory plug or sperm during mating periods in both generations gave birth; their gestational length was therefore indeterminable.

ORGAN WEIGHTS (PARENTAL ANIMALS)
In the F1 adult males, significantly higher absolute and relative weights of the liver, lung and heart in the 25% dose group, higher absolute and relative weights of the lung in the 10% dose group, and higher relative lung weight in the 1% dose group were observed. The higher absolute and/or relative lung weight was not considered toxicologically significant as there was no dose-related linear relationship in all dose groups among the changes at the 1% and 10% dose levels. Also no morphologic changes were noted in the lungs. In the F1 adult females, significantly higher absolute and relative weights of liver, heart and kidney and the relative lung weight of the 25% dose group, higher absolute and relative heart weights and relative liver weights of the 10% dose group were noted.

GROSS PATHOLOGY (PARENTAL ANIMALS)
At necropsy, in the F0 generation, a significantly lower (p<0.05) carcass weight was observed only in the 25% dose group females, yet their absolute and relative organ weights were comparable to the controls. In the F1 generation, the carcass weight of the adult males and females were not affected.

HISTOPATHOLOGY (PARENTAL ANIMALS)
There were no significant differences in testicular histology from all test material treated rats and the controls in these two generations.

OTHER FINDINGS
According to the scoring table for skin reactions, individual skin irritation scores for all rats in all dose groups was zero throughout the F0 and F1 generations. The test material did not cause erythema or edema. However, both male and female rats in the 10% and 25% dose groups had dry and flaking skin. The discoloration of the application sites was noted in all treated rats including the controls. Possibly it was caused by the repeated shaving of the hair coat and dermal applications of the vehicle (water) or test solutions and was considered not to be compound related.

Dose descriptor:

NOAEL

Remarks:

reprotox

Effect level:

>= 250 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

corresponding to 25% (w/v)

Sex:

male/female

Basis for effect level:

other: No treatment-related effects observed.

Dose descriptor:

NOEL

Remarks:

systemic

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

corresponding to 10% (w/v)

Sex:

male/female

Basis for effect level:

other: No treatment-related effects observed.

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

>= 250 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

corresponding to 25% (w/v)

Sex:

male/female

Basis for effect level:

other: Changes in body weight and organ weights without associated pathological findings.

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

VIABILITY (OFFSPRING)
No compound-related effects on litter size, number of live pups and sex ratio of pups in the F1 and F2 generations were observed during lactational days 1, 4, 7, 14, 21 and 28. Litter sizes were 8.2, 9.6, 7.9 and 6.4 in the F1 generation and 6.9, 8.3, 8.0 and 8.4 in the F2 generation of the 0, 1, 10 and 25% dose groups, respectively. The mean litter size of the 25% dose group in the F1 generation was smaller than the control, but that of the control was the smallest in the F2 generation. However, there were no significant differences among the dose groups when compared to the controls. No compound-related effect on survival indices in all dose groups was noted. All pups dying during the pre-weaning period, including the control group, were examined grossly. Two pups, one male from a litter of the F1 10% dose group and one female from another litter of the F2 25% dose group were found dead, and they appeared to have been dehydrated. No pathologic finding was noted in these pups.

BODY WEIGHT (OFFSPRING)
There were no differences in body weights of the F1 and F2 pups in any dose group when compared to the control.

ORGAN WEIGHTS (OFFSPRING)
In the F1 pups, there were no differences in organ weights in any dose group when compared to the controls. In the F2 pups higher values of the absolute weights of liver, kidney, heart, spleen and ovary, and the lower relative brain weight were considered to be secondary to the higher carcass weights in this group (25% dose group) when compared to the controls. In addition to lack of dose response, there were no morphological differences among these affected organs when compared to the controls.

GROSS PATHOLOGY (OFFSPRING)
In the F1 pups, there were no differences in carcass weights in any dose group when compared to the controls. In the F2 pups, a significantly higher (p<0.05) carcass weight in the 25% dose group females was observed, but this increase was of no toxicological significance.

HISTOPATHOLOGY (OFFSPRING)
No treatment-related findings were recorded during histopathology, neither in the F1 pups nor in the F2 pups.

OTHER FINDINGS (OFFSPRING)
There was no compound-related effect on the development of the pups. Eye opening was observed at approximately 16.1-16.9 days for the F1 pups and 17.2-17.6 days postnatally for the F2 pups in all dose groups.

Dose descriptor:

NOAEL

Remarks:

reprotox

Generation:

F1

Effect level:

>= 250 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

corresponding to 25% (w/v)

Sex:

male/female

Basis for effect level:

other: No treatment-related effects observed.

Dose descriptor:

NOEL

Remarks:

systemic

Generation:

F1

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

corresponding to 10% (w/v)

Sex:

male/female

Basis for effect level:

other: No treatment-related effects observed.

Dose descriptor:

NOAEL

Remarks:

systemic

Generation:

F1

Effect level:

>= 250 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

corresponding to 25% (w/v)

Sex:

male/female

Basis for effect level:

other: Changes in body weight and organ weights without associated pathological findings.

Dose descriptor:

NOAEL

Remarks:

dev tox

Generation:

F1

Effect level:

>= 250 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

corresponding to 25% (w/v)

Sex:

male/female

Basis for effect level:

other: No treatment-related effects observed.

Dose descriptor:

NOAEL

Remarks:

dev tox

Generation:

F2

Effect level:

>= 250 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

corresponding to 25% (w/v)

Sex:

male/female

Basis for effect level:

other: No treatment-related effects observed.

Reproductive effects observed:

not specified

Table 1: Animal assignment for mating

Dose Group	Number of rats and sex at start of study	Nominal value of test material in solution (% w/v)	Number of rats at scheduled necropsy
F0 Generation
A	30 M	0	30
	30 F	0	30
B	30 M	1	30
	30 F	1	30
C	30 M	10	30
	30 F	10	30
D	30 M	25	30
	30 F	25	30
F1 Generation
A	20 M	0	19 a
	40 F	0	40
B	20 M	1	20
	40 F	1	40
C	20 M	10	20
	40 F	10	39 a
D	20 M	25	19 a
	38 F	25	36 a

M: males

F: females

(a): deaths occurred before scheduled necropsy

Table 2: Reproductive parameters for F0, F1 and F2 generation

Parameter		Generation	Controls	1% (w/v)	10% (w/v)	25% (w/v)	Dose-response
Reproductive Performance
Mating index	%	F0	73.3	83.3	83.3	93.3	–
		F1	65.0	70.0	82.1	83.8	–
Fertility index	%	F0	77.3	64.0	84.0	53.6	–
		F1	88.5	67.9	87.5	77.4	–
Duration of pregnancy	Mean [days]	F0	22.2	22.1	22.2	22.3	–
		F1	21.8	22.1	22.0	22.0	–
Live birth index	%	F1	100	99.0	98.7	98.4	–
		F2	98.6	100	100	98.8	–
Litter size	Mean	F1	8.2	9.6	7.9	6.4	–
		F2	6.9	8.3	8.0	8.4	–
Pup weight (a) (day 1)	Mean [g]	F1	5.4	5.43	5.41	5.62	–
		F2	5.56	5.65	5.66	5.74	–
Pup weight (a) (day 28)	Mean [g]	F1	59.06	59.13	58.53	60.62	-
		F2	55.89	57.76	59.34	57.81	-
Sex ratio	% Males	F1	46	40	47	45	–
		F2	46	44	52	50	–
Survival index (day 1)	%	F1	100	98.6	98.9	97.8	–
		F2	98.4	99.6	98.3	97.3	–
Survival index (day 28)	%	F1	100	100	94.5	99.2	-
		F2	98.5	100	98.3	98.2	-
Lactation index	%	F1	100	100	98.6	100	–
		F2	98.5	98.8	97.4	97.4	–

(a): mean pup weights were calculated from litter weights divided by number of pups per litter

Table 3: Sperm characterisation for F0 and F1 males

Dose level in % (w/v)		Testes weight (g) (a)	Sperm/testes (million)	Sperm/g testes (million)	LDH-X activity (U/testes)
F0 Generation
0	Mean S.D: S.E: N	1.43 0.06 0.01 30	226.0 38.1 7.0 30	158.5 27.4 5.0 30	99.0 12.7 2.3 30
1	Mean S.D: S.E: N	1.42 0.05 0.01 30	211.2 23.8 4.4 30	148.6 16.6 3.0 30	97.2 12.8 2.3 30
10	Mean S.D: S.E: N	1.40 0.05 0.01 30	211.2 23.8 4.4 30	148.6 16.6 3.0 30	93.7 14.1 2.6 30
25	Mean S.D: S.E: N	1.42 0.06 0.01 30	204.7* 24.2 4.4 30	144.1* 17.5 3.2 30	97.0 11.1 2.0 30
F1 Generation
0	Mean S.D: S.E: N	1.40 0.09 0.02 19	247.6 36.4 8.3 19	178.1 28.8 6.6 19	113.18 7.19 1.65 19
1	Mean S.D: S.E: N	1.39 0.21 0.05 20	246.0 69.9 15.6 20	174.5 43.6 9.8 20	111.22 18.28 4.09 20
10	Mean S.D: S.E: N	1.41 0.08 0.02 20	250.3 40.3 9.0 20	17.7 29.7 6.6 20	114.57 7.03 1.57 20
25	Mean S.D: S.E: N	1.36 0.29 0.07 19	236.0 65.9 15.1 19	167.8 39.4 9.0 19	108.87 25.11 5.76 19

(a): detunicated

*: p ≤0.05 (one-tailed Dunnett´s t-test)

N: number of animals

S.D.: standard deviation

S.E.: standard error

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

250 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

Toxicity to reproduction

In a two-generation reproduction study, groups of 30 weanling Fischer 344 rats of each sex were dermally exposed to 1 mL/kg bw C9-11AE6 (CAS 68439-46-3) at concentrations of 0, 1, 10 or 25% w/v three times a week except during the mating periods. This treatment equals exposure levels of about 0, 10, 100 and 250 mg/kg bw/day. No mortalities were observed in the parental generation, and the five deaths in the F1 adult males and females in the control and treatment groups were not considered to be compound-related. In the highest dose group, body weights of both males and females in both treated generations were sporadically decreased compared to controls. There was no effect on maternal body weight during gestational and lactational periods in both generations. At necropsy organ weight differences in liver, lung, kidney and heart were observed in the F1 generation. However no pathological findings were associated with these affected organs. There were no compound-related effects on mating and fertility indices and mean gestational length in both generations. No effects on testicular weights, sperm counts and LDH-X activities in F0 and F1 male adults were observed. Macroscopic and microscopic examination of the reproductive organs did not reveal significant differences in the treated groups compared to the controls. Based on these observations the NOAEL for reproductive and developmental toxicity can be established at 250 mg/kg bw/day, the highest dermal tested dose.

Further evidence for the lack of reproductive toxicity of alcohol ethoxylates has been provided by a range of subchronic oral feeding studies which investigated also any potential effects on the organs of the reproductive system (see Chapter 7.5). None of these studies revealed any adverse effects of exposure to AE on the reproductive system.

 

Based on the information above, even though application by the dermal route is not the first choice to investigate reproductive effects (see Chapter 7.1), conducting an oral two-generation reproductive toxicity study is scientifically not of high priority. In addition, data need aspects have to be balanced with animal welfare considerations.

However, a reproductive toxicity study on a structurally similar material, C14-15AE7 (CAS 68951-67-7) was conducted at dietary levels of 25, 50 and 250 mg/kg bw/day. The 2-generation study (Procter and Gamble Ltd., 1977: Long term reproduction and teratology study in rats with Neodol 45-7; unpublished report) did not show any potential for reproductive toxicity at the tested dose levels. The NOAEL for reproductive effects was greater than the highest tested dose of 250 mg/kg bw/day. Although the study was pre-GLP and not in full compliance with current OECD guidelines, the study provided sufficient information and was assessed to be scientifically reliable.

The comparable toxicokinetic and metabolic profiles, as well as their toxicological similarities for this and other toxicological endpoints, support the conclusion that insights from the reproductive toxicity study on higher ethoxylated AE are applicable to AE with an ethoxylation degree of 1-2.5. With regard to animal welfare this read across should be considered to close the data gap in case that the presented reproductive toxicity study via the dermal route in combination with the oral subchronic repeated dose studies is regarded as not sufficient to cover this endpoint.

Effects on developmental toxicity

Description of key information

OECD 416, rat, 2-generation, dermal: not teratogenic
Parental/F1: NOAELsystemic = 250 mg/kg bw/day; LOAELsystemic > 250 mg/kg bw/day
F1/2: NOAELdev = 250 mg/kg bw/day; LOAELdev > 250 mg/kg bw/day

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:

Refer to the Category Approach Justification document provided in IUCLID6 Section 13.

Reason / purpose for cross-reference:

read-across source

Historical control data:

no data

Dose descriptor:

NOEL

Remarks:

maternal

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

corresponding to 10% (w/v)

Basis for effect level:

other: No treatment-related effects observed.

Dose descriptor:

NOAEL

Remarks:

maternal

Effect level:

>= 250 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

corresponding to 25% (w/v)

Basis for effect level:

other: Changes in body weight and organ weights without associated pathological findings.

Dose descriptor:

NOAEL

Remarks:

developmental

Effect level:

>= 250 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

corresponding to 25% (w/v)

Sex:

male/female

Basis for effect level:

other: No treatment-related effects observed.

Abnormalities:

effects observed, non-treatment-related

Localisation:

external: eye

external: limb

Developmental effects observed:

yes

Lowest effective dose / conc.:

100 mg/kg bw/day (nominal)

Treatment related:

no

Relation to maternal toxicity:

developmental effects in the absence of maternal toxicity effects

Dose response relationship:

no

Relevant for humans:

no

Conclusions:

Dermal treatment of pregnant rats with the test substance at doses of 10, 100 and 250 mg/kg bw/day resulted in no maternal toxicity and hence a dermal NOAEL for maternal systemic toxicity of >/= 250 mg/kg bw/day. Fetal abnormalities observed include malformations of eyes and front as well as hind limbs. All developmental effects were due to spontaneous occurrence and were considered not to be treatment-related. The dermal developmental NOAEL was thus determined to be >/= 250 mg/kg bw/day.

Executive summary:

The developmental toxicity of the target substance is estimated based on an adequate and reliable two-generation reproductive toxicity study of a structural analogue source substance with subsequent detailed examination of fetuses. Dermal treatment of pregnant rats with the test substance at doses of 10, 100 and 250 mg/kg bw/day resulted in no maternal toxicity and hence a dermal NOAEL for maternal systemic toxicity of >/= 250 mg/kg bw/day. Fetal abnormalities observed include malformations of eyes and front as well as hind limbs. All developmental effects were due to spontaneous occurrence and were considered not to be treatment-related. The dermal developmental NOAEL was thus determined to be >/= 250 mg/kg bw/day. No developmental toxicity is therefore expected for the target substance. As explained in the category justification, the differences in molecular structure between the target and the source substances are unlikely to lead to differences in the developmental toxicity and teratogenicity.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

250 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

Developmental toxicity

In a two-generation reproduction study, groups of 30 weanling Fischer 344 rats of each sex were dermally exposed to 1 mL/kg bw C9-11AE6 (CAS 68439-46-3) at concentrations of 0, 1, 10 or 25% w/v three times a week except during the mating periods. This treatment equals exposure levels of about 0, 10, 100 and 250 mg/kg bw/day. The complete study protocol has been described above. No compound related effects on litter size, number of live pubs and sex ratio of pups in the F1 and F2 generations were observed. Low incidences of foetal malformations were observed, but these were not dose related and considered to be of spontaneous nature. At necropsy, no effects were observed in the F1 pups. In the F2 pups, a significantly higher carcass weight in the females of the 250 mg/kg bw/day dose group was noted and some minor organ weight differences. Due to the lack of a dose-response and no associated morphological findings, these effects were considered to be of no toxicological significance. It was concluded that dermal application of C9-11AE6 to rats did not induce any adverse effects on the growth and development of the offspring during two generations. The NOAEL of C9-11AE6 with respect to developmental and teratogenic toxicity can be assumed to be higher than the highest dose level dermally applied in this study (i.e., 250 mg/kg bw/day).

 

Based on the information above, even though application by the dermal route is not the first choice to investigate reproductive effects (see Chapter 7.1), conducting an oral developmental toxicity study is scientifically not of high priority. In addition, data need aspects have to be balanced with animal welfare considerations.

However, a reproductive toxicity study on a structurally similar material, C14-15AE7 (CAS 68951-67-7) was conducted at dietary levels of 25, 50 and 250 mg/kg bw/day. The 2-generation study (Procter and Gamble Ltd., 1977: Long term reproduction and teratology study in rats with Neodol 45-7; unpublished report) did not show any potential for reproductive toxicity at the tested dose levels. The NOAEL for reproductive effects was greater than the highest tested dose of 250 mg/kg bw/day. Although the study was pre-GLP and not in full compliance with current OECD guidelines, the study provided sufficient information and was assessed to be scientifically reliable.The comparable toxicokinetic and metabolic profiles, as well as their toxicological similarities for this and other toxicological endpoints, support the conclusion that insights from the reproductive toxicity study on higher ethoxylated AE are applicable to AE with an ethoxylation degree of 1-2.5.

With regard to animal welfare this read across should be considered to close the data gap in case that the presented reproductive toxicity study via the dermal route in combination with the oral subchronic repeated dose studies is regarded as not sufficient to cover this endpoint.

Justification for classification or non-classification

According to the classification criteria of Regulation (EC) No. 1272/2008 the substance does not need to be classified for toxicity to reproduction. No data available on breastfed babies.